[1st Edition] 9780444639387, 9780444639325

Table of contents :
Content:
Front MatterPage iii
CopyrightPage iv
ContributorsPages xiii-xiv
PrefacePages xv-xviAtta-Ur-Rahman
Chapter 1 - Potentially Chemopreventive Triterpenoids and Other Secondary Metabolites From Plants and FungiPages 1-50Toshihiro Akihisa, Jie Zhang, Harukuni Tokuda
Chapter 2 - Structural Diversity, Natural Sources and Pharmacological Potential of Naturally Occurring A-Seco-TriterpenoidsPages 51-149Victoria V. Grishko, Natalia V. Galaiko
Chapter 3 - Kaurenoic Acid: A Diterpene With a Wide Range of Biological ActivitiesPages 151-174Nemesio Villa-Ruano, Edmundo Lozoya-Gloria, Yesenia Pacheco-Hernández
Chapter 4 - Review of Patents Based on Triterpene Glycosides of Sea CucumbersPages 175-200Dmitry L. Aminin, Ekaterina S. Menchinskaya, Evgeny A. Pislyagin, Alexandra S. Silchenko, Sergey A. Avilov, Natalia I. Stadnichenko, Peter D. Collin, Vladimir I. Kalinin
Chapter 5 - Bioactive Dietary Compounds Regulate Mitochondrial Apoptosis Signaling in Ambivalent Way to Function as Neuroprotective or Antitumor AgentsPages 201-222Makoto Naoi, Yuqiu Wu, Masayo Shamoto-Nagai, Wakako Maruyama
Chapter 6 - Dietary Carotenoids for Reduction of Cancer RiskPages 223-251José M. Lorenzo, Paulo E. Munekata
Chapter 7 - Dihydrochalcones: Occurrence in the Plant Kingdom, Chemistry and Biological ActivitiesPages 253-381Céline Rivière
Chapter 8 - Synthetic Advances in the Indane Natural Product Scaffolds as Drug Candidates: A ReviewPages 383-434Naseem Ahmed
Chapter 9 - Garcinoic Acid: A Promising Bioactive Natural Product for Better Understanding the Physiological Functions of Tocopherol MetabolitesPages 435-481Stefan Kluge, Martin Schubert, Lisa Schmölz, Marc Birringer, Maria Wallert, Stefan Lorkowski
Chapter 10 - Antibiotics Derived From Marine Organisms: Their Chemistry and Biological Mode of ActionPages 483-515Bibi Nazia Auckloo, Bin Wu
IndexPages 517-535

Citation preview

Studies in Natural Products Chemistry Volume 51

Edited by

Atta-ur-Rahman, FRS International Center for Chemical and Biological Sciences H.E.J. Research Institute of Chemistry University of Karachi Karachi, Pakistan

AMSTERDAM l BOSTON l HEIDELBERG l LONDON NEW YORK l OXFORD l PARIS l SAN DIEGO SAN FRANCISCO l SINGAPORE l SYDNEY l TOKYO

Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States Copyright © 2016 Elsevier B.V. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-444-63932-5 ISSN: 1572-5995 For information on all Elsevier publications visit our web site at https://www.elsevier.com

Publisher: John Fedor Acquisition Editor: Anneka Hess Editorial Project Manager: Anneka Hess Production Project Manager: Paul Prasad Chandramohan Cover Designer: Greg Harris Typeset by TNQ Books and Journals

Contributors Naseem Ahmed (383), Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India Toshihiro Akihisa (1), Tokyo University of Science, Noda, Japan Dmitry L. Aminin (175), G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Vladivostok, Russia Bibi Nazia Auckloo (483), Ocean College, Zhejiang University, Hangzhou, China Sergey A. Avilov (175), G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Vladivostok, Russia Marc Birringer (435), University of Applied Sciences Fulda, Fulda, Germany Peter D. Collin (175), Coastside Bio Resources, Deer Isle, ME, United States Natalia V. Galaiko (51), Russian Academy of Sciences, Perm, Russian Federation Victoria V. Grishko (51), Russian Academy of Sciences, Perm, Russian Federation Vladimir I. Kalinin (175), G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Vladivostok, Russia Stefan Kluge (435), Friedrich Schiller University Jena, Jena, Germany; Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD), Halle-Jena-Leipzig, Germany Jose´ M. Lorenzo (223), Centro Tecnolo´gico de la Carne de Galicia, Ourense, Spain Stefan Lorkowski (435), Friedrich Schiller University Jena, Jena, Germany; Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD), HalleJena-Leipzig, Germany Edmundo Lozoya-Gloria (151), Centro de Investigacio´n y de Estudios Avanzados del IPN, Irapuato, Guanajuato, Me´xico Wakako Maruyama (201), Aichi Gakuin University, Nisshin, Japan Ekaterina S. Menchinskaya (175), G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Vladivostok, Russia Paulo E. Munekata (223), University of Sa˜o Paulo, Pirassununga, Sa˜o Paulo, Brazil Makoto Naoi (201), Aichi Gakuin University, Nisshin, Japan Yesenia Pacheco-Herna´ndez (151), Centro Interdisciplinario de Investigacio´n para el Desarrollo Integral Regional, Sta Cruz Xoxocotla´n, Oaxaca, Me´xico Evgeny A. Pislyagin (175), G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Vladivostok, Russia xiii

xiv Contributors Ce´line Rivie`re (253), Univ. Lille, INRA, ISA, Univ. Artois, Univ. Littoral Coˆte d’Opale, EA 7394 e ICV, Institut Charles Viollette, F-59000 Lille, France Lisa Schmo¨lz (435), Friedrich Schiller University Jena, Jena, Germany; Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD), Halle-Jena-Leipzig, Germany Martin Schubert (435), Friedrich Schiller University Jena, Jena, Germany; Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD), HalleJena-Leipzig, Germany Masayo Shamoto-Nagai (201), Aichi Gakuin University, Nisshin, Japan Alexandra S. Silchenko (175), G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Vladivostok, Russia Natalia I. Stadnichenko (175), G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Vladivostok, Russia Harukuni Tokuda (1), Kyoto University, Kyoto, Japan Nemesio Villa-Ruano (151), Universidad de la Sierra Sur, Miahuatla´n de Porfirio Dı´az Oaxaca, Me´xico Maria Wallert (435), Friedrich Schiller University Jena, Jena, Germany; Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD), Halle-Jena-Leipzig, Germany Bin Wu (483), Ocean College, Zhejiang University, Hangzhou, China Yuqiu Wu (201), Aichi Gakuin University, Nisshin, Japan Jie Zhang (1), China Pharmaceutical University, Nanjing, China

Preface Twenty eight years have passed since the series Studies in Natural Products Chemistry began to be published in 1988 under my editorship. This represents the 51st volume of this popular series of books that have covered most of the important facets of the chemical treasures of nature. The EpsteineBarr virus (EBV) is a herpes virus that infects human B lymphocytes, and it has been regarded as a causative agent of some human cancers. Many triterpenoids as well as other secondary metabolites such as chalcones, flavonoids, and phloroglucinols exhibit potent inhibitory and chemopreventive effects on the induction of EBV-early antigen (EBV-EA). In Chapter 1, Akihisa et al. have provided a comprehensive review on such chemopreventive agents isolated mainly from edible plants, fungi, and crude herbal drugs. In Chapter 2, Grishko and Galaiko review the biological activity, structural diversity, and pharmacological activity, such as the antitumor, antiinflammatory, anti-HIV, and antiviral properties, of tetracyclic and pentacyclic A-seco-triterpenoids, including those belonging to the lanostane, cycloartane, dammarane, tirucallane, lupane, oleanane, friedelane, and ursane structural classes. Kaurenoic acid is a tetracyclic diterpene, which plays an important role in plant metabolism. It has also been found to be important in the field of medicinal chemistry. Villa-Ruano et al. discuss the medicinal and pharmacological activities, such as the hypoglycemic, analgesic, and cytotoxic properties, of kaurenoic acid and its potential for development of new drugs in Chapter 3. Sea cucumbers (holothurians) contain a wide variety of biologically active compounds, but the most characteristic secondary metabolites of sea cucumbers are triterpene glycosides of the lanostane series. Isolation of medically active triterpene glycosides from sea cucumbers and their immunostimulatory and antiinflammatory properties have been discussed by Aminin et al. in Chapter 4. Protection of neuronal cells against cell death or apoptosis can be achieved by various naturally occurring compounds such as polyphenols. In Chapter 5, Naoi et al. have highlighted the neuroprotective and antitumor functions of bioactive dietary compounds that can regulate mitochondrial apoptosis signaling. It has been reported that several dietary carotenoids such as lycopene, b-carotene, a-carotene etc., that are found in foods may reduce the risk of cancer. The consumption of fruits and vegetables has been found to reduce the incidence of cancer risk. In Chapter 6, Lorenzo and Munekata present a

xv

xvi Preface

comprehensive overview of the role of carotenoids and plant micronutrients as cancer protective agents. About 256 dihydrochalcones have been isolated from more than 46 plant families. Ce´line Rivie`re has reviewed the occurrence, biological properties, and chemistry of dihydrochalcones in Chapter 7. Indane and its derivatives are considered to be a central structural unit in various natural products. These compounds are potentially antipathogenic and serve as an important source for the synthesis of novel drugs. A comprehensive discourse on the use of indane scaffolds in synthesis of bioactive compounds is presented by Naseem Ahmed in Chapter 8. Garcinia kola is used by African medicine men in traditional medicine for its purgative, antiparasitic, and antimicrobial properties. It is therefore used to treat respiratory infections such as coughs, colds, and bronchitis. Kluge et al. have reviewed the physiological role of garcinoic acid and its potential in the preparation of antiinflammatory drugs in Chapter 9. The marine environment offers an exciting source of new and novel bioactive compounds. A wide variety of natural products have been derived from marine animals such as sponges, cnidarians, and molluscs, whereas some are isolated from microbes. Many of these natural products are used in antibiotics preparation. In Chapter 10, Wu and Auckloo review the chemical and biological properties as well as the mode of action of antibiotics derived from marine organisms. I hope that all these eminent contributions will provide readers with a wealth of important information that will stimulate further research. I would like to thank Ms. Taqdees Malik and Ms. Humaira Hashmi for their assistance in the preparation of this volume. I am also grateful to Mr. Mahmood Alam for editorial assistance. Prof. Atta-Ur-Rahman, FRS International Center for Chemical and Biological Sciences H.E.J. Research Institute of Chemistry University of Karachi Karachi, Pakistan

Chapter 1

Potentially Chemopreventive Triterpenoids and Other Secondary Metabolites From Plants and Fungi Toshihiro Akihisa,*, 1 Jie Zhangx, Harukuni Tokuda{

*Tokyo University of Science, Noda, Japan; xChina Pharmaceutical University, Nanjing, China; { Kyoto University, Kyoto, Japan 1 Corresponding author: E-mail: [email protected]

Chapter Outline Introduction 2 EBV-EA Induction Test 3 Two-Stage Carcinogenesis Test on Mouse Skin 3 DMBA/TPA-Induced Carcinogenesis Test 3 PN/TPA-Induced Carcinogenesis Test 4 UVB/TPA-Induced Carcinogenesis Test 4 Plant and Fungal Materials Investigated 5 Inhibitory Effects on TPA-Induced EBV-EA Activation 5 Inhibitory Effects on Mouse Skin Carcinogenesis 9 Chemopreventive Effects of Triterpenoids 23 Cucurbitane-Type Triterpenoids 23

Cycloartane-Type Triterpenoids Dammarane-Type Triterpenoids Euphane-Type Triterpenoids Lanostane-Type Triterpenoids Limonoids Lupane-Type Triterpenoids Multiflorane-Type Triterpenoids Oleanane-Type Triterpenoids Taraxastane-Type Triterpenoids Tirucallane-Type Triterpenoids Ursane-Type Triterpenoids Chemopreventive Effects of Diterpenoids Chemopreventive Effects of Steroids Chemopreventive Effects of Chalcones

Studies in Natural Products Chemistry, Vol. 51. http://dx.doi.org/10.1016/B978-0-444-63932-5.00001-2 Copyright © 2016 Elsevier B.V. All rights reserved.

25 27 27 28 29 31 31 31 32 32 32 33 33 34

1

2 Studies in Natural Products Chemistry Chemopreventive Effects of Flavonoids Chemopreventive Effects of Phloroglucinols Chemopreventive Effects of Other Secondary Metabolic Compounds Phenolic Compounds Alkylresorcinols Azaphilonoids Caffeoylquinic Acids Coumarins Diarylheptanoids Jasmonic Acid Derivatives Tannins Chemopreventive Effects of Fatty Acids

35 35 36 36 36 36 37 37 37 38 38

Toxicity, Side Effects, and Improvement of Bioavailability of Triterpenoids Toxicity and Side Effects Reciprocal Effect to Another Agent Improvement of Bioavailability Type of Preventive Malignancy by Triterpenoids Potential Mechanisms of Chemoprevention Concluding Remarks Abbreviations References

39 39 40 41 41 42 43 44 44

38

INTRODUCTION Prevention is one of the most important and promising strategies to control cancer. Carcinogenesis is generally recognized as a multistep process in which distinct molecular and cellular alterations occur. From the study of experimentally induced carcinogenesis in rodents, tumor development is considered to consist of several separate, but closely linked stages: tumor initiation, promotion, and progression [1e8]. Chemoprevention is defined as the use of natural or synthetic agents that reverse, suppress, or arrest carcinogenic and/or malignant phenotype progression toward invasive cancer [3e6]. Phytochemicals derived from vegetables, fruits, spices, herbs, and medicinal plants, and various groups of compounds such as terpenoids, flavonoids, phenolic compounds, and organosulfur compounds have been shown promise in suppressing experimental carcinogenesis in various organs [3e17]. In the course of our search for potential chemopreventive agents mostly in edible plants, fungi, and crude herbal drugs, we have evaluated a number of compounds for their inhibitory effects on the induction of EpsteineBarr virus early antigen (EBV-EA) induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells as a primary evaluation of antitumor promoters and have found that many triterpenoids as well as other secondary metabolites such as chalcones, flavonoids, and phloroglucinols exhibited potent inhibitory effects. In addition, over 20 of these compounds have been demonstrated to possess inhibitory effects in a two-stage carcinogenesis test on mouse skin using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter. The present review deals with the chemopreventive effects of

Potentially Chemopreventive Triterpenoids Chapter j 1

3

triterpenoids and other compounds mostly from plant and fungal materials. The emphasis is on our own work published in the last 15 years.

EBV-EA INDUCTION TEST The EBV genome-carrying lymphoma cells, Raji cells, derived from Burkitt’s lymphoma, were cultured in RPMI-1640 medium. The Raji cells were incubated for 48 h at 37 C in a medium containing n-butanoic acid (4 mmol), TPA (32 pmol), and a known amount (32, 16, 3.2, 0.32 nmol) of test compounds. Smears were made from the cell suspension, and the EBV-EA-inducing cells were stained by means of an indirect immunofluorescence technique. The viability of treated Raji cells was assessed by the trypan blue staining method. Details of the assay procedure have been reported previously [18,19]. The inhibitory potency of test compound was expressed as the IC50 value which represents the molar ratio of test compound, relative to TPA, required to inhibit 50% of the positive control activated with 32 pmol TPA. The EBV, a herpes virus latently infecting human B-lymphocytes (Raji cells derived from Burkitt’s lymphoma), has been thought to be causative of some human cancers [20] such as Hodgkin’s lymphoma, Burkitt’s lymphoma, gastric cancer, and nasopharyngeal carcinoma [21,22]. Nowadays, it is proven that EBV can cause infectious mononucleosis and lymphomas in immunosuppressed patients, and also lymphomas in AIDS patients [23]. The EBV-EA activation assay induced by a well-known tumor promoter, TPA, is one of the screening methods employed as a convenient primary in vitro assay for the evaluation of antitumor-promoting activity. Tumor promoters induce EBV activation possibly through the activation of protein kinase C and mitogenactivated protein kinase [4,24]. Inhibitory potentials against the induction of the lytic or the productive cycle of EBV by the tumor promoter are well correlated with those in the in vivo two-stage carcinogenesis test [9], and the EBV-EA inhibition assay using Raji cells is effective for the primary screening of inhibitors of tumor promotion [25]. This assay has an advantage since it obtains information on the cytotoxicity from the viability of Raji cells. High viability of these cells is an important factor in developing a compound for the chemoprevention of cancer [26].

TWO-STAGE CARCINOGENESIS TEST ON MOUSE SKIN DMBA/TPA-Induced Carcinogenesis Test Each group of the specific pathogen-free ICR mice was composed of 15 mice housed five per cage and given H2O ad libitum. The back of each mouse was shaved with surgical clippers, and the mouse was treated topically with DMBA (100 mg, 390 nmol) in acetone (0.1 mL) for the initiation treatment. One week after the initiation, papilloma formation was promoted by the application of

4 Studies in Natural Products Chemistry

TPA (1 mg, 1.7 nmol) in acetone (0.1 mL) on the skin twice a week for 20 weeks. Group I received the TPA treatment alone, and group II received the topical application of the test sample (85 nmol) in acetone (0.1 mL) 1 h after each TPA treatment. The incidence and numbers of papillomas were observed and detected weekly for 20 weeks. Only typical papillomas larger than ca. 1 mm in diameter were counted. Details of this two-stage mouse skin carcinogenesis test have been reported previously [27], and this in vivo test is a well-established animal model for prediction of chemopreventive ability of a compound [28,29].

PN/TPA-Induced Carcinogenesis Test Peroxynitrite (ONOOe; PN), which is produced by the reaction of nitric oxide with superoxide, is a potent tumor-initiating agent, as well as an oxidant, and nitrating and hydroxylating agent [30]. Tumors were induced with PN and promoted with TPA. The animals were divided into two experimental groups (15 mice each). The back of each mouse was shaved with surgical clippers, and the mice were topically treated with PN (390 nmol) in NaOH (1 mM, 0.1 mL) as an initiation treatment. For group I (positive control group), 1 week after the initiation, papilloma formation was promoted by a twice-weekly application of TPA (1 mg, 1.7 nmol) in acetone (0.1 mL) on the skin (no papilloma formation was observed with topical application of the acetone solvent alone). For group II (test group), 0.0025% test compound (2.5 mg/ 100 mL in drinking water) was orally administered for 2 weeks before the promotion treatment (1 week both before and after the initiation), and subsequently promoted by a twice-a-week application of TPA (1.7 nmol) in acetone (0.1 mL). The incidence of papilloma bearers and numbers of papillomas per mouse were detected weekly for 20 weeks. Only typical papillomas larger than ca. 1 mm in diameter were counted. Details of this two-stage mouse skin carcinogenesis test have been reported previously [31,32].

UVB/TPA-Induced Carcinogenesis Test Brief exposure of mouse skin to ultraviolet light has been reported to cause permanent cellular changes that do not result in skin tumors unless the mice are treated with TPA for several weeks, which suggested that UV can function as an initiator and TPA as a promoter of tumorigenesis in mouse skin [33]. Irradiation with ultraviolet B (UVB) has been demonstrated to produce reactive oxygen species (ROS; superoxide, and peroxy and hydroxy radicals) in the cells and skin, which cause DNA damage, leading to tumor initiation through gene mutation and abnormal cell proliferation [34]. Tumors were induced with UVB and promoted with TPA. The animals were divided into two

Potentially Chemopreventive Triterpenoids Chapter j 1

5

experimental groups (15 mice each). The back of each mouse was shaved with surgical clippers, and the mice were initiated by irradiation directly of UVB (wavelength 280e320 nm) for 15 min each for three days with UVB lamps. For group I (positive control group), 1 week after initiation with UVB, mice were promoted by the application with TPA (1.7 nmol) in acetone (0.1 mL) twice a week. For group II (test group), 0.0025% test compound (2.5 mg/ 100 mL in drinking water) was orally administered for 2 weeks, while the mice were received the initiation treatment with UVB irradiation for 15 min each for three days, and then promoted by the application with TPA (1.7 nmol) in acetone (0.1 mL) twice a week for 20 weeks. The incidence of papillomas was observed weekly for 20 weeks. For the detailed protocol for this in vivo assay, cf. [31].

PLANT AND FUNGAL MATERIALS INVESTIGATED The plant and fungal materials including edible plants and mushrooms, and crude herbal drugs investigated for their chemopreventive constituents are listed in Table 1.1. From these materials, a number of compounds consisted of various types of triterpenoids, i.e., cucurbitane- (Cu), cycloartane- (Cy), dammarane- (Da), euphane- (Eu), fernane- (Fe), hopane- (Ho), lanostane(La), lemaphyllane- (Le), limonoid- (Li), lupane- (Lp), multiflorane- (Mu), oleanane- (On), taraxastane- (Ta), tirucallane- (Ti), and ursane- (Ur) types of triterpenoids, and other compounds such as chalcones (CH), flavonoids (FL), phenolic compounds (PH), phloroglucinols (PL), and steroids (ST) have been isolated and identified [31,32,35e86]. Fatty acids and their derivatives derived from the liver oil of sunfish also have been investigated [87].

INHIBITORY EFFECTS ON TPA-INDUCED EBV-EA ACTIVATION Among a number of compounds isolated from the plant and fungal materials listed in Table 1.1, 772 compounds including 535 of triterpenoids, 46 of other terpenoids and steroids, and 146 of other plant and fungal secondary metabolites, in addition to 45 of fatty acids (derived from the liver oil of ocean sunfish) and their derivatives, have been evaluated for their inhibitory effects against TPA (32 pmol)-induced EBV-EA activation in Raji cells. All tested compounds exhibited inhibitory effects with IC50 values ranging from 187 (i.e., 26-hydroxyporicoic acid DM (La29) [85]) to 620 (i.e., xanthomonascin B, a furanoisophthalide [79]) molar ratio/32 pmol TPA and showed high viability (60e80%) of Raji cells even at the highest concentration of 1000 molar ratio/TPA [31,32,35e87] indicating their low cytotoxicity which is an important factor in developing a cancer chemopreventive agent [26].

6 Studies in Natural Products Chemistry

TABLE 1.1 Plant and Fungal Materials Investigated for Their Chemopreventive Constituents Source of Compounds

Type of Compounds

References

Higher Plants Aceraceae

Acer nikoense (megusurino-ki)

Diarylheptanoid, FL

[35]

Apiaceae

Angelica keiskei (ashitaba)

Alkylresorcinol, CH, CO, DI, Diacetylene, FL

[36e38]

Asteraceae

Artemisia princeps (moxa)

CO, FL, Quinic acid, TR (Cy, Fe, Ho, On, Ur)

[39]

Calendula officinalis (marigold)

FL, TR (On, Ta)

[40,41]

Chrysanthemum morifolium (chrysanthemum)

TR (Lp, On, Ur, Ta)

[42,43]

Helianthus annuus (sunflower)

DI, Estoride, TR (Ti)

[44,45]

Stevia rebaudiana (stevia)

DI

[46]

Burseraceae

Boswellia carteri (frankincense)

DI, TR (Lp, On, Ur, Ti)

[47]

Cannabaceae

Humulus lupulus (hop)

CH, FL, PL, TR (Lp, On, Ur)

[48]

Combretaceae

Terminalia chebula (myrobalan)

PH, Tannin, TR (On)

[49]

Cucurbitaceae

Bryonia dioica (white bryony)

TR (Cu)

[50]

Momordica charantia (bitter gourd)

TR (Cu)

[32]

Siraitia grosvenorii (Buddha fruit)

TR (Cu, Eu, On)

[51e53]

Trichosanthes kirilowii (snake gourd)

TR (Mu)

[54,55]

Shorea javanica (dammar resin)

TR (Da)

[56]

Dipterocarpaceae

Potentially Chemopreventive Triterpenoids Chapter j 1

7

TABLE 1.1 Plant and Fungal Materials Investigated for Their Chemopreventive Constituentsdcont’d Source of Compounds

Type of Compounds

References

Euphorbia antiquorum (antique spurge)

TR (Eu, Le, Ti)

[57]

E. kansui (gan sui)

TR (Eu)

[58]

Fabaceae

Peltophorum pterocarpum (yellow flame)

PH

[59]

Gramineae

Oryza sativa (Asian rice)

TR (Cy)

[60]

Gramineae (corn, rye, wheat)

Alkylresorcinol, ST

[61]

Lamiaceae

Perilla frutescens (perilla)

TR (On, Ur)

[62]

Meliaceae

Azadirachta indica (neem tree)

TR (Li)

[63e65]

Melia azedarach (chinaberry tree)

FL, ST, TR (Li, Ti)

[66,67]

Passifloraceae

Passiflora edulis (passion flower)

Cyano-glycoside, FL, TR (Cy)

[68]

Rosaceae

Eriobotrya japonica (loquat)

TR (Lp, On, Ur)

[69]

Rubiaceae

Morinda citrifolia (noni)

Anthraquinone, FA, MO, PH

[70,71]

Sapotaceae

Vitellaria paradoxa (shea butter tree)

FL, Jasmonate derivative, PH, ST, TR (Eu, Lp, On, Ur)

[72e74]

Theaceae

Camellia japonica (camellia)

TR (Da, Lp, Ta)

[75]

Others

Betulin derivatives

TR (Lp)

[76]

Higher plants, semisynthetic

TR (Cy)

[77]

Higher plants, semisynthetic

TR (Cy, Eu, La, Lp, Ta, Ur)

[78]

Monascus pilosusfermented rice

Azaphilonoid pigment

[31,79]

Higher Plants Euphorbiaceae

Fungi Ascomycota

Continued

8 Studies in Natural Products Chemistry

TABLE 1.1 Plant and Fungal Materials Investigated for Their Chemopreventive Constituentsdcont’d Source of Compounds

Type of Compounds

References

Ganoderma lucidum (reishi mushroom)

ST, TR (La), TR (La)

[80,81]

Hypsizigus marmoreus (bunashimeji)

ST, Polyisoprenepolyol

[82]

Poria cocos (hoelen)

DI, TR (La)

[83e85]

Chlorella vulgaris (chlorella)

ST

[86]

Mola mola (ocean sunfish)

FA

[87]

Fungi Basidiomycota

Green Alga

Fish

CH, chalcone; Cu, cucurbitane; Cy, cycloartane; Da, dammarane; DI, diterpenoid; Eu, euphane; FA, fatty acid; Fe, fernane; FL, flavonoid; Ho, hopane; La, lanostane; Le, lemaphyllane; Li, limonoid; Lp, lupane; MO, monoterpenoid; Mu, multiflorane; On, oleanane; PH, phenolic compound; PL, phloroglucinol; ST, steroid; Ta, taraxastane; Ti, tirucallane; TR, triterpenoid; Ur, ursane.

Among the compounds tested, 163 compounds (excluded fatty acids) exhibited potent inhibitory effects against EBV-EA induction with IC50 values less than 300 molar ratio/32 pmol TPA (i.e., IC50 < 9.6 nmol). These compounds, in addition to 10 other compounds which suppressed the promoting effects in two-stage mouse skin carcinogenesis test, are listed in Tables 1.3 and 1.5 together with their IC50 values and biological sources. Four reference compounds, b-carotene [4], curcumin [88], retinoic acid [89,90], and glycyrrhetic acid [89,91] (Fig. 1.1), all of which have been COOH COOH β-Carotene O

Retinoic acid

OH

MeO

O

OMe

HO

H H

OH Curcumin (enol-form)

HO

H

FIGURE 1.1 Structures of reference compounds.

Glycyrrhetic acid

Potentially Chemopreventive Triterpenoids Chapter j 1

9

TABLE 1.2 Inhibitory Effects of Four Reference Compounds on the Induction of EBV-EA Compound

IC50a

References

b-Carotene

397

[62]

Curcumin

341

[32]

Retinoic acid

482

[53]

Glycyrrhetic acid

553

[55]

a

IC50 values represent the molar ratios of compounds, relative to TPA, required to inhibit 50% of the positive control activated with 32 pmol TPA.

intensively studied in cancer chemoprevention by using animal models, exhibited the inhibitory effects with IC50 values in the range of 341e553 molar ratio/32 pmol TPA (Table 1.2).

INHIBITORY EFFECTS ON MOUSE SKIN CARCINOGENESIS The inhibitory effects against mouse skin carcinogenesis evaluated for 23 compounds by the DMBA/TPA system [32,37,38,48,49,53,59,62,69,72 ,74,77,81,83e85,87,92], three compounds by the PN/TPA system [31,32,63], and one compound by the UVB/TPA system [31] were shown in Table 1.4. Most of the compounds evaluated are those possessing potent inhibitory effects against EBV-EA induction (Tables 1.3, 1.5, and 1.6). The inhibitory effects of test compounds on mouse skin carcinogenesis were expressed as percentage of mice bearing papillomas and average number of papillomas per mouse at 10 and 20 weeks of promotion. Values in parentheses are those of control group (TPA alone). The percent inhibitory ratio (IR) was then calculated based on the papillomas per mouse value by the equation: IR (%) ¼ (A e B/A)  100, where A is papillomas/mouse of the control group (TPA alone) and B is the papillomas/mouse of the test group (test compound þ TPA). Three reference compounds, b-carotene [74], curcumin [93], and glycyrrhetic acid [94], exhibited the IR values of 36e63% and 30e46% at 10 and 20 weeks, respectively, on the DMBA/TPA system. All compounds tested on the DMBA/TPA system showed potent inhibitory effects of tumor promotion with the IR-values of 54e79% and 30e65% at 10 and 20 weeks, respectively, which were almost equivalent to or more potent than those of the three reference compounds. As can be seen from the inhibitory potencies of the compounds in Tables 1.3e1.6, highly potent inhibitors against EBV-EA induction, in general, suppressed the tumor promotion more potently in two-stage carcinogenesis. This may suggest that the in vitro EBV-EA induction test is highly correlated with the in vivo papilloma

TABLE 1.3 Inhibitory Effects of Selected Triterpenoids on the Induction of EBV-EA Compound

IC50a

Source

References

Cucurbitane-Type Triterpenoid (Cu) Cu1

10a-Cucurbitadienol

290

Siraitia grosvenorii

[51]

Cu2

Mogrol

288

S. grosvenorii

[51]

Cu3

11-Oxomogrol (bryodulcosigenin)

278

S. grosvenorii

[51]

Cu4

11-Oxomogroside I E1 (cabenoside D)

295

S. grosvenorii

[51]

Cu5

Bryosigenin

288

Bryonia dioica

[50]

Cu6

Bryonioside F

298

B. dioica

[50]

Cu7

Bryoamaride

299

B. dioica

[50]

Cu8

5a,6a-Epoxymogroside I E1

291

S. grosvenorii

[51]

Cu9

Bryonioside D (5a,6a-epoxycarbenoside D)

298

B. dioica

[50]

Cu10

3b-Hydroxy-7b-methoxycucurbita-5,23,25-trien19-al

291

Momordica charantia

[32]

Cu11

3b,25-Dihydroxy-7b-methoxycucurbita-5,23-dien19-al

251

M. charantia

[53]

Cu12

3b,7b-Dihydroxy-25-methoxycucurbita-5,23-dien19-al

264

M. charantia

[53]

Cu13

Karavilagenin D

242

M. charantia

[53]

Cu14

25-O-Methylkaravilagenin D

249

M. charantia

[53]

Cu15

5b,19-Epoxy-19-methoxycucurbita-6,23,25-trien3b-ol

203

M. charantia

[32]

Cu16

5b,19-Epoxy-19,25-dimethoxycucurbita-6,23-dien3b-ol

200

M. charantia

[32]

10 Studies in Natural Products Chemistry

Code

Cycloartane-Type Triterpenoid (Cy) Cycloartanol

294

Cucurbitaceae

[77]

Cy2

Cycloartenol

276

Oryza sativa

[78]

Cy3

Cimicifugenol

282

Cimicifuga simplex

[77]

Cy4

24-Methylenecycloartanol

272

Artemisia princeps

[39]

Cy5

Cyclobranol

295

Gramineae

[77]

Cy6

Cyclolaudenol

279

Cucurbitaceae

[77]

Cy7

Polysthicol

275

Polypodium sp.

[77]

Cy8

24-Oxocycloartanol

253

B. dioica

[77]

Cy9

3b-Hydroxycycloart-25-en-24-one

290

B. dioica

[77]

Cy10

Cycloart-25-ene-3b,24-diol

201

Chrysanthemum sp.

[77]

192

Biotransformed product

[77]

Cy11

1

24-Methylcycloartane-3b,24,24 -triol 1

Cy12

24 -Methoxy-24-methylcycloartane-3b,24-diol

210

Biotransformed product

[77]

Cy13

(24R)-Cycloartane-3b,24,25-triol

228

Chrysanthemum sp.

[77]

Cy14

(24S)-Cycloartane-3b,24,25-triol

208

Chrysanthemum sp.

[77]

Cy15

25-Methoxycycloartane-3b,24-diol

297

Chrysanthemum sp.

[77]

Cy16

Cyclopassifloside I

296

Passiflora edulis

[68]

Cy17

Cyclopassifloside VIII

299

P. edulis

[68]

Cy18

(31R)-Passiflorine

288

P. edulis

[68]

11

Continued

Potentially Chemopreventive Triterpenoids Chapter j 1

Cy1

Code

Compound

IC50a

Source

References

Cy19

(31S)-Passiflorine

283

P. edulis

[68]

Cy20

29-nor-Cycloartenol

296

Gramineae

[77]

Cy21

29-nor-Cycloartane-3b,24,25-triol

210

Chrysanthemum sp.

[77]

Cy22

Cycloeucalenol

278

Oryza sativa

[77]

Cy23

3-Epicycloeucalenol

293

Musa sapientum

[77]

Cy24

3-Epicyclomusalenol

292

M. sapientum

[77]

Cy25

24-Methylenepollinastanol

298

M. sapientum

[77]

Dammarane-Type Triterpenoid (Da) Da1

Isofouquierol

270

Shorea javanica

[56]

Da2

Isofouquierone

272

S. javanica

[56]

Da3

Dammarenolic acid

226

S. javanica

[56]

Da4

Dammarenolic acid methyl ester

279

Semisynthetic

[56]

Da5

3,4-seco-Dammara-4(28),24-dien-3,20-diol

208

Semisynthetic

[56]

Da6

20-Hydroxy-3,4-seco-dammara-4(28),24-dien-3-al

212

Semisynthetic

[56]

Da7

23-Dehydro-25-hydroxydammarenolic acid

272

S. javanica

[56]

12 Studies in Natural Products Chemistry

TABLE 1.3 Inhibitory Effects of Selected Triterpenoids on the Induction of EBV-EAdcont’d

Euphane-Type Triterpenoid (Eu) Eu1

Euphol

271

Euphorbia antiquorum

[57,58]

Eu2

Antiquol C

289

E. antiquorum

[57]

Eu3

Isohelianol

298

E. antiquorum

[57]

Lanostane-Type Triterpenoid (La) Dihydrolanosterol

298

Fabaceae

[78]

La2

Lanosterol

281

Fabaceae

[78]

La3

Tumulosic acid

269

Poria cocos

[83]

La4

Pachymic acid

286

P. cocos

[84]

La5

25-Hydroxy-3-epitumulosic acid

238

P. cocos

[85]

La6

16a,25-Dihydroxyeburiconic acid

299

P. cocos

[85]

La7

16a,27-Dihydroxydehydrotrametenonic acid

269

P. cocos

[85]

La8

Dehydrotumulosic acid

289

P. cocos

[84]

La9

3-Epidehydrotumulosic acid

295

P. cocos

[84]

La10

Polyporenic acid C

294

P. cocos

[84]

La11

Dehydropachymic acid

284

P. cocos

[84]

La12

25-Hydroxy-3-epidehydrotumulosic acid

258

P. cocos

[83]

La13

15a-Hydroxydehydrotumulosic acid

268

P. cocos

[84]

La14

5a,8a-Peroxydehydrotumulosic acid

202

P. cocos

[84]

13

Continued

Potentially Chemopreventive Triterpenoids Chapter j 1

La1

Code

Compound

IC50a

Source

References

La15

Poricoic acid G

271

P. cocos

[83]

La16

Poricoic acid GM

216

P. cocos

[85]

La17

Poricoic acid H

267

P. cocos

[83]

La18

Poricoic acid HM

219

P. cocos

[85]

La19

25-Hydroxyporicoic acid H

202

P. cocos

[84]

La20

16-Deoxyporicoic acid B

262

P. cocos

[84]

La21

Poricoic acid B

266

P. cocos

[83]

La22

Poricoic acid A

279

P. cocos

[83]

La23

Poricoic acid AM

195

P. cocos

[84]

La24

25-Methoxyporicoic acid A

268

P. cocos

[85]

La25

Poricoic acid C

273

P. cocos

[84]

La26

25-Hydroxyporicoic acid C

201

P. cocos

[85]

La27

Poricoic acid D

198

P. cocos

[84]

La28

Poricoic acid DM

207

P. cocos

[84]

La29

26-Hydroxyporicoic acid DM

187

P. cocos

[85]

La30

6,7-Dehydroporicoic acid H

193

P. cocos

[85]

14 Studies in Natural Products Chemistry

TABLE 1.3 Inhibitory Effects of Selected Triterpenoids on the Induction of EBV-EAdcont’d

Demethylincisterol A3

293

Ganoderma lucidum

[81]

La32

Ganoderic acid T-Q

281

G. lucidum

[80]

La33

Ganoderic acid A

291

G. lucidum

[81]

La34

Ganoderic acid C2

290

G. lucidum

[81]

La35

Ganoderic acid E

281

G. lucidum

[80]

La36

Ganoderic acid F

293

G. lucidum

[80]

La37

Methyl ganoderate F

289

G. lucidum

[80]

La38

Lucidenic acid A

280

G. lucidum

[80]

La39

Methyl lucidenate A

287

G. lucidum

[80]

La40

Methyl lucidenate F

285

G. lucidum

[80]

La41

Methyl lucidenate Q

283

G. lucidum

[80]

La42

Lucidenic acid D2

287

G. lucidum

[80]

La43

Methyl lucidenate D2

290

G. lucidum

[80]

La44

Lucidenic acid E2

280

G. lucidum

[80]

La45

Methyl lucidenate E2

288

G. lucidum

[80]

La46

Methyl lucidenate L

275

G. lucidum

[80]

La47

Lucidenic acid C

284

G. lucidum

[80]

La48

Lucidenic acid P

286

G. lucidum

[80]

La49

Methyl lucidenate P

293

G. lucidum

[80]

15

Continued

Potentially Chemopreventive Triterpenoids Chapter j 1

La31

Code

Compound

IC50a

Source

References

La50

20-Hydroxylucidenic acid E2

290

G. lucidum

[81]

La51

20-Hydroxylucidenic acid N

288

G. lucidum

[81]

La52

20-Hydroxylucidenic acid P

288

G. lucidum

[81]

Li1

7a-Acetoxy-3-oxoisocopala-1,13-dien-15-oic acid

230

Azadirachta indica

[63]

Li2

Azadirachtin B

384

A. indica

[63]

Li3

3-Deacetyl-28-oxoisosalanninolide

299

Melia azedarach

[67]

Limonoid (Li)

Lupane-Type Triterpenoid (Lu) Lp1

Calenduladiol

296

Chrysanthemum sp.

[43]

Lp2

Lupeol cinnamate

379

Vitellaria paradoxa

[72]

Lp3

Betulin

402

Betula platyphylla

[76]

Lp4

Lupane-3b,20-diol

277

Camellia japonica

[75]

Lp5

4,28-Dihydroxy-3,4-seco-lup-20(29)-en-3-oic acid

292

Biotransformed product

[76]

Lp6

4-Hydroxy-3,4-seco-lup-20(29)-ene-3,28-dioic acid

289

Biotransformed product

[76]

Lp7

4,7b,17-Trihydroxy-3,4-seco-28-norlup-20(29)-en3-oic acid

280

Biotransformed product

[76]

16 Studies in Natural Products Chemistry

TABLE 1.3 Inhibitory Effects of Selected Triterpenoids on the Induction of EBV-EAdcont’d

Multiflorane-Type Triterpenoid (Mu) Mu1

Karounidiol

446

Trichosanthes kirilowii

[55]

Oleanane-Type Triterpenoid (On) Oleanolic acid

388

Perilla frutescens

[62]

On2

Arjunic acid

279

Terminalia chebula

[49]

On3

Arjunolic acid

283

T. chebula

[49]

On4

Terminolic acid

269

T. chebula

[49]

On5

Arjungenin

271

T. chebula

[49]

276

Chrysanthemum sp.

[43]

Taraxastane-Type Triterpenoid (Ta) Ta1

Faradiol

Tirucallane-Type Triterpenoid (Ti) Ti1

Helianol

295

Helianthus annuus

[44]

Ti2

(24R)-24,25-Dihydroxyhelianol

275

H. annuus

[44]

Ti3

(24R)-24,25-Dihydroxyhelianyl octanoate

293

H. annuus

[44]

Ti4

(24S)-24,25-Dihydroxyhelianol

280

H. annuus

[44]

Ti5

(24S)-24,25-Dihydroxyhelianyl octanoate

289

H. annuus

[44]

Ti6

(24R)-4a,5a:24,25-Diepoxyhelianol

296

H. annuus

[44]

Ti7

(24S)-4a,5a:24,25-Diepoxyhelianol

298

H. annuus

[44]

17

Continued

Potentially Chemopreventive Triterpenoids Chapter j 1

On1

Code

Compound

IC50a

Source

References

Ti8

(24R)-24,25-Dihydroxy-4a,5a-epoxyhelianol

284

H. annuus

[44]

Ti9

(24R)-24,25-Dihydroxy-4a,5a-epoxyhelianyl octanoate

297

H. annuus

[44]

Ti10

(24S)-24,25-Dihydroxy-4a,5a-epoxyhelianol

285

H. annuus

[44]

Ti11

23E-Dehydro-25-hydroxysunpollenol

287

H. annuus

[45]

Ti12

(24S)-24,25-Epoxysunpollenol

297

H. annuus

[45]

Ti13

(24R)-24,25-Epoxysunpollenol

290

H. annuus

[45]

Ti14

(24R)-24,25-Dihydroxysunpollenol

293

H. annuus

[45]

Ti15

(24S)-24,25-Dihydroxysunpollenol

298

H. annuus

[45]

Ursane-Type Triterpenoids (Ur) Ur1

Ursolic acid

419

P. frutescens

[62]

Ur2

Tormentic acid

409

P. frutescens

[62]

Ur3

Euscaphic acid

306

Eriobotrya japonica

[69]

Ur4

1b-Hydroxyeuscaphic acid

291

E. japonica

[69]

a

IC50 values represent the molar ratios of compounds, relative to TPA, required to inhibit 50% of the positive control activated with 32 pmol TPA.

18 Studies in Natural Products Chemistry

TABLE 1.3 Inhibitory Effects of Selected Triterpenoids on the Induction of EBV-EAdcont’d

TABLE 1.4 Inhibitory Effects of Compounds on Mouse Skin Carcinogenesis Initiated by DMBA, PN, or UVB, and Promoted by TPA 10 weeks of Promotion

Code

Compound

20 weeks of Promotion

% Papilloma Bearersa

Papillomas/ Mousea

IRb

% Papilloma Bearersa

Papillomas/ Mousea

IRb

References

c

Cu13

Karavilagenin D

33.3 (100)

1.3 (3.7)

65

93.3 (100)

3.9 (8.6)

55

[53]

Cu14

25-O-Methylkaravilagenin D

33.3 (100)

1.7 (3.7)

54

93.3 (100)

4.4 (8.6)

49

[53]

Cu15

5b,19-Epoxy-19-methoxycucurbita-6,23,25-trien-3b-ol

33.3 (100)

1.7 (5.4)

69

80.0 (100)

4.0 (9.3)

57

[32]

Cu16

5b,19-Epoxy-19,25-dimethoxycucurbita-6,23-dien-3b-ol

33.3 (100)

2.1 (5.4)

61

80.0 (100)

3.9 (9.3)

58

[32]

Cy11

24-Methylcycloartane3b,24,241-triol

20.0 (100)

1.2 (5.2)

77

80.0 (100)

4.0 (9.3)

57

[77]

Cy12

241-Methoxy-24methylcycloartane-3b,24-diol

26.6 (100)

1.2 (5.2)

77

86.6 (100)

4.2 (9.3)

55

[77]

La15

Poricoic acid Gd

20.0 (100)

1.1 (4.3)

74

93.3 (100)

4.1 (9.7)

58

cf [83].

La20

16-Deoxyporicoic acid B

20.0 (86.6)

1.2 (3.7)

68

86.6 (100)

3.6 (8.6)

58

[84]

La24

25-Methoxypolyporic acid A

13.3 (86.6)

0.8 (3.7)

78

80.0 (100)

3.0 (8.6)

65

[85]

La25

Poricoic acid C

13.3 (86.6)

1.0 (3.7)

73

80.0 (100)

3.2 (8.6)

63

[84]

19

Continued

Potentially Chemopreventive Triterpenoids Chapter j 1

DMBA/TPA System

10 weeks of Promotion

20 weeks of Promotion

Code

Compound

% Papilloma Bearersa

Papillomas/ Mousea

IRb

% Papilloma Bearersa

Papillomas/ Mousea

IRb

References

La51

20-Hydroxylucidenic acid N

20.0 (100)

1.2 (5.2)

77

93.3 (100)

3.2 (9.3)

64

[81]

Lp2

Lupeol cinnamate

26.6 (86.6)

1.6 (3.7)

57

93.3 (100)

4.1 (8.6)

52

[72]

On1

Oleanolic acid

26.8 (100)

1.7 (5.4)

69

86.6 (100)

5.9 (9.4)

37

[92]

On5

Arjungenin

26.6 (100)

1.6 (3.9)

59

86.6 (100)

5.6 (8.0)

30

[49]

Ur2

Tormentic acid

26.6 (93.3)

1.4 (4.8)

71

100 (100)

5.1 (9.1)

44

[62]

Ur3

Euscaphic acid

26.6 (100)

1.4 (5.2)

73

93.3 (100)

4.2 (9.3)

55

[69]

CH1

Isobavachalcone

20.0 (100)

1.1 (5.2)

79

80.0 (100)

4.1 (9.3)

56

[37]

00

00

00

CH9

7 -Hydroxy-6 ,7 dihydroxanthoangelol F

20.0 (86.6)

1.0 (3.5)

71

93.3 (100)

4.2 (8.0)

48

[38]

FL3

Isoxanthohumold

26.6 (86.6)

1.1 (3.5)

69

86.6 (100)

5.4 (8.0)

32

cf [48].

FL7

6-Prenylnaringenin

13.3 (86.6)

1.2 (3.7)

68

86.6 (100)

3.2 (8.6)

63

[48]

PL3

Lupulone C

20.0 (86.6)

1.1 (3.7)

70

86.6 (100)

3.8 (8.6)

56

[48]

MS2

Bergenin

26.6 (86.6)

1.1 (3.5)

69

86.6 (100)

5.0 (8.0)

38

[59]

MS4

Glucosylcucurbic acid

30.0 (100)

1.2 (3.7)

68

100 (100)

5.9 (8.6)

31

[74]

FA7

Methyl docosahexaenoate

26.6 (100)

1.6 (5.4)

70

80.0 (100)

4.8 (9.3)

48

[87]

20 Studies in Natural Products Chemistry

TABLE 1.4 Inhibitory Effects of Compounds on Mouse Skin Carcinogenesis Initiated by DMBA, PN, or UVB, and Promoted by TPAdcont’d

Reference Compound b-Carotene

33.0 (100)

1.5 (3.7)

59

100 (100)

6.0 (8.6)

30

[74]

Curcumin

27.5 (100)

1.5 (4.1)

63

93.4 (100)

4.9 (9.1)

46

[93]

Glycyrrhetic acid

48.0 (100)

2.8 (4.4)

36

94.8 (100)

6.0 (9.1)

34

[94]

e

PN/TPA System

5b,19-Epoxy-19-methoxycucurbita-6,23,25-trien-3b-ol

33.3 (86.6)

1.5 (2.4)

47

80.0 (100)

4.7 (7.0)

33

[32]

Cu16

5b,19-Epoxy-19,25-dimethoxycucurbita-6,23-dien-3b-ol

20.0 (86.6)

1.3 (2.9)

55

80.0 (100)

4.5 (7.0)

36

[32]

Li2

Azadirachtin B

13.3 (53.3)

0.9 (2.3)

61

82.6 (100)

3.7 (6.8)

46

[63]

MS3

Monascin

20.0 (73.3)

1.1 (2.5)

66

80.0 (100)

4.0 (7.3)

45

[31]

6.6 (80.0)

0.4 (1.1)

64

53.3 (100)

2.9 (5.2)

44

[31]

UVB/TPA Systemf MS3 a

Monascin

Values in parentheses are those of control group. IR (% inhibitory ratio) ¼ (A  B/A)  100, where A is papillomas/mouse of the control group; and B is papillomas/mouse of the test group. Tumor promotion was initiated with DMBA (390 nmol) and promoted with TPA (1.7 nmol) alone (control group) and with TPA (1.7 nmol) + test compound (85 nmol) (test group). d Unpublished results. e Tumor promotion was initiated with PN (390 nmol) and promoted with TPA (1.7 nmol) alone (control group) and with TPA (1.7 nmol) + test compound (0.025%; 2.5 mg/ 100 mL in drinking water) (test group). f Tumor promotion was initiated with UVB irradiation and promoted with TPA (1.7 nmol) alone (control group) and with TPA (1.7 nmol) + test compound (0.025%; 2.5 mg/ 100 mL in drinking water) (test group). b c

Potentially Chemopreventive Triterpenoids Chapter j 1

Cu15

21

22 Studies in Natural Products Chemistry

TABLE 1.5 Inhibitory Effects of Selected Diterpenoids, Steroids, Chalcones, Flavonoids, and Other Compounds on the Induction of EBV-EA Code

Compound

IC50a

Source

References

Diterpenoid (DI) DI1

Methyl dehydroabietate

291

P. cocos

[83]

DI2

7-Oxo15-hydroxydehydroabietic acid

238

P. cocos

[85]

DI3

ent-Trachyloban-19-oic acid

292

H. annuus

[44]

DI4

Grandiflorolic acid angelate

295

H. annuus

[44]

1b,16a-Dihydroxy-4(14)eudesmene

276

Shorea javanica

[56]

ST1

6-O-Methylcerevisterol

298

Hypsizigus marmoreus

[82]

ST2

5a,6a-Epoxyergosta8,22-diene-3b,7b-diol

192

H. marmoreus

[82]

ST3

9(11)-Dehydroergosterol peroxide

235

G. lucidum

[81]

ST4

Schottenol

281

Fabaceae

[61]

Sesterterpenoid (SE) SE1 Steroid (ST)

Chalcone (CH) CH1

Isobavachalcone

274

Angelica keiskei

[36]

CH2

4-Hydroxyderricin

280

A. keiskei

[36]

CH3

Xanthoangelol

283

A. keiskei

[36]

CH4

Xanthoangelol F

289

A. keiskei

[36]

CH5

Xanthoangelol J

264

A. keiskei

[37]

CH6

Xanthoangelol I

273

A. keiskei

[37]

CH7

00

4,3 -Dihydroxy-2 ,3 dihydroderricin

210

Biotransformed product

[38]

CH8

700 -Hydroxy-600 ,700 dihydroxanthoangelol

211

Biotransformed product

[38]

CH9

700 -Hydroxy-600 ,700 dihydroxanthoangelol F

215

Biotransformed product

[38]

00

00

Potentially Chemopreventive Triterpenoids Chapter j 1

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TABLE 1.5 Inhibitory Effects of Selected Diterpenoids, Steroids, Chalcones, Flavonoids, and Other Compounds on the Induction of EBV-EAdcont’d Code

Compound

IC50a

Source

References

Flavonoid (FL) FL1

Isobavachin

225

A. keiskei

[37]

FL2

Munduleaflavanone A

230

A. keiskei

[36]

FL3

Isoxanthohumol

293

Humulus lupulus

[48]

FL4

Munduleaflavanone B

230

A. keiskei

[37]

FL5

8-Geranylnaringenin

215

A. keiskei

[49]

FL6

8-Prenylnaringenin

263

H. lupulus

[49]

FL7

6-Prenylnaringenin

263

H. lupulus

[49]

0

FL8

4 -O-Geranylnaringenin

289

A. keiskei

[36]

FL9

Prostratol F

270

A. keiskei

[36]

Phloroglucinol (PL) PL1

Lupulone E

283

H. lupulus

[48]

PL2

Colupox a

239

H. lupulus

[48]

PL3

Lupulone C

215

H. lupulus

[48]

Miscellaneous (MS) MS1

Osthenol

290

A. keiskei

[37]

MS2

Bergenin

224

Peltophorum sp.

[59]

MS3

Monascin

421

Red-mold rice

[79]

MS4

Glucosylcucurbic acid

414

Vitellaria paradoxa

[74]

a

IC50 values represent the molar ratios of compounds, relative to TPA, required to inhibit 50% of the positive control activated with 32 pmol TPA.

formation test in mice [9,49]. Individual groups of compounds are discussed below in terms of the structures and their chemopreventive potencies.

CHEMOPREVENTIVE EFFECTS OF TRITERPENOIDS Cucurbitane-Type Triterpenoids The inhibitory effects on the induction of EBV-EA induced by TPA were examined for 69 cucurbitane-type triterpenoids isolated from Cucurbitaceae

24 Studies in Natural Products Chemistry

TABLE 1.6 Inhibitory Effects of Fatty Acids as the Free and Esterified Forms on the Induction of EBV-EA Compound

Free Form, IC50a

Methyl Ester, IC50a

Saturated Acid C10:0

Capric acid

526

526

C12:0

Lauric acid

520

531

C14:0

Myristic acid

528

295 (FA1)

C15:0

Pentadecanoic acid

532

360

C16:0

Palmitic acid

544

381

C17:0

Heptadecanoic acid

C18:0

Stearic acid

395 569

399

389

421

Monounsaturated Acid C16:1 (n-7)

Palmitoleic acid

C17:1

7-Methyl-7-hexadecenoic acid

C18:1 (n-9)

Oleic acid

C20:1 (n-11)

Eicosenoic acid

449

C22:1 (n-11)

Docosenoic acid

426

448 429

446

n-6 Polyunsaturated Acids C18:2 (n-6)

Linoleic acid

390

427

C20:2 (n-6)

Eicosadienoic acid

453

C20:4 (n-6)

Arachidonic acid (AA)

418

C22:4 (n-6)

Docosatetraenoic acid

435

n-3 Polyunsaturated Acids C18:3 (n-3)

Linolenic acid

C18:4 (n-3)

Octadecatetraenoic acid

C20:5 (n-3)

Eicosapentaenoic acid (EPA)

355

425 402

279 (FA2)

283 (FA3)

Potentially Chemopreventive Triterpenoids Chapter j 1

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TABLE 1.6 Inhibitory Effects of Fatty Acids as the Free and Esterified Forms on the Induction of EBV-EAdcont’d Compound

Free Form, IC50a

Methyl Ester, IC50a

C22:3 (n-3)

Docosatrienoic acid

292 (FA9)

432

C22:5 (n-3)

Docosapentaenoic acid (DPA)

285 (FA4)

296 (FA5)

C22:6 (n-3)

Docosahexaenoic acid (DHA)

276 (FA6)

289 (FA7)

C22:6 (n-3)

DHA ethyl ester

291 (FA8)

a

IC50 values represent the molar ratio of compounds, relative to TPA, required to inhibit 50% of the positive control activated with 32 pmol TPA.

plant materials, the fruits of Siraitia grosvenorii (Buddha fruit) [51,52], the roots of Bryonia dioica (white bryony) [50], and the fruits [32] and leaves of Momordica charantia (bitter gourd) [53]. All compounds exhibited inhibitory effects with IC50 values of 200e487 molar ratio/32 pmol TPA and, among which, 16 compounds, Cu1eCu16, were the potent inhibitors with IC50 values less than 300 molar ratio/32 pmol TPA (Table 1.3; Fig. 1.2). The fruits of S. grosvenorii grown in Kwangshi, China, are used as expectorant as well as natural sweet food in that country, and many cucurbitanetype triterpene glycosides have been isolated from them [51]. The roots of B. dioica, are used as purgative, emmenagogue, and a treatment for gout [52]. M. charantia has been used medicinally by tradition in developing countries mostly for healing diabetes and as a carminative and in the treatment of colic [29]. Benzoylation of the hydroxy group(s), and tri-, tetra-, and pentaglycosylation of cucurbitane aglycons led to a reduction of the inhibitory effects [32,50e53]. Compounds Cu13 and Cu14, and Cu15 and Cu16, isolated from the leaves and fruits of M. charantia, respectively, exhibited marked inhibitory effects in DMBA/TPA-induced mouse skin carcinogenesis test [32,53] (Table 1.4). In addition, compounds Cu15 and Cu16 showed inhibitory effects in PN-initiated carcinogenesis on mouse skin (Table 1.4) suggesting that these may be able to intercept and neutralize potent chemical carcinogens [32].

Cycloartane-Type Triterpenoids Two cycloartane-type triterpenoids, Cy2 and Cy4, are common in most higher plants [95]. The inhibitory effects on EBV-EA induction, evaluated for 66 natural cycloartanes [39,68,77,78] and their derivatives [77,78], were in the range of IC50 192e496 molar ratio/32 pmol TPA. Twenty-five of these

26 Studies in Natural Products Chemistry

FIGURE 1.2 Structures of cucurbitane- and cycloartane-type triterpenoids described in this review.

compounds, including Cy1 and Cy4, were the potent exhibitors (Table 1.3; Fig. 1.2). On the basis of the results for 48 cycloartanes tested, the following conclusions can be drawn about the structureeactivity relationship (SAR) of the cycloartanes: (1) The 3-oxo group exerts almost no influence on the activity or reduces the activity when compared with the 3b-OH group; (2) feruloylation at 3b-OH group decreases the activity; (3) hydroxylation at C-24 and C-25 enhances the activity [77]. In addition, as far as concerned with the cycloartane glycosides from the leaves of Passiflora edulis (passion flower; Passifloraceae), methylation of C-31 hydroxy group of passiflorines (Cy18 and Cy19) reduced inhibitory effects. Moreover, whereas cyclopassiflosides (Cy16 and Cy17) without glycosyl group at C-31 were potent inhibitors of EBV-EA

Potentially Chemopreventive Triterpenoids Chapter j 1

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Dammarane (Da) OH

OH H

H

R

H

H Da3 Da4 Da5 Da6

Da1 R = α-H, β-OH Da2 R = O

Euphane (Eu)

R = COOH R = COOMe R = CH2OH R = CHO

HOH C HO

H

Eu1

HO

OH

HOOC H

H R

OH

H

OH

H

Eu2

Da7

H

Eu3

FIGURE 1.3 Structures of dammarane- and euphane-type triterpenoids described in this review.

induction, glycosylation at 31-OH reduced the activity [68]. Two cycloartanes having a C-24 hydroxylated side chain, Cy11 and Cy12, which were the biotransformation products of Cy4 by the fungus Glomerella fusarioides [96], inhibited markedly the promotion on DMBA/TPA-induced mouse skin carcinogenesis test [77] (Table 1.4).

Dammarane-Type Triterpenoids Among 32 dammarane-type triterpenoids tested [56,75], four natural dammaranes, Da1eDa3 and Da7, isolated from dammar resin obtained from Shorea javanica (Dipterocarpaceae), and three semisynthetic derivatives of Da3, i.e., Da4eDa6, inhibited markedly the induction of EBV-EA (Table 1.3; Fig. 1.3). On the basis of the results collected in dammaranes, some conclusions about the SAR can be drawn: (1) those compounds possessing a linear side chain at C-17 exhibited more potent inhibitory effects than those with a cyclic side chain at the same position, and (2) the 3-oxo group exerts almost no influence on the activity when compared with 3b-OH group [56], consistent with the observation on the cycloartanes [77]. In addition, as far as Da3 derivatives are concerned, reduction to alcohol and aldehyde at C-3 enhances activity [56].

Euphane-Type Triterpenoids Upon evaluation of the inhibitory effects on EBV-EA induction of seven euphane-type triterpenoids (IC50 261e380 molar ratio/32 pmol TPA) [57,72,78], three compounds, Eu1eEu3, isolated from the latex of Euphorbia antiquorum (Euphorbiaceae), exhibited potent inhibitory effects (Table 1.3; Fig. 1.3). Compound Eu1 occurs as the most predominant triterpenoid constituent in the latex of E. antiquorum which is native to India and Sri Lanka [57]. The latex of E. antiquorum is used for dropsy, as nerve tonic, and for bronchitis.

28 Studies in Natural Products Chemistry

Lanostane-Type Triterpenoids Eighty-two lanostane-type triterpenoids [78,80,81,83e85], most of which were isolated from two medicinal mushrooms, i.e., the sclerotia of Poria cocos (Hoelen; Polyporaceae) [83e85] and the fruiting bodies of Ganoderma lucidum (Reishi mushroom; Polyporaceae) [80,81], exhibited the inhibitory effects on EBV-EA induction with IC50 values in the range of 187e465 molar ratio/ 32 pmol TPA. Among these, 52 compounds including 28 compounds (La3eLa30) from P. cocos and 22 compounds (La31eLa52) from G. lucidum, were the potent inhibitors of EBV-EA induction (Table 1.2; Fig. 1.4).

FIGURE 1.4 Structures of lanostane-type triterpenoids described in this review.

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The sclerotia of P. cocos are traditionally used in Chinese herbal prescriptions as a diuretic and as a sedative and contain various lanostane-type triterpene acids, which were suggested to be the major medicinal principles of the fungus [97,98]. It is worthy to note that all of the 28 potent inhibitors of EBV-EA induction from P. cocos are the triterpene acids possessing carboxy group(s) in the molecule [83e85]. On the basis of the results of the lanostanes from P. cocos, some conclusions about their SAR can be drawn: hydroxylation at C-16a and C-25, and cleavage of ring A to form 3,4-seco-3-oic acid appear to enhance the activity. Four 3,4-seco-triterpene acids, La15, La20, La24, and La25, from P. cocos have been demonstrated to markedly suppress the promoting effect of TPA on skin tumor formation in mice following initiation with DMBA [83e85] (Table 1.3). The fruiting bodies of G. lucidum are widely used in China, Japan, and Korea as a valuable crude drug, especially in the treatment of chronic hepatitis, nephritis, hepatopathy, neurasthenia, arthritis, bronchitis, asthma, gastric ulcer, and insomnia [98]. Over 100 oxygenated triterpenoids, possessing wide range of biological activities, have been isolated from this mushroom [80,81,99]. With the exception of compound La31, all the potent inhibitors of EBV-EA induction from G. lucidum are the triterpene acids possessing either ganoderic acid (La32eLa37) or lucidenic acid (La38eLa52) skeleton (Fig. 1.4). Compound La51 from G. lucidum suppressed markedly the promoting effect in DMBA/TPA-induced mouse skin carcinogenesis test [81] (Table 1.4). From the results of the in vitro EBV-EA induction test and in vivo twostage carcinogenesis, it appears that the lanostane-type triterpene acids isolated from the sclerotia of P. cocos [83e85] and the fruiting bodies of G. lucidum [80,81] may be valuable as potential chemopreventive agents in chemical carcinogenesis. On the other hand, the triterpene acids from P. cocos do not seem to be candidates as potential anticancer agents because they exhibited only weak cytotoxicities against several cancer cell lines [85].

Limonoids Limonoids (tetranortriterpenoids) are highly oxygenated, modified triterpenoids with a prototypical structure either containing or derived from a precursor with a 4,4,8-trimethyl-17-furanylsteroid skeleton. Compounds belonging to this group have exhibited a range of biological activities like insecticidal, insect antifeedant, and growth regulating activity on insects as well as antibacterial, antifungal, antimalarial, anticancer, antiviral, and a number of other pharmacological activities on humans [100]. Limonoids are abundant in citrus fruits and other plants of the families Rutaceae and Meliaceae. The inhibitory effects on the induction of EBV-EA were tested for 87 limonoids isolated from Azadirachta indica (neem tree) [63e65] and Melia

30 Studies in Natural Products Chemistry

FIGURE 1.5 Structures of limonoid-, lupane-, multiflorane-, oleanane-, taraxastane-, tirucallane-, and ursane-type triterpenoids described in this review.

azedarach (chinaberry tree) [66,67] of the family Meliaceae. Whereas two compounds, Li1 and Li3, exhibited potent inhibitory effects (Table 1.3, Fig. 1.5), most of the others were weak inhibitors, i.e., 69 compounds among the others showed IC50 > 400 molar ratio/32 pmol TPA [63e67]. Upon evaluation of azadirachtin B (Li2) (IC50 384 molar ratio/32 pmol TPA) for its antitumor-initiating activity in PN/TPA-induced mouse skin carcinogenesis test, it was found that it markedly inhibited tumor promotion (Table 1.4). The limonoids of A. indica [63e65] and M. azedarach [66,67] have been suggested to be useful as skin whitening, anti-inflammatory, and anticancer agents.

Potentially Chemopreventive Triterpenoids Chapter j 1

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Lupane-Type Triterpenoids Eighteen lupane-type triterpenoids showed IC50 277e496 molar ratio/32 pmol TPA on the EBV-EA induction test [43,47,69,72,75,76,78] and, among which, five compounds, i.e., Lp1 from the edible flower extract of Chrysanthemum morifolium (chrysanthemum, Asteraceae) [43], Lp4 from camellia oil from Camellia japonica (Theaceae) [75], and Lp5eLp7, the biotransformation of products of Lp3 and betulonic acid by the fungus Chaetomium longirostre [76], inhibited the induction potently (Table 1.3; Fig. 1.5). Compound Lp2 (IC50 379 molar ratio/32 pmol TPA), isolated from the kernel fat (shea butter) of shea tree (Vitellaria paradoxa, Sapotaceae), has been revealed to suppress the promoting effect in DMBA/TPA-induced mouse skin carcinogenesis test [72] (Table 1.3). Chemopreventive potential of the other lupanes such as Lp3, abundantly available from birch bark [76], and lupeol, lupeol acetate, and betulinic acid has also been reported [101,102].

Multiflorane-Type Triterpenoids The seeds of Trichosanthes kirilowii (snake gourd, Cucurbitaceae) have been used in Chinese medicine as an anti-inflammatory agent, a cough medicine, and an expectorant [98], and its extract contains karounidiol (Mu1) and its 3-O-benzoate as the most predominant triterpenoid constituents [103]. Compound Mu1 (IC50 446 molar ratio/32 pmol TPA) [55] (Table 1.3; Fig. 1.5) has been revealed to suppress the tumor promotion in DMBA/TPA-induced mouse skin carcinogenesis test [54]. Fifty-two multiflorane-type triterpenoids, including natural compounds isolated from T. kirilowii [55] and Siraitia grosvenori (Cucurbitaceae) [51], and their semisynthetic derivatives, were evaluated for their inhibitory effects on EBV-EA induction. All compounds evaluated showed a moderate or only a weak inhibitory effect with IC50 values in the range of 375e561 molar ratio/32 pmol TPA while these are almost comparable with or more potent than that of reference glycyrrhetic acid (IC50 553 molar ratio/32 pmol TPA) (Table 1.3). As has been observed also in the cucurbitane-type triterpenoids [32,50e53], benzoylation of the hydroxy group at C-3 of multiflorane-type triterpenoids induced the reduction of the activity [55].

Oleanane-Type Triterpenoids Oleanane-type triterpenoids constitute the most ubiquitous and important group of triterpenoids in the plant kingdom. Glycyrrhetic acid was the first triterpenoid shown to inhibit the tumor promotion with DMBA and TPA in mouse skin [104]. Oleanolic acid (On1), which possesses various pharmacological activities [105e107], also suppressed the promotion in the two-stage carcinogenesis test [27,92] (Table 1.4; Fig. 1.5).

32 Studies in Natural Products Chemistry

The inhibitory effects on the induction of EBV-EA were tested for 51 oleananes isolated from various plant materials [39,41,43,47,49,56,69,72,73]. They inhibited the EBV-EA induction with IC50 values in the range of 269e488 molar ratio/32 pmol TPA and, among which, four acidic oleananes, On2eOn5, isolated from the galls of Terminalia chebula (myrobalan tree, Combretaceae) exhibited potent inhibitory effects [49] (Table 1.3). Arjungenin (On5) has been revealed to suppress the tumor promotion in DMBA/ TPA-induced mouse skin carcinogenesis test [49] (Table 1.4).

Taraxastane-Type Triterpenoids The flower petals of the plants belonging to the family Asteraceae are a rich source of pentacyclic triterpenoids including taraxastane-type triterpenoids [108]. Nine di- and trihydroxy taraxastanes isolated from the edible flower petals of C. morifolium (chrysanthemum, Asteraceae) [43] and the seed oil of C. japonica (Theaceae) [75] have been evaluated for their inhibitory effects of EBV-EA induction. They showed the inhibitory effects with IC50 276e498 molar ratio/32 pmol TPA with faradiol (Ta1), a dihydroxy taraxastane isolated from chrysanthemum flowers, being the most potent inhibitor (Table 1.3; Fig. 1.5). Compound Ta1 and heliantriol C, a trihydroxy taraxastane, have been revealed to markedly suppress the promoting effect of TPA on skin tumor formation in mice following initiation with DMBA [42]. The pentacyclic triterpenoids, especially heliantriol C, from chrysanthemum and other Asteraceae flowers possess potent anti-inflammatory activity on TPA-induced ear edema in mice [108,109].

Tirucallane-Type Triterpenoids Twenty-eight tirucallane-type triterpenoids, isolated from the pollen grains of Helianthus annuus (sunflower, Asteraceae) [44,45], the resin of Boswellia carteri [47], and from the latex of E. antiquorum [57], exhibited IC50 275e482 molar ratio/32 pmol TPA against EBV-EA induction. Among them, 15 tirucallanes, all are from sunflower pollens [44,45] and possess 3,4-secotirucallane-type (helianol) [44] or rearranged 3,4-seco-tirucallane-type (sunpollenol) skeletal structure [45], exhibited potent inhibitory effects (Table 1.3; Fig. 1.5). As far as the helianol-type tirucallanes are concerned, it was suggested that hydroxylation at C-24 and C-25 in the side chain and deesterification at C-3 in the ring system enhance the inhibitory effects [44]. Similar SAR has been observed also in the cucurbitane-type triterpenoids [50].

Ursane-Type Triterpenoids Upon evaluation of the inhibitory effects on EBV-EA induction, 28 ursanetype triterpenoids isolated from the resin of B. carteri [47], the leaves of

Potentially Chemopreventive Triterpenoids Chapter j 1

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Perilla frutescens (perilla, Labiatae) [62] and Eriobotrya japonica (loquat, Rosaceae) [69], and from several other plant materials [39,43,56,72] exhibited inhibitory effects with IC50 values 291e509 molar ratio/32 pmol TPA. Among these ursanes, only 1b-hydroxyeuscaphic acid (Ur4), isolated from loquat leaves [69], exhibited potent activity with IC50 291 molar ratio/32 pmol TPA (Table 1.3; Fig. 1.5), while tormentic acid (Ur2) (from perilla leaves) [62] and euscaphic acid (Ur3) (from loquat leaves) [69] have been revealed to suppress the tumor promotion in DMBA/TPA-induced mouse skin carcinogenesis test (Table 1.4). Ursolic acid (Ur1) is a ubiquitous triterpenoid in the plant kingdom, medicinal herbs, and is an integral part of the human diet, and is reported to possess a wide range of pharmacological activities [107,108]. Compound Ur1 has been, moreover, demonstrated to inhibit the tumor promotion with DMBA and TPA in mouse skin [27].

CHEMOPREVENTIVE EFFECTS OF DITERPENOIDS Two each of abietane-type [83], ent-trachyloban-type [44], ent-kaurane-type [44], and cembrane-type [47] diterpenoids, in addition to stevioside, a beyerane-type diterpenoid, and its derivatives [46] have been shown to inhibit EBV-EA induction with IC50 238e499 molar ratio/32 pmol TPA and, among which, DI1 and DI2, two abietanes isolated from P. cocos [83,85], DI3, an enttrachyloban, and DI4, an ent-kaurane, isolated from sunflower pollen [44], are the potent inhibitors of EBV-EA induction (Table 1.5; Fig. 1.6). Stevioside, a sweet-tasting beyerane-type diterpenoid glycoside derived from stevia plant, exhibited moderate inhibitory effect on the EBV-EA induction test (IC50 452 molar ratio/32 pmol TPA) [46]. This diterpenoid glycoside and its aglycons, steviol and isosteviol, have been revealed to inhibit the tumor promotion in both DMBA/TPA- and PN/TPA-induced mouse skin carcinogenesis tests [110].

CHEMOPREVENTIVE EFFECTS OF STEROIDS Twenty-nine steroids, isolated from various plant [39,51,67,73] and fungal materials [81,82], exhibited inhibitory effects against EBV-EA induction with IC50 192e525 molar ratio/32 pmol TPA. Among these, three fungal sterols (3-hydroxy steroids), ST1 and ST2, isolated from an edible mushroom, Hypsizigus marmoreus [82], and ST3, isolated from G. lucidum [81], and one plant sterol (phytosterol), ST4, from Gramineae plants [51], exhibited potent inhibitory effects (Table 1.5; Fig. 1.6). Whereas sitosterol and stigmasterol, the most common phytosterols [95], were not the potent inhibitors of EBV-EA induction (IC50 489 and 492 molar ratio/32 pmol TPA, respectively) [61], these phytosterols suppressed the promoting effect in DMBA/TPA-induced mouse skin carcinogenesis test [9]. It might be worthy noting that phytosterols, especially sitosterol, are suggested to have a protective effect against

34 Studies in Natural Products Chemistry

FIGURE 1.6 Structures of diterpenoids, steroids, chalcones, flavonoids, and other compounds described in this review.

the most common cancers including colon, prostate, and breast cancers [111e113] in the developed countries [114,115]. Although ergosterol and ergosterol peroxide, the most common fungal sterols, were the weak inhibitors against EBV-EA induction (IC50 516 and 501 molar ratio/32 pmol TPA, respectively) [81,82], these also have been demonstrated to suppress tumor promotion in DMBA/TPA-induced mouse skin carcinogenesis test [9].

CHEMOPREVENTIVE EFFECTS OF CHALCONES Angelica keiskei (Japanese name: Ashitaba, Umbelliferae) is a hardy perennial herb, growing mainly along the Pacific coast of Japan, that is traditionally used

Potentially Chemopreventive Triterpenoids Chapter j 1

35

as a diuretic, laxative, analeptic, and lactagogue [116]. The fresh leaves of this plant and its dry powder are used for food. Various chalcones, in addition to coumarins and flavanones, have been isolated from the plant. Ten chalcones isolated from the exudate of Ashitaba stems and three chalcones, CH7eCH9 (Table 1.5; Fig. 1.6) [36,37], derived from CH2eCH4, respectively, by biotransformation using the fungus Aspergillus saitoi [38], were examined for their inhibitory effects on the EBV-EA induction. Among the compounds tested, nine compounds, CH1eCH9, exhibited potent inhibitory effects (Table 1.5). All of the highly inhibitory compounds from Ashitaba exudate, i.e., CH1eCH6, possess a prenyl or a geranyl group in the molecule. This suggests that prenylation or geranylation of the parent chalcone skeletal structure gives rise to more potent activity in this bioassay system [37]. Hydration of the prenyl or geranyl chain, i.e., CH7eCH9, enhanced the activity [38]. Compounds CH1 and CH9 have suppressed the promoting effect in DMBA/TPA-induced mouse skin carcinogenesis test [38] (Table 1.4). In addition, CH2 and CH3 have already been proved to have potent activity in DMBA/TPA-induced mouse skin carcinogenesis test [117].

CHEMOPREVENTIVE EFFECTS OF FLAVONOIDS Both epidemiological and experimental evidence have described the beneficial effects of dietary flavonoids on the reduction of the risk of chronic diseases, including cancer [118e121]. Twenty-eight flavonoids isolated from the exudate of Ashitaba stems [36e38], the female inflorescences of hop Humulus lupulus (hop plant, Cannabaceae) [45], and from several other plant materials [39,41,67,73] have been examined for their inhibitory effects on the EBV-EA induction. Prenylated or geranylated flavonoids, i.e., FL1eFL9 (Fig. 1.6), exhibited potent inhibitory effects (Table 1.5), which is consistent with the observation on the chalcone group compounds described above. Among these flavonoids, FL3 and FL7, isolated from hop cones, suppressed tumor promotion in DMBA/TPA-induced mouse skin carcinogenesis test [48]. Luteolin, a flavonoid isolated from moxa, the processed leaves of Artemisia princeps (Asteraceae), exhibited moderate inhibitory effect (IC50 392 molar ratio/ 32 pmol TPA) [30]. This compound also has been revealed to suppress the tumor promotion in DMBA/TPA-induced mouse skin carcinogenesis test [122]. Glycosylation of the parent skeletal structure of flavonoids gives rise to less potent activity in the EBV-EA induction bioassay system [39,41,48,68].

CHEMOPREVENTIVE EFFECTS OF PHLOROGLUCINOLS The female inflorescences of hop (H. lupulus), hop cones, contain prenylated phloroglucinols, in addition to prenylated chalcones and flavonoids [48]. Evaluation of the inhibitory effects of EBV-EA induction of five prenylated phloroglucinols from hop cones has shown that three compounds, PL1ePL3

36 Studies in Natural Products Chemistry

(Fig. 1.6), exhibit potent inhibitory effects. Among these, compound PL3 has been revealed to be the potent inhibitor of promotion in DMBA/TPA-induced mouse skin carcinogenesis test [48].

CHEMOPREVENTIVE EFFECTS OF OTHER SECONDARY METABOLIC COMPOUNDS Phenolic Compounds Four phenolic acids, vanillic acid and protocatechuic acid [39], and gallic acid and 4-O-methylgallic acid [49], and three other phenolic compounds, (þ)-rhododendrol [35], and arbutin and isotachioside [73], have been evaluated for their inhibitory effects on the EBV-EA induction. These compounds showed moderate inhibitory effects with IC50 values of 392e519 molar ratio/32 pmol TPA. The aqueous extract of Peltophorum pterocarpum (yellow flame tree, Fabaceae) wood exhibited potent inhibitory effect against EBV-EA activation [59]. Bergenin (MS2), a C-glucoside of 4-O-methylgallic acid, has been isolated from the extract as the most predominant constituent, accompanied with gallic acid. This compound exhibited potent inhibitory effects against EBV-EA induction (IC50 224 molar ratio/32 pmol TPA) (Table 1.5; Fig. 1.6), and against tumor promotion in DMBA/TPA-induced mouse skin carcinogenesis test (Table 1.4) [59]. In addition to the potential cancer chemopreventive effect, compound MS2 has been reported to exhibit a wide range of biological activities including anti-inflammatory, antiarthritic, antitussive, hypolipidemic, antidiabetic, anti-HIV, antiarrhythmic, hepatoprotective, neuroprotective, gastroprotective, antiulcer, antioxidant, and antifungal activities [59]. Chemopreventive effects of gallic acid [123,124] and other phenolic compounds [124] have been reviewed recently.

Alkylresorcinols Wheat bran and rye bran oils from Gramineae plants have been shown to contain 1.9 and 3.8% of 5-alkylresorcinol (5-alkyl-1,3-dihydroxybenzene), respectively [61]. Eight 5-alk(en)ylresorcinols with C17eC25 alk(en)yl chains isolated from wheat bran and rye bran oils [61], and 5-n-pentadecylresorcinol from A. keiskei [36] exhibited only a moderate or a weak activity against EBV-EA induction (IC50 452e520 molar ratio/32 pmol TPA), and it was observed that increasing the chain length resulted in decreasing activity as for the 5-n-alkylresorcinols [36,61].

Azaphilonoids Species of the fungi Monascus (Eurotiaceae) have been utilized for making fermented food and preserving meat for hundreds of years. Red-mold rice fermented using Monascus spp. is effective in decreasing blood pressure and

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lowering plasma cholesterol levels and has antibacterial activity [79]. Six azaphilonoid pigments including monascin (MS3), isolated from the extract of Monascus pilosus-fermented rice, exhibited moderate or weak inhibitory effects with IC50 421e610 molar ratio/32 pmol TPA against EBV-EA induction [79]. Compound MS3 (IC50 421 molar ratio/32 pmol TPA) exhibited marked inhibitory activity on both PN- and UVB-induced mouse skin carcinogenesis tests (Table 1.4) suggesting that MS3 may be valuable as a potential cancer chemopreventive agent in chemical and environmental carcinogenesis [31].

Caffeoylquinic Acids The hair and fiber parts of the leaves of Artemisia plants (Asteraceae) are called moxa (“Mogusa” in Japanese) used in moxibustion, a traditional medical practice of China, Japan, Korea, and several other Asian countries for analgesic purposes in acupuncture-cautery procedures. Seven caffeoylquinic acids including chlorogenic acid (5-caffeoylquinic acid) isolated from moxa, and four semisynthetic chlorogenic acid ester derivatives have been tested for their inhibitory effects on the EBV-EA induction [39]. Whereas chlorogenic acid exhibited inhibitory effect (IC50 340 molar ratio/32 pmol TPA), almost equivalent to that of reference curcumin (IC50 341 molar ratio/32 pmol TPA), the others exhibited moderate or weak inhibitory effects (IC50 421e562 molar ratio/32 pmol TPA) [39]. Caffeoylquinic acids from moxa exhibited potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical-scavenging activities [39].

Coumarins Fourteen coumarin-group compounds isolated from the exudates of A. keiskei [36,37] and from moxa [39] have been evaluated for their inhibitory effects on the EBV-EA induction. All compounds tested, except for osthenol (MS1) [37], exhibited moderate inhibitory effects with IC50 380e490 molar ratio/32 pmol TPA. Compound MS1, possessing a prenyl chain in the molecule, has been revealed to exhibit potent inhibitory effect with IC50 290 molar ratio/ 32 pmol TPA.

Diarylheptanoids The Aceraceae plant Acer nikoense is indigenous to Japan (Japanese name, Megusurino-ki) and its stem bark has been used as a folk medicine for the treatment of hepatic disorders and eye disease [35]. Nine cyclic and one acyclic diarylheptanoids were isolated from the stem bark of A. nikoense. All these diarylheptanoids exhibited moderate inhibitory effects with IC50 356e491 molar ratio/32 pmol TPA against EBV-EA induction [35]. The diarylheptanoid constituents of A. nikoense tree bark have been suggested to be useful as skin whitening agents as well as natural antioxidants [125].

38 Studies in Natural Products Chemistry

Jasmonic Acid Derivatives Two jasmonic acid derivatives, glucosylcucurbic acid (MS4) and methyl glucosylcucurbate, were isolated from the extract of defatted shea (V. paradoxa; Sapotaceae) kernels [58]. These and their deglucosylated derivatives, cucurbic acid and methyl cucurbate, were evaluated for their inhibitory effects against EBV-EA activation. While all four jasmonic acid derivatives exhibited moderate inhibitory effects, compound MS4, upon DMBA/TPA-induced mouse skin carcinogenesis test, suppressed tumor promotion (Table 1.4).

Tannins T. chebula (myrobalan tree, Combretaceae) is widely grown in tropical regions as a shade and ornamental tree. The plant has a long history of medicinal uses in many Asian and African countries, including India, China, and Thailand. Its medical applications are as astringent, as purgative supplements for antiaging, and for impartment of longevity as well as boosting the immune system. It contains many hydrolyzable tannins and related compounds [49]. While seven hydrolyzable tannins including chebulinic acid, isolated from the gall extract of T. chebula, exhibited potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicalscavenging activities, these showed moderate or weak inhibitory effects against EBV-EA induction (IC50 460e518 molar ratio/32 pmol TPA) [49]. Chebulinic acid (IC50 492 molar ratio/32 pmol TPA) exhibited weak inhibitory effect on skin-tumor promotion in a DMBA/TPA-induced mouse skin carcinogenesis test [49].

CHEMOPREVENTIVE EFFECTS OF FATTY ACIDS There is both epidemiologic and experimental evidence that the n-3 polyunsaturated fatty acids (PUFA) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which occur at high levels in some fish oils, exert protective effects against some common cancers, notably those of breast, colon, endocervix, pancreas, and, perhaps, prostate [126e130]. Twenty-two fatty acids, as the methyl ester forms as well as free forms (for 14 acids) and ethyl ester form (for one acid), most of which were derived from the liver oil of Mola mola (ocean sunfish), have been evaluated for in vitro inhibition of EBV-EA activation induced by TPA (Table 1.6) [87]. Among these, both methyl esters and free forms of three n-3 PUFA, EPA (FA2 and FA3), docosapentaenoic acid (DPA) (FA4 and FA5), and DHA (FA6 and FA7), as well as DHA ethyl ester (FA8) and docosatrienoic acid (n-3, FA9) (Fig. 1.7) showed potent inhibitory effects on EBV-EA activation with IC50 276e296 molar ratio/32 pmol TPA. While free forms of long-chain saturated acids (>C14:0) showed lower inhibitory effects than their methyl ester forms,

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Fatty acid (FA) COOH

COOR

FA1 COOR FA4 R = H FA5 R = Me FA9

FA2 R = H FA3 R = Me COOR

COOH

FA6 R = H FA7 R = Me FA8 R = Et

FIGURE 1.7 Structures of fatty acids exhibited potent inhibitory effects against EBV-EA induction.

monounsaturated acids and short-chain saturated acids exhibited almost equivalent inhibitory effects between free and methyl ester forms. A more potent activity in the free form than in the esterified forms, however, was observed as for EPA, docosatrienoic acid, DPA, DHA, and other PUFA. Compound FA7 suppressed the tumor promotion in DMBA/TPA-induced mouse skin carcinogenesis test (Table 1.4). This evidence has, thus, supported the chemopreventive potential of n-3 PUFA.

TOXICITY, SIDE EFFECTS, AND IMPROVEMENT OF BIOAVAILABILITY OF TRITERPENOIDS To successfully convert a potent chemopreventive compound to a clinically viable drug will require detailed consideration on many aspects including its toxicity, side effect, and improvement of bioavailability. Various triterpenoids have so far been investigated on these subjects as shown below.

Toxicity and Side Effects In addition to potential chemopreventive, chemotherapeutic, antioxidative, and anti-inflammatory effects, many triterpenoids possess antibacterial or antifungal actions that are clearly of direct survival benefit to the plant itself or to its fruit. Many of the plants that biosynthesize triterpenoids are readily edible by both wild animals and humans, indicating that the natural molecules are relatively nontoxic and can be ingested safely for long periods of time [131,132]. However, toxicities do occur in certain circumstances. For example, low-doses of oleanolic acid (On1) are hepatoprotective, while the high-dose could produce cholestasis and hepatotoxicity. Low-dose of On1 could produce adaptive responses, similar to “hormesis” [133]. Several triterpenoids have been evaluated for their potential subacute and subchronic toxicities. Thus, the subacute toxicity of 2a,3b,21b,23,28-pentahydroxyolean-12-ene, isolated from the roots of Laportea crenulata (Urticaceae), has been studied on albino mice. The triterpenoid was administered on intraperitoneal route at 300 mg/mouse (20e27 g) daily for 14 consecutive days. Histopathologically no abnormality was found on liver, kidney, heart, and lung of experimental

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group mice after treatment when compared to that of control group mice. In subacute toxicity studies, the triterpenoid was found to be nontoxic [134]. 3b,23-Dihydroxyurs-12-en-28-oic acid, one of the semisynthetic derivatives of asiaticoside, a biologically active ursane-type triterpenoid present in Centella asiatica (Apiaceae), has been investigated for its potential subacute toxicity by a 4-week repeated oral administration in SpragueeDawley rats. In the condition of this study, target organ was not observed and the no-observedadverse-effect level (NOAEL) was considered to be 1000 mg/kg per day for the rats [135]. Lupeol distributes widely in common fruit plants such as olive, mango, fig, etc. Oral administration of this triterpenoid in a dose of 2 g/kg body weight has been reported to produce no adverse effects in rats and mice, and no mortality after 96 h of observation [136]. The potential subchronic toxicity of (20S)-ginsenoside Rg3, a dammarane-type triterpenoid saponin, was studied by repeated intramuscular administration in Beagle dogs over a 26-week period [137]. The NOAEL of this triterpenoid saponin for the dogs were considered to be 7.20 mg/kg per day [137]. Whereas phytosterol treatments were reported to cause certain side effects at very high doses, no obvious side effect has been observed after its long-term feeding in animals and humans [138]. High dose (0.5e5 mg/kg per day subcutaneously) of sitosterol in rats reduced sperm concentrations as well as weights of testis and accessory sex tissues in a time-dependent manner [138]. It might be worthy to note that a series of new synthetic oleanane-type triterpenoids with excellent safety and noncytotoxic properties have been prepared by chemical modification of On1 [132,139,140]. Methyl 2-cyano3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me; bardoxolone methyl), one of the semisynthetic oleananes, has completed a phase 1 first-in-human trial in patients with melanoma as well as colorectal, renal, anaplastic thyroid, and other types of cancer. CDDO-Me was administered orally once a day for 21 days for a 28-day cycle with an accelerated titration design used until a grade 2 (moderate; minimal intervention indicated; some limitation of activities) adverse event occurred. The results of this study showed the doselimiting toxicities to be grade 3 (severe but not life-threatening; hospitalization required; limitation of patient’s ability to care for him/herself) reversible liver transaminase elevations and the maximum tolerated dose (MTD) was established at 900 mg/day [141].

Reciprocal Effect to Another Agent Reciprocal effects of several triterpenoids have been found in the chemopreventive and chemotherapeutic studies. A combination of CDDO-Me and the rexinoid LG100268, a synthetic agent that binds specifically to a retinoid “X” receptor, has been found to be more effective than the individual agents for the prevention of mammary tumorigenesis [140]. On the other hand, the anticancer activity of betulinic acid can be markedly increased when it is

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used in combination with conventional chemotherapy, ionizing radiation, or cytokine TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) [142]. b-Escin, an oleanane-type triterpenoid saponin, which is the major bioactive principle found in the seeds of horse chestnut (Aesculus hippocastanum), in combination with paclitaxel or doxorubicin, potentiated the apoptotic effects of the chemotherapeutic compounds; thus it potentiated suppression of proliferation and chemosensitization of hepatocellular carcinoma [142].

Improvement of Bioavailability One potential reason of weak or moderate chemopreventive efficacy of many natural triterpenoids and other secondary metabolites described in this review could be limited water solubility affecting bioavailability. Several techniques which may be used to improve their hydrophilicity include noncovalent complexes with hydrophilic cyclodextrins and preparation of formulation with liposomes, colloids, micelles as well as nanoparticles [133,143,144]. The poor bioavailability of betulinic acid has been improved by the preparation of its spray dried mucoadhesive microparticle formulation [145]. Liposomal ursolic acid (Ur1) has been subjected to human clinical trials [143]. The clinical data reported that liposomal Ur1 had manageable toxicities with the MTD of 98 mg/m2 [132]. Another approach to overcome the poor bioavailability may be the chemical modification of triterpenoids to synthesize more polar derivatives [133,140]. Thus, a series of new synthetic oleanane-type triterpenoids, including 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and CDDO-Me, have been prepared by chemical modification of On1, some of which are considered to be the most potent anti-inflammatory, anticarcinogenic, and chemopreventive triterpenoids [132,140]. To improve the oral absorption property and bioavailability of CDDO, a novel CDDO anhydride was synthesized with the same potency as CDDO-Me, but with greater bioavailability [142].

Type of Preventive Malignancy by Triterpenoids While we have demonstrated that natural triterpenoids and other secondary metabolites exhibit chemopreventive effects on the mouse skin tumor models as shown in Table 1.4, triterpenoids have been reported to exhibit chemopreventive potential in various animal models of cancer. Thus, accumulating studies provide extensive evidence that several natural [142,143,145] and semisynthetic triterpenoids [142,143] exhibit cancer preventive efficacy in mouse or rat models of blood, breast, colon, liver, lung, neuron, pancreas, prostate, and skin cancers (Table 1.7). For the details of the chemoprevention studies on the triterpenoids shown in Table 1.7, refer to literature [132,142,143,146].

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TABLE 1.7 In Vivo Carcinogenesis Target of Chemoprevention by Triterpenoids in Animal Models of Cancer In Vivo Carcinogenesis Target

References

Acetyl-11-keto-b-boswellic acid (AKBA)

Colon, prostate

[142]

Asiatic acid

Skin

[142]

Avicins

Skin

[142]

Betulinic acid

Melanoma

[142]

Celastrol

Breast, glioma, melanoma, prostate

[142]

Glycyrrhizin

Skin

[142]

Glycyrrhetinic acid

Skin

[142]

25-Hydroxy-3-oxoolean-12-en-28-oic acid (Amooranin; AMR)

Breast

[146]

Lupeol

Liver, melanoma, pancreas, skin

[142]

Oleanolic acid (On1)

Colon, skin

[142]

Ursolic acid (Ur3)

Breast, colon, leukemia, liver, prostate, skin, stomach

[143]

AMR-Methyl ester (AMR-Me)

Breast

[146]

2-Cyano-3,12-dioxooleana-1,9(11)dien-28-oic acid methyl ester (CDDO-Me)

Breast, lung, pancreas

[132]

Triterpenoid Natural Triterpenoid

Semi-Synthetic Triterpenoid

POTENTIAL MECHANISMS OF CHEMOPREVENTION Chemoprevention may involve a variety of steps in tumor initiation, promotion, and progression. Compounds that inhibit cancer initiation are traditionally termed “blocking agents.” Once initiation has occurred, chemopreventive compounds may influence the promotion and progression of initiated cells, such compounds are often termed “suppressing agents.” Potential mechanisms of tumor-blocking agents include (1) scavenging of free radicals, (2) antioxidant activity, (3) induction of phase II (glucuronidation, sulfation, acetylation, methylation, and conjugation with glutathione) drug-metabolizing enzymes,

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(4) inhibition of phase I (oxidation, reduction, and hydrolysis) drugmetabolizing enzymes, (5) induction of DNA repair, and (6) blockade of carcinogen uptake, while potential mechanisms of tumor-suppressing agents include (1) alteration of gene expression, (2) inhibition of cell proliferation and clonal expansion, (3) induction of terminal differentiation and senescence, (4) induction of apoptosis in preneoplastic lesions, and (5) modulation of signal transduction [147,148]. It is likely that many chemopreventive agents appear to possess both blocking effects and suppressing effects. The mechanisms by which chemopreventive compounds suppress the tumor promotion may be due to the modulation of the molecular targets including (1) cytokines, (2) chemokines, (3) reactive oxygen intermediates, (4) oncogenes, (5) inflammatory enzymes such as COX-2 (cyclooxygenase-2), 5-LOX (lipoxygenase), and MMPs (matrix metalloproteinases), (6) antiapoptotic proteins, (7) transcription factors such as NF-kB (nuclear factor-kB), STAT3 (signal transducer and activator of transcription 3), AP-1 (activation protein-1), CREB (c-AMP response element binding protein), and (8) Nrf2 (nuclear factor erythroid 2-related factor) [136,147,148].

CONCLUDING REMARKS A number of natural triterpenoids and other secondary metabolites such as chalcones, flavonoids, and phloroglucinols isolated mostly from edible plants, fungi, and crude herbal drugs have been demonstrated to possess potent inhibitory effects against in vitro EBV-EA induction test. The SAR study has suggested that tetracyclic triterpenoids possessing a linear side chain at C-17 suppressed the induction more strongly than pentacyclic triterpenoids, and prenylation or geranylation of the parent skeletal structures gives rise to more potent activity for chalcone-, coumarin-, flavonoid-, and phloroglucinol-group compounds. Among the tetracyclic triterpenoids, hydroxylation at C-24 and C25, and cleavage of ring A to form 3,4-seco-3-oic acid appeared to enhance the activity. In some groups of compounds, glycosylation of the parent skeletal structure led to a reduction of the inhibitory effects. In addition, in both tetracyclic and pentacyclic triterpenoids as well as in diterpenoids, acidic compounds possessing carboxy group(s) in the molecule have been encountered as effective inhibitors. Furthermore, it was shown that more potent inhibitors against EBV-EA induction are, in general, suppressed more effectively the tumor promotion on the two-stage carcinogenesis which may suggest that the in vitro EBV-EA induction test is highly correlated with the in vivo papilloma formation test in mice. The triterpenoids and other secondary metabolites which exhibited potent inhibitory effects against EBV-EA induction and against in vivo two-stage carcinogenesis, therefore, warrant more attention for possible development as a cancer chemopreventive therapy drug. It appears that the extracts of A. keiskei [36e38], C. morifolium [43], G. lucidum [80,81], H. annuus [44,45], H. lupulus [48], M. charantia [32,53], P. pterocarpum [59],

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and P. cocos [83e85] might be of importance from the point of view of chemoprevention because they contain various highly inhibitory constituents against EBV-EA induction (Table 1.3). It might be worthy to note that this review provided the supporting evidence of chemopreventive potential of n-3 polyunsaturated fatty acids. Cancer chemopreventive agents should be safe and nontoxic. Further studies are, therefore, needed to determine the chronic toxicity and side effects by longterm administration for the potentially chemopreventive triterpenoids and other secondary metabolites from plants and fungi described in this review.

ABBREVIATIONS AP-1 CDDO CDDO-Me COX-2 CREB DHA DMBA DPA DPPH EBV-EA EPA ICR 5-LOX MMPs MTD NF-kB NOAEL Nrf2 PN PUFA ROS RPMI SAR STAT3 TPA TRAIL UVB

activation protein-1 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate cyclooxygenase-2 c-AMP response element binding protein docosahexaenoic acid 7,12-dimethylbenz[a]anthracene docosapentaenoic acid 1,1-diphenyl-2-picrylhydrazyl EpsteineBarr virus early antigen eicosapentaenoic acid Institute of Cancer Research 5-lipoxygenase matrix metalloproteinases maximum tolerated dose nuclear factor-kB no-observed-adverse-effect level nuclear factor erythroid 2-related factor peroxynitrite polyunsaturated fatty acid reactive oxygen species Roswell Park Memorial Institute structureeactivity relationship signal transducer and activator of transcription 3 12-O-tetradecanoylphorbol-13-acetate tumor necrosis factor-related apoptosis-inducing ligand ultraviolet B

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Chapter 2

Structural Diversity, Natural Sources and Pharmacological Potential of Naturally Occurring A-SecoTriterpenoids Victoria V. Grishko1, Natalia V. Galaiko Russian Academy of Sciences, Perm, Russian Federation 1 Corresponding author: E-mail: [email protected]

Chapter Outline Introduction Isolation and Structure Elucidation Seco-Triterpenoids as Biomarkers Biosynthesis Biological Activity Antitumor Activity Effects of A-seco-triterpenoids on the Immune System Antiviral Activity Antibacterial Activity Other Types of Biological Activity The Main Approaches to Synthesis of A-seco-triterpenoids Conclusion A-Seco-Lanostane Triterpenoids

52 53 55 57 59 60 64 67 69 70 73 75 124

A-Seco-Cycloartane Triterpenoids A-Seco-Dammarane Triterpenoids A-Seco-Tirucallane Triterpenoids Schisandra Nortriterpenoids Other Tetracyclic A-SecoTriterpenoids A-Seco-Oleanane Triterpenoids A-Seco-Ursane Triterpenoids A-Seco-Friedelane Triterpenoids A-Seco-Lupane Triterpenoids Other Pentacyclic A-SecoTriterpenoids Other A-Seco-Triterpenoids Abbreviations Acknowledgments References

Studies in Natural Products Chemistry, Vol. 51. http://dx.doi.org/10.1016/B978-0-444-63932-5.00002-4 Copyright © 2016 Elsevier B.V. All rights reserved.

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INTRODUCTION Medicinal plants are widely used in folk medicine and as a health supplement to integrative medicine, especially in Africa, South America, India, and Pacific regions, including China, Japan, Taiwan, and etc. [1e3]. Plant extracts are characterized by diverse activities without side effects and have been used for the treatment of hypertension, dermatitis, cancer, dysentery, gastric ulcers, and ischemic heart disease, as well as antiseptics, antihelminthics, antiplasmodics, antiinflammatories, sedatives, antiviral, and antiasthmatic agents [3]. Many pharmacological properties of herbal extracts are attributed to secondary metabolites producible by the plants. Secondary metabolites of medicinal plants are regarded as one of valuable sources of new compounds or structures applicable to both drug discovery and the drug development process toward new medicines [1e4]. Among secondary metabolites, polycyclic triterpenoids are identified as compounds exhibiting different pharmacological effects, including antiinflammatory, analgesic, cardioprotective, antiulcerative, antimicrobial, antitumor, anti-HIV, and antiplasmodial activities, combined with low toxicity [5e9]. Therefore, triterpenoids are attractive for medicinal chemistry in terms of finding new original structures with diverse biological properties. The triterpenoids are a large group of natural products derived from more than 100 skeletons [10]. The triterpenoid library is constantly expanding, as evidenced by regular review articles by Hill and Connolly [11] on the isolation of new natural triterpenoids. Continuous improvement of separation techniques and equipment for isolation and identification of organic compounds contributes to the discovery of new triterpenoids contained in plant sources, even in microquantities [12,13]. Triterpenoids with the cleaved carbonecarbon bond in the ring A (the so-termed A-seco-triterpenoids) are minor triterpene compounds producible by plants. Most of these compounds are formed from cyclic precursors with conventional tetracyclic or pentacyclic triterpene skeleton, such as lanostane, cycloartane, dammarane, tirucallane, oleanane, ursane, friedelane, and lupane [14]. Among unusual skeletons, triterpenoids from the Schisandraceae family, biosynthetically derived from cycloartane-type triterpenoids and relating to schisanartane, schiartane, 18-norschiartane, 18(13/14)-abeo-schiartane, preschisanartane, and wuweiziartane types can be noted as a special group (Fig. 2.1) [8]. Information on these compounds can usually be found in phytochemical publications or in more general discussions dedicated to triterpenoids or secondary plant metabolites. The only specialized review devoted to A-seco-triterpenoids is published by Baas in 1985 [14]. We analyze the related works published over the period 1986e2014 to appraise the state-of-the-practice in the purposeful search, structural identification, and detection of biological properties of A-seco-triterpenoids.

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

53

H

Lanostane

Cycloartane

H H

FIGURE 2.1 The basic types of triterpene skeletons.

ISOLATION AND STRUCTURE ELUCIDATION A-seso-triterpenoids can most often be found in extracts of ethnomedicinal plants growing in the AsiaePacific region [8]. More rarely, these compounds can be found in plants of South America [15e19] and Africa [20e22]. A-seso-triterpenoids extractable from European plant sources are reported scarcely [23]. General property of A-seco-triterpenoids is their lipophilicity enabling these compounds to be isolated from either fresh or dry-powdered parts of plants and of mushrooms by means of extraction with organic solvents, such as methanol [24e27], ethanol [28,29], n-hexane [30,31], acetone [32], dichloromethane [33,34], etc. Solvent mixtures, e.g., n-hexane/ethanol [35] or aqueouseorganic mixtures [36e41] are also used to extract A-seco-triterpenoids. Plant exudates of the Gardenia genus are directly dissolvable in dichloromethane [42] or in a dichloromethane-methanol mixture [43,44]. Seed oil from Camellia sasanqua Thunb. must be hydrolyzed in an alkaline solution before extraction [45]. For most applications, relatively simple techniques, e.g., percolation and maceration, are effective to extract plant material. More sophisticated extraction techniques, such as supercritical-fluid extraction,

54 Studies in Natural Products Chemistry

accelerated solvent extraction, microwave-assisted extraction, ultrasoundassisted extraction equipment, and large-scale steam distillation apparatus are rarely used to isolate triterpenoids from plants [13]. Highly sophisticated hyphenated techniques combining modern chromatographic and spectral methods, such as gas chromatography coupled with mass spectrometry, liquid chromatography coupled with photodiode array detection, liquid chromatographyemass spectrometry, liquid chromatography coupled with Fourier transform infrared spectroscopy, liquid chromatography with parallel NMR spectrometry (LCeNMR), LCeNMReMS, and capillary electrophoresis coupled with mass spectrometry, are effective in phytochemical preanalyses of crude plant extracts [13]. Isolation of individual natural products is one of the main and routine stages in natural products research [46]. For isolation of a known compound, it is easy to select the most appropriate isolation method, using the literature information on its chromatographic behavior [13]. As generally, multistep separation methods of column and flash chromatography (preparative thinlayer chromatography [TLC] [30,47], high-performance liquid chromatography [48,49], or recrystallization [42,50] being more rarely) are used for fractionation of a crude plant extracts for isolation of A-seco-triterpenoids. Separation and purification techniques applied after the extraction stage can yield 101% to 106% proportions of individual A-seco-triterpenoids in airdried powders [22,26,29,31,41]. Nigranoic acid (1), extractable from stems of Schisandra sphaerandra, appears to be the only exception with up to 2.5% of dry weight [50]. The full spectra of modern physical methods, such as IR, ultravioletevisible spectroscopy, polarimetry, mass spectrometry, NMR spectroscopy, etc., are used to ascertain the structure of isolated natural triterpenoids [5,51]. The NMR spectroscopy is most widely used to determine triterpenoid structures. So, 1H and 13C NMR spectra are often quite informative to shed more light on triterpenoid structures that are similar to those of the earlier described compounds. For example, the already known structure of nigranoic acid (1) [50,52] is helpful to ascertain the structure of nigranoic acid 3-ethyl ester (2) isolated from Schisandra henryi [53]. The structure of seco-dinortriterpenoid dzununcanone (3) from Giardia intestinalis is determined with the use of NMR findings of the known cyclic triterpenoid pristimerin (4) [35]. One-dimensional 1H and 13C NMR spectroscopy is not always unambiguous at revealing polyfunctional A-seco-triterpenoids with a new triterpene skeleton. At the same time, being effective in identification and structure elucidation of natural products [12,54,55] homonuclear and heteronuclear bidimensional NMR studies are only capable to determine relative configuration of chiral centers in a molecule of A-seco-triterpenoid, and only rarely can work out the absolute triterpene structure [24,30,56e58], whereas the Mosher method [58], X-ray crystallography [49,56,57,59], and circular

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

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dichromism spectroscopy [27,60] are applied to determine the absolute configuration of chiral centers of A-seco-triterpenoids. Conformational studies usable to determine three-dimensional structures of A-seco-triterpenoids are based on spectroscopic (NMR spectroscopy) and computational methods [61]. Conformational analysis of molecules of A-secotriterpenoids is based on the use of theoretical molecular mechanics calculations and simulation techniques by means of specialized computer programs [22,32,48,62]. Thus, calculations of the most stable conformation of semisynthetic 3,4-seco-tirucallane isohelianol acetate (5) are performed using the Macro Model version 6.0 with extended MM3 parameters and the Metropolis Monte Carlo procedure [45]. COOMe COOH ROOC

H

MeOOC O

H

H

O

H

MeOCO

HO

H

1, R = H 2, R = Et

COOMe

4

3

5

SECO-TRITERPENOIDS AS BIOMARKERS Biomarkers, being specific chemical compounds or chemical “signatures,” are present in environmental samples and give useful information on the sources of the organic matter. The most effective biomarkers have a limited number of clearly defined sources; these biomarkers are lesser amenable to geochemical changes and can be easily analyzed in environmental samples. Triterpenoids are used as biomarkers, in some cases, for geochemical research. So, identification of angiosperm triterpenoids, as components of sedimentary organic matter is useful for studies devoted to reconstitution of past environmental changes [63]. Biodegradation, oxidation, and photochemical processes impact the composition of sediments. For example, sun exposure of 3-oxo triterpenoids can be a potential source of A-seco-triterpenoids with a saturated C-4(23) bond in sediments [64,65]. Simoneit et al. [65] conduct a series of experiments to evidence photochemical formation of A-seco-triterpenoids (including taraxerane dihydrolacunosic acid (6)) and to prove the photochemical origin of the 3,4-seco-triterpenoids in mangrove sediments and in fresh mangrove leaves.

HOOC H

6

56 Studies in Natural Products Chemistry

The triterpenoids also play an important role as characteristic markers in chemotaxonomic research for establishing relationships between the species, genera, and families of plants [66,67]. In addition, chemotaxonomy allows a probability of detection of various structures in new materials to be predicted and to find promising producers of biologically active compounds. It promotes the rational and effective use of plant resources. There is available only a small number of papers directly connected to the study and evaluation of A-seco-triterpenoids as chemotaxonomic markers [68]. Certain accompanying findings, observations, and conclusions are more frequent in phytochemistry investigations [42,69,70]. As a rule, interpretation of results of the chemotaxonomic research of A-seco-triterpenoids requires caution in each particular case, as we cannot judge with certainty about the origin of A-seco-triterpenoids (biosynthetic or microbial) or about their occurrence in the course of ontogenesis. Nevertheless, we herein try to reflect some of our thoughts and to make some generalizations based on available publications. As chemotaxonomic markers, A-seco-triterpenoids may have a different weighting in different groups of taxons of various ranks [14]. Thus, A-secotriterpenoids are marginally informative as diagnostic features for considering the plant “family.” We can mention A-seco-fridelane triterpenoids that are often found in plants of the family Celastraceae [28,30,31,35]. The taxonomic significance of A-seco-triterpenoids is increased during the transition to a lower taxonomic category “genus.” At this point, producers of certain A-seco-triterpenoids may belong to different taxons (“orders” or even “kingdoms”). For example, saprophytic fungi of genera Poria [25,71e75] and Ganoderma [57,76,77], gymnosperms of genus Abies [78e85] and angiosperms of genus Kadsura [58,86e88] produce tetracyclic lanostane-type A-seco-triterpenoids. At the same time, 3,4-seco-cycloartane triterpenoids are usually accumulated in the representatives of the genera Gardenia [24,42e44,89e92] and Schisandra [40,50,52,53,93,94]. An interesting fact is that the biogenetically related compounds, in this case, cycloartane and lanostane A-seco-triterpenoids [93] are found in the groups of phylogenetically related plants of genera Kadsura and Schisandra, belonging to the family Schisandraceae [8]. Detection of cycloartane and lanostane A-seco-triterpenoids in the family Illiciaceae has great importance for chemotaxonomy. This detection confirms the close relationship between Illiciaceae and Schisandraceae, and these families combine into the order Illiciales [41]. The chemotaxonomic significance of triterpenoid accumulation in Meliaceae indicating wide distribution of dammarane and 3,4-seco-dammarane derivatives in Aglaia species (Meliaceae) is recently discussed [68,95e98]. A-seco-dammarane triterpenoids, while used as markers, enable reinforcing the chemotaxonomic position of Cabralea canjerana (Vell.) Mart. in the

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Meliaceae family as a representative of the Melioideae subfamily, Harms’ tribe Trichilieae [68]. Among the pentacyclic triterpenoids, only A-seco-lupane glycosides are frequently found in plants of the genus Acanthopanax [14,99e103]. In some cases, A-seco-triterpenoids can serve as chemotaxonomic markers for the level of species. So, among the tetracyclic protostane triterpenoids reported in respect of higher plants, most of them were isolated from Alisma genus of the family Alismataceae, whereas A-seco-protostane triterpenoids are producible only by the plant Alisma orientale [69,104]. In general, there is no conclusive evidence to support the use of A-secotriterpenoids as chemotaxonomic markers at the moment. In exceptional cases, they may be used to solve taxonomic problems within the framework of genus or species. It is more justified to use A-seso-triterpenoids as chemotaxonomic markers along with the cyclic triterpenoids produced by the plant with the same type of skeleton.

BIOSYNTHESIS The acyclic squalene (7) is known to be a biosynthetic precursor of triterpenoids [105]; examples of its cyclization with subsequent formation of triterpenoids of various structural types are described [106e109].

Squalene (7)

The features of the biosynthetic fragmentation and further transformations of ring A of the triterpenoids are discussed in this section. In the majority of cases, the BaeyereVilliger oxidation of triterpenoids with seven-membered lactone or anhydride intermediate formations is the key step before cleavage of the carbonecarbon bond in ring A [49]. Furthermore, 2,3- or 3,4-secoderivatives are formed as a result of either hydrolysis or hydrolysis followed by dehydration of anhydrides or lactones, respectively. It is assumed that the cleavage of the C-3 oxygenated triterpenoids leads, in most cases, to the formation of 3,4-seco-cycle (Scheme 2.1) [15,93,110,111]. The formation of 2,3-seco-derivatives, hypothetically, occurs in a more extensive oxidation, with formation of 2,3-dioxygenated cyclic precursors in the first stage, that are further subjected to the BaeyereVilliger oxidation and to ring opening [49,112]. The biogenetic pathways of 2,3-seco-derivative formation from either the intermediates or natural 2,3-dihydroxytriterpenoids, including stages of oxidation, decarboxylation, isomerization, and further cleavage of the C-2eC3 bond of ring A, are proposed (Scheme 2.2) [113,114]. Cleavage of the two

58 Studies in Natural Products Chemistry

HO

3

Baeyer-Villiger oxidation

PathwayA

HOOC

O

O

4

O

3,4-Seco-triterpenoids

PathwayB

O

Baeyer-Villiger oxidation

O

O

2

HOOC HOOC3

O O

SCHEME 2.1 The hypothetical biogenetic pathways of fragmentation of the ring A of triterpenoids.

HO

PathwayA

HO

2

HOOC OHC 3

2,3-Seco-triterpenoids

PathwayB O

HO

HO

O

PathwayC

2

HOOC HOOC 3

2,3-Seco-triterpenoids

2 HOOC

O

4

2,4-Seco-triterpenoids

SCHEME 2.2 Possible biogenetic pathways of formation of 2,3-seco- and 2,4-seco-triterpenoids.

carbonecarbon bonds of ring A in triterpenoids may lead to the formation of 2,4-seco-3-norderivatives [114,115]. Frequently, transformations of triterpenoids in the nature do not discontinue in the stage of A-seco-derivatives. Further transformations lead to formation of seco-triterpenoids with a unique skeleton. For example, a dihydropyran ring A of 3,4-seco-triterpene terminalin A (8) [21] and gracilipene (9) [116] is presumably formed from 3,4-seco-triterpenoids by enzymatic oxidation and by subsequent reduction of the hydroxyl group (Scheme 2.3). An unprecedented cyclization with formation of a new C-3eC-9 bond is a key stage in the formation of 2,3-seco-fernane triterpenoid alstonic acid B (10) [113]. Aphanamgrandiol A (11), a novel triterpenoid with a bicyclo[3,2,1]octane ring skeleton, is presumably formed from 2,3-seco-precursor after its oxidation and esterification with subsequent lactone-ring formation, 2,6-ring closure, and formation of a new C-7eC-8 double bond [112].

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H

H

O

H

H

H

O

8

9

OH

HOOC O

R

3,4-Seco-triterpenoids

SCHEME 2.3 The formation of dihydropyran A ring from 3,4-seco-triterpenods.

Plants of the genus Schisandra produce unusual nortriterpenoids of the shiartane group [117e120], for which the biosynthetic precursors are presumably 3,4-seco-cycloartane derivatives of schizandronic acid (12) [37,94]. H HOOC

COOH

H

H

H O

10

11

H

12

O

BIOLOGICAL ACTIVITY Plants have a therapeutic effect due to availability of a wide range of biologically active compounds, among them, the triterpenoids playing an important role. Numerous works report antiviral, antitumor, antibacterial, and other types of activity of natural A-seco-triterpenoids and confirm their expediency as being biologically active agents. Statistical data processing results in a pie chart (Fig. 2.2) that mirrors percentage of biologically active compounds among natural A-seco-triterpenoids. As is apparent from Fig. 2.2, antitumor activity is the most typical for natural A-seco-triterpenoids. Cytotoxicity Antibacterial activity

Antiviral activity Effects of A-seco-triterpenoids on the immune system Multiactive compounds

Other activities

39% 19%

7% 14%

13%

8%

FIGURE 2.2 Percentage composition of biologically active compounds among natural A-secotriterpenoids.

60 Studies in Natural Products Chemistry

Types of biological activities and compounds promising for further research are considered in more detail in the following section.

ANTITUMOR ACTIVITY Analysis of the published data shows the cytotoxicity to be more carefully examined and to be most typical of tetracyclic A-seco-triterpenoids of lanostane and cycloartane series and less so of pentacyclic A-seco-triterpenoids (Fig. 2.3A and B). Among the tumor cell lines, the lines of HL60 [58,73,75,87,88,111,121] and A549 [39,75,82,85,87,88,111,122] are most commonly used for the screening of cytotoxicity of A-seco-triterpenoids. However, cytotoxicity against these lines usually exceeds 20.0 mM for most A-seco-triterpenoids [82,87,88,111]. By example of the structureeactivity relationships of A-secolanostane triterpenoids from Poria cocos and the genus Kadsura’s species, seco-coccinic acid A (13) shows the highest cytotoxicity against HL60 cells with a concentration that inhibited 50% of cell growth (GI50) of 6.8 mM [58,75,87,88]. Certain decrease in the cytotoxicity is observed when the side chain of the triterpene molecule has an additional double C]C bond (secococcinic acid B (14), GI50 13.3 mM) or hydroxyl group (seco-coccinic acid C (15), GI50 12.1 mM) [58]. A further decrease in activity is registered for secococcinic acid E (16) (GI50 42.1 mM) that combines a double bond and a hydroxyl group in the side chain [58]. Generally, isomerization of the double bond in the cyclic moiety or the presence of an additional double bond in the cyclic moiety and the presence of additional oxygen-containing substituents in ring A or in the alicyclic side chain (including a six-membered lactone as a substituent) lead to moderate activity of poricoic acids A, C, G, H (17e20) isolated from P. cocos [75] or to a dramatic reduction (or loss) of cytotoxicity in compounds (21e26) from plants of the Kadsura species [87,88].

At the same time, 3,4-seco-lanostane triterpenoids (27 and 28) from Abies holophylla with structures containing a five-membered lactone moiety, exhibit cytotoxicity at concentration of compound causing death of 50% of the cells (IC50) 3.2e6.4 mM against COLO 205 and QGY-7703 cells [85].

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

(A) 70

61

Active compounds

Tested compounds

Number of tested compounds

60 50 40 30 20 10 0 n La

t os

an

e C

l yc

r oa

ta

ne D

am

m

ar

an

“S

(B)

e ru Ti

ch

a is

l ca

nd

ra

la

ne

r no

tri

Tested compounds

t

p er

o en

id

s”

er

th

O

Skeletone type

Active compounds

Number of tested compounds

18 16 14 12 10 8 6 4 2

th er O

Lu

pa

ne

ne la de ie

Skeletone type

Fr

an rs U

O

le

an

an

e

e

0

FIGURE 2.3 Antitumor activity of A-seco-triterpenoids derived from triterpenoids with tetracyclic (A) and pentacyclic (B) skeletones.

Among A-seco-lanostane triterpenoids, the highest cytotoxicity against Kato III and Ehlrich cells (IC50 1.1 mg/mL) is observed for elfvingic acid H methyl ester (29) from the fruit body of Elfvingia applanata [123].

62 Studies in Natural Products Chemistry

R

O

O

O

27, R =

OH

HOOC H

28, R =

O

O

COOH

MeOOC O H

H

OH

29

As seen from the cytotoxicity data for A-seco-triterpenoids, the cycloartane-type compounds have the highest activity against various tumor cell lines. CHAGO, Hep-G2, SW-620 [43,89], KATO-3 [89], and P-388 [92] cells, as the most sensitive to the action of A-seco-cycloartane triterpenoids, are noted. Among these triterpenoids, sootepin A (30) (SW-620, IC50 1.8 mg/ mL) and sootepin E (31) (KATO-3, IC50 1.9 mg/mL) from Gardenia sootepensis act as the most active compounds [89]. Although the IC50 values of dikamaliartane-A (32) from dikamali gum resin are moderate against HeLa and MCF-7 cells (29.6 mg/mL and 30.0 mg/ mL, respectively), this compound significantly increases the mean survival time and the percentage increase in life span in experiments in vivo with Ehrlich Ascites Carcinoma bearing mice when compared with standard drug or tumor controls. At the same time, compound (32) decreases the tumor volume, packed cell volume, and viable tumor cell count [124].

Tetracyclic triterpenoids, seco-apotirucallane-type argentinic acids AeI are purified from Aglaia argentea in the form of their methyl esters (33e40) that demonstrate cytotoxicity (IC50 1.0e3.5 mg/mL) against KB cells [125]. The corresponding acids are inactive. O

O H

H

H

OH

R O

33, R = MeOOC

HO

H

OR

H O

,R =

34, R =

37, R = HO

H O

,R =

HO O

H O

O

H

OH

35, R = HO

36, R = HO

MeOOC

O H

OH

H

H

OH

OR O

OH

OH 38, R =

,R = O

O OH 39, R =

40, R =

OH ,R =

O

HO

H O

O

HO ,R =

H O

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Among the pentacyclic A-seco-triterpenoids, cytotoxic active compounds are also found. For example, 3,4-seco-fernane FS-2 (41) and 3,4-seco-oleanane FS-4 (42) triterpenoids of Euphorbia chamaesyce L. are active against 39 tumor cell lines, with log GI50 values from () 5.68 to () 4.61 [126]. Adianane dorstenic acid A (43) from the roots of Dorstenia brasiliensis exhibits cytotoxicity against L-1210 (IC50 5.0 mM) and HL60 (IC50 10.0 mM) [16]. The 2,3-seco-taraxane 2,3-dimethyl ester (44) from Elateriospermum tapos is cytotoxic to NCI-H187 and BC cells, with IC50 values of 4.6 and 7.1 mg/mL, respectively [127]. Although taraxane pycanocarpine (45) from Pleiocarpa pycnantha demonstrates weak cytotoxicity against MCF-7 cells, with an IC50 of 20.0 mM, it is absolutely inactive against HeLa and HT-29 cells [128]. Unfortunately, information on the mechanisms of the cytotoxic effect of A-seco-triterpenoids is limited. It is shown that, as is the case with many triterpenoids [7], their A-seco-derivatives mainly induce apoptosis in tumor cells (a form of programmed cell death that occurs through the activation of cell-intrinsic suicide machinery). So, the ability to induce this form of cell death is detected in sentulic acid (46) from Sandoricum koetjape Merr [129]. Interestingly, sentulic acid is more effective at inducing apoptosis than its metabolic precursor 3-oxoolean-12-en-27-oic acid (47). Lanostane-type australic acid (48) from the fungus Ganoderma australe induces the inhibition of cell growth, partially through apoptosis activation and, probably, by other factors related to cell growth (i.e., the cell cycle) [76]. At the same time, lanostane (28 and 49) (IC50 42.6e75.7 mM) [81] and cycloartane (50e53) (IC50 20.0 mM) seco-triterpenoids selectively inhibit the activity of topoisomerase II [92].

Kadsuracoccinic acid A (54) from Kadsura coccinea induces significant cleavage arrest of the cell cycle of Xenopus laevis embryos with an IC50 0.3 mg/mL [86]. Authors connect this activity with possible preservation of the M phase’s progression of embryonic cells.

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The antitumor-promoting effects of lanostane acids (17e20, 55e65) from P. cocos Wolf [25,73,121] and oleanane koetjapic acid (66) from S. koetjape Merr [130] in the in vitro EpsteineBarr virus early antigen induction test and/ or in the in vivo two-stage carcinogenesis test on mouse skin reveal their high potency as chemopreventive agents, rather than as potential antitumor agents. At the same time, a potassium koetjapate salt has a more enhanced cytotoxicity against the HCT 116 cells in comparison with koetjapic acid as its starting compound (66) [131]. The enhanced efficiency of potassium koetjapate is, apparently, attributed to its more high solubility, to ability in apoptotic induction of nuclear condensation, and to disruption of the mitochondrial membrane potential in cells. It is worth noting that potassium koetjapate is found to be safe for rats with median lethal dose (LD50) > 2000 mg/kg after being orally administered. HOOC COOH H

HOOC

HOOC R R

R OOC

H

HOOC H

H

H

54

Δ8

Δ 7,9(11)

55, R1 = Me; R2 = OH; R3 =

60, R1 = Me; R2 = OH; R3 =

56, R1 = Me; R2 = OH; R3 =

Δ 7,9(11)

H

66 OH

61, R1 = H; R2 = OH; R3 = OH OH

62, R1 = Me; R2 = OH; R3 = OH

57, R1 = H; R2 = H; R3 = OH 63, R1 = H; R2 = H; R3 =

OMe

58, R1 = H; R2 = OH; R3 = 64, R1 = H; R2 = OH; R3 = 59, R1 = Me; R2 = OH; R3 =

Δ6,8 65, R1 = H; R2 = OH; R3 =

EFFECTS OF A-SECO-TRITERPENOIDS ON THE IMMUNE SYSTEM Many triterpenoids significantly suppress chronic inflammation by inhibiting proinflammatory enzymes, such as nitric oxide synthase, cyclooxygenase-2 or 5-lipoxygenase, overproduction of which may lead to inflammation or carcinogenesis [9,132,133]. Special studies focus on the ability of triterpenoids to inhibit transcription factors, including nuclear factor kappa-light-chainenhancer of activated B cells (NF-kB) and signal transducer and activator of

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

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transcription 3, that are the major regulators of inflammation, cellular transformation, and tumor cell survival, proliferation, invasion, angiogenesis, and metastasis [134,135]. Although the ability to affect the immune system is typical of triterpenoids, information on this kind of activity for A-seco-triterpenoids is not rich [131e135]. So, A-seco-triterpenoids are shown to be effective at inhibiting angiogenesis. Noncytotoxic koetjapic acid (66) [136,137] can inhibit in ovo neovascularization by affecting the expression of angiogenic protein vascular endothelial growth factor, endothelial cell migration/differentiation and tubule formation [138]. Cycloartane sootependial (67) from G. sootepensis shows potent selective cytotoxicity to HepG2 and an ex vivo antiangiogenic effect, which occurs mainly by suppressing endothelial cell proliferation and tubule formation [139]. The experimental and the computer-aided molecular modeling data allow Li et al. [41] to deduce that 85% to 90% effective inhibition of lipopolysaccharides (LPS)einduced tumor necrosis factor alpha (TNF-a) production by 3,4; 9,10-seco-cycloartane illiciumolide A (68) and by illiciumolide B (69) isolated from Illicium difengpi, at a concentration 25 mg/mL, may be attributed to their inhibition of the NF-kB signal pathway through the interaction with mitogen-activated protein kinase kinase 1. The 50% inhibitory effect on the TNFa-induced NF-kB luciferase reporter activity in HepG2 cells is achieved using oleanane triterpenoid (70) from Kalopanax pictus at a concentration of 9.4 mM [140]. Lupane triterpenoids (71e75) from Acanthopanax sessiliflorus show moderate potencies (with IC50 values 11.3e47.0 mM) in inhibiting NO production in LPS-activated RAW 264.7 macrophages [141]. For the tissue plasminogen activator (TPA)-induced mouse ear edema test, percentage of edema inhibition of seco-lupane lippiolic acid (76) in doses of 1 mmol/ear reaches 74.5% [142].

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The antiinflammatory effect analyzed by means of a doseeresponse curve, indicating that galphimine-A (77) (Emax 99.0%, dose of drug therapeutically effective for 50% of a group of experimental animals [ED50] 0.8 mg/ear) is more active than compound (78) but that galphimine-E (78) (Emax 90.8%, ED50 0.3 mg/ear) is more potent [19]. 20-Epi-koetjapic acid (79) from Maytenus undata dose dependently inhibits rat neonatal brain microglia agonist-stimulated release of neuroinflammatory mediators such as thromboxane B2 (IC50 0.5 mM) and superoxide anion (IC50 1.9 mM) [143]. HOOC MeOOC H

OH

O HO

R

H

H

HOOC

O OH

H

79

77, R = OH; 78, R = OAc

Other seco-derivatives (80) and (81) from Microtropis fokienensis show significant antiinflammatory activity against superoxide anion generation and elastase release by neutrophils in response to formyl-Met-Leu-Phe/ cytochalasin B, with IC50 values of 2.1/2.9 and 0.1/1.0 mg/mL, respectively [144]. The antiinflammatory effects of glycoside chiisanoside (82) and its aglycone chiisanogenin (83) from Acanthopanax chiisanensis at 10 or 30 mg/kg dose are supported by reduction of carrageenan-induced lipid peroxidation and hydroxyl radical in serum, as well as a reduction of rheumatoid arthritis and C-reactive protein factors in the rat, induced by Freund’s complete adjuvant reagent [145]. Moreover, as scavengers of reactive oxygen species, both compounds inhibit xanthine oxidase activity and increase superoxide dismutase, glutathione peroxidase and catalase caused by injection of inflammation-inducing agent carrageenan. Interestingly, the aglycone (83) shows a much more potent activity as an antiinflammatory drug. 29-Nor-3,4-seco-cycloartanes (84) and (85) from Antirhea acutata show moderate inhibitory activities in cyclooxygenase-1 and cyclooxygenase-2 assays (IC50 43.7e45.7 and 4.7e18.4 mM, respectively) [146,147]. HOH C

O

O

H H

H

O H

HOOC HOOC

O O

HOH C

HO

H

H

H

80

81

H HO

COOR

H

R OOC

H H

82, R = α–L-rhmanopyranosyl(1 4)β–D-glucopyranosyl(1 6)-β-D-glucopyranosyl-; 83, R = H

H

OH

84, R = Me; R = 85, R = H; R =

OOH

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

67

ANTIVIRAL ACTIVITY The antiviral activity of natural A-seco-triterpenoids is studied to a lesser extent. The information retrieval shows dammarane-type shoreic acid (86), eichlerianic acid (87) and dammarenolic acid (88) isolated from dammar resin to be active against herpes simplex virus (HSV)-1 (IC50 3.0e7.0 mg/mL) and HSV-2 (IC50 2.0e8.0 mg/mL) [148]. Additionally, dammarenolic acid (88) effectively inhibits replication of simian immunodeficiency virus (IC50 1.3 mg/ mL) and murine leukemia virus (IC50 1.5 mg/mL) in vector-based antiviral screening studies [98]. Time-of-addition studies also reveal dammarenolic acid (88) to strongly inhibit the postentry stage in the respiratory syncytial virus (IC50 0.1 mg/mL) [149] and HIV-1 (IC50 0.5 mg/mL) [98] replication cycles. Some seco-cycloartanes also demonstrate antiviral properties. Kadsuphilactone B (89) exhibits strong inhibitory activity toward hepatitis B virus (IC50 6.0 mg/mL) [150]. Among publications, we find differing information on the activity of nigranoic acid (1) against HIV-1 [50,151]. So, the paper [50] presents nigranoic acid (1) as a 99.4% inhibitor of human immunodeficiency virus 1 reverse transcriptase (HIV-1 RT) at a dose of 200 mg/mL, whereas the paper [151] demonstrates absolute inactivity of 11.1 mg/mL nigranoic acid (1) in a test with HIV-1 RT, and the strong (85%) inhibition activity against HIV-1 protease (PR) at a concentration of 10 mg/mL. Dikamaliartane-D (90) and carinatin C (50) from Gardenia carinata demonstrate weak activity against HIV-1 RT with IC50 values 68.7 and 85.7 mM, respectively [92]. In addition, dikamaliartane-D (90) exhibits significant anti-HIV-1 activity by reducing the number of syncytium formations with concentration of compound providing 50% protection of cells (EC50) < 8.3 mM. Although being a methylated derivative of dikamaliartane-D from Gardenia obtusifolia, compound (91) is similar to dikamaliartane-D in the HIV-1 RT assay and cytotoxic in the syncytium formation infectivity assay [24]. OH HO H HOOC

O H

H

OH H

H H

HOOC H H

86, 24R 87, 24S

H H

88

O

O

H

89

O

O O

H

ROOC HO

H

90, R = H; 91, R = Me

18-Norschiartanes (92e95), schisanartanes (96e106), preschisanartanes (107 and 108), wuweizilactone acid (109), schiartanes (110, 111), and 18(13/14)-abeo-schiartanes (112e115) from the plants of the genus Schisandra demonstrate different anti-HIV-1 activities with EC50 values ranging from 7.7 to 100.0 mg/mL in the syncytium formation infectivity assay or in the virus neutralization test [37,119,120,152,153].

68 Studies in Natural Products Chemistry

O O

O O

R O

H

HO

H O

O

92, R = =O; 93, R = α–OAc

HO O

H OH

H O OH

H

H O

HO O

O

O O

O H

R H

O

H O

O

H

O H O OH

H OH

H O

H O

O

O

H O OH

R

H

O

H O H

H O

H O H

H O O

H

O

HO

O

H

O O O

H

O

H O

O H

O

O

O O

H

R

O H

O

H O

O

102

O H O

H O

O

O H

O

104, R = α -Me; 105, R = β -Me;

103

O

H

H

O

O

H

101

O

O H

H O H

96, R = β-Me; 97, R =α– Me

O

HO

O

O

O OH

O H O

99, R = β -Me 100, R = α -Me

O

HO

R H

O

95

H O OH

H

H

H

O

O

O

HO H

O

O

O O

98

H

O

O O

H

O

HO O

94

H

O

O

H

O

O

O H

O

H

O

O

H O

AcO O

H

H

H

O

O

O H

O

HO

O

H O H

H O

O

H O

OH

H

H

106

H

O

O

O H O

107, R =

OAc

OH O

O

H O

108, R =

O O

O O

H

HOOC

H

109

OH

H O

O

H O

HO

H H

H H

110

O

O

O

OH

O

H O

HO H

H

O

HO

H

111

O

O

R

O

H

H

OH

112, 113, 114, 115,

R R R R

O

HO

H

H

O

OH

= OAc; = H; R = H; R = H; R

R

R = = =

O H

R

= OH; R = H OH; R = H OAc; R = H OAc; R = OH

Nigranoic acid (1) and koetjapic acid (66) show reasonable inhibiting activity when interacting with DNA polymerase b (IC50 16.6 and 20.0 mM, respectively) [50,154]. Computer-aided molecular docking predicts some targets, including gag-pol polyprotein and protease, for illiciumolide A (68), illiciumolide B (69) and sootepin E (31) as potential anti-HIV-1 agents [41]. Cycloartane triterpenoids nigranoic acid (1) and kadsuranic acid A (116) from Kadsura heteroclita, at a concentration of 10.0 mg/mL, show strong inhibition of HIV-1 PR with inhibition ratios of 85.0% and 89.2%, respectively [151]. Among other compounds with antiprotease activity, colossolactone V (117), colossolactone VII (118), colossolactone G (119), and schisanlactone A (120) from mushroom Ganoderma colossum may be mentioned with IC50 values of 5.0e13.8 mg/mL [77], as well as the lupane triterpenoid 16b-hydroxy2,3-seco-lup-20(29)-ene-2,3-dioic acid (121) with an IC50 of 8.7 mg/mL [38].

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

69

Triterpenoids with the unique skeleton from K. heteroclita longipedlactone J (122) exhibit the ability to prevent the cytopathic effect (EC50 3.8 mg/mL) of HIV-1 in C8166 cells [155], as well as some another lactones of this type that show weak inhibition on HIV-1 protease and are also found in the stems of this plant [151]. In the similar test with infected C8166 cells, the anti-HIV activity of cycloartane triterpenoids angustific acid A (123) and nigranoic acid (1) from Kadsura angustifolia reaches EC50 values of 6.1 and 10.5 mg/mL, respectively [156]. O

R COOH H

HOOC

O

MeOCO MeOOC

OCOMe

117, R =

HO H

H

H

O

O

R

O

119, R = OAc; R = OH 120, R = H; R = H

O

116

R

COOH

118, R = H H

H

HO

O

H HOOC HOOC

H H

121

OH

H O

H

O

122

H

H O

O

COOH

O

OAc

123

ANTIBACTERIAL ACTIVITY The antibacterial activity is one of the most frequently tested activities of pentacyclic seco-oleanane triterpenoids. Among the tested compounds, dysoxyhainic acid G (124) shows strong inhibitory activities against Staphylococcus epidermidis ATCC 12228, Micrococcus luteus ATCC 9341 and Bacillus subtilis ATCC 6633, with minimal inhibitory concentration (MIC) 3.1 mg/mL; dysoxyhainic acid I (125) exerts a more selective inhibitory activity against B. subtilis ATCC 6633 (MIC 1.6 mg/mL); koetjapic acid (66) and 20-epi-koetjapic acid (79) demonstrate inhibitory activities against B. subtilis ATCC 6633, S. epidermidis ATCC 12228, Staphylococcus areus ATCC 6535 and methicillin-resistant strain S. areus ATCC 33591 (MIC 3.3e12.5 mg/mL) [143,157]. The previously mentioned 3,4-seco-oleanane triterpenoids are mainly active against gram-positive bacteria and are inactive against fungi and gram-negative bacteria [157]. However, information on the inhibitory activity of koetjapic acid (66) and 20-epi-koetjapic acid (79) against Pseudomonas aeruginosa ATCC 15442 (MIC 6.3 mg/mL) was reported previously [143]. 2,3-Seco-oleanane dillenic acid D (126) combines bactericidal activity against Gram-positive (B. subtilis ATCC 6633, M. luteus ATCC 9341) and Gramnegative (Escherichia coli ATCC 25922) cultures in doses of 0.5e1.0 mg in the test of minimum growth inhibition amounts on TLC [158]. Dysoxyhainanin B (127), with rearranged oleanane skeleton, is inactive against all the tested strains of Gram-positive bacteria, such as S. aureus ATCC 25923,

70 Studies in Natural Products Chemistry

S. epidermidis ATCC 12228, M. luteus ATCC 9341, and B. subtilis CMCC 63501 [56]. COOH

COOH

HO H

MeOOC

H

HOOC

H

H OHC MeOOC

H

H

HO

124

H

H

125

126

H

O

H

H

O O

H

127

Among other pentacyclic triterpenoids, it may be noted that onocerane A,C-bis-seco-triterpenoids, lamesticumin A (128) and lansic acid 3-ethyl ester (129), are active only against Gram-positive bacteria Bacillus subtilis ATCC 6633, Bacillus cereus (a clinical isolate), M. luteus ATCC 9341, Micrococcus pyogenes (a clinical isolate), S. aureus ATCC 25923 and S. epidermidis ATCC 12228 (MIC 3.1e12.5 mg/mL, in more cases) [29]; lupane-type dysoxyhainic acid H (130) exhibits inhibitory activities against M. luteus ATCC 9341 and B. subtilis ATCC 6633 (MIC 3.1 mg/mL) [157]; and 2,3-seco-taraxer-14-ene-2,3,28-trioic acid 2,3-dimethyl ester (44) has activity against Mycobacterium tuberculosis H37Ra (MIC 3.1 mg/mL) [127]. The moderate activity (MIC 12.5 mg/mL) against Gram-positive bacteria S. aureus and B. subtilis among the tetracyclic triterpenoids of Abies species can be noted for rearranged lanostane abiesanolide A (131) and 3,4-secomariesane acid (132) [80], whereas ()-rel-abiesonic acid 3-methyl ester (133) is weakly active (MIC 25 mM) against S. aureus [122]. COOH

COOH H

H

H

HOOC H

H HO

H

EtOOC

MeOOC

H

128

O HOOC H H

131

HO

H

H

H

H

129

130

O

O HOOC

O

O

MeOOC

H

132

COOH

H

H H

133

OTHER TYPES OF BIOLOGICAL ACTIVITY Certain publications relate to the research of the antiprotozoal activity of A-seco-triterpenoids. Moderate growth inhibition activity against Leishmania major is estimated for the seco-oleanane triterpenoids (134) and (135)

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

71

from Dillenia philippinensis (IC50 46.6 and 56.7 mM, respectively) [159]. The nor-seco-friedelanes, galphin A (136), galphin B (137), and galphin C (138) from Galphimia glauca are inactive (IC50 > 100 mM) against tested microorganisms (including Plasmodium falciparum K1, Trypanosoma brucei brucei, and Leishmania donovani) [160], whereas dinor-seco-friedelane dzununcanone (3) has a weak activity (IC50 22.4 mM) against Giardia intestinalis [35]. Several studies relate to the study of the activity of A-seco-triterpenoids against various enzymes, many of them playing a key role in biochemical processes. Triglycosides sessiloside (139) and chiisanoside (82) from Acanthopanax species are found to inhibit pancreatic lipase activity in vitro (IC50 0.3 and 0.7 mg/mL, respectively) [102,103]. At the same time, addition of the triglycoside-rich fraction to a high-fat diet suppresses the body-weight gain of mice and can be useful in the treatment of obesity [103]. MeOOC R H HOOC

H

HOOC H

134, R = Me 135, R = Bu

O

COOR

H

H

H OH

R

H

HOOC

O

COOR

H O

OAc OAc

136, R1 = H; R2 = H 137, R1 = H; R2 = OAc 138, R1 = OAc; R2 = OAc

H

139, R = α -L-rhamnopyranosyl(1 β -D-glucopyranosyl-(1 6)-β-Dglucopyranosyl-

4)-

Chiisanoside (82) and its aglycone chiisanogenin (83) are weak inhibitors (IC50 0.4e0.5 mg/mL) of b-glucuronidase. Additionally, chiisanogenin (83) inhibits Hþ/KþATPase (IC50 0.5 mg/mL) [101]. Seco-dammarane glycosides cyclocariosides DeG (140e143) and secodammarane cyclocarin A (144) from Cyclocarya paliurus show weak inhibitory activities (2.9%e23.2%) against lipase, aldose reductase, inhibitors of dipeptidyl peptidase 4, and a-glucosidase at doses of 5e40 mM [161]. Schindilactone A (96), schindilactone I (145), preschisanartanin E (146), and propindilactone Q (147) from Schisandra chinensis, at a concentration of 50.0 mM, show antiacetylcholinesterase activity with 10.7%, 12.7%, 16.6% and 32.1% inhibition, respectively [162]. Fornicatins B (148), D (149) and F (150) from Ganoderma cochlear lower the alanine transaminase and aspartate transaminase levels in HepG2 cells treated with H2O2, suggesting that they can display in vivo hepatoprotective activities [163]. Fornicatins A (151) and B (148) from Ganoderma fornicatum exhibit modest inhibitory effects (41.2e44.3%) on rabbit platelet aggregation induced by platelet activating factor [57].

72 Studies in Natural Products Chemistry

OH

OR H

R

R OOC

HO HO

OMe

OH

;R =

HO OH HO

H O OH OH

H

OMe

OH

H

H O O

145 ;R =

O

143, R = Et; R =

O

O

O

HO

H

O

HO

OH

141, R = Et; R = HO

142, R = H; R =

;R =

O

H H

O

O

140, R = H; R =

OMe

OH

;R =

O

OMe

OH

144, R = Me; R = H; R = O O H

O O

O

O H O OH

H

O

H H OH

AcO

O H

O

O

HO

COOH

O O

H

O

R OOC

HOOC

H O OH

H

146

COOR

O

H

147

OH HO

148, R = H; R =H 149, R = Me; R =H 150, R = Me; R =Me

H O

151

3,4-Seco-lupane acids (152) and (153) from A. sessiliflorus demonstrate high levels of antiplatelet aggregation activity (IC50 4.2 and 5.6 mM, respectively), which is similar to that of positive-control acetylsalicylic acid on adenosine diphosphate-induced platelet aggregation [164]. Limonoids (154e160) from Trichilia rubra are found to be the most potent inhibitors of LFA-l:ICAM-1emediated cell adhesion with IC50 values of 10e25 nM [165]. OH HOOC R

H

HO

HOOC

H

R COOH

H

152, R = H 153, R = OH

154, R =

O

O

;R = O

O

OH

155, R =

MeOCO

H

O

O

O HO

O

O O

OH R COOMe

O

;R =

O OH

156, R =

O

O

;R =

O

O OH

157, R =

O

;R =

O O

O OH

158, R =

O

; R = =O O

159, R =

O

O

;R =

O O

O OH

160, R =

O

;R = O

O O

6b-Hydroxy nigranoic acid (161) from Schisandra glaucescens exhibits significant antagonistic effect with an IC50 value of 1.5 mM against farnesoid X receptor that affects many aspects of human metabolism by regulating bile acids, lipid, and glucose homeostasis [40]. Inhibitory activity (IC50 73.2 mM) of terminalin A (8) from Terminalia glaucescens is detected against prolyl

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

73

endopeptidase (PEP EC 3.4.21.26) playing an important role in learning and memory processes [21]. The central nervous system (CNS)edepressant activity is detected in secocycloartane dikamaliartane-A (32) from dikamali gum resin [166] and nor-secofriedelane galphimine-B (162) from G. glauca [167,168]. It is revealed that compound (162) demonstrates a selective inhibiting effect on ventral tegmental area dopaminergic neurons in rats through the non-GABAergic mechanism [168,169]. The ability of compound (162) to modulate the induced response of 5HT1A receptors in an allosteric manner is confirmed [170]. Galphimines A (77) and B (162) show the highest anxiolytic activity [171]. The pharmacokinetic study of compound (77) gives evidence of its presence in brain tissue and confirms that this anxiolytic compound can access the target organ and act directly on the CNS [172]. Another compound, galphimine-F (163), isolated from G. glauca has a significant spasmolytic effect with an EC50 of 5.4 mg/mL in the model of the isolated guinea-pig ileum [173]. MeOOC COOH H

HOOC

H

OH

H

O O H

OH

OH HO

162 Δ 20

161

163 Δ 20(29)

THE MAIN APPROACHES TO SYNTHESIS OF A-SECOTRITERPENOIDS High therapeutic potential of natural A-seso-triterpenoids and extremely low levels of these compounds in plant sources induce development of alternative methods for their preparation from triterpenoids that can be readily isolated from plant (betulinic acid (164), oleanolic acid (165), ursolic acid (166), glycyrrhetic acid (167), etc.). Currently, fragmentation of ring A in triterpenoids is performed with the use of chemical, photochemical, and microbiological methods. Many of semisynthetic A-seco-triterpenoids and their functionalized derivatives exhibit high levels of biological activity, including cytotoxic, antiviral, anti-HIV, and immunotropic activities [174e182]. COOH H

O H

COOH

H

H HO

H

164

COOH

H

H HO

H

165

COOH

H

H HO

H

166

H HO

H

167

Methods of chemical synthesis are most commonly used to obtain A-secoderivatives [183]. So, the oxidative cleavage of triterpene diosphenols and 2-hydroxymethylene derivatives in the presence of hydrogen peroxide leads to

74 Studies in Natural Products Chemistry

formation of 2,3-seco-triterpenoids [175e177,184e186]. The ozonation reaction of triterpene derivatives allows 2,3-seco- [187] and 4,5-seco- [188,189] derivatives to be obtained. The most significant part of studies on the synthesis of A-seco-derivatives includes cleavage of oximes by the Beckmann fragmentation as the main reaction leading to formation of 2,3-seco- [190e192] or 3,4-seco-triterpenoids [193e201]. In some cases, this reaction provides semisynthetic analogues of natural A-seso-triterpenoids. For example, cytotoxic manwuweizic acid (24), naturally produced by the plant Schisandra propinqua, can be synthesized by the Beckman fragmentation of ketoxime of anwuweizonic acid (168) followed by hydrolysis of semisynthetic 2-cyano-3,4-secolanosta-26-oic acid (169) [193]. Another synthetic approach to manwuweizic acid (24) can be designed from more available triterpenoid lanosterol (170) and includes stereoselective introduction of the terminal (Z)-carboxylic group into the side chain with formation of anwuweizonic acid (171), followed by the Beckmann fragmentation of ring A and formation of key intermediate (169), hydrolysis of which affords manwuweizic acid (24) [194].

There are also available other organic reagent systems that lead to the ring A opening. For example, 3,4-seco-derivatives are obtained in two-stage processes using m-chloroperoxybenzoic acid for the BaeyereVilliger oxidation and p-toluenesulfonic acid for cleavage of ring A of the lactone intermediate [202]. Triterpene 3,5-seco-4-nor-derivative is formed under conditions of the BaeyereVilliger reaction through the ring opening followed by an unusual rearrangement [203]. Oxidation of diosphenols with the O2/t-BuOK/t-BuOH reagent system, followed by fragmentation of the formed lactols, leads to 1,3-seco-derivatives [185]. A-seco-triterpenoids can also be formed from triterpene derivatives with a five- or six-membered ring A (for example, lactones, anhydrides, ketones, hydroxyketones, diosphenols, olefins, unsaturated ketones, or diketones) with reagents such as NaOH [204e206], NaBH4 [205], LiAlH4 [205,206], H2SO4 [204], a mixture of K2Cr2O7/20% H2SO4 [207], H5IO6 or KMnO4 in the presence of a phase-transfer catalyst [208e210], or RuO4 [205,211,212]. Extracted from the mature stems of Lasianthus gardneri, 3,4-seco-lupa4(23),20(29)-dien-3-ol (172) can be obtained synthetically from lupeol (173) with the PbAc4/CaCO3/toluene reagent system followed by LiAlH4 reduction of the obtained seco-intermediate [47]. Certain examples of the microbial transformation of ring A of triterpenoids, with participation of filamentous fungi and bacteria, are described elsewhere [213e218]. As a rule, 3,4-seco-triterpenoids are regarded as biotransformation products. It is assumed that microbial transformation of a

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

75

3-oxo or 3-hydroxy triterpenoids with the formation of 3,4-seco-derivatives proceeds via the BayereVilliger oxidation-type reaction through formation of seven-membered lactones as intermediates [219]. Methods of callus and cell suspension cultures of G. glauca are developed for production and accumulation of the sedative nor-seco-triterpenoid galphimine-B (162) [220,221]. Another technique of controlled galphimineB production deals with micropropagation of G. glauca [222]. Photochemical methods for the synthesis of A-seco-triterpenoids are rarely used in practice. For example, the Suarez cleavage of betulin (174) ring A occurs under irradiation (425 W) in the presence of diacetoxyiodobenzene and I2 [223]. H

H H

HOH C H H

172

H H

H

HO

H

173

CH OH

H

H HO

H

174

Formation of various 3,4-seco-triterpenoids under the action of sunlight and artificial irradiation is reported previously [65].

CONCLUSION In this work, we try to review natural sources, diversity of structural types, and biological activities of A-seco-triterpenoids. Information on these compounds is systematically presented in Table 2.1. We highlight their isolation, structure ascertainment, and biosynthesis, as well as we try to identify problems related to possibilities of using A-seco-triterpenoids as chemotaxonomic markers of plants. Analysis of available publications shows A-seco-triterpenoids to be available in the nature, mainly as compounds with a tetracyclic and pentacyclic carbon skeleton (Fig. 2.4A; Table 2.1). A-seso-triterpenoids with a fragmented bond between C-3 and C-4 represent one of the most abundant group of A-seso-triterpenoids in plants. The 3,4-seco-triterpenoids are isolated from plants in the form of free acids and in related form as esters or glycosides. Another part of the A-seco-triterpenoids is represented by compounds of 2,3-seco-type, along with compounds with more degraded seco-ring A (Fig. 2.4B; Table 2.1). Summarizing the reviewed data, it may be noted that, among natural A-seco-triterpenoids, tetracyclic 3,4-seco-derivatives with lanostane and cycloartane carbon skeletons that are mainly produced by plants of genera Abies, Kadsura, Gardenia, and Schisandra are mostly widespread. Pentacyclic triterpenoids, represented mainly by oleanane, lupane (plants of Acanthopanax species), and fridelane (plants of family Celastraceae) derivatives with 3,4-seco- or 2,3-seco-type, lesser occur in the plant kingdom.

76 Studies in Natural Products Chemistry

(A)

(B) Tetracyclic A-seco-triterpenoids Pentacyclic A-seco-triterpenoids

3,4-Seco-triterpenoids 2,3-Seco-triterpenoids Schinortriterpenoid groups Other A-seco-triterpenoids

67%

75%

6% 25%

9%

18%

FIGURE 2.4 Diversity of natural A-seco-triterpenoid structures: (A) percentage of tetracyclic and pentacyclic triterpenoids in nature; (B) types of natural A-seco-triterpenoids.

In most cases, the biosynthetic pathway in formation of triterpene A-secoring involves the BaeyereVilliger oxidation of C-3 or C-2 carbon atoms of cyclic 3-hydroxytriterpenoids as the key precleavage step. Weak dissemination of 2,3-seco-triterpenoids among the secondary plant metabolites may be attributed to either low contents of native 2,3-dioxygenated triterpenoids (key intermediates in the biosynthesis of 2,3-seco-triterpenoids) in vegetable sources or a complexity of their formation during biooxidation. Naturally occurring A-seco-triterpenoids differ in diverse biological activities. However, cytotoxic properties are most typical of this group of compounds. The mechanisms of antitumor action of A-seco-triterpenoids are associated with induction of apoptosis or inhibition of topoisomerase II. In addition, A-seco-triterpenoids are effective at inhibiting angiogenesis, owing to their ability to inhibit transcription factors or to affect expression of angiogenic proteins. This review also examines main approaches to obtain semisynthetic A-seco-triterpenoids, including those most commonly used in chemical synthesis methods, as well as microbiological and photochemical methods. According to the reported data, the Beckmann fragmentation and oxidative cleavage with participation of hydrogen peroxide can be distinguished among the most effective chemical methods that involve cleavage of the C-2eC-3 and C-3eC-4 bonds in ring A of triterpenoids. At the same time, triterpenoids such as betulinic acid (164), oleanolic acid (165), ursolic acid (166), and glycyrrhetic acid (167) are most often used as main sources for preparation of semisynthetic A-seco-triterpenoids. Synthetic methods allow the semisynthetic A-seco-triterpenoids (new, natural, or structure analogues of natural compounds) to be highly yielded. These methods significantly increase availability of biologically active A-seco-triterpenoids and expand their prospects for development of new therapeutic agents with high levels of biological activities.

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activities Sources (Parts Used)

Compound Name (No.)

Information About Biological Activity

References

Abies balsamea (oleoresin)

()-Rel-abiesonic acid 3-methyl ester (133)

No cytotoxicity; antibacterial activity

[122]

A. balsamea (oleoresin)

()-Rel-(24E)-23-oxo-3,4-seco-9bH-lanosta4(28),6,8(14),24-tetraen-3,26-dioic acid (175)

No cytotoxicity; no antibacterial activity

[122]

A. balsamea (oleoresin)

()-Rel-(24E)-23-oxo-3,4-seco-9bH-lanosta4(28),7,24-trien-3,26-dioic acid (180)

No cytotoxicity; no antibacterial activity

[122]

A. balsamea (oleoresin)

(25R)-3,4- seco-9bH-lanosta-4(28),7-dien3,26-dioic acid (181)

No cytotoxicity; no antibacterial activity

[122]

A. balsamea (oleoresin)

Abiesonic acid (185)

Cytotoxicity; no antibacterial activity

[122]

A. balsamea (oleoresin); Abies holophylla (aerial parts)

3,4-Seco-9bH-lanosta-4(28),7,22,25-tetraen23,26-olid-3-oic acid (27)

Cytotoxicity; no antibacterial activity

[85,122]

A. balsamea (oleoresin), Abies koreana (root bark)

(24E)-3,4-seco-9bH-lanosta-4(28),7,24-trien3,26-dioic acid (182)

Cytotoxicity; no antibacterial activity

[82,122]

A. balsamea (oleoresin); Abies holophylla (aerial parts); Abies sachalinensis (bark)

(23R,25 R)-3,4-seco-17,14-friedo9bH-lanosta-4(28),6,8(14)-trien-26,23-olid3-oic acid (176)

Cytotoxicity; no antibacterial activity

[81,85,122]

A. balsamea (oleoresin); A. holophylla (aerial parts); A. sachalinensis (bark); Abies sibirica (oleoresin)

(23R,25 R)-3,4-seco-9bH-lanosta4(28),7-dien-26,23-olid-3-oic acid (28)

Inhibitory activity against topoisomerase II; cytotoxicity; no antibacterial activity

[78,81, 85,122]

A-Seco-Lanostane Triterpenoids

Naturally Occurring A-Seco-Triterpenoids Chapter j 2 Continued

77

Sources (Parts Used)

Compound Name (No.)

Information About Biological Activity

References

A. holophylla (aerial parts); A. sachalinensis (bark)

Methyl (23R,25 R)-3,4-seco-9bH-lanosta 4(28),7-dien-26,23-olid-3-oate (49)

Inhibitory activity against topoisomerase II; cytotoxicity;

[81,85]

A. holophylla (aerial parts); A. sachalinensis (needles)

Abiesanolide C (189)

Cytotoxicity; no antibacterial activity

[80,83,85]

A. sachalinensis (needles)

Abiesanolide A (131)

Antibacterial activity

[80]

A. sachalinensis (needles)

Abiesanolide B (186)

No antibacterial activity

[80]

A. sachalinensis (needles)

Abiesanolide D (190)

No antibacterial activity

[80]

A. sachalinensis (needles)

Abiesanolide E (177)

No information

[224]

A. sachalinensis (needles)

Abiesanolide F (183)

No information

[224]

A. sachalinensis (needles)

Abiesanolide I (192)

No information

[225]

A. sachalinensis (needles)

Abiesanolide J (191)

No information

[225]

A. sachalinensis (needles)

3,4-Seco-8-(14/13R)abeo-17,13-friedo9b-lanosta-4(28),7,14,24-tetraen-26,23-olide23-hydroxy-3-oic acid (187)

No information

[83]

A. sachalinensis (needles)

Methyl 3,4-seco-8-(14/13R)abeo-17,13friedo-9b-lanosta-4(28),7,14,24-tetraen26,23-olide-23-hydroxy-3-oate (188)

No information

[83]

78 Studies in Natural Products Chemistry

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d

Anhydrosibiric acid (3,4-seco-mariesa4(28),6,8 (14),22Z,24-pentaen-26,23-olide3-oic acid) (132)

Antibacterial activity

[79,80]

A. sibirica (needles)

Dimethyl ester of cis-sibiric acid (178)

No information

[79]

A. sibirica (needles)

Methyl ester of anhydrosibiric acid (179)

No information

[79]

Elfvingia applanata (fruiting bodies)

Elfvingic acid H (193)

No cytotoxicity

[123]

E. applanata (fruiting bodies)

Elfvingic acid H methyl ester (29)

Cytotoxicity

[123]

Fomitopsis pinicola (fruiting bodies)

Pinicolic acid C (194)

No information

[226]

Ganoderma australe (fungus)

Australic acid (48)

Cytotoxicity

[76]

Ganoderma cochlear (fruiting bodies)

Cochlate A (199)

No information

[163]

G. cochlear (fruiting bodies)

Cochlate B (200)

No information

[163]

G. cochlear (fruiting bodies)

Fornicatin D (149)

Inhibitory activity against ALT and AST

[163]

G. cochlear (fruiting bodies)

Fornicatin E (201)

Inhibitory activity against AST

[163]

G.cochlear (fruiting bodies)

Fornicatin F (150)

Inhibitory activity against ALT and AST

[163]

Ganoderma colossum (fruiting bodies)

Colossolactone C (202)

No information

[227]

Continued

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

A. sachalinensis and A. sibirica (needles)

79

Sources (Parts Used)

Compound Name (No.)

Information About Biological Activity

References

G. colossum (fruiting bodies)

Colossolactone D (203)

No information

[227]

G. colossum (fruiting bodies)

Colossolactone E (204)

Antiviral activity against HIV-1 protease

[77,227]

G. colossum (fruiting bodies)

Colossolactone F (205)

No information

[227]

G. colossum (fruiting bodies)

Colossolactone G (119)

Antiviral activity against HIV-1 protease

[77,227,228]

G. colossum (fruiting bodies)

Colossolactone IV (207)

No information

[228]

G. colossum (fruiting bodies)

Colossolactone V (117)

Antiviral activity against HIV-1 protease

[77]

G. colossum (fruiting bodies)

Colossolactone VI (208)

No antiviral activity against HIV-1 protease

[77]

G. colossum (fruiting bodies)

Colossolactone VII (118)

Antiviral activity against HIV-1 protease

[77]

G. colossum (fruiting bodies)

Colossolactone VIII (206)

Antiviral activity against HIV-1 protease

[77]

G. colossum (fruiting bodies)

Schisanlactone A (120)

Antiviral activity against HIV-1 protease

[77,228]

G. colossum and Ganoderma fornicatum (fruiting bodies)

Fornicatin A (151)

Inhibitory effect on platelet aggregation

[57,163]

80 Studies in Natural Products Chemistry

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d

Fornicatin C (148)

Inhibitory effect on platelet aggregation; inhibitory activity against ALT, AST

[57,163]

Kadsura ananosma (stems)

Kadnanolactone A (209)

No cytotoxicity

[87]

K. ananosma (stems)

Kadnanolactone B (210)

No cytotoxicity

[87]

K. ananosma (stems)

Kadnanolactone C (21)

No cytotoxicity

[87]

K. ananosma (stems)

Kadnanolactone D (22)

No cytotoxicity

[87]

K. ananosma (stems)

Kadnanosic acid A (197)

No cytotoxicity

[87]

K. ananosma (stems)

Kadnanolactone E (211)

No cytotoxicity

[87]

K. ananosma (stems)

Schisanlactone F (212)

No cytotoxicity

[87]

K. ananosma and Kadsura coccinea (stems)

Kadcoccilactone R (198)

No cytotoxicity

[39,87]

K. ananosma and Kadsura polysperma (stems); Schisandra propinqua (stems and roots)

Manwuweizic acid (24)

No cytotoxicity

[87,88,193]

Kadsura coccinea (rhizomes)

Kadsuracoccinic acid A (54)

Cytotoxicity

[86]

K. coccinea (rhizomes)

Kadsuracoccinic acid B (213)

No cytotoxicity

[86]

K. coccinea (rhizomes, roots)

Kadsuracoccinic acid C/seco-coccinic acid F (214)

No information

[58,86]

K. coccinea (rhizomes); Schisandra micrantha and Schisandra chinensis (leaves and stems)

Kadsuric acid (215)

No cytotoxicity

[37,86,93]

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

G. colossum and G. fornicatum (fruiting bodies)

81

Continued

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d Compound Name (No.)

Information About Biological Activity

References

K. coccinea (rhizomes); S. micrantha and S. chinensis (leaves and stems)

Micranoic acid A (217)

No cytotoxicity

[37,86,93]

K. coccinea (roots)

Seco-coccinic acid A (13)

Cytotoxicity

[58]

K. coccinea (roots)

Seco-coccinic acid B (14)

Cytotoxicity

[58]

K. coccinea (roots)

Seco-coccinic acid C (15)

Cytotoxicity

[58]

K. coccinea (roots)

Seco-coccinic acid D (184)

No information

[58]

K. coccinea (roots)

Seco-coccinic acid E (16)

Cytotoxicity

[58]

K. coccinea (roots)

Coccinilactone A (218)

No information

[58]

Kadsura polysperma (stems)

Kadpolysperin B (219)

No information

[88]

K. polysperma (stems)

Kadpolysperin H (23)

No cytotoxicity

[88]

K. polysperma (stems)

Kadpolysperin I (26)

No cytotoxicity

[88]

K. polysperma (stems)

Kadpolysperin J (25)

No cytotoxicity

[88]

K. polysperma (stems)

Kadpolysperin K (196)

Cytotoxicity

[88]

Poria cocos (surface layer, sclerotium and epidermis of the sclerotia)

Poricoic acid A (17)

Cytotoxicity; inhibitory activity against EBV-EA

[71e73, 75,121]

P. cocos (epidermis of the sclerotia)

25-Methoxyporicoic acid A (64)

No cytotoxicity; inhibitory activity against EBV-EA

[73]

P.cocos (surface layer)

Poricoic acid AE (220)

No information

[74]

P. cocos (surface layer)

Poricoic acid CE (221)

No information

[74]

82 Studies in Natural Products Chemistry

Sources (Parts Used)

Poricoic acid AM (59)

Cytotoxicity; inhibitory activity against EBV-EA

[25,72,73]

P. cocos (surface layer and epidermis of the sclerotia)

Poricoic acid C (61)

No sytotoxic activity; inhibitory activity against EBV-EA

[71e73,121]

P. cocos (epidermis of the sclerotia)

16-Deoxyporicoic acid B (57)

Inhibitory activity against EBV-EA

[25]

P. cocos (surface layer and epidermis of the sclerotia)

Poricoic acid C (18)

Cytotoxicity; inhibitory activity against EBV-EA

[25,72,75]

P. cocos (epidermis of the sclerotia)

25-Hydroxyporicoic acid C (63)

Cytotoxicity; inhibitory activity against EBV-EA

[73]

P. cocos (epidermis of the sclerotia)

Poricoic acid CM (222)

Inhibitory activity against EBV-EA

[25]

P. cocos (surface layer and epidermis of the sclerotia)

Poricoic acid D (58)

Inhibitory activity against EBV-EA

[25,72]

P.cocos (surface layer and epidermis of the sclerotia)

Poricoic acid DM (60)

No cytotoxicity; inhibitory activity against EBV-EA

[25,72,73]

P. cocos (epidermis of the sclerotia)

Poricoic acid GM (55)

Inhibitory activity against EBV-EA

[73]

P.cocos (epidermis of the sclerotia)

Poricoic acid HM (56)

Inhibitory activity against EBV-EA

[73]

P. cocos (epidermis of the sclerotia)

26-Hydroxyporicoic acid DM (62)

No cytotoxicity; inhibitory activity against EBV-EA

[73]

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

P. cocos (surface layer and epidermis of the sclerotia)

83

Continued

Sources (Parts Used)

Compound Name (No.)

Information About Biological Activity

References

P. cocos (epidermis of the sclerotia)

6,7-Dehydroporicoic acid H (65)

No cytotoxicity; inhibitory activity against EBV-EA

[73]

P. cocos (epidermis of the sclerotia)

25-Hydroxyporicoic acid H (195)

Inhibitory activity against EBV-EA

[25]

P. cocos (sclerotium and epidermis of the sclerotia)

Poricoic acid G (19)

Inhibitory activity against EBV-EA; cytotoxicity

[73,75,121]

P. cocos (sclerotium and epidermis of the sclerotia)

Poricoic acid O (20)

Inhibitory activity against EBV-EA; cytotoxicity

[73,75,121]

Pseudolarix kaempferi (root bark)

Pseudoferic acid B (225)

No cytotoxicity; inhibitory activity against mouse and human 11b-HSD1

[111]

P. kaempferi (root bark)

Pseudoferic acid C (226)

No cytotoxicity; inhibitory activity against mouse and human 11b-HSD1

[111]

Sabal causiarum (leaves)

Sablacaurin A (227)

No information

[36]

S. blackburniana (leaves)

Sablacaurin B (228)

No information

[36]

Schisandra sphenanthera (fruits)

Schisanlactone G (216)

No information

[229]

Spongiporus leucomallellus (fruit bodies)

(þ)-Spongiporic acid A (223)

Antibacterial activity

[230]

S. leucomallellus (fruit bodies)

(þ)-Spongiporic acid B (224)

No information

[230]

84 Studies in Natural Products Chemistry

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d

A-Seco-Cycloartane Triterpenoids Cytotoxicity

[231,232]

Aglaia rubiginosa (leaves)

17-Octanor-cycloartane-ring-A-seco-acid (252)

No information

[233]

Antirhea acutata (aerial parts)

(6S)-Hydroxy-25-methoxy-29-nor-3,4-secocycloart-4(30),23-dien-3-oic acid methyl ester (230)

No inhibitory activity against COX-1 and COX-2

[146]

A. acutata (aerial parts)

(6S,25)-Dihydroxy-29-nor-3,4-seco-cycloart4(30),23-dien-3-oic acid methyl ester (231)

No inhibitory activity against COX-1 and COX-2

[146]

A. acutata (aerial parts)

(6S)-Hydroxy-24-oxo-29-nor-3,4-secocycloart-4(30),25-dien-3-oic acid methyl ester (232)

No inhibitory activity against COX-1 and COX-2

[146]

A. acutata (aerial parts)

(6S)-Hydroxy-(24x)-hydroperoxy-29-nor-3,4seco-cycloart-4(30),25-dien-3-oic acid methyl ester (84)

Inhibitory activity against COX-1 and COX-2

[146]

A. acutata (aerial parts)

(6S)-Hydroxy-29-nor-3,4-seco-cycloart4(30),24-dien-3-oic acid (85)

Inhibitory activity against COX-1 and COX-2

[147]

Gardenia aubryi (aerial parts); Gardenia carinata (leaves and twigs)

Secaubryolide (51)

Cytotoxicity; no inhibitory activity against HIV-1 reverse transcriptase and syncytium formation

[42,92]

Gardenia aubryi (aerial parts)

Secaubrytriol (233)

No cytotoxicity

[42]

G. aubryi (aerial parts); Gardenia thailandica and Gardenia tubifera (exudate); Gardenia obtusifolia and Gardenia sootepensis (apical buds)

Secaubryenol (234)

No cytotoxicity

[42e44, 89,90]

85

24-Methylene-3,4-seco-cycloart-4(28)-en-3oic acid (229)

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

Abies koreana and Abies sibirica (needles)

Continued

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d Compound Name (No.)

Information About Biological Activity

References

Gardenia carinata (leaves and twigs)

Carinatin C (50)

Cytotoxicity; no inhibitory activity against syncytium formation; inhibitory activity against HIV-1 reverse transcriptase

[92]

G. carinata (leaves and twigs)

Carinatin D (52)

Cytotoxicity; no inhibitory activity against syncytium formation; inhibitory activity against HIV-1 reverse transcriptase

[92]

G. carinata (leaves and twigs)

Carinatin E (235)

No cytotoxicity; inhibitory activity against syncytium formation; inhibitory activity against HIV-1 reverse transcriptase

[92]

G. carinata (leaves and twigs)

Carinatin F (253)

No cytotoxicity; inhibitory activity against syncytium formation; no inhibitory activity against HIV-1 reverse transcriptase

[92]

G. carinata (leaves and twigs)

Carinatin G (53)

Cytotoxicity; inhibitory activity against syncytium formation; no inhibitory activity against HIV-1 reverse transcriptase

[92]

G. carinata (leaves and twigs)

Carinatin H (255)

No information

[92]

G. carinata (leaves and twigs); Gardenia gummifera and G. lucida (gum resin); Gardenia obtusifolia (apical buds)

Dikamaliartane-D (90)

No cytotoxicity; no antibacterial activity; inhibitory activity against syncytium formation; inhibitory activity against HIV1 reverse transcriptase

[90,92,234]

Gardenia coronaria (leaves and stems); G. sootepensis (apical buds); G. tubifera (leaves and twigs)

Coronalolide (256)

Cytotoxicity; no inhibitory activity against syncytium formation; inhibitory activity against HIV-1 reverse transcriptase

[89,235,236]

86 Studies in Natural Products Chemistry

Sources (Parts Used)

Coronalolide methyl ester (257)

Cytotoxicity; no inhibitory activity against syncytium formation; inhibitory activity against HIV-1 reverse transcriptase

[89,139, 235,236]

G. coronaria (leaves and stems); G. thailandica and G. sootepensis (exudate)

Coronalolic acid (236)

No cytotoxicity

[44,139,235]

G. gummifera (leaf buds)

Gummiferartane-1 (265)

No information

[91]

G. gummifera (leaf buds)

Gummiferartane-5 (266)

No information

[91]

G. gummifera (leaf buds)

Gummiferartane-8 (267)

No information

[91]

G. gummifera and G. lucida (gum resin); G. obtusifolia (apical buds)

Dikamaliartane-A (32)

No antibacterial activity; cytotoxicity; antitumor activity in vivo; locomotor activity and anticonvulsant activity in vivo

[90,124, 166,234]

G. gummifera and G. lucida (gum resin)

Dikamaliartane-B (268)

No antibacterial activity

[234]

G. gummifera and G. lucida (gum resin); G. obtusifolia (apical buds)

Dikamaliartane-C (269)

No cytotoxicity; no antibacterial activity

[90,234]

G. gummifera and G. lucida (gum resin)

Dikamaliartane-E (258)

No antibacterial activity

[234]

G. gummifera and G. lucida (gum resin)

Dikamaliartane-F (270)

No antibacterial activity

[234]

Continued

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

G. coronaria (leaves and stems); G. sootepensis (apical buds and exudate); G. tubifera (leaves and twigs)

87

Sources (Parts Used)

Compound Name (No.)

Information About Biological Activity

References

G. obtusifolia (leaves and twigs)

Methyl 3,4-seco-cycloart-4(28),24-diene29-hydroxy-23-oxo-3-oate (91)

Cytotoxicity; no inhibitory activity against syncytium formation; inhibitory activity against HIV-1 reverse transcriptase

[24]

G. obtusifolia (apical buds)

Gardenoin G (237)

No cytotoxicity

[90]

G. obtusifolia (apical buds)

Gardenoin H (238)

No cytotoxicity

[90]

G. sootepensis (apical buds)

Sootepin A (30)

No cytotoxicity

[89,139]

G. sootepensis (apical buds)

Sootepin B (259)

No cytotoxicity

[89]

G. sootepensis (apical buds)

Sootepin C (239)

Cytotoxicity

[89,139]

G. sootepensis (apical buds)

Sootepin D (240)

Cytotoxicity

[89]

G. sootepensis (apical buds); G. thailandica (exudate); Illicium difengpi (stem bark)

Sootepin E (31)

Cytotoxicity; no inhibitory activity against TNF-a production

[41,44,89]

G. sootepensis (exudate)

Sootependial (67)

Cytotoxicity; antiangiogenic activity ex vivo

[139]

G. sootepensis (exudate)

Sootepenoic acid (260)

Cytotoxicity; no antiangiogenic activity ex vivo

[139]

88 Studies in Natural Products Chemistry

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d

Cytotoxicity; no inhibitory activity against syncytium formation; no inhibitory activity against HIV-1 reverse transcriptase

[89,139,236]

G. thailandica (exudate)

Gardenoin I (271)

No cytotoxicity

[44]

G. thailandica (exudate)

Gardenoin J (275)

No cytotoxicity

[44]

G. tubifera (exudate)

Gardenoin A (262)

Cytotoxicity

[43]

G. tubifera (exudate)

Gardenoin B (263)

No cytotoxicity

[43]

G. tubifera (exudate)

Gardenoin C (264)

Cytotoxicity

[43]

G. tubifera (exudate)

Gardenoin D (241)

No cytotoxicity

[43]

G. tubifera (leaves and twigs)

Tubiferaoctanolide (254)

No cytotoxicity; no inhibitory activity against syncytium formation; no inhibitory activity against HIV-1 reverse transcriptase

[236]

I. difengpi (stem bark)

Illiciumolide A (68)

Inhibitory activity against TNF-a production and NF-kB release

[41]

I. difengpi (stem bark)

Illiciumolide B (69)

Inhibitory activity against TNF-a production and NF-kB release

[41]

Illicium dunnianum (fresh leaves and twigs)

3,4-Seco-(24Z)-cycloart-4(28),24-diene3,26-dioic acid 3-methyl ester (242)

No information

[237]

Illicium verum (leaves)

3,4-Seco-(24Z)-cycloart-4(28),24-diene3,26-dioic acid 26-methyl ester (243)

No information

[238]

I. verum (leaves); Kadsura angustifolia (branches); Kadsura heteroclita, Schisandra henryi and Schisandra sphaerandra (stems)

Nigranoic acid (1)

Inhibitory activity against HIV-1 RT, HIV-2 RT, HIV-1 PR, mutant RT, AMV RT, DNA pol. B, RNA pol.; no inhibitory activity against DNA pol. A; antiviral activity against HIV-1; cytotoxicity

[50,52,151, 156,238,239]

89

Tubiferolide methyl ester (261)

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

G. sootepensis (exudate); G. tubifera (leaves and twigs)

Continued

Sources (Parts Used)

Compound Name (No.)

Information About Biological Activity

References

K. angustifolia (branches)

Angustific acid A (123)

Antiviral activity against HIV-1

[156]

K. angustifolia (branches)

Angustific acid B (276)

Antiviral activity against HIV-1

[156]

K. angustifolia (branches)

Angustifodilactone A (277)

Antiviral activity against HIV-1

[156]

K. angustifolia (branches)

Angustifodilactone B (278)

Antiviral activity against HIV-1

[156]

K. angustifolia (branches); Schisandra micrantha (leaves and stems)

Micranoic acid B (279)

Antiviral activity against HIV-1

[93,156]

K. heteroclita (stems)

Kadsuranic acid A (116)

Cytotoxicity; inhibitory activity against HIV-1 PR; no inhibitory activity against HIV-1 RT

[151]

K. heteroclita (stems)

(8R,9S,22R)-3-Ethoxy-3-oxo-9,19-cyclo3,4-seco-lanosta-4(28),24-dien-26-oic acid 22,26-lactone (281)

No information

[60]

K. heteroclita (stems)

(8R,9S,22R)-3-Ethoxy-3-oxo-9,19-cyclo3,4-seco-lanosta-4,24-dien-26-oic acid 22,26-lactone (282)

No information

[60]

K. heteroclita (stems)

(8R,9S,22R)-3-Ethoxy-3-oxo-9,19-cyclo3,4-seco-lanosta-4(28),6,24-trien-26-oic acid 22,26-lactone (283)

No information

[60]

K. heteroclita (stems)

Heteroclitalactone A (284)

No cytotoxicity

[239]

K. heteroclita (stems)

Heteroclitalactone B (285)

No cytotoxicity

[239]

K. heteroclita (stems)

Heteroclitalactone C (286)

Cytotoxicity

[239]

90 Studies in Natural Products Chemistry

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d

Heteroclitalactone F (244)

No cytotoxicity

[239]

K. heteroclita (stems); Kadsura longipedunculata (root bark)

Schisanlactone E (245)

Cytotoxicity

[60,239,240]

K. heteroclita (stems); K. longipedunculata (root bark)

Schisanlactone B (287)

No cytotoxicity

[239,240]

K. heteroclita (stems); K. longipedunculata (root bark)

Changnanic acid (288)

Cytotoxicity

[239,240]

Kadsura philippinensis (leaves and stems); Schisandra glaucescens Diels. (stems)

Kadsuphilactone B (89)

No cytotoxicity; antiviral activity against HBV; no inhibitory activity against FXR

[40,150]

Lithocarpus polystachyus (cupules)

Lithocarpic acid A (289)

Antibacterial activity; inhibitory activity against human and mouse 11b-HSD1

[241]

Lithocarpus polystachyus (cupules)

Lithocarpic acid B (290)

No antibacterial activity

[241]

L. polystachyus (cupules)

Lithocarpic acid C (291)

No information

[241]

L. polystachyus (cupules)

Lithocarpic acid D (292)

No antibacterial activity

[241]

L. polystachyus (cupules)

Lithocarpic acid E (293)

Antibacterial activity

[241]

L. polystachyus (cupules)

Lithocarpic acid F (294)

Antibacterial activity; inhibitory activity against human and mouse 11b-HSD1

[241]

L. polystachyus (cupules)

Lithocarpic acid G (295)

No information

[241]

L. polystachyus (cupules)

Lithocarpic acid H (296)

Inhibitory activity against human and mouse 11b-HSD1

[241]

L. polystachyus (cupules)

Lithocarpic acid I (297)

Antibacterial activity

[241]

L. polystachyus (cupules)

Lithocarpic acid J (298)

Antibacterial activity

[241]

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

K. heteroclita (stems)

91

Continued

Sources (Parts Used)

Compound Name (No.)

Information About Biological Activity

References

L. polystachyus (cupules)

Lithocarpic acid K (299)

Antibacterial activity; inhibitory activity against human and mouse 11b-HSD1

[241]

L. polystachyus (cupules)

Lithocarpic acid L (300)

No information

[241]

L. polystachyus (cupules)

Lithocarpic acid M (301)

No information

[241]

L. polystachyus (cupules)

Lithocarpic acid N (302)

No information

[241]

L. polystachyus (cupules)

Coccinetane E (303)

Antibacterial activity

[241]

Neoboutonia macrocalyx L. (leaves)

Neomacrolactone (304)

Inhibitory activity against Plasmodium falciparum; cytotoxicity

[242]

N. macrocalyx L. (leaves)

22a-Acetoxyneomacrolactone (305)

Inhibitory activity against P. falciparum; no cytotoxicity

[242]

N. macrocalyx L. (leaves)

6-Hydroxyneomacolactone (306)

Inhibitory activity against P. falciparum; cytotoxicity

[242]

N. macrocalyx L. (leaves)

22a-Acetoxy-6-hydroxyneomacrolactone (307)

Inhibitory activity against P. falciparum; cytotoxicity

[242]

N. macrocalyx L. (leaves)

6,7-Epoxyneomacrolactone (308)

Inhibitory activity against P. falciparum; no cytotoxicity

[242]

N. macrocalyx L. (leaves)

22a-Acetoxy-6,7-epoxyneomacrolactone (309)

Inhibitory activity against P. falciparum; cytotoxicity

[242]

N. macrocalyx L. (leaves)

4-Methylen-neomacrolactone (310)

Inhibitory activity against P. falciparum; cytotoxicity

[242]

92 Studies in Natural Products Chemistry

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d

Neomacroin (311)

Inhibitory activity against P. falciparum; no cytotoxicity

[242]

Schisandra chinensis (stems and leaves)

Wuweizilactone acid (109)

Antiviral activity against HIV-1; no cytotoxicity

[37]

Schisandra glaucescens Diels (stems)

Schiglausin K (312)

No information

[40]

S. glaucescens Diels (stems)

Schiglausin L (280)

No antagonistic effect against FXR

[40]

S. glaucescens Diels (stems)

Schiglausin M (313)

No antagonistic effect against FXR

[40]

S. glaucescens Diels (stems)

Schiglausin O (314)

No antagonistic effect against FXR

[40]

S. glaucescens Diels (stems)

Schiglausin N (315)

Antagonistic effect against FXR

[40]

S. glaucescens Diels (stems)

6b-Hydroxy nigranoic acid (161)

Antagonistic effect against FXR

[40]

Schisandra henryi Clarke (stems)

Nigranoic acid 3-ethyl ester (2)

No information

[53]

Schisandra propinqua var. propinqua (stems)

Propinic lactone A (316)

No information

[94]

Sinocalycanthus chinensis (leaves)

Sinocalycanchinensin A (246)

No cytotoxicity

[27]

S. chinensis (leaves)

Sinocalycanchinensin B (247)

Cytotoxicity

[27]

S. chinensis (leaves)

Sinocalycanchinensin D (248)

Cytotoxicity

[27]

S. chinensis (leaves)

Sinocalycanchinensin E (249)

Cytotoxicity

[27]

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

N. macrocalyx L. (leaves)

Continued

93

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d Compound Name (No.)

Information About Biological Activity

References

S. chinensis (leaves)

Sinocalycanchinensin S (317)

No cytotoxicity

[27]

S. chinensis (leaves)

Sinocalycanchinensin F (318)

Cytotoxicity

[27]

Tillandsia usneoides (fresh plant)

Dimethyl-3,4-seco-cycloart-4(29),24E-diene3,26-dioate (250)

No information

[243,244]

T. usneoides (fresh plant)

Methyl (24E)-26-carboxy-3,4-seco-cycloarta4(29),24-dien-3-oate (251)

No information

[244]

T. usneoides (fresh plant)

Methyl (23E)-25-hydroxy-3,4-seco-cycloart23-en-3-oate (272)

No information

[244]

T. usneoides (fresh plant)

Methyl (23E)-25-methoxy-3,4-secocycloart23-en-3-oate (273)

No information

[244]

T. usneoides (fresh plant)

Methyl 24-hydroxy-3,4-seco-cycloart-25-en3-oate (274)

No information

[244]

Aglaia abbreviata (twigs and leaves)

3,4-Seco-4,20(S)-dihydroxydammar-24-en-3oic acid (319)

No information

[245]

Aglaia foveolata (bark); Aglaia silvestris (root bark)

Foveolin A (320)

No information

[95,96]

A. foveolata (bark); A. silvestris (root bark)

Foveolin B (321)

No information

[95,96]

A. foveolata (bark)

Dymalol (322)

No information

[95]

A. foveolata (bark); A. silvestris (leaves, stem and root bark); Cabralea canjerana (Vell.) Mart (stems); dammar resin

Shoreic acid (86)

Antiviral activity against HSV-1, HSV-2

[68,95e97,148]

A-Seco-Dammarane Triterpenoids

94 Studies in Natural Products Chemistry

Sources (Parts Used)

Eichlerianic acid (87)

Antiviral activity against HSV-1, HSV-2

[68,95,96,148]

Aglaia ignea (bark); dammar resin

Dammarenolic acid (88)

Antiviral activity against HIV-1, HSV-1, HSV-2, RSV; Cytotoxicity

[98,148,149]

A. silvestris (leaves, stem and root bark)

Methylisofoveolate B (323)

No information

[97]

A. silvestris (leaves, stem and root bark)

Methylfoveolate B (324)

No information

[97]

A. silvestris (leaves, stem and root bark)

Isoeichlerianic acid (325)

No information

[96,97]

A. silvestris (leaves, stem and root bark)

Methyl isoeichlerianate (326)

No information

[96,97]

A. silvestris (leaves, stem and root bark)

Aglasilvinic acid (327)

No information

[97]

Ailanthus altissima (bark)

Altissimanin D (328)

No cytotoxicity

[246]

A. altissima (bark)

Altissimanin E (329)

No cytotoxicity

[246]

Alnus japonica (male flowers)

Methyl (24E)-3,4-secodammara4(28),20,24-trien-26-oic acid-3-oate (330)

No information

[247]

A. japonica (male flowers)

(24E)-3,4-Secodammara-4(28),20,24-trien3,26-dioic acid (331)

No information

[247]

A. japonica (male flowers)

(20S,24S)-20,24-Dihydroxy3,4-secodammara-4(28),25-dien-3-oic acid (332)

No information

[247]

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

A. foveolata (bark); A. silvestris (root bark); C. canjerana (Vell.) Mart (stems); dammar resin

95 Continued

Sources (Parts Used)

Compound Name (No.)

Information About Biological Activity

References

A. japonica (male flowers)

(23E)-(20S)-20,25-Dihydroxy3,4-secodammara-4(28),23-dien-3-oic acid (333)

No information

[247]

A. japonica (male flowers)

(23E)-(20S)-20,25,26-Trihydroxy3,4-secodammara-4(28),23-dien-3-oic acid (334)

No information

[247]

A. japonica (male flowers)

(23E)-(12R,20S)-12,20,25-Trihydroxy3,4-secodammara-4(28),23-dien-3-oic acid (335)

No information

[247]

Cabralea canjerana (Vell.) Mart (stems)

(20S,24S)-Epoxy-7b,25-dihydroxy3,4-secodammar-4(28)-en-3-oic acid (336)

No information

[68]

C. canjerana (Vell.) Mart (stems)

(20S,24S)-Epoxy-7b,15a,25-trihydroxy3,4-secodammar-4(28)-en-3-oic acid (337)

No information

[68]

C. canjerana (Vell.) Mart (stems)

(20S,24 R)-epoxy-7b,22x,25-trihydroxy3,4-secodammar-4(28)-en-3-oic acid (338)

No information

[68]

Cyclocarya paliurus (leaves)

Cyclocarioside D (140)

Inhibitory activity against lipase, aldose reductase, DPP-IV, and a-glucosidase

[161]

C. paliurus (leaves)

Cyclocarioside E (141)

Inhibitory activity against lipase, aldose reductase, DPP-IV, and a-glucosidase

[161]

96 Studies in Natural Products Chemistry

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d

Cyclocarioside F (142)

Inhibitory activity against lipase, aldose reductase, DPP-IV, and a-glucosidase

[161]

C. paliurus (leaves)

Cyclocarioside G (143)

Inhibitory activity against lipase, aldose reductase, DPP-IV, and a-glucosidase

[161]

C. Paliurus (leaves)

Cyclocarin A (144)

Inhibitory activity against lipase, aldose reductase, DPP-IV, and a-glucosidase

[161]

Pterocarya paliurus (leaves and stems)

Pterocaryoside A (339)

Not toxic in acute toxicity tests in mice; no mutagenic effect against in Salmonella typhimurium TM677

[248]

P. paliurus (leaves and stems)

Pterocaryoside B (340)

Not toxic in acute toxicity tests in mice; no mutagenic effect against in S. typhimurium TM677

[248]

Aglaia argentea (bark)

Argentinic acid A methyl ester (33)

Cytotoxicity

[125]

A. argentea (bark)

Argentinic acid B methyl ester (34)

Cytotoxicity

[125]

A. argentea (bark)

Argentinic acid C methyl ester (35)

Cytotoxicity

[125]

A. argentea (bark)

Argentinic acid D methyl ester (36)

Cytotoxicity

[125]

A. argentea (bark)

Argentinic acid E methyl ester (37)

Cytotoxicity

[125]

A. argentea (bark)

Argentinic acid F methyl ester (38)

Cytotoxicity

[125]

A. argentea (bark)

Argentinic acid G methyl ester (39)

Cytotoxicity

[125]

A. argentea (bark)

Argentinic acid H methyl ester (40)

Cytotoxicity

[125]

A. argentea (bark)

Argentinic acid I methyl ester (341)

No information

[125]

Aphanamixis grandifolia (stems)

Aphanamgrandiol A (11)

Cytotoxicity

[112]

A. grandifolia Blume (stems)

Aphanamgrandin A (342)

No information

[49]

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

C. paliurus (leaves)

A-Seco-Tirucallane Triterpenoids

97 Continued

Sources (Parts Used)

Compound Name (No.)

Information About Biological Activity

References

A. grandifolia Blume (stems)

Aphanamgrandin B (343)

No information

[49]

A.grandifolia Blume (stems)

Aphanamgrandin C (344)

No information

[49]

A. grandifolia Blume (stems)

Aphanamgrandin D (345)

No information

[49]

A. grandifolia Blume (stems)

Aphanamgrandin G (346)

No information

[49]

A. grandifolia Blume (stems)

Aphanamgrandin H (347)

No information

[49]

A. grandifolia Blume (stems)

Aphanamgrandin I (348)

No information

[49]

A. grandifolia Blume (stems)

Aphanamgrandin J (349)

No information

[49]

Camellia sasanqua Thunb. and C. japonica L. (seeds)

Isohelianol (350)

No information

[45,110]

C. sasanqua Thunb. and Camellia japonica L. (seeds); Helianthus annus (tabular flowers)

Helianol (351)

No information

[45,110,249]

Entandrophragma angolense (leaves)

3,4-Secotirucalla-23-oxo-4(28),7,24-trien21-al-3-oic acid (352)

No information

[22]

E. angolense (leaves)

3,4-Secotirucalla-23-oxo-4(28),7,24-trien3,21-dioic acid 21-methyl ester (353)

No information

[22]

98 Studies in Natural Products Chemistry

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d

3,4-Secotirucalla-4(28),7,24-triene-3,21-dioic acid (354)

No information

[250]

E. delevoyi (bark)

Delevoyin A (355)

No information

[250]

E. delevoyi (bark)

Delevoyin B (356)

No information

[250]

Helianthus annus (pollen grains of sunflower)

Sunpollenol (357)

Inhibitory activity against EBV-EA

[251]

H. annus (pollen grains of sunflower)

(24S)-24,25-Epoxysunpollenol (358)

Inhibitory activity against EBV-EA

[251]

H. annus (pollen grains of sunflower)

(24R)-24,25-Epoxysunpollenol (359)

Inhibitory activity against EBV-EA

[251]

H. annus (pollen grains of sunflower)

(23E)-23-Dehydro-25-hydroxysunpollenol (360)

Inhibitory activity against EBV-EA

[251]

H. annus (pollen grains of sunflower)

(24S)-24,25-Dihydroxysunpollenol (361)

Inhibitory activity against EBV-EA

[251]

H. annus (pollen grains of sunflower)

(24R)-24,25-Dihydroxysunpollenol (362)

Inhibitory activity against EBV-EA

[251]

Kadsura ananosma (stems)

Kadnanolactone F (363)

No cytotoxicity

[87]

K. ananosma (stems)

Kadnanolactone G (368)

No cytotoxicity

[87]

K. ananosma (stems)

Kadnanolactone H (369)

No cytotoxicity

[87]

K. ananosma (stems)

Kadnanolactone I (370)

No cytotoxicity

[87]

K. ananosma (stems); Schisandra chinensis (leaves and stems, aerial parts); Schisandra micrantha (leaves and stems)

Micrandilactone B (110)

No antiviral activity against HIV-1; no cytotoxicity

[37,87, 117e119, 152,153,252]

Schisandra Nortriterpenoids [8]

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

Entandrophragma delevoyi (bark)

99 Continued

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d Compound Name (No.)

Information About Biological Activity

References

K. ananosma (stems); S. micrantha (leaves and stems)

Micrandilactone C (111)

Antiviral activity against HIV-1; no cytotoxicity

[87,117, 118,153]

K. ananosma (stems); S. chinensis (leaves and stems, fruit); Schisandra propinqua var. propinqua (aerial parts)

Wuweizidilactone H (95)

No antiviral activity against HIV-1; no antiviral activity against HBsAg and HBeAg, no anti-AChE and anti-BuChE activities; no cytotoxicity

[37,87, 162,253, 254]

Schisandra arisanensis (fruits)

Arisanlactone A (371)

No antiviral activity against HSV-1; no anti-inflammatory activity

[255]

S. arisanensis (fruits); S. chinensis (leaves and stems)

Arisanlactone B (372)

No anti-AChE and anti-BuChE activities; antiviral activity against HSV-1; antiinflammatory activity

[162,255]

S. arisanensis (fruits); S. chinensis (leaves and stems)

Arisanlactone C (373)

No anti-AChE and anti-BuChE activities; no antiviral activity against HSV-1; no antiinflammatory activity

[162,255]

S. arisanensis (fruits)

2b-Hydroxyarisanlactone C (374)

Antiinflammatory activity; no antiviral activity against HSV-1

[255]

S. arisanensis (fruits)

Arisanlactone D (375)

No antiviral activity against HSV-1; no antiinflammatory activity

[255]

S. arisanensis (fruits); S. chinensis (leaves and stems)

Schindilactone D (99)

No antiviral activity against HIV-1 and HSV-1; no cytotoxicity; no anti-AChE and anti-BuChE activities; no antiinflammatory activity

[37,162,255]

S. arisanensis (fruits); S. chinensis (leaves and stems)

Schindilactone E (100)

No antiviral activity against HIV-1 and HSV-1; no cytotoxicity; no anti-AChE and anti-BuChE activities; no antiinflammatory activity

[37,162,255]

100 Studies in Natural Products Chemistry

Sources (Parts Used)

Antiviral activity against HIV-1; no antiviral activity against HSV-1; no cytotoxicity; no anti-AChE and antiBuChE activities; no antiinflammatory activity

[37,152, 162,255]

S. arisanensis (fruits); S. chinensis (leaves and stems)

Pre-schisanartanin B (108)

No antiviral activity against HIV-1 and HSV-1; no cytotoxicity; no anti-AChE and anti-BuChE activities; no antiinflammatory activity

[37,162,255]

S. chinensis (leaves and stems, aerial parts, fruit)

Wuweizidilactone A (92)

Antiviral activity against against HIV-1; no cytotoxicity

[37,119,254]

S. chinensis (leaves stems, aerial parts, fruit)

Wuweizidilactone C (112)

No antiviral activity against HIV-1; no cytotoxicity; no anti-AChE and antiBuChE activities

[37,119, 162,254]

S. chinensis (leaves and stems, aerial parts)

Wuweizidilactone D (113)

No antiviral activity against HIV-1; no cytotoxicity

[37,119]

S. chinensis (leaves and stems, aerial parts)

Wuweizidilactone E (114)

No antiviral activity against HIV-1; no cytotoxicity

[37,119]

S. chinensis (leaves and stems, aerial parts)

Wuweizidilactone F (115)

No antiviral activity against HIV-1; no cytotoxicity

[37,119]

S. chinensis (leaves and stems)

Wuweizidilactone G (94)

No antiviral activity against HIV-1; no cytotoxicity

[37]

S. chinensis (fruit)

Wuweizidilactone I (364)

No information

[254]

S. chinensis (fruit)

Schindilactone H (376)

No information

[254]

S. chinensis (leaves and stems)

Wuweizidilactone J (377)

No anti-AChE and anti-BuChE activities

[162]

S. chinensis (leaves and stems)

Wuweizidilactone K (378)

No anti-AChE and anti-BuChE activities

[162]

S. chinensis (leaves and stems)

Wuweizidilactone L (365)

No anti-AChE and anti-BuChE activities

[162]

101

Pre-schisanartanin/Pre-schisanartanin A (107)

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

S. arisanensis (fruits); S. chinensis (leaves and stems, aerial parts)

Continued

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d Compound Name (No.)

Information About Biological Activity

References

S. chinensis (leaves and stems)

Wuweizidilactone M (366)

No anti-AChE and anti-BuChE activities

[162]

S. chinensis (leaves and stems)

Wuweizidilactone N (367)

No anti-AChE and anti-BuChE activities

[162]

S. chinensis (leaves and stems)

Wuweizidilactone O (379)

No anti-AChE and anti-BuChE activities

[162]

S. chinensis (leaves and stems)

Wuweizidilactone P (380)

No anti-AChE and anti-BuChE activities

[162]

S. chinensis (leaves and stems, aerial parts)

Schindilactone A (96)

Anti-AChE activity; no anti-BuChE activity; no antiviral activity against HIV1; no cytotoxicity

[37,152,162]

S. chinensis (leaves and stems, aerial parts, fruit)

Schindilactone B (97)

No antiviral activity against HIV-1; no cytotoxicity; no anti-AChE and antiBuChE activities

[37,152, 162,254]

S. chinensis (leaves and stems, aerial parts)

Schindilactone C (98)

No antiviral activity against HIV-1; no cytotoxicity

[37,152]

S. chinensis (leaves and stems)

Schindilactone F (101)

No antiviral activity against HIV-1; no cytotoxicity

[37]

S. chinensis (leaves and stems)

Schindilactone G (102)

No antiviral activity against HIV-1; no cytotoxicity

[37]

S. chinensis (leaves and stems)

Schindilactone I (145)

Anti-AChE activity; no anti-BuChE activity

[162]

S. chinensis (leaves and stems)

Schindilactone J (381)

No anti-AChE and anti-BuChE activities

[162]

S. chinensis (leaves and stems)

Schindilactone K (382)

No anti-AChE and anti-BuChE activities

[162]

102 Studies in Natural Products Chemistry

Sources (Parts Used)

Antiviral activity against HIV-1; no antiAChE and anti-BuChE activities

[162,252]

S. chinensis (leaves and stems, aerial parts)

Schintrilactone B (384)

Antiviral activity against HIV-1; no antiAChE and anti-BuChE activities

[162,252]

S. chinensis (leaves and stems); Schisandra sphenanthera (stems and roots)

Pre-schisanartanin E (146)

Anti-AChE and anti-BuChE activities; no cytotoxicity

[162,256]

S. chinensis (leaves and stems); S. sphenanthera (stems and roots)

Pre-schisanartanin F (385)

No cytotoxicity; no anti-AChE and antiBuChE activities

[162,256]

S. chinensis (leaves and stems)

Pre-schisanartanin N (386)

No anti-AChE and anti-BuChE activities

[162]

S. chinensis (leaves and stems)

Schisdilactone J (387)

No anti-AChE and anti-BuChE activities

[162]

Schisandra chinensis (fruit, aerial parts, leaves and stems), Schisandra henryi var. yunnanensis and S. micrantha (leaves and stems)

Henridilactone D (104)

No antiviral activity against HIV-1; no cytotoxicity; no anti-AChE and antiBuChE activities

[37,117, 118,152, 162,254, 257]

S. chinensis (fruit, aerial parts, leaves and stems); S. propinqua var. propinqua (aerial parts)

Wuweizidilactone B (93)

Antiviral activity against HIV-1; antiviral activity against HBsAg and HBeAg; cytotoxicity

[37,119, 253,254]

S. chinensis, Schisandra lancifolia, S. micrantha and Schisandra wilsoniana (leaves and stems); S. propinqua var. propinqua (aerial parts)

Micrandilactone A (388)

No anti-AChE and anti-BuChE activities

[117,118, 120,162, 258e260]

103

Schintrilactone A (383)

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

S. chinensis (leaves and stems, aerial parts)

Continued

Sources (Parts Used)

Compound Name (No.)

Information About Biological Activity

References

S. chinensis (fruit, aerial parts, leaves and stems); S. lancifolia, S. micrantha and S. wilsoniana (leaves and stems)

Lancifodilactone C (105)

No antiviral activity against HIV-1; no cytotoxicity; no anti-AChE and antiBuChE activities

[37,117,118, 120,152, 162,254, 259,261]

S. chinensis, S. micrantha, S. lancifolia and S. wilsoniana (leaves and stems)

Lancifodilactone D (106)

No anti-AChE and anti-BuChE activities

[117, 118,120, 162,259, 261]

S. chinensis (fruit); S. chinensis and S. wilsoniana (leaves and stems)

Lancifodilactone I (103)

No anti-AChE and anti-BuChE activities

[120,162, 254]

S. chinensis (fruit); S. lancifolia and S. wilsoniana (leaves and stems)

Lancifodilactone L (389)

No information

[120,254, 259]

S. chinensis (fruit); S. sphenanthera (stems and roots); S. wilsoniana (leaves and stems)

Lancifodilactone N (390)

No cytotoxicity

[120,254, 256]

S. chinensis (leaves and stems); S. propinqua var. propinqua (aerial parts)

Propindilactone Q (147)

Anti-AChE activity; no anti-BuChE activity; no antiviral activity against HBsAg and HBeAg

[162,253]

S. chinensis (leaves and stems); S. propinqua var. propinqua (stems)

Propintrilactone A (391)

No cytotoxicity; no anti-AChE and antiBuChE activities

[162,262]

104 Studies in Natural Products Chemistry

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d

Propintrilactone B (392)

No cytotoxicity; no anti-AChE and antiBuChE activities

[162,262]

S. henryi var. yunnanensis, S. micrantha and S. wilsoniana (leaves and stems), S. sphenanthera (stems and roots)

Henridilactone A (393)

No cytotoxicity

[117, 118,120, 256,257]

S. henryi var. yunnanensis and S. micrantha (leaves and stems), S. propinqua var. propinqua (aerial parts)

Henridilactone B (394)

No information

[117,118, 257,258]

S. henryi var. yunnanensis and S. micrantha (leaves and stems)

Henridilactone C (395)

No information

[117,118, 257]

S. lancifolia, S. micrantha and S. wilsoniana (leaves and stems)

Lancifodilactone A (396)

No information

[117,118, 120,263]

S. lancifolia (leaves and stems); S. sphenanthera (stems and roots)

Lancifodilactone G (397)

No cytotoxicity; no antiviral activity against HIV-1

[256,264]

S. lancifolia, S. micrantha and S. wilsoniana (leaves and stems); S. propinqua var. propinqua (aerial parts); S. sphenanthera (stems and roots)

Micrandilactone D (398)

No antiviral activity against HIV-1; no cytotoxicity

[117,118,120, 256,258,259]

105

Continued

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

S. chinensis (leaves and stems); S. propinqua var. propinqua (stems)

Sources (Parts Used)

Compound Name (No.)

Information About Biological Activity

References

S. lancifolia, S. micrantha and S. wilsoniana (leaves and stems)

Micrandilactone F (400)

No antiviral activity against HIV-1; no cytotoxicity

[117,118, 120,259]

S. lancifolia, S. micrantha and S. wilsoniana (leaves and stems); S. sphenanthera (stems and roots)

Lancifodilactone B (401)

No cytotoxicity

[117,118, 120,256,261]

S. lancifolia and S. micrantha (leaves and stems)

Lancifodilactone E (402)

No information

[117,118,261]

S. lancifolia (leaves and stems); S. sphenanthera (stems and roots)

Lancifodilactone O (403)

No cytotoxicity

[256,259]

S. lancifolia (leaves and stems)

Lancifodilactone P (404)

No cytotoxicity

[259]

S. lancifolia (leaves and stems)

Lancifodilactone Q (405)

No cytotoxicity

[259]

S. lancifolia (leaves and stems)

Lancifodilactone R (406)

No information

[259]

S. micrantha and S. wilsoniana (leaves and stems); S. propinqua var. propinqua (aerial parts); S. sphenanthera (stems and roots)

Micrandilactone E (399)

No antiviral activity against HIV-1; no cytotoxicity

[117,118,120, 256,258]

106 Studies in Natural Products Chemistry

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d

No antiviral activity against HIV-1; no cytotoxicity

[117,118]

S. propinqua var. propinqua (stems)

Propinic lactone B (408)

No information

[94]

S. propinqua var. propinqua (stems)

Pre-schisanartanin S (409)

No cytotoxicity

[262]

S. propinqua var. propinqua (stems)

Pre-schisanartanin D (410)

No cytotoxicity

[262]

S. propinqua var. propinqua (aerial parts); S. sphenanthera (stems and roots)

Propindilactone A (411)

No cytotoxicity

[256,258]

S. propinqua var. propinqua (aerial parts)

Propindilactone B (412)

No information

[258]

S. propinqua var. propinqua (aerial parts)

Propindilactone C (413)

No information

[258]

S. propinqua var. propinqua (aerial parts); S. sphenanthera (stems and roots)

Propindilactone D (414)

No cytotoxicity

[256,258]

S. propinqua var. propinqua (aerial parts)

Propindilactone P (415)

No information

[253]

S. propinqua var. propinqua (aerial parts)

Propindilactone R (416)

No antiviral activity against HBsAg and HBeAg

[253]

S. propinqua var. propinqua (aerial parts)

Propindilactone S (417)

No information

[253]

Schisandra rubriflora (leaves and stems); S. sphenanthera (stems and roots)

Schirubridilactone A (418)

Antiviral activity against HIV-1; no cytotoxicity

[256,265]

107

Micrandilactone G (407)

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

S. micrantha (leaves and stems)

Continued

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d Compound Name (No.)

Information About Biological Activity

References

S. rubriflora (leaves and stems)

Schirubridilactone B (419)

Antiviral activity against HIV-1; no cytotoxicity

[265]

S. rubriflora (leaves and stems)

Schirubridilactone C (420)

Antiviral activity against HIV-1

[265]

S. rubriflora (leaves and stems); S. sphenanthera (stems and roots)

Schirubridilactone D (421)

No antiviral activity against HIV-1; no cytotoxicity

[256,265]

S. rubriflora (leaves and stems)

Schirubridilactone E (422)

No antiviral activity against HIV-1; no cytotoxicity

[265]

S. rubriflora (leaves and stems)

Schirubridilactone F (423)

Antiviral activity against HIV-1; no cytotoxicity

[265]

S. rubriflora (leaves and stems)

Rubriflordilactone A (424)

No antiviral activity against HIV-1; no cytotoxicity

[266]

S. rubriflora (leaves and stems)

Rubriflordilactone B (425)

Antiviral activity against HIV-1; no cytotoxicity

[266]

S. sphenanthera (leaves, stems and roots)

Sphenadilactone A (426)

No cytotoxicity; no antiviral activity against HIV-1

[256,267]

S. sphenanthera (leaves and stems)

Sphenadilactone B (427)

No cytotoxicity

[267]

S. sphenanthera (stems and roots)

Pre-schisanartanin G (428)

No cytotoxicity

[256]

S. sphenanthera (roots and stems)

Pre-schisanartanin H (429)

No cytotoxicity

[256]

S. sphenanthera (stems and roots)

Pre-schisanartanin I (430)

No cytotoxicity

[256]

108 Studies in Natural Products Chemistry

Sources (Parts Used)

Pre-schisanartanin J (431)

No cytotoxicity

[256]

S. sphenanthera (stems and roots)

Sphenadilactone D (432)

No cytotoxicity

[256]

S. sphenanthera (stems and roots)

Sphenadilactone E (433)

No cytotoxicity

[256]

S. sphenanthera (stems and roots)

Sphenadilactone F (434)

No cytotoxicity

[256]

S. wilsoniana (leaves and stems)

Wilsonianadilactone A (435)

Antiviral activity against HIV-1

[120]

S. wilsoniana (leaves and stems)

Wilsonianadilactone B (436)

Antiviral activity against HIV-1

[120]

S. wilsoniana (leaves and stems)

Wilsonianadilactone C (437)

No antiviral activity against HIV-1

[120]

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

S. sphenanthera (stems and roots)

Other Tetracyclic A-Seco-Triterpenoids Alisma orientale (rhizomes)

Alisol P (438)

No information

[268]

Allium porrum (whole herb)

2,3-Seco-porrigenin (439)

Cytotoxicity

[269]

A. porrum (whole herb)

25S epimer of 2,3-seco-porrigenin (440)

No information

[269]

Camellia sasanqua (seeds)

Sasanquol (441)

Inhibitory activity against TPA-induced inflammation

[110,270]

Kadsura heteroclita (stems)

Kadheterilactone A (442)

Cytotoxicity; no inhibitory activity against HIV-1 RT, HIV-1 PR

[151]

K. heteroclita (stems)

Kadheterilactone B (443)

Cytotoxicity; no inhibitory activity against HIV-1 RT, HIV-1 PR

[151]

109

Continued

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d Compound Name (No.)

Information About Biological Activity

References

K. heteroclita (stems); Kadsura longipedunculata (leaves and stems)

Longipedlactone A (444)

Cytotoxicity; no inhibitory activity against HIV-1 RT, HIV-1 PR

[151,271]

K. heteroclita (stems); K. longipedunculata (leaves and stems)

Longipedlactone F (445)

Cytotoxicity; no inhibitory activity against HIV-1 RT, HIV-1 PR

[151,271]

K. heteroclita (stems); K. longipedunculata (leaves and stems)

Longipedlactone H (447)

Cytotoxicity; no inhibitory activity against HIV-1 RT, HIV-1 PR

[151,271]

K. heteroclita (stems)

Longipedlactone J (122)

Antiviral activity against HIV-1

[155]

K. heteroclita (stems)

Heteroclitalactone D (450)

Cytotoxicity

[239]

K. heteroclita (stems)

Heteroclitalactone E (451)

Cytotoxicity

[239]

K. longipedunculata (leaves and stems)

Longipedlactone B (448)

Cytotoxicity

[273]

K. longipedunculata (leaves and stems)

Longipedlactone C (449)

Cytotoxicity

[271]

K. longipedunculata (leaves and stems)

Longipedlactone D (452)

No cytotoxicity

[271]

K. longipedunculata (leaves and stems)

Longipedlactone E (446)

No information

[271]

K. longipedunculata (leaves and stems)

Longipedlactone G (453)

No cytotoxicity

[271]

110 Studies in Natural Products Chemistry

Sources (Parts Used)

Longipedlactone I (454)

No information

[271]

K. longipedunculata Finet et Gagnep. (leaves and stems)

Kadlongilactone A (455)

Cytotoxicity

[62,272]

K. longipedunculata Finet et Gagnep. (leaves and stems)

Kadlongilactone B (456)

Cytotoxicity

[272]

K. longipedunculata Finet et Gagnep. (leaves and stems)

Kadlongilactone C (457)

Cytotoxicity

[62]

K. longipedunculata Finet et Gagnep. (leaves and stems)

Kadlongilactone D (458)

Cytotoxicity

[62]

K. longipedunculata Finet et Gagnep. (leaves and stems)

Kadlongilactone E (459)

Cytotoxicity

[62]

K. longipedunculata Finet et Gagnep. (leaves and stems)

Kadlongilactone F (460)

No information

[62]

Kadsura philippinensis (leaves and stems)

Kadsuphilactone A (461)

No antiviral activity against HBsAg, No cytotoxicity

[150]

Pseudolarix kaempferi (seeds)

Pseudolarolide O (462)

No information

[273]

P. kaempferi (seeds)

Pseudolarolide P (463)

No information

[273]

Russula amarissima and Russula lepida (fruiting bodies)

(24E)-3,4-Secocucurbita-4,24-diene3,26-dioic acid (464)

No cytotoxicity

[23,274,275]

Continued

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

K. longipedunculata (leaves and stems)

111

Sources (Parts Used)

Compound Name (No.)

Information About Biological Activity

References

R. amarissima and R. lepida (fruiting bodies)

(24E)-3,4-Secocucurbita-4,24-diene3,26,29-trioic Acid (465)

No cytotoxicity

[23,274,275]

R. amarissima and R. lepida (fruiting bodies)

3,4-Secocucurbita-4,24E-diene-3-hydroxy26-carboxylic acid (466)

Cytotoxicity

[23]

Russula aurora and Russula minutula (fruiting bodies)

Roseic acid (467)

No cytotoxicity

[276]

R. aurora and R. minutula (fruiting bodies)

Roseolactone A (468)

Cytotoxicity

[276]

R. aurora and R. minutula (fruiting bodies)

Roseolactone B (469)

Cytotoxicity

[276]

R. lepida (fruiting bodies)

Lepidolide (470)

No information

[275]

Trichilia rubra (root)

Rubrin A (154)

Inhibitory activity against LFA-l:ICAM1emediated cell adhesion

[165]

T. rubra (root)

Rubrin B (155)

Inhibitory activity against LFA-l:ICAM1emediated cell adhesion

[165]

T. rubra (root)

Hispidin A (156)

Inhibitory activity against LFA-l:ICAM-1 mediated cell adhesion

[165]

T. rubra (root)

Rubrin D (157)

Inhibitory activity against LFA-l:ICAM1emediated cell adhesion

[165]

T. rubra (root)

Nymania I (158)

Inhibitory activity against LFA-l:ICAM1emediated cell adhesion

[165]

112 Studies in Natural Products Chemistry

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d

T. rubra (root)

Rubrin F (159)

Inhibitory activity against LFA-l:ICAM1emediated cell adhesion

[165]

T. rubra (root)

Rubrin G (160)

Inhibitory activity against LFA-l:ICAM1emediated cell adhesion

[165]

Betula platyphylla var. japonica (floral spikes)

3,4-Seco-olean-4(23),13(18)-dien-3-oic acid (471)

Cytotoxicity

[277]

Camellia japonica (fruit peels)

Camelliaolean A (472)

No inhibitory activity against PTP1B; no cytotoxicity

[278]

C. japonica (fruit peels)

Camelliaolean B (473)

No inhibitory activity against PTP1B; no cytotoxicity

[278]

Dillenia papuana (leaves and stems)

Dillenic acid D (126)

Antibacterial activity

[158]

Dillenia philippinensis (leaves)

Compound 2 (474)

No cytotoxicity; no activity against L.major

[159]

D. philippinensis (leaves)

Compound 3 (475)

No cytotoxicity; no activity against L. major

[159]

D. philippinensis (leaves)

Compound 4 (134)

Cytotoxicity; Activity against L. major

[159]

D. philippinensis (leaves)

Compound 5 (135)

Cytotoxicity; Activity against L.major

[159]

Dillenia hainanensf (leaves and twigs)

Dysoxyhainanin B (127)

No antibacterial activity

[56]

D. hainanensf (leaves and twigs)

Dysoxyhainic acid F (476)

No antibacterial activity

[157]

D. hainanensf (leaves and twigs)

Dysoxyhainic acid G (124)

Antibacterial activity

[157]

D. hainanensf (leaves and twigs)

Dysoxyhainic acid I (125)

Antibacterial activity

[157]

A-Seco-Oleanane Triterpenoids

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

113 Continued

Sources (Parts Used)

Compound Name (No.)

Information About Biological Activity

References

D. hainanensf (leaves and twigs)

Dysoxyhainic acid J (477)

No antibacterial activity

[157]

D. hainanense (leaves and twigs); Maytenus undata (aerial parts); Sandoricum indicum (stem bark); Sandoricum koetjape (stems, bark, stem bark and wood)

Koetjapic acid (66)

Inhibitory activity against EBV-EA; Inhibitory activity against TPA-induced two stage skin carcinogenesis; Antiangiogenic activity; Inhibitory activity against DNA polymerase b; no cytotoxicity; Antibacterial activity

[130, 136e138, 143,154,157]

Euphorbia chamuesyce L. (whole herb)

3,4-Seco-oleana-4(23),18-dien-3-oic acid (42)

Cytotoxicity

[33,126]

Fagus hayatae (leaves and twigs)

1,10-Seco-3a,10a,23-trihydroxyolean12-ene-1,28-dioic acid 1,23-lactone (478)

Inhibitory activity against a-glucosidase IV

[279]

Gentiana lutea (rhizomes And roots)

2,3-Seco-3-oxoolean-12-en-2-oic acid (479)

No information

[280]

Junellia tridens (aerial parts)

3,4-Seco-olean-12-ene-3,28-dioic acid (480)

No activity against Mycobacterium tuberculosis

[15]

Kalopanax pictus (stem bark)

4,23,29-Trihydroxy-3,4-seco-olean-12-en3-oate-28-oic acid (70)

Inhibitory activity against TNFa-induced NF-kB luciferase reporter

[140]

Maytenus undata (aerial parts); S. indicum (stem bark)

20-Epi-koetjapic acid (79)

Inhibitory activity against neonatal rat brain microglia phorbol ester-stimulated thromboxane B2, superoxide anion generation; Antibacterial activity; no cytotoxicity

[137,143]

114 Studies in Natural Products Chemistry

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d

11a,30-Dihydroxy-2,3-seco-olean-12-en2,3-dioic anhydride (80)

Inhibitory activity against superoxide anion generation, elastase

[144]

Microtropis japonica (stems)

28-Hydroxy-2,3-seco-olean-12-ene-2,3-dioic acid 3-methyl ester (481)

No cytotoxicity

[281]

Phoradendron reichenbachianum (aerial parts)

3,4-Seco-olean-18-ene-3,28-dioic acid (482)

No information

[32]

Sandoricum koetjape Merr (bark)

Sentulic acid (46)

Cytotoxicity

[129]

Saponaria officinalis (whole plants)

Saponarioside K (483)

No information

[282]

Vahlia capensis (aerial parts)

3,4-Seco-olean-4,(23),18-dien-3-oic acid (484)

No information

[20]

Betula platyphylla var. japonica (floral spikes)

3,4-Seco-urs-4(23),20(30)-dien-3-oic acid (485)

No cytotoxicity

[277]

Davidia involucrata (branch bark)

2,3-Seco-3-methoxy-3,19a,23-trihydroxy-urs12-en-2-al-28-oic acid (486)

Cytotoxicity

[283]

Diospyros decandra (stem bark)

Diospyric acid D (487)

No activity against C. albicans, M. tuberculosis, Plasmodium falciparum

[114]

D. decandra (stem bark)

Diospyric acid E (488)

No information

[114]

Gentiana lutea (rhizomes and roots)

2,3-Seco-3-oxours-12-en-2-oic acid (489)

No information

[280]

Musanga cesropioides (stem bark); Ziziphus jujuba var. spinosa (fruits)

Cecropiacic acid (490)

No information

[70,284,285]

A-Seco-Ursane Triterpenoids

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

Microtropis fokienensis (stems)

115 Continued

Sources (Parts Used)

Compound Name (No.)

Information About Biological Activity

References

M. cesropioides (stem bark)

Musangic acid (491)

No information

[285]

M. cesropioides (rootwood)

Musangic acid A (492)

No information

[286]

M. cesropioides (rootwood)

Musangic acid B (493)

No information

[286]

Austroplenckia populnea and Maytenus imbricata (leaves)

3,4-Secofriedelan-3-oic acid (494)

Herbicidal activity

[30,31]

A. populnea (leaves)

3,4-Seco-28-hydroxyfriedelan-3-oic acid (495)

No information

[30]

Casearia velutina Bl. (stems), Garcia parviflora (leaves)

Friedelin-3,4-lactone/friedelin-2,3-lactone (496)

Cytotoxicity

[18,287]

Crossopetalum lobatum Lundell (leaves)

Lobatanhydride (497)

No information

[28]

Galphimia glauca (aerial parts)

Galphin A (136)

No activity against Leishmania donovani, P. falciparum K1, Trypanosoma brucei brucei

[160]

G. glauca (aerial parts)

Galphin B (137)

No activity against L. donovani, P. falciparum K1, T. b. brucei

[160]

G. glauca (aerial parts)

Galphin C (138)

No activity against L. donovani, P. falciparum K1, T. b. brucei

[160]

A-Seco-Friedelane Triterpenoids

116 Studies in Natural Products Chemistry

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d

Galphimine-A (77)

Antiinflammatory activity; no cytotoxicity; Anxiolytic activity; Spasmolytic activity

[19,48, 171e173]

G. glauca (leaves, aerial parts)

Galphimine-B (162)

No antiinflammatory activity; no cytotoxicity; CNS depressant activity; no anticonvulsant activity; Anxiolytic activity; Spasmolytic activity

[19,48, 167e171, 173]

G. glauca (leaves, aerial parts)

Galphimine-C (498)

No cytotoxicity

[48,173]

G. glauca (aerial parts)

Galphimine-D (499)

No cytotoxicity

[48]

G. glauca (leaves, aerial parts)

Galphimine-E (78)

Antiinflammatory activity; Spasmolytic activity; no anxiolytic activity, No cytotoxicity

[19,48, 171e173]

G. glauca (leaves, aerial parts)

Galphimine-F (163)

Spasmolytic activity; no cytotoxicity

[48,173]

G. glauca (leaves, aerial parts)

Galphimine-G (500)

No cytotoxicity; no spasmolytic activity

[48,173]

G. glauca (aerial parts)

Galphimine-H (501)

No cytotoxicity

[48]

G. glauca (aerial parts)

Galphimine-I (502)

No cytotoxicity

[48]

G. glauca (leaves)

Galphimine-J (503)

No spasmolytic activity

[173]

G. glauca (leaves)

Galphimine-K (504)

No information

[19]

G. glauca (leaves)

Galphimine-L (505)

No information

[19]

Garcia parviflora (leaves)

1,2-Dehydro-2,3-secofriedelan-3-oic acid (506)

Cytotoxicity

[18]

Hippocratea excelsa (root bark)

Dzununcanone (3)

Activity against Giardia intestinalis

[35]

Itoa orientalis (bark and twigs)

Itoaic acid (507)

No information

[288]

Peritassa campestris (roots)

Campestrine-I (508)

No information

[289]

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

G. glauca (leaves, aerial parts)

117

Continued

Sources (Parts Used)

Compound Name (No.)

Information About Biological Activity

References

P. campestris (roots)

Campestrine-II (509)

No information

[289]

Phyllanthus oxyphyllus (roots)

29-Nor-3,4-seco-friedelan-4(23),20(30)-dien3-oic acid (510)

No information

[290]

Acanthopanax chiisanensis (leaves and stem bark), Acanthopanax divaricatus var. albeofructus and Acanthopanax senticosus (leaves); Acanthopanax sessiliflorus (leaves and fruits)

Chiisanoside (82)

Inhibitory activity against pancreatic lipase, b-glucuronidase; no inhibitory activity against gastric Hþ/Kþ ATPase, urease and growth of Helicobacter pylori; antiinflammatory activity; antirotaviral activity; no cytotoxicity; no inhibitory activity against LPS-induced NO production in RAW 264.7 macrophages; no antibacterial activity; no protective activity against the formation of AGEs

[99, 101e103, 141,145, 291e295]

A. chiisanensis (leaves and stem bark); A. divaricatus (leaves)

Isochiisanoside (511)

No information

[291e293]

A. chiisanensis (leaves and stem bark)

Methyl ester of isochiisanoside (512)

No information

[291]

A. divaricatus (leaves), A. sessiliflorus (fruits)

Divaroside (517)

No cytotoxicity; no inhibitory activity against LPS induced NO production in RAW264.7 macrophages

[141,292]

A. divaricatus (leaves), A. sessiliflorus (fruits)

22a-Hydroxychiisanoside (520)

No cytotoxicity; no inhibitory activity against LPS induced NO production in RAW264.7 macrophages

[141,293]

A-Seco-Lupane Triterpenoids

118 Studies in Natural Products Chemistry

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d

Chiisanogenin (83)

Cytotoxicity; inhibitory activity against b-glucuronidase and gastric Hþ/Kþ ATPase; no inhibitory activity against urease and growth of Helicobacter pylori; antiinflammatory activity; antibacterial activity; Protective activity against the formation of AGEs; no antirotaviral activity

[99,101, 145,294,295]

A. senticosus forma inermis (leaves)

11-Deoxyisochiisanoside (513)

No information

[100]

A. senticosus forma inermis (leaves)

1-Deoxychiisanoside (518)

No information

[100]

A. senticosus forma inermis (leaves)

24-Hydroxychiisanoside (519)

No information

[100]

A. senticosus forma inermis (leaves)

Inermoside (523)

No information

[100]

A. senticosus (Rupr. et Maxim) (pulp), A. sessiliflorus (fruits)

3,4-Secolup-20(29)-ene-3,28-dioic acid (514)

No cytotoxicity; no inhibitory activity against LPS induced NO production in RAW264.7 macrophages

[141,296]

A. senticosus, A. sessiliflorus (leaves)

Sessiloside (139)

Inhibitory activity against pancreatic lipase

[102,103]

A. sessiliflorus (fruits)

(1R,11a)-1,4-Epoxy-11-hydroxy-3,4-secolup20(29)-ene-3,28-dioic acid (152)

Antiplatelet aggregation activity

[164]

A. sessiliflorus (fruits)

(1R,11a,22a)-1,4-Epoxy-11,22-hydroxy3,4-secolup-20(29)-ene-3,28-dioic acid (153)

Antiplatelet aggregation activity

[164]

A. sessiliflorus (fruits)

22a-Hydroxychiisanogenin (521)

No inhibitory activity against LPS induced NO production in RAW264.7 macrophages; no cytotoxicity

[141,293]

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

A. senticosus (leaves)

119 Continued

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d Compound Name (No.)

Information About Biological Activity

References

A. sessiliflorus (fruits)

Acanthosessiligenin I (71)

Inhibitory activity against LPS induced NO production in RAW264.7 macrophages; no cytotoxicity

[141]

A. sessiliflorus (fruits)

Acanthosessilioside A (72)

Inhibitory activity against LPS induced NO production in RAW264.7 macrophages; no cytotoxicity

[141]

A. sessiliflorus (fruits)

Acanthosessiligenin II (73)

Inhibitory activity against LPS induced NO production in RAW264.7 macrophages; no cytotoxicity

[141]

A. sessiliflorus (fruits)

Acanthosessilioside B (74)

Inhibitory activity against LPS induced NO production in RAW264.7 macrophages; no cytotoxicity

[141]

A. sessiliflorus (fruits)

Acanthosessilioside C (515)

No inhibitory activity against LPS induced NO production in RAW264.7 macrophages; no cytotoxicity

[141]

A. sessiliflorus (fruits)

Acanthosessilioside D (75)

Inhibitory activity against LPS induced NO production in RAW264.7 macrophages; no cytotoxicity

[141]

A. sessiliflorus (fruits)

Acanthosessilioside E (516)

No inhibitory activity against LPS induced NO production in RAW264.7 macrophages; no cytotoxicity

[141]

A. sessiliflorus (fruits)

Acanthosessilioside F (522)

No inhibitory activity against LPS induced NO production in RAW264.7 macrophages; no cytotoxicity

[141]

Dysoxylum hainanensf (leaves and twigs)

Dysoxyhainic acid H (130)

Antibacterial activity

[157]

120 Studies in Natural Products Chemistry

Sources (Parts Used)

2,3-Seco-20(29)-lupene-2,3-dioic acid (524)

Inhibitory activity against a-glucosidase IV and HIV-1 PR; no inhibitory activity against HCV PR, renin and trypsin

[177,279]

Lasianthus gardneri (stems)

3,4-Secolup-4(23),20(29)-dien-3-ol (172)

No information

[47]

Lippia mexicana (aerial parts)

Lippiolidolic acid (525)

No information

[142]

L. mexicana (leaves, flowers, and stems)

Lippiolic acid (76)

Antiinflammatory activity

[142]

Microtropis fokienensis (stems)

30-Hydroxy-2,3-secolup-20(29)-ene-2,3-dioic acid (81)

Antiinflammatory activity; no cytotoxicity

[26,144]

Salacia hainanensis (stems and roots)

Salacinin A (526)

No information

[297]

Stauntonia obovatifoliola Hayata subsp. Intermedia (stems)

16b-Hydroxy-2,3-secolup-20(29)-ene2,3-dioic acid (121)

Inhibitory activity against HIV-1 PR

[38]

Viburnum awabuki (leaves and twigs)

3,4-Secolup-4,20-dihydroxy-3,28-dioic acid3-oic acid methyl ester (527)

Cytotoxicity

[298]

Viburnum aboricolum (leaves)

Viburolide (528)

No information

[299]

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

Fagus hayatae (leaves and twigs)

Other Pentacyclic A-Seco-Triterpenoids Adiantum cuneatum (leaves)

4,23-Bisnor-3,4-secofilic-5(24)-en-3-al (529)

No information

[300]

A. cuneatum (leaves)

4,23-Bisnor-3,3-dimethoxy-3,4-secofilic5(24)-ene (530)

No information

[300]

Aglaia foveolata (stem bark)

17,24-Epoxy-25-hydroxy-21-methoxy3,4-secobaccharane (532)

No cytotoxicity

[301]

121

Continued

Sources (Parts Used)

Compound Name (No.)

Information About Biological Activity

References

Alstonia scholaris (leaves)

Alstonic acid A (533)

No information

[113]

A. scholaris (leaves)

Alstonic acid B (10)

No information

[113]

Calophyllum gracilipes (leaves)

Gracilipene (9)

No information

[116]

Dorstenia brasiliensis (roots)

Dorstenic acid A (43)

Cytotoxicity

[16]

D. brasiliensis (roots)

Dorstenic acid B (531)

Cytotoxicity

[16]

Elateriospermum tapos (leaves)

2,3-Seco-taraxer-14-ene-2,3,28-trioic acid 2,3-dimethyl ester (44)

Cytotoxicity; inhibitory activity against M.tuberculosis

[127]

E. tapos (leaves)

2,3-Seco-taraxer-14-ene-2,3,28-trioic acid 3-methyl ester (534)

No cytotoxicity; no inhibitory activity against M. tuberculosis

[127]

Euphorbia chamaesyce L. (whole herb)

3,4-Seco-8bH-ferna-4(23),9(11)-dien-3-oic acid (41)

Cytotoxicity

[34,126]

Lansium domesticum (twigs)

Lamesticumin A (128)

Antibacterial activity

[29]

L. domesticum (twigs)

Lansic acid 3-ethyl ester (129)

Antibacterial activity

[29]

Mallotus barbatus (leaves)

3,4-Secotaraxer-14-en-3-oic acid (535)

No information

[302]

Megacodon stylophorus (whole plant)

2,3-Seco-22(29)-hopene-2-carboxyl3-aldehyde (536)

Cytotoxicity; antibacterial activity

[303]

M. stylophorus (whole plant)

2,3-Seco-4(23),22(29)-hopene-2-carboxyl3-aldehyde (537)

Cytotoxicity; antibacterial activity

[303]

122 Studies in Natural Products Chemistry

TABLE 2.1 Naturally Occurring A-Seco-Triterpenoids and Their Biological Activitiesdcont’d

Pycanocarpine (45)

Cytotoxicity

[128]

Terminalia glaucescens (stem bark)

Terminalin A (8)

Inhibitory activity against prolyl endopeptidase

[21]

Tripterygium wilfordii (roots)

D:A-Friedo-3-nor-2,3-seco-oleanane2,29-dioic acid (538)

No information

[304]

T. wilfordii Hook fil. var regelii (stem bark)

Regelone (539)

No information

[305]

Graminol A (540)

No information

[110]

Other A-Seco-Triterpenoids Rice bran and wheat germ oil

11b-HSD1, 11b-hydroxysteroid dehydrogenase 1; AGEs, advanced glycation end products; ALT, alanine transaminase; AST, aspartate transaminase; CNS, central nervous system, COX, cyclooxygenase; DPP-IV, inhibitors of dipeptidyl peptidase 4; EBV-EA, EpsteineBarr virus early antigen; HBV, hepatitis B virus; HIV-1 PR, human immunodeficiency virus 1 protease; HSV, herpes simplex virus; LPS, lipopolysaccharides; RSV, respiratory syncytial virus; TPA, tissue plasminogen activator.

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

Pleiocarpa pycnantha (leaves)

123

124 Studies in Natural Products Chemistry

A-SECO-LANOSTANE TRITERPENOIDS R

R

R

15

R OOC

HOOC

R OOC

COOH

175, R1 = H, R2 = O O

181, R =

186, R1 = Me; R2 =

O

Δ 7,14

O O

O

O

184, R =

O

O

O

O

O

190, R1 = Me; R2 = OH

O HOOC

HOOC H

COOH

OH

193

R

R

R

R OOC

R OOC

194, R1 = H; R2 = H; R3 = HO

195, R1 = H; R2 = α -OH; R3 =

197, R1 = H; R2 =

H

OH

198, R1 = H; R2 =

OR RO

O

O

R H

H COOMe O

O

COOH H

COOH

196, R1 = Me; R 2 = H; R3 =

O

O

191, R1 = Et; R2 =

H HOOC

O

HO O

O

H

O

O

189, R1 = H; R2 =

O

H

O

188, R1 = Me; R2 =

OH

OH

192

O

HO

183, R =

COOMe

O

O

187, R1 = H; R2 =

HO O

O HO

COOH

182, R =

O

179, R1 = Me, R2 =

O COOH

O

OH

178, R1 = Me, R2 =

COOH

185, R1 = H; R2 =

O

176, R1 = H, R2 =

177, R1 = H, R2 =

30

Δ 7,14(30)

COOH

180, R =

14

7

H

H

H

8

H

H

H

O

O

O R

MeOCO

HOOC O

O H

199, R1 = H; R2 = Me 200, R1 = Me; R2 = H

H

OH

O

OR H O

201

202

203, 204, 205, 206,

O

R1 R1 R1 R1

H

= H; R2 = H; R3 = H = H; R2 = Ac; R3 = H = OH; R2 = Ac; R3 = H = H; R2 = Ac; R3 = OH

O

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

OCOMe

H

H O COOH

MeOCO MeOOC

HO

O

O

H

H

H

O

O

O

O

H

HO O

H

O

O

125

H HOOC

H

H HO

207

208

209

H

R O

O

O

O

O

O

HO

210

H

H

R OOC

HOOC

HOOC

H

H

H

211

212

H

H

213, R = H; R =

217 COOH

214, R = H; R =

215, R = H; R =

COOH

216, R = Me; R =

H

O

O R

R O H O

R

COOH

R

R OOC

MeOOC

H O

H

H

218

219

H

220, R = Et; R = OH; R = COOH; R = H; R = 221, R = Et; R = H; R = COOH; R = H; R = 222, R = Me; R = H; R = COOH; R = H; R = COOH

223, R = H; R = H; R = Me; R = H; R = O

COOH

224, R = H; R = H; R = Me; R = OH; R =

O R

H

COOH

HOOC

H

O

O

O O

HOOC

H

H

H

H

225

226

H

H H

COOH H

227, R = 228, R =

126 Studies in Natural Products Chemistry

A-SECO-CYCLOARTANE TRITERPENOIDS R

H

R OOC R H

229, R = H; R = Me; R = H; R =

R

241, R = H; R = CH OH; R = H; R =

230, R = Me; R = H; R = α -OH; R =

OMe

231, R = Me; R = H; R = α -OH; R =

OH

232, R = Me; R = H; R = α -OH; R =

O

233, R = H; R = CH OH; R = H; R =

OH

OH

242, R = Me; R = Me; R = H; R =

COOH

243, R = H; R = Me; R = H; R =

COOMe

244, R = Me; R = Me; R = H; R =

H

245, R = H; R = Me; R = H; R =

OH

H

234, R = H; R = CH OH; R = H; R =

O

O

O

O

246, R = H; R = H; R = H; R =

COOH

235, R = Me; R = COOH; R = H; R = 247, R = Me; R = H; R = H; R =

O

O

236, R = H; R = CH OH; R = H; R = CHO

H

248, R = H; R = H; R = H; R = 237, R = H; R = CH OH; R = β -OH; R =

O O

OH

COOH

CHO

R

O H

O

H

O

253, R = O

254, R =

O

252

COOMe

251, R = Me; R = Me; R = H; R =

240, R = Me; R = CH OH; R = H; R =

O

O

250, R = Me; R = Me; R = H; R =

239, R = Me; R = CH OH; R = H; R =

HOOC

H

249, R = Me; R = H; R = H; R =

238, R = H; R = Me; R = H; R =

H

COOH

O

H O

O

H H OH

255

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

R

R CHO

256, R1 = H; R2 = H; R3 = H

R OOC

127

CHO

H

HOOC

257, R1 = Me; R2 = H; R3 = R

HO

O

258, R1 = H ; R2 = α -OH; R3 =

O

H

HO

O

265, R = OH

266, R =

259, R1 = H; R2 = H; R3 = COOH

260, R1 = Me; R2 = H; R3 = 261, R1 = Me; R2 = H; R3 = 262, R1 = H; R2 = H; R 3 =

O

263, R1 = Me; R2 = H; R3 =

O

264, R1 = Me; R2 = β– OH; R3 =

O R

R OH

H

H

HOOC

O OH

R

HO

H

267

H

R OOC

O H

H

268, R =

270, R1 = H; R2 = CH2OH; R 3 =

269, R =

271, R1 = H; R2 = CH2OH; R 3 =

O

O

272, R1 = Me; R2 = Me; R3 =

OH

273, R1 = Me; R2 =Me; R 3 = OH

OMe

274, R1 = Me; R 2 = Me; R 3 = OH

CHO

OH OH

H

HOOC HO

HO

H

HOOC

H

H O

H

O

O

H

281

Δ4 282

Δ 4(28),6 283

H

H

OH

279, R = H 280, R = Me

O

H

O

O COOH H

HOOC OAc

Δ 4(28)

O

H

R OOC

EtOOC

H

284, R1 = H 285, R1 = Me 286, R1 = Et

H

ROOC

277, R = CH2 OH 278, R = Me

276

275

O

O

O

OH OH

H

R

HO

COOH

O O

H

287

H

288

128 Studies in Natural Products Chemistry

R H H

HOOC

H OAc O

289, R =

294, R = OH

OH

H

299, R =

OH

OH

H OH

O

290, R =

HOH C 295, R = H

OH

OAc

OH

O H

291, R = H

296, R =

297. R =

OH

OAc

H

298, R =

O OAc

H

OH

OH

O OAc

H

OH O OCOMe

H

HOOC

O O

R

R R R R

303, R =

O OAc

H

CH OH

OH

H

O

304, 305, 306, 307,

H

302, R = H

OR

O H

301, R =

OH

OAc

O

H

OR

O

OAc OH

OAc

292, R =

H

H

300, R =

O

H

OH

OH OH

293, R =

O

= H; R = H = H; R = Ac = OH; R = H = OH; R = Ac

H

O

O

308, R = H 309, R = Ac

H

H

311

310

H O O COOH H

MeOOC

H

MeOOC

COOH H

HOOC

H

MeOOC OH

H

312

H

R

H

R

313, R = H; R = β– OH 314, R = OH; R = OH

H

O

315

316

COOH

COOH

O

H

O H

317

H

AcO H COOMe

318

O

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

129

A-SECO-DAMMARANE TRITERPENOIDS HO H

20

H

HOOC

O

OH

24

H

H

O

ROOC

ROOC H

HO

OH

H

HO

H

320, 321, 322, 323, 324,

H

319

R = H; 20S, 24S R = H; 20S,24R R = Me; 20S,24S R = Me; 20S,24R R = Me; 20R,24S

325, R = H 326, R = Me

H

OR OH H MeO MeO

OH

OR

O H

O

OC H

H

HOOC

OH

H

O

H

Sh =

H

H

H

328, R = H; R = Sh 329, R = Sh; R = H

327

R R

R

HO OR H

OH

H

H

H

R OOC

O

24

HOOC H

H

H

H COOH

330, R = Me; R = H; R =

OH

HOOC H

R OH

H

339, R = D-quinovose 340, R = L-arabinose

336, R = H; R = H; 24S 337, R = OH; R = H; 24S 338, R = H; R = OH; 24R

COOH

331, R = H; R = H; R = OH HO

332, R = H; R = H; R =

333, R = H; R = H; R =

334, R = H; R = H; R =

HO OH

HO

CH OH OH

HO

335, R = H; R = β -OH; R =

OH

A-SECO-TIRUCALLANE TRITERPENOIDS O H

H O

MeCOO MeOOC O O

H H

341

OCOMe

O

O OO

O

H

342

O

O HOOC

343

O

HO

H

344 Δ 24

345

130 Studies in Natural Products Chemistry

R

R O H

HOH C

R OOC

H

H

HOH C

H

HOOC H

R

H

H O

346, R = H; R = O 347, R = Me; R = O

351

350

352, R = CHO; R = O

Δ 24

353, R = COOMe; R =

348, R = Me; R = O 349, R = H; R = CH

354, R = COOH; R = 355, R = Me; R = R

O OAc

H

O

357, R =

H

360, R =

O

OH OH

O

H

358, R =

O

OAc

H OAc

361, R =

OH

OH OH

O

356

359, R =

362, R =

OH

SCHISANDRA NORTRITERPENOIDS O R O

H

HO O O

H

O

H

H

O

O

O

H

H

O

O R

H

H

HO O O

364, R = α–OH; R = α

O

H

H

H

363, R = β–OAc; R = α–OH O

H

O HO O

O

H H

O

H O

OH

OH

H

H

O

H

O OH

OH

H

HOH C

HOH C

368

H

HO O

370

369

O

365, R = =O; R = H 366, R = =O; R = α–OAc 367, R = α–OH; R = H O

H

H

H

O O H

O

OH

O

O

HO O

HO O

O

O

O

H O H H O OH

O

H

H

371

O

O

O O

H

376

H O

O

O

H

OH

H O H

O OH

HO O

R H

O

H

H

R

R O H

H

O

R

OH O

373, R = H; R = β–OH; R = OH 374, R = OH; R = β– OH; R = OH 375, R = H; R = α -OH; R = OAc

O O

HO O

OAc

H

377, R = H; R = =O 378, R = OH; R = OH

H

O

O

H

O

O O

H O

O

H O

H

O

H H

O

R

372

O HO

O H

O

O

O O

H O

H

HO O

OH O

H

379

H

O

H H H

380

O

O OH

O

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

O

O H

H

O

O

O HO O

H O OH

H

O

OH

H

O

O

O

O

H

H

H O

HO O

H

O

O O

O O

H

O

R R

HO

OH

H

382

383, R = Me, R = H 384, R = H, R = Me O

O H H OH

O

O H

O HO

H O OH

O H

385 H O HO OH

H

O H

O

O

OH

O

O

H

O O

O

H

HO

O

H

O

O

H

400

H

O

O H

406

H O OH

H

H

H

OH

O

O

H

OH

HO

H O OH

O H

O

O

O

H

O H

407

H O OH

O H

O

H

OH

H

O H

H O OAc

O O

H

H

O O

H

H H OH

HO O

H

OH H O

O H

H

408

H O

R

403, R = H; R = OH 404, R = OH; R = H 405, R = H; R = H

OH O

O

O H

OH

HO O

O H

R H

H

O O

H O

O

H

H

H H O

402

H H O

H O OH

O

O

H

H

O O

O

O O

H O

H

R H H O

398, R = OH; R = Me 399, R = Me; R = OH

O

O H

O

O

O

O H H O

401

O

O O

H

HOH C

O

O

O

OH

O

O O

H

H

O

O H

H

397

O

H

H

O

O

O

H

O R H

O

O H H O

O

H

O

396

O HO O

O

391, R = β– Me 392, R =α -Me

H OH

H

393, R = Me; R = OH; R = H 394, R = Me; R = OH; R = OH 395, R = H R = Me; R = H

O

O

O

H

H

O

R O

O H

HOH C

O

O

H

O

OAc

HO

H

OH

O

R H O

O

O

O

O H

H

O

H O

390

O

O

388

H

O R R

H

H O

H

O H

O H

O

389

O

H

387

H O

H O

O

O

OH O

H

H O OH

O

O

OH H O

O

H O

H

O

O

O

O

OH

O

386

H

O

O H

H O OH

H

O HO

O O

O

OH

O

O

O

O

H H

O

O

H

O

H

O

O

O

O

O

H O

H

381

131

409

O

O

132 Studies in Natural Products Chemistry

H O O

HO O

H O

H OH

O

OH

H

O

O H

HO

O

OH

O

OH

410

H

HO

O

H

H

415

O

O H

OH H H

O O

OH

H

O

H H OH

O

O O

H

H

O H OH

O H

H O

H

H O

O

O

O OH

OH

H O

H O H

H

O

O

H

432

H

430

O

H

O

H O

HOH C

433

H H OH

H

H OH H

O

O

O O

O

H

O

O

O

H OH H OH

O

O

H H OH

429

O

HOH C

431

426

H O

HOH C

428

H

H

HOH C

O

O

O

H

O OH

O

O

O

H O

O

H

O

O

O

H O

427

H

H

H

425

O

O

HOH C

H

O

O

O

OH O

O

O

H

O O

O

O

H

H H

O H OH H

O

O O

O

HH

O

O

O

HOH C

H

H H

H

H

O

O

H

OH

H

H

H

O H H OH

H

422

H

424

O

O

O

H O O

O

H

H

O

423

O

H

H

O

O

H

O

H OH

H

H

O

H

O

O

OH H

O

421

O

O H

OH

O

O

O

O O

O

H

O O

H

H

O

O

H

H

420

HO

H

O H

H O

O

OH O

O

O

O

O

OH H O

418

O

O

H O

H O

O

O

419

O H

O

H

H

HOH C

O

417

H

H

O

O

OH

O H

OH

O

H

H

O

O

O

H

O

O-C

O

O O

O

H

H H

O COOH

O

H H O

414

O HO

416

O

O H

HO

O O

H

H

H

H O

H

H

O

O

H

O

O

O

OH

O

O

O

HO

O

O

412, R = OH 413, R = H

AcO

O

O

H O

R O

O HOH C

O

H

H

O

O H

H O

O

O H

H

O

O

411

AcO O

H O O

O O

OH

H

HOH C

O

O HO

O

H H OAc

O

H

O HO

O

H O O

H

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

O

H

O O

O

H O

H O

O

OH

OH O

COOEt H

O

O

434

H O

H

O O

O

O H O

H

H O OCOMe

O

H

H O

H

O

O H

H O

O O

O H HO HO OH

H

435

H

H O

O

O H O

H O OH

H

H

133

OH H H O O

O H

437

436

OTHER TETRACYCLIC A-SECO-TRITERPENOIDS R R

OH O

O

H

OH

OH

O

HOOC

H

HOOC

H

H O

H

HOH C

H

H

H

HO

H

O

O

H

OH

Δ 13(17),15 442

Δ12,16 443

R H

HO H

H

H

O

441

OAc

H

O O

R

R O O

O

H

O

R

444, R = H; R = H 445, R = OH; R = H 446, R = H; R = OH

O

H

O

439, R = H; R = Me 440, R = Me; R = H

438

O

HO

O

H

H

O

O

O

H

O

O

H

R

450, R = H

447, R = OH; R = OH 448, R = H; R = H 449, R = H; R = OH

6

451, R = OH O H

H

HO

H

H

HO

H OH

O

O

H

O

H

R

O

O

O

H

O

H

O

O

H

455, R = α– OH 456, R = =O 457, R = α– OMe 458, R = β-OH 459, R = β– OMe

454

O H HO HO H O O

H

O H

O

O O

O

O

H

H O

O

OAc

O

O

H

H H O O

O

H

O

O

463

462

461 R

COOH

COOH H

R

H

HOOC

H

H

R O

464, R = COOH; R = Me 465, R = COOH; R = COOH 466, R = CH OH; R = Me

O

H

H

O

460

O O H

H

R

H

O

OH

452, R = H 453, R = OH

H

HO

O

O

O H

H

HOOC

467, R = H

O O

468, R = H

469, R =

H

COOH

O

O

O

O

470

134 Studies in Natural Products Chemistry

A-SECO-OLEANANE TRITERPENOIDS

HOOC

H

MeOOC H

H H

HO

H

HOOC

OH OH

H

H

H

HOOC H

474, R = COOH; R = Me 475, R = Me; R = COOH

H

COOH HOOC OHC

H

476

H

HOOC

H

H

H

478

CH OH

H

HOOC

H

O

477

H

R

H H

H O

HOOC MeOOC

HOOC HOOC

472, R = H; R = CH OH; R = CH OH 473, R = OH; R = OH; R = Me

471

HO

H

R O

R

H

COOH

R

R

479

COOH

HOOC

H

HOH C

H

H

480

H

HOOC

H

H

481

COOR HOOC OH

H

483, R = β -D-glucopyranosyl-(1 β -D-glucopyranosyl-(1 6)] β– D-glucopyranoside

482

484

3)-

]

A-SECO-URSANE TRITERPENOIDS

HO

HO OHC

H

HOOC

HO MeO

H H

HOH C

485

H H

H H

488

H

COOH

487 HO H

R OOC R

OH COOH

H

R OH COOH

H H

O

486

H H

HOOC

H

HO

HOOC HOOC

COOH

R R

HOOC HOOC

489, R1 = H; R 2 = CHO; R3 = H; R 4 = Me; R 5 = H 490, R1 = H; R 2 = COOH; R3 = OH; R 4 = COOH; R5 = H 491, R1 = H; R 2 = COOH; R3 = OH; R 4 = COOH; R5 = OH

H

R

R

H

492, R1 = OH; R2 = H 493, R1 = H; R2 = OH

COOH

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

A-SECO-FRIEDELANE TRITERPENOIDS

135

136 Studies in Natural Products Chemistry

A-SECO-LUPANE TRITERPENOIDS

OTHER PENTACYCLIC A-SECO-TRITERPENOIDS OH

H H

R

O H

HOOC

HOOC OHC

H R

HO

529, R = CHO; R = CH 530, R = CH(OCH ) ; R = CH 531, R = COOH; R = O

H H

536

H H

534, R = COOMe; R = COOH; R = COOH 535, R = H; R = COOH; R = Me

533

COOH

O

H H

H

H OHC

R R R

H

532

H

HOOC

H

H

COOMe

HOOC OHC

H

HOOC

H

H

H MeOOC O

O

H

537

538

539

OH

Naturally Occurring A-Seco-Triterpenoids Chapter j 2

137

OTHER A-SECO-TRITERPENOIDS

HOH2 C

H

H H

540

ABBREVIATIONS ADP AGEs ALT AST ATCC BC CEeMS CHAGO CMCC CNS COLO 205 COX DNA DPP-IV EBV-EA EC50 ED50 fMLP/CB GABA GCeMS GI50 HBV HCT 116 HeLa Hep-G2 HIV HIV-1 PR HIV-1 RT H+/K+ATPase HL60 HPLC 11b-HSD1 HSV IC50 ICAM-1

adenosine diphosphate advanced glycation end products alanine transaminase aspartate transaminase American type culture collection human breast cancer capillary electrophoresis coupled with mass spectrometry undifferentiated lung carcinoma Canadian Memorial Chiropractic College central nervous system colorectal adenocarcinoma, Dukes’ type D cyclooxygenase deoxyribonucleic acid inhibitors of dipeptidyl peptidase 4 Epstein-Barr virus early antigen concentration of compound providing 50% protection of cells dose of drug therapeutically effective for 50% of a group of experimental animals formyl-Met-Leu-Phe/cytochalasin B g-aminobutyric acid gas chromatography coupled with mass spectrometry concentration that inhibited 50% of cell growth hepatitis B virus colon carcinoma epitheloid cervix carcinoma liver hepatoblastoma human immunodeficiency virus human immunodeficiency virus 1 protease human immunodeficiency virus 1 reverse transcriptase gastrichydrogen potassium adenylpyrophosphatase human promyelocytic leukemia high-performance liquid chromatography 11b-hydroxysteroid dehydrogenase 1 herpes simplex virus concentration of compound causing death of 50% of the cells Inter-Cellular Adhesion Molecule 1

138 Studies in Natural Products Chemistry infrared spectroscopy gastric carcinoma human epidermoid carcinoma liquid chromatography coupled with Fourier transform infrared spectroscopy LCeMS liquid chromatographyemass spectrometry LCeNMR liquid chromatography with parallel NMR spectrometry LCeNMReMS liquid chromatography with parallel NMR and mass spectrometry LCePDA liquid chromatography coupled with photodiode array detection median lethal dose LD50 LFA-1 Lymphocyte Function-associated Antigen 1 LPS lipopolysaccharides m-CPBA m-chloroperoxybenzoic acid MCF-7 breast adenocarcinoma MIC minimal inhibitory concentration MLV murine leukemia virus MM3 molecular mechanics force field, the 1991 version MPKK1 mitogen-activated protein kinase kinase 1 NCI-H187 human small cell lung cancer NF-kB nuclear factor kappa-light-chain-enhancer of activated B cells NMR nuclear magnetic resonance P388 lymphoma PEP, EC3.4.21.26 prolyl endopeptidase QGY-7703 hepatocellular carcinoma RSV respiratory syncytial virus SARs structureeactivity relationships SIV simian immunodeficiency virus STAT3 signal transducer and activator of transcription3 SW-620 colorectal adenocarcinoma, Duke’s type C TLC thin-layer chromatography TNFa tumor necrosis factor alpha TPA tissue plasminogen activator p-TSA p-toluenesulfonic acid UV ultravioletevisible spectroscopy VEGF vascular endothelial growth factor IR KATO-3 KB LCeFTIR

ACKNOWLEDGMENTS This work was financially supported by the Russian Science Foundation (No. 16-13-10245), by the Russian Foundation for Basic Research (No. 14-03-96007-r_ural_a), and by the MK5386.2016.3.

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Chapter 3

Kaurenoic Acid: A Diterpene With a Wide Range of Biological Activities Nemesio Villa-Ruano,*, 1 Edmundo Lozoya-Gloriax, Yesenia Pacheco-Herna´ndez{

*Universidad de la Sierra Sur, Miahuatla´n de Porfirio Dı´az Oaxaca, Me´xico; xCentro de Investigacio´n y de Estudios Avanzados del IPN, Irapuato, Guanajuato, Me´xico; {Centro Interdisciplinario de Investigacio´n para el Desarrollo Integral Regional, Sta Cruz Xoxocotla´n, Oaxaca, Me´xico 1 Corresponding author: E-mail: [email protected]

Chapter Outline Introduction Biosynthesis of Kaurenoic Acid Pharmacological Effects of Kaurenoic Acid Antidiabetic Activity Smooth Muscle Relaxant Effect Analgesic and Antiinflammatory Properties Diuretic and Antioxidant Activities Cytotoxic and Antitumoral Activities Role in Neurological Diseases Microbiological and Insecticide Effect of Kaurenoic Acid

151 152 155 155 156 158 158 158 160

Antibacterial Activity Antifungal Activity Antiprotozoal Activity Antiviral Activity Insecticidal Activity Anthelmintic and Molluscicidal Activity Platforms to Produce Kaurenoid Compounds Concluding Remarks Abbreviations Acknowledgments References

162 166 167 168 168 168 169 169 170 171 171

162

INTRODUCTION Kaurenoic acid (ent-kaur-16-en-19-oic acid; KA) is an active tetracyclic diterpenoid involved in both primary and secondary metabolism of plants [1]. KA is also a key compound used as a precursor for the semisynthesis of novel Studies in Natural Products Chemistry, Vol. 51. http://dx.doi.org/10.1016/B978-0-444-63932-5.00003-6 Copyright © 2016 Elsevier B.V. All rights reserved.

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kaurane-type diterpenoids with pharmacological activity [2]. This compound is well known as a constituent of higher plants because of the gibberellin biosynthetic studies, but it has also been found in some fungal and bacterial species. It was discovered in 1964 as a leaf metabolite of a Bayeria species [3]. Since then, this diterpene has been detected and isolated from several botanical families such as Euphorbiaceae, Celastraceae, Apiaceae, Velloziaceae, Lamiaceae, Fabaceae, Rutaceae, Chrysobalanaceae, Jungermanniaceae, Erythroxylaceae, Rhizophoraceae, and especially in medicinal plants from the Asteraceae family [2]. NOESY (Nuclear overhauser spectroscopy) and NOE (nuclear overhauser effect) difference spectra revealed that the tridimensional conformation of KA in solution and crystal is similar to other structures commonly found in plant sources [4,5]. The pharmacological properties of KA are mainly based on its overall shape and its exceptional stability in boiling aqueous solutions [6]. Current in silico molecular mechanics calculations confirm that KA is thermodynamically able to interact with hydrophilic and hydrophobic media and with key proteins involved in the inflammatory response such as the nuclear factorkB (NF-kB) [7,8]. According to the semiempirical calculations reported by several researchers and summarized in a structureeactivity study of 15 diterpenoids with antibacterial effect [9], the amphipathic properties of KA allow its interaction with phospholipid bilayers and support the structural requirements for the antibacterial activity. Other in vitro and in vivo biological/ pharmacological activities already found in several medicinal plant sources led to deeper studies, which coincidentally recognized the presence of KA in the corresponding extracts. This makes this diterpene an interesting compound and potentially responsible for the mentioned effects and for the biological properties presented in this review and postulates the KA as an attractive multifunctional drug for the pharmaceutical industry [10e12].

BIOSYNTHESIS OF KAURENOIC ACID KA belongs to the group of compounds known as terpenes. This word comes from turpentine, from the Greek terebinthine, the name of the terebinth tree (Pistacia terebinthus). Turpentine is the fluid obtained by the distillation of the resin obtained mainly from pine trees. In general, terpenes biosynthesis starts with the formation of isopentenyl pyrophosphate (IPP), a five-carbon molecule produced either from mevalonic acid by the 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase pathway, or from the 2-methyl-D-erythritol-4phosphate pathway (Fig. 3.1A). Further elongation of the IPP molecule by addition of other 5 C molecules like dimethylallyl pyrophosphate, head-totail linkage of longer pyrophosphate molecules, and/or cyclization of specific molecules results in the huge amount of terpenes compounds. If oxygen is included into terpenes, they are named as terpenoids. Compounds so apparently different like the volatile essential oils such as limonene, which are part of the smell of some plants, oily sterols substances (cholesterol), pigments (carotenoids), and even polymers that include rubber,

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FIGURE 3.1 Biosynthesis of ent-kaurenoic acid. (A) General reactions of the terpene route. Dark area includes those reactions carried out in plastids like chloroplast. The other reactions take place in the cytosol. DMAPP, dimethylallyl pyrophosphate; FPP, farnesyl pyrophosphate; GFPP, geranyl farnesyl pyrophosphate; GGPP, geranylgeranyl pyrophosphate; GPP, geranyl pyrophosphate; IPP, isopentenyl pyrophosphate; MEP, 2-methyl-D-erythritol-4-phosphate; MVA, mevalonic acid. Sesquiterpenes and diterpenes are produced by cyclization reactions. Triterpenes and tetraterpenes are produced by a head-to-tail join of two identical pyrophosphate molecules (2X). Some representative compounds are shown on the right side of each step. (B) Specific reactions for the synthesis of KA. CPP, ent-copalyl pyrophosphate; KO, ent-kaurene oxidase; KS, bifunctional ent-kaurene synthase (dotted line); KSI, ent-kaurene synthase I; KSII, ent-kaurene synthase II.

gutta percha, and chicle, all are terpenes biosynthesized from the same basic pathway. The world “chicle” may have come from the Nahuatl (tziktli) or from the Mayan (tsicte), which means “sticky stuff.” Aztecs and Mayas knew this compound, and early European used it for its flavor and sugar content. The ancient word chicle is still used in Latin America, representing a common term for chewing gum in Spanish.

154 Studies in Natural Products Chemistry

KA depends on the cyclization of geranylgeranyl pyrophosphate (GGPP) into ent-copalyl pyrophosphate. Next, this molecule is fully cyclized in order to produce ent-kaurene, which is finally oxidized in the C19, resulting in KA (Fig. 3.1B) [13]. In higher plants and some bacterial species such as Bradyrhizobium japonicum, the steps to biosynthesize ent-kaurene depend on two different ent-kaurene synthases, I and II (KSI and KSII). However, only a single bifunctional enzyme (ent-kaurene synthase KS) is required in specific organisms such as the moss Physcomitrella patens and the fungus Phaeosphaeria sp. L487 [14]. Interestingly, evolutionary associations on KS enzymes have been raised from studies on substrate specificity in divergent organisms, revealing that ent-kaurene synthases are able to cyclize GGPP into different diterpene skeletons [15]. Ent-kaurene oxidases (KO) are a family of cytochrome P450 enzymes typically involved in the oxidation of the ent-kaurene skeleton to produce KA in three consecutive steps [16]. Currently, at least 30 putative nucleotide sequences with KO identity are deposited in the National Center for Biotechnology Information. However, only less than 20% have been subjected to studies of functional genomics and kinetic characterization so far [17]. Biochemical analyses on the KO from Arabidopsis thaliana (AtKO) and its modified protein version (rAtKO), demonstrated that KO possesses multisubstrate properties on ent-isokaurene, ent-beyerene, and ent-kaurene diterpenes [16]. Previous work with different plant cell-free extracts suggested that cytochromes P450s (CYPs) were responsible for the oxygen addition for the production of specific diterpenoids. OsKOL4 (CYP701A8) from rice is another KO, which not only catalyzes the expected conversion of ent-kaurene to ent-kaurenoic acid, but also additionally reacts with ent-sandaracopimaradiene and ent-cassadiene to produce the corresponding C3a-hydroxylated diterpenoids. Monocot phytoalexins belong to these compounds like the kauralexins, the phytoalexins from corn [18] (Fig. 3.2). Up to now, KO enzymes have been mostly characterized in plant and fungal models. However, there is a lack of information on the biochemical properties of KO from plants that actively biosynthesize and accumulate high amounts of kaurenoids. CYP701B1 from P. patens and MtKO (CYP701A type) from Montanoa tomentosa were expressed in yeast and characterized at

FIGURE 3.2 Kauralexins from corn. These are produced in maize stem as responses to herbivory by larvae of the European corn borer (Ostrinia nubilalis).

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biochemical level. The respective enzymes were highly efficient in the production of KA and showed resistance to high concentrations of azolic compounds [19,20]. Only those from Stevia rebaudiana and M. tomentosa, which are considered plant sources of kaurane type diterpenes, were partially characterized at the biochemical level in heterologous systems so far [20,21]. The enzymatic oxidation of C18 to produce the KA epimer (ent-kaur16-en-18-oic acid), which is highly accumulated in specific plants as Croton antisyphiliticus, also remains unclear [22]. KA is not only an active precursor of gibberellins, but also a central precursor of other metabolites with medicinal properties such as steviol and grandiflorenic acid in S. rebaudiana and M. tomentosa, respectively [23,24]. Genes involved in the biosynthesis of KA were used to construct innovative strains of Saccharomyces cerevisiae generated by metabolic engineering [25]. Currently, there are promising tools to attain a controlled production of KA and to scale up its production for pharmacological aims.

PHARMACOLOGICAL EFFECTS OF KAURENOIC ACID Antidiabetic Activity Intraperitoneal administration of KA extracted from Wedelia paludosa in hyperglycemic rats induced with alloxan showed a more potent and prolonged effect than glibenclamide [26]. Similar results were found in two subsequent studies carried out in the same murine model, with the same dose of KA isolated from Smallanthus sonchifolius and using the antidiabetic drug glimepiride as a standard of reference [27,28]. The effect of the oral administration of KA showed immediate but relatively short duration of hypoglycemic activity [28]. Therefore, the intraperitoneal administration is apparently the best mechanism to achieve a significant hypoglycemic effect, at least in murine models like alloxan diabetic and normoglycemic mice, specifically male albino mice (Mus musculus L.) of an inbred ICR strain (8 weeks old). Interestingly, the teas of latter plants and some others as those as Annona squamosa and Zaluzania montagnifolia have been consumed by people with ethnobotanical legacy, representing just some examples among dozens of antidiabetic plants containing KA as an active ingredient [29,30]. Considering the exceptional stability of KA in boiling aqueous solutions [6], this compound could reasonably contribute in some way to the antidiabetic effect, or probably act synergistically with other compounds also dissolved in traditional aqueous preparations [28]. Nevertheless, this hypothesis must be urgently tested to demonstrate the real effect of KA in humans. It has been proposed that the combined activity of KA and insulin could be synergistic to inhibit the mitochondrial activity resulting in a decrease of the cellular energy change. This may have effect on some enzymes like 50 adenosine monophosphate (AMP)eactivated protein kinase, leading later on to an increase in glucose

156 Studies in Natural Products Chemistry

transport, glycolysis and glycogenolysis [28]. Likewise, recent studies revealed that KA could be exerting its hypoglycemic properties on the protein tyrosine phosphatase 1B [31], which is a negative regulator of the insulinsignaling pathway and is considered a promising potential therapeutic target, in particular for treatment of type 2 diabetes. Table 3.1 summarizes the main works related to the antihyperglycemic activity of KA.

Smooth Muscle Relaxant Effect The uterotonic or uterine-relaxing properties of KA were subjects of controversial scientific reports and patents since 1970, because of its possible application as a contraceptive [32e34]. However, histological investigations on the in vitro rat uterus contractility induced by acetylcholine, oxytocin, and serotonin clearly demonstrated that KA acts as a potent antagonist of those molecules, and its carboxylic group plays an important role in calcium uptake [34]. Contrarily, the methyl-esterified forms of KA exhibited an inhibitory effect much lower than its respective acid [34]. Cunha et al. [35] showed that the uterine-relaxant effect of KA occurs through calcium blockade as a consequence of the opening of adenosine triphosphate (ATP)esensitive potassium channels. The intravenous injection of KA and its ketone derivative (ent-kaur-16-en-15-one-19-oic acid) in normotensive rats engendered a fast decrease in systolic blood pressure, exhibiting its antihypertensive properties [36]. Experiments on rat aortic rings previously induced with phenylephrine revealed that KA produced a more pronounced antispasmodic effect than that of its methyl ester form (ent-methyl-kaur-16-en-19-oate), thus corroborating once again, that C19 carboxylic group is essential for the vasorelaxant action of the diterpene [37]. KA is also an effective in vitro antispasmodic of visceral TABLE 3.1 Antidiabetic Properties of KA Isolated From Different Plant Sources Source

Effect

Concentration

References

Wedelia paludosa

Hyperglycemic rats reduced glucose levels after 1e3 h by intraperitoneal administration

10 mg/kg

[26]

Smallanthus sonchifolius

Hyperglycemic rats reduced glucose levels after 1e3 h by oral and intraperitoneal administration

10 mg/kg

[27,28]

Aralia continentalis

In vitro inhibitor of PTP1B

IC50 ¼ 4.64 mM

[31]

IC50, half maximal inhibitory concentration; KA, kaurenoic acid; PTP1B, protein tyrosine phosphatase 1B.

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muscle tissue, but the activity of monoginoic acid that is a related natural compound is apparently better at lower concentrations [38]. Likewise, the relaxant effect of KA is ostensibly related to the nitric oxideecyclic guanosine monophosphate pathway (NO-cGMP) to exert its vasorelaxant activity [39]. Observations on the conformationeactivity relation of KA and related kaurenoids suggested that changes in ring D determine the potency of the antispasmodic effect. This conclusion has led to the design of novel KA-semisynthetic derivatives in order to improve the efficiency on these biological activities [40]. Despite the progress on this subject, semiempirical predictions to demonstrate the direct interaction of KA with ionic channels (Kþ, Caþþ) or key enzymes involved in NO-cGMP pathway are still missing. Table 3.2 summarizes the scientific reports on smooth muscle relaxant properties of KA. TABLE 3.2 Smooth Muscle Relaxant activity of KA Isolated From Different Plant Sources Source

Effect

Concentration

References

Montanoa frutescens

In vitro relaxant activity on rat uterus

20 mg/mL

[34]

Copaifera langsdorffii

In vitro rat uterorelaxant on sustained tonic contraction induced by acetylcholine, oxytocin, BaCl2, and KCl

40e160 mM

[35]

Xylopia aethiopica and Alepidea amatymbica

Normotensive rats decreased blood pressure after intravenous administration

10 mg/kg

[36]

Viguiera robusta

In vitro contraction in both endothelium-intact and denuded rat aortic rings

50e100 mM

[37]

Viguiera hypargyrea

Antispasmodic activity in guinea pig’s ileum after intraluminal perfusion

10 mg/L

[38]

Viguiera robusta

Vasorelaxant activity in either endotheliumintact or denuded rat aortic rings

10e100 mM

[39]

KA, kaurenoic acid.

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Analgesic and Anti-inflammatory Properties In 1998, the antinociceptive properties of KA were formally studied for the first time [41]. Showing the inhibition of acetic acideinduced abdominal constriction in mice was reduced in 80% by KA. It was even more active than some well-known analgesic drugs, such as acetyl salicylic acid, acetaminophen, dipyrone, and indomethacin. The diterpene isolated from Sphagneticola trilobata was also tested in mice, corroborating its ability to inhibit inflammatory pain [42]. KA inhibited the production of the hyperalgesic cytokines TNF-a (tumor necrosis factor alpha) and IL-1b (interleukin 1 beta). When the analgesic effect of KA was inhibited by NG-nitro-L-arginine methyl ester, KT5823, and glibenclamide treatment, it was clearly demonstrated that such activity depended on the activation of the NO-cGMPeprotein kinase G-ATPesensitive potassium channel-signaling pathway. Studies performed by Sosa-Sequera et al. [43] confirmed that KA produced acute anti-inflammatory and antipyretic effects in mice after 1e2 h of administration. According to those authors, the target was proposed to be the inhibition of NF-kB. Molecular mechanics calculations in silico confirmed the fact that the diterpene is thermodynamically able to interact with NF-kB [8]. Simultaneous in vitro studies performed by Choi et al. [44] in RAW264.7 macrophages showed that KA dose dependently (10e100 mM) modified nitric oxide levels, prostaglandin E2 release, as well as the expression of cyclooxygenase-2 and inducible nitric oxide synthase (iNOS). This evidence could coherently explain the anti-inflammatory effect of KA and the antipyretic one, considering that nitric oxide is an important mediator of febrile responses and also that some kaurenoids efficiently inhibit the enzymatic activity of iNOS [45]. Table 3.3 summarizes the anti-inflammatory properties of KA.

Diuretic and Antioxidant Activities Diuretic and natriuretic effects of KA were similar to the effects of chlorothiazide, suggesting inhibition of Naþ and Kþ reabsorption in the early portion of the distal tubule from rats [36]. However, since 2001, there has been no other study corroborating the proposed effect. The antioxidant activity of KA is currently linked to its known immunomodulatory properties [46]. KA induced the total reactive antioxidant potential in macrophages of BALB/c mice. This effect was also observed in the reduction of lipid peroxidation and in the nitrite levels produced by macrophages [46]. Table 3.4 summarizes the diuretic and antioxidant activities of KA.

Cytotoxic and Antitumoral Activities KA showed a nonselective inhibition of cyclooxygenase 1 and 2 in mice embryos [47]. Selective and nonselective cyclooxygenase-inhibitors are antiinflammatory agents and exert prenatal toxicity. KA interferes with the

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TABLE 3.3 Analgesic and Anti-inflammatory Properties of KA Isolated From Different Plant Sources Source

Effect

Concentration

References

Wedelia paludosa

Antinociceptive activity in mice by reducing 80% the acetic acidinduced abdominal constriction in mice

ID50 ¼ 43e51 mM/kg

[41]

Sphagneticola trilobata

Analgesic activity in mice by oral and intraperitoneal administration in mice. Inhibition of TNF-a and IL-1b

110 mg/kg

[42]

Espeletia semiglobulata

Antipyretic, acute and subacute antiinflammatory activity on rats, mice, and rabbits

ED50 ¼ 74e83 mg/kg

[43]

Aralia continentalis

In vitro antiinflammatory activity by inhibition of iNOS and COX-2 in macrophages

IC50 ¼ 51.73 mM

[44]

COX-2, cyclooxygenase 2; ED50, effective dose, 50%; IC50, half maximal inhibitory concentration; ID50, infectious dose, 50%; iNOS, inducible nitric oxide synthase; KA, kaurenoic acid.

nidation process and also causes postimplantation loss, without maternal toxicity signs. Contrastingly, the diterpenoid-induced immobilization of human sperm but caused only a weak or negligible capacity to kill spermatozoids [48]. In microculture assay for tetrazolium test, KA produced 95% growth inhibition on CEM-leukemia cells, whereas in MCF-7 breast and HCT-8 colon cancer TABLE 3.4 Diuretic and Antioxidant activities of KA Isolated From Different Plant Sources Source

Effect þ

Concentration

References

Xylopia aethiopica and Alepidea amatymbica

Inhibition of Na and Kþ reabsorption in the early portion of the distal tubule of rats

50 mg/kg

[36]

Sphagneticola trilobata

In vitro induction of TRAP in macrophages

50e90 mM

[46]

KA, kaurenoic acid; TRAP, tartrate-resistant acid phosphatase.

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cells, it was 45% each [10]. In vitro and in vivo cytotoxic properties of KA were demonstrated by the inhibition of B16F1 melanoma cell line and on the induced melanoma in C57BL/6 transgenic male mice [49]. When compared with taxol (LD50/ED50 ¼ 21.75/10.78 mg/kg), KA showed a significant reduction of melanoma although it was less effective. The expression of the Bcl-xL gene was modified in the presence of KA, being a possible target to exert its antitumoral activity. In this context, KA has shown genotoxicity in hamster lung fibroblasts (V79) cells in vitro at relatively high doses [12]. The limiting property was attributed to the double bond of C16eC17 and corroborated in mice in vivo [50]. However, while KA apparently shows changes in the morphology of cell nuclei of vital organs of mice at 50e100 mg/kg, taxol is even much more genotoxic at lower concentration in the same murine model (0.6e1.8 mg/kg) [51]. Controversially, human erythrocytes and leukocytes were apparently damaged by 10e60 mM KA, whereas RAW264.7 macrophages resisted the same assayed concentrations [44,50,52]. Antiproliferative qualities of KA were demonstrated in vitro on human embryonic kidney cells expressing SV40 large T-antigen (293T), pancreatic tumor cells, HeLa cervical cancer cells, with an apparent cytostatic effect for at least a dozen of cancer cell lines [53e55]. Additional studies demonstrated that KA epimer (ent-kaur16-en-18-oic acid) had a potent inhibitor effect in melanoma cell lines B-16 and showed similar selectivity for the C19 carboxylic acid form [12,52]. Moreover, the apoptosis and necrosis assays with HL-60 leukemic cells showed that KA induced an increase in the number of apoptotic cells in a dose-dependent manner, after 4 h of treatment [52]. The induction of apoptosis was documented in glioblastoma cells (U87) inoculated with 70 mM KA, which induced 31% of the number of apoptotic cells after 48 h treatment [56]. These findings showed an increase in the expression of apoptotic genes (caspases 8 and 3) and a decrease in the expression of antiapoptotic genes (miR-21 and c-FLIP). Table 3.5 shows the cytotoxic properties of KA.

Role in Neurological Diseases KA inhibited the tonic hindelimb extension, being fourfold more potent than any other anticonvulsant drug such as carbamazepine or phenytoin, and 100-fold more potent than valproic acid. This when assayed in spinal seizures induced by sudden cooling in amphibians and seizures induced by pentylenetetrazole in mice [57]. In rats previously treated with pentylenetetrazole and picrotoxin to induce convulsions, KA showed a significant dose-dependent delay in the onset of both myoclonic spasms and toniceclonic phases of seizures [58]. The combination of KA (400 mg/kg) and diazepam offered 80% and 100% protection, respectively, against pentylenetetrazole-induced deaths. According to these results, KA could be considered as a new anticonvulsant compound through enhancement of central inhibitory mechanisms mediated by GABAA-receptor chloride channel complex. Remarkably, in these studies,

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TABLE 3.5 Cytotoxic and Antitumoral activities of KA Isolated From Different Plant Sources Source

Effect

Concentration

References

Copaifera langsdorffii

In vivo cytotoxic activity in mice embryos

50 mg/kg

[47]

Montanoa frutescens

In vitro cytostatic activity on human spermatozoa

C. langsdorffii

In vitro growth inhibition of CEM-leukemic cells, MCF-7 breast and HCT-8 colon cancer cells

78 mM

[10]

Espeletia semiglobulata

Antiproliferative activity in B16F1 melanoma and induced melanoma in mice

LD50 /ED50 ¼ 21.75/ 10.78 mg/kg

[49]

C. langsdorffii

Genotoxic in hamster lung fibroblasts (V79)

>30 mg/L

[12]

Xylopia sericea

Genotoxic in human leukocytes

>30 mg/L

[50]

Annona senegalensis

Antiproliferative qualities on 293T, PANC-1 and HeLa cancer cell lines

TC50 ¼ 125.89, 266.07, and 211.35 mg/mL, respectively, for each cell line

[54,55]

Wedelia paludosa

In vitro antiproliferative activity on IGROV, IGROV-et, K-562, PANC-1, HT-29, LoVo, LoVo-DOX, HeLa

GI50 > 9.92 mM

[53]

Croton antisyphiliticus

In vitro growth inhibition of melanoma cell lines B-16

IC50 ¼ 59.41 mg/L

[22]

[48]

Continued

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TABLE 3.5 Cytotoxic and Antitumoral activities of KA Isolated From Different Plant Sourcesdcont’d Source

Effect

Concentration

References

X. sericea

In vitro induction of apoptosis in HL60 leukemic cells, PBMC, K562, MDA-MB435 and SF295

IC50 ¼ 9.1, 12.6, 11.8, 14.3, and 12.5 mg/L respectively for each cell line

[52]

Mikania hirsutissima

Induction of apoptosis in glioblastoma cells (U87)

70 mM

[56]

ED50, effective dose, 50%; GI50, growth inhibition, 50%; IC50, half maximal inhibitory concentration; KA, kaurenoic acid; LD50, lethal dose, 50%; TC50, toxic dose, 50%.

the acute toxicity of KA was also estimated by Lorke’s method, observing a LD50 ¼ 3800 mg/kg, which is quite contrasting with previous reports [50,52]. Guadeloupean parkinsonism is linked epidemiologically to the consumption of Annonaceae fruits [59]; KA was found in the pulp of Annona cherimola (w6 g/mg of fresh fruit) among other potential compounds considered as cytotoxic. However, treatment of rat embryonic striatal primary cultures with high concentrations of KA did not exhibit symptoms of neuronal death or astrogliosis, suggesting that this molecule is not involved in human neurodegenerative diseases [59]. In addition, KA was able to inhibit the b-site amyloid precursor protein cleaving enzyme 1, acetylcholinesterase, and butyrylcholinesterase, and inhibited the production of peroxynitrite and nitric oxide, showing its anti-Alzheimer activity [60]. Table 3.6 summarizes the main works on the neuronal activity of KA.

MICROBIOLOGICAL AND INSECTICIDE EFFECT OF KAURENOIC ACID Antibacterial Activity KA shows selective cytotoxic activity against a wide spectrum of Grampositive bacteria, but also on a few Gram-negative and mycobacteria species. In silico studies of KA suggested that the bactericidal activity is mainly conferred by its insertion and disruption of the lipophilic cell membrane in some bacterial species [9]. A hydrogen-bond-donor (HBD) group strategically positioned in the molecule is apparently an important quality of KA to interact with cell membrane [9]. In order to exert its activity, the diterpene orients itself in the bilayer interface (in phosphatidylcholine bilayer model), with the

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TABLE 3.6 Activity of KA Isolated From Different Plant Sources in Neurological Diseases Source

Effect

Concentration

References

Espeletia semiglobulata

In vivo inhibition of the tonic hind-limb extension in mice

ED50 ¼ 2.5 mg/kg

[57]

Annona senegalensis

In vivo anticonvulsant activity by the decreasing of myoclonic spasms (MSs) and toniceclonic phases of seizures in mice

100e400 mg/kg

[58]

Annona cherimola

In vitro innocuous in rat embryonic striatal primary cultures, then discarded as Parkinson’s agent

50 mM IC50

[59]

Aralia cordata

In vitro inhibitor of BACE1, AChE, BChE, enzymes and ONOOe, and NO production

IC50 ¼ 41.42, 93.49, and 22.39 mM, respectively, for each enzyme and IC50 > 100 mM for free radicals

[60]

ED50, effective dose, 50%; IC50, half maximal inhibitory concentration; KA, kaurenoic acid.

hydrophobic decalinic ring moiety surrounded by the hydrocarbon chains of the lipid. The hydrophilic carboxylic group projects itself away from the hydrophobic region, interacting with the phosphorylated groups of the micellar system through hydrogen bonds [9]. Padmaja et al. [61] demonstrated a growth inhibition of Staphylococcus, Pseudomonas, Bacillus, Salmonella, Escherichia, and Klebsiella species. Mendoza et al. [62] coincidently described an antibacterial effect on Bacillus and Staphylococcus, and additionally, on Micrococcus and Clavibacter species. The same work revealed that 3-b-hydroxylation of KA considerably reduced its antibacterial activity. Wilkens et al. [63] evidenced for the first time the bactericidal effect of KA on Bacillus cereus; however, the minimum inhibitory concentration was higher at acidic or basic pH compared with neutral. According to these studies, liquid media with neutral pH are more effective than solid media to test the antibacterial effect of KA. Additional experiments demonstrated that the bactericidal activity of KA in B. cereus and Staphylococcus aureus was associated to the stimulation of oxygen consumption and proton conduction of

164 Studies in Natural Products Chemistry

the bacterial species [64]. Results suggested that KA also acts as a respiratory chain uncoupler. Padla et al. [65] corroborated the effect of KA on S. aureus at moderate concentrations, as well as in Staphylococcus epidermidis, but controversially with other works [62], Bacillus subtilis was considerably less affected. KA and its epimer have shown antibacterial activity in Escherichia coli in the order of milligrams; apparently, the KA epimer is more effective [66]. Thus, the carboxylic acid position in C18 or C19 makes a difference in the antibacterial activity. In some bacterial species associated to bovine mastitis, KA has a growth inhibition effect according to Fonseca et al. [67]. Interestingly, in this study S. epidermidis showed 10 times more sensitiveness than that reported by Padla et al. [65] for the same species. Coy et al. [68] reported 91.3% growth inhibition of Mycobacterium tuberculosis at 50 mg/mL. The anticariogenic properties of KA were tested on Streptococcus, Enterococcus, and Lactobacillus showing bacteriostatic activity [69,70]. Experiments carried out in resin tooth surfaces revealed that KA is an effective inhibitor of the Streptococcus mutans biofilm formation at low concentrations [71]. Table 3.7 summarizes the antibacterial activity of KA.

TABLE 3.7 Antibacterial Activity of KA Isolated From Different Plant Sources Source

Organism Tested

Concentration

References

Annona glabra

Staphylococcus pyogenes, Pseudomonas pyocyanea, Bacillus brevis, Salmonella typhi, Escherichia coli, and Klebsiella aerogenes

250 mg/mL

[61]

Pseudognaphalium cheiranthifolium, Pseudognaphalium heterotrichium, Pseudognaphalium viravira, and Pseudognaphalium robustum

Bacillus cereus, Staphylococcus aureus, Bacillus subtilis, Micrococcus luteus, and Clavibacter michiganensis

MIC ¼ 16, 125, 31,31 and 63 mg/ mL, respectively, for each species

[62]

P. viravira

Bactericidal activity on B. cereus

MIC ¼ 0.08 mg/ mL at pH 7

[63]

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TABLE 3.7 Antibacterial Activity of KA Isolated From Different Plant Sourcesdcont’d Source

Organism Tested

Concentration

References

Pseudognaphalium vira

Bactericidal activity on B. cereus and S. aureus by interfering in the bacterial respiratory chain

5 mg/mL

[64]

Smallanthus sonchifolius

S. aureus, Staphylococcus epidermidis, and B. subtilis

MIC ¼ 125, 250 and 1000 mg/mL, respectively, for each species

[65]

Croton antisyphiliticus

S. aureus and E. coli

MIC ¼ 250 and 1000e2000 mg/ mL respectively for each species

[66]

Mikania hirsutissima and Copaifera langsdorffii

S. epidermidis, Streptococcus agalactiae, and Streptococcus dysgalactiae

MIC ¼ 25, 3.12, and 3.12 mg/mL, respectively, for each species

[67]

Pleurothyrium cinereum

91.3% growth inhibition of Mycobacterium tuberculosis

50 mg/mL

[68]

Aspilia foliacea, M. hirsutissima

Bacteriostatic activities against Streptococcus mutans, Streptococcus salivarius, Streptococcus sanguinis, Streptococcus sobrinus, Streptococcus mitis, Enterococcus faecalis, Lactobacillus casei

MIC ¼ 10, 100, 10, 10, 10, 200, and 10 mg/mL

[69,70]

M. hirsutissima

Inhibitor of the S. mutans biofilm in resin tooth surfaces

4 mg/mL

[71]

KA, kaurenoic acid; MIC, minimum inhibitory concentration.

166 Studies in Natural Products Chemistry

Antifungal Activity Padmaja et al. [61] demonstrated a noteworthy antifungal activity on Penicillium, Microsporum, Epidermophyton, Mycosphaerella, and Fusarium species. Assays performed by Sartori et al. [72] and Boeck et al. [73] revealed none antifungal activity of KA on Candida, Cryptococcus, Saccharomyces, Aspergillus and Microsporum. But in contrary to the studies of Padmaja et al. [61] and Padla et al. [65], Epidermophyton and Trichophyton species were slightly affected by KA. The diterpene causes changes in the hyphal development of Aspergillus nidulans and could be directly or indirectly involved in the blocking of the Caþþ channels to exert its fungicidal activity [74]. Previous findings proposed that the carboxyl group of KA and related diterpenes are required to produce such effect [2]. Some evidence also suggested that HBD groups participate in the enhancement of the activity [75]. This is the case of hydroxylated derivatives of KA (3-b-hydroxy-kaurenoic acid) in Botrytis cinerea, which are even more active than that of natural KA [75]. Recently, it was reported that the diterpene might be used in combination with azolic compounds for the control of fluconazole-resistant Candida parapsilosis [76]. Table 3.8 summarizes the antifungal activity of KA.

TABLE 3.8 Antifungal Activity of KA Isolated From Different Plant Sources Source

Organism Tested

Concentration

References

Annona glabra

Penicillium notatum, Microsporum gypseum, and Epidermophyton floccosum

50, 250, and 250 mg/mL

[61]

A. glabra

Inhibition of spore germination of Mycosphaerella henningsii and Fusarium lateritium was 66% and 62%, respectively

250 mg/mL

[61]

Wedelia paludosa

Candida albicans, Candida tropicalis, Cryptococcus neoformans, Saccharomyces cerevisiae, Aspergillus niger, Aspergillus flavus, Aspergillus fumigatus

MIC > 250 mg/mL

[72,73]

Kaurenoic Acid Chapter j 3

167

TABLE 3.8 Antifungal Activity of KA Isolated From Different Plant Sourcesdcont’d Source

Organism Tested

Concentration

References

W. paludosa

Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis, Microsporum gypseum, and E. floccosum

MIC ¼ 100 mg/mL for all the species except for E. floccosum (MIC ¼ 50 mg/mL)

[72,73]

Smallanthus sonchifolius

Aspergillus nidulans

MIC ¼ 10 mg/mL

[65]

Mikania hirsutissima

A. nidulans by blocking Caþþ channels

0.3 mM

[74]

Pseudognaphalium viravira

Growth inhibition by permeabilization changes in cell membrane of Botryris cinerea

40e160 mg/mL

[75]

Xylopia sericea

Candida parapsilosis when combined with fluconazole

FICI ¼ 0.50

[76]

FICI, fractional inhibitory concentration indices; KA, kaurenoic acid; MIC, minimum inhibitory concentration.

Antiprotozoal Activity The antiprotozoal activity of KA on causal agents of Chagas and Leishmaniasis diseases was observed by alteration of the cell membrane integrity and mitochondrial membrane depolarization, in promastigote and amastigote forms of Leishmania amazonensis and epimastigote forms of Trypanosoma cruzi [77,78]. KA showed a cytotoxic activity of half maximal inhibitory concentration (IC50) ¼ 0.5 mg/mL, against the trypomastigote blood form of the T. cruzi [78,79]. Latest findings revealed that the mode of action of KA in infected macrophages was the reestablishment of the production of NO in a constitutive NO synthase- (cNOS-) dependent manner, disrupting the NO-depleting escape mechanism of L. amazonensis. Similarly, KA increased the production of IL-1b and expression of the inflammasome-activating component NLRP12. Those results demonstrated the leishmanicidal capability of KA against L. amazonensis in macrophage cultures by triggering an NLRP12/IL-1b/cNOS/NO mechanism [80]. A cytotoxicity activity on Plasmodium falciparum was exerted by KA, exhibiting comparable activity

168 Studies in Natural Products Chemistry

TABLE 3.9 Antiprotozoal Activity of KA Isolated From Different Plant Sources Source

Organism Tested

Concentration

References

Mikania obtusata

Trypomastigote blood form of the Trypanosoma cruzi

0.5 mg/mL

[79]

Copaifera officinalis

Amastigote of Leishmania amazonensis

IC50 ¼ 4.0 mg/mL

[78]

Croton pseudopulchellus

Plasmodium falciparum

IC50 ¼ 31.77 mg/mL

[81]

Wedelia paludosa

P. falciparum

IC50 ¼ 21.1 mM

[53]

Schefflera umbellifera

P. falciparum

32.2 mg/mL

[82]

IC50, half maximal inhibitory concentration; KA, kaurenoic acid.

with that of chloroquine [53,81,82] and demonstrating that low amounts of KA are required to eliminate the protozoa causing malaria. Table 3.9 summarizes the antiprotozoal activity of KA.

Antiviral Activity Semliki Forest virus replication using baby hamster kidney cells as the host confirmed a moderate virus replication inhibition (28%) at a concentration of 50 mM KA [81]. Despite absence of clear evidence on the mechanism of action, it is known that the anti-inflammatory effects of KA are associated to IL-10 production. This cytokine prevents tissue damage caused by bacterial and viral infections, as well as by regulating and repressing the expression of proinflammatory cytokines [83].

Insecticidal Activity Insecticidal activity was studied against 10-week-old adults of sweetpotato weevil (Cylas formicarius), finding that 1% KA produced 50% mortality on the seventh day after 48 h of the treatment, which consisted in the direct contact of insects with KA solutions and fed with fresh sweet potato chips 24 h after the treatment [61]. Slimestad et al. [84] demonstrated that the diterpene was also active against larvae from Aedes aegypti.

Anthelmintic and Molluscicidal Activity The nematicidal activity of KA was tested against Haemonchus contortus [61]. A concentration of 0.25 mg/mL was enough to achieve 100% mortality of the worms in just 7 min. Medina et al. [85] tested the trematodicide and

Kaurenoic Acid Chapter j 3

169

molluscicidal activity of KA. The diterpene acid isolated from the Brazilian tree Croton floribundus (Euphorbiaceae) was evaluated against cercariae of Schistosoma mansoni. KA produced 100% mortality on cercaries at 10 mg/mL in just 1 h. In addition, the snail vector Biomphalaria glabrata was eliminated with a lethal concentration, 50% (LC50) ¼ 1.16 mg/mL. This evidence postulates KA as an integral alternative for the biological control of both the trematode and the mollusk vector of schistosomiasis.

PLATFORMS TO PRODUCE KAURENOID COMPOUNDS In 1967, Mori and Matsui described a route to synthesize KA. In their approach, they relied on pure organic chemistry starting with a condensation reaction of methyl acroylacetate and b-tetralone to afford the corresponding tricyclic ester. Upon methylation with methyl iodide and potassium tert-butoxide, it resulted in the formation of b-ketoester as an intermediate en route to KA. Attempts to reduce the aromatic C-ring were unsuccessful, but a hydrogenation protocol relying on Raney nickel was able to afford the desired reduction product as a crucial intermediate toward KA [86]. Hong and Tantillo [87] proposed an alternative biosynthetic pathway for the tetracyclic ent-kaurene diterpenoids. However, as far as we know, there is not any demonstration of this biosynthesis in any organism so far. Recently, the incorporation of KO gene from S. rebaudiana (KO_Sr) into plasmid pSY400 together with the electron transfer partner NADPH (nicotinamide adenine dinucleotide phosphate reduced)-dependent cytochrome P450 reductase (CPR) from S. rebaudiana (CPR_Sr), resulted in the production of KA by the Escherichia coli strain SSY10 pSY414. As much as 42.49 mg/L KA was produced at 30 C after addition of 0.02 mM of isopropyl b-D-1-thiogalactopyranoside (IPTG). The functional expression of KO_Sr was enhanced after optimization of the temperature and IPTG concentration. Under these conditions, the highest yield of KA was 100.23 mg/L at 22 C and 0.1 mM of IPTG [88].

CONCLUDING REMARKS The availability of KA in diverse plant sources, many of them considered like medicinal, has led to its evaluation for a wide range of biological activities. The amphipathic character of the diterpene sustains its interaction with lipid bilayers, and probably this is the main mechanism for its translocation into cells to interact with different targets [9]. Antidiabetic properties of KA could be related to an insulinogenic effect by its possible direct or indirect interaction with Caþþ and/or Kþ channels. This may induce depolarization of pancreatic b-cells or stimulation of the 50 AMP-activated protein kinase, to increase glucose transport, glycolysis, and glycogenolysis [28,35,74]. However, up to now, there has been no evidence of changes in insulin levels in

170 Studies in Natural Products Chemistry

murine models treated with KA. Other biological activities such as the diuretic and the analgesic properties should be related to the same KA property for interacting with ionic transporters. As shown in this work, KA is selectively cytotoxic or cytostatic for different types of eukaryotic or prokaryotic cells. However, KA may have a limited cytotoxic effect with poor therapeutic potential due to the lack of selectivity to tumor cells [52]. In spite of all these inconvenient, the diterpene is still an attractive agent to be used in chemotherapy, considering that it is less aggressive than current chemotherapeutic drugs such as taxol in murine models. In addition, the molecule could be used as template for the semisynthesis of new potent and more selective diterpenes for this and other aims [53]. A similar case occurs with antibacterial, antifungal, and antiprotozoal activities where the concentrations are usually contradictory for some species. Nevertheless, the methods used to test the KA activity as well as its solubilization in different culture media play a key role in the reproducibility of those experiments [63]. KA is not only effective as antimicrobial, insecticidal, or anthelmintic, but also exerts activities as an inhibitor of key enzymes and shows analgesic and cytotoxic properties, thus demonstrating its unusual pleiotropism. The discovery of the multifunctional enzymes involved in KA biosynthesis is a promising tool to scale up its production by metabolic engineering [25]. Last reports on steviol biosynthesis by synthetic biology were successful for the production of KA at industrial scale [88]. A huge amount of possibilities are now envisioned in order to synthesize new products with pharmacological and other useful biological activities based on KA.

ABBREVIATIONS AMP AMPK ATP cNOS CPP DMAPP ED GFPP GGPP GMP GPP HBD HMG-CoA IC50 iNOS IPP IPTG KA

adenosine monophosphate AMP-activated protein kinase adenosine triphosphate constitutive NO synthase ent-copalyl pyrophosphate dimethylallyl pyrophosphate effective dose geranyl farnesyl pyrophosphate geranylgeranyl pyrophosphate guanosine monophosphate geranyl pyrophosphate hydrogen-bond-donor 3-hydroxy-3-methyl-glutaryl-Coenzyme A half maximal inhibitory concentration inducible nitric oxide synthase isopentenyl pyrophosphate isopropyl b-D-1-thiogalactopyranoside kaurenoic acid (ent-kaur-16-en-19-oic acid)

Kaurenoic Acid Chapter j 3 KO KSI, KSII LC50 LD MEP MIC MVA NCBI NF-kB NO NO-cGMP PTP1B SFV

171

ent-kaurene oxidases ent-kaurene synthases I and II lethal concentration, 50% lethal dose 2-methyl-D-erythritol-4-phosphate minimum inhibitory concentration mevalonic acid National Center for Biotechnology Information nuclear factor-kB nitric oxide nitric oxideecyclic guanosine monophosphate protein tyrosine phosphatase 1B Semliki Forest virus

ACKNOWLEDGMENTS The authors deeply thank the financial support of the grant CB-2010-151144Z from Consejo Nacional de Ciencia y Tecnologı´a (CONACyT), Me´xico. NVR thank the kind suggestions of MSc Martha G. Betancourt Jime´nez from Centro de Investigacio´n y Estudios Avanzados del Instituto Polite´cnico Nacional (CINVESTAV-IPN), Irapuato for the organization of this document.

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174 Studies in Natural Products Chemistry [68] E.D. Coy, L.E. Cuca, M. Sefkow, J. Nat. Prod. 72 (2009) 1245e1248. [69] S.R. Ambrosio, N.A.J.C. Furtado, D.C.R. De Oliveira, F.B. Da Costa, C.H.G. Martins, T.C. De Carvalho, T.S. Porto, R.C.S. Veneziani, Z. Naturforsch. 63c (2008) 326e330. [70] B.B. De Andrade, M.R. Moreira, S.R. Ambrosio, N.A.J.C. Furtado, W.R. Cunha, V.C.G. Helenoa, A.N. Silva, M.R. Sima˜o, E.M.P. Da Rocha, C.H.G. Martins, R.C.S. Veneziani, Nat. Prod. Commun. 6 (2011) 777e780. [71] S.-I. Jeong, B.-S. Kim, K.-S. Keum, K.-H. Lee, S.-Y. Kang, B.-I. Park, Y.-R. Lee, Y.-O. You, Evid. Based Complement. Altern. Med. 2013 (2013) 1e9. [72] M.R.K. Sartori, J.B. Pretto, A.B. Cruz, L.F.V. Bresciani, R.A. Yunes, M. Sortino, S.A. Zacchino, C. Filho, Pharmazie 58 (2003) 567e569. [73] P. Boeck, M.M. Sa´, B.S. De Souza, R. Cercena´, A.M. Escalante, S.A. Zachino, V.C. Filho, R.A. Yunes, J. Braz, Chem. Soc. 16 (2005) 1360e1366. [74] J.A. Rafael, N.S. Arakawa, S.R. Ambrosio, F.B. Da Costa, S. Said, Adv. Microbiol. 3 (2013) 438e444. [75] M. Cotoras, C. Folch, L. Mendoza, J. Agric. Food Chem. 52 (2004) 2821e2826. [76] J.B.A. Neto, C.R. Da Silva, R.S. Campos, F.B.S.A. Nascimiento, S. Sampaio, A.R. Da Silva, R.A.C. Silva, D.D. De Freitas, M.A. Josino, L.N.D. Andrade, H.I.F. Magalha˜es, D.M. Gaspar, M.O. De Moraes, E.R. Silveira, A.O.C.V. Gomes, C.A.G. Camara, I.S.P. Lima, B.C. Cavalcanti, H.V.N. Junior, Int. J. Curr. Microbiol. Appl. Sci. 4 (2015) 68e79. [77] E. Izumi, T. Ueda-Nakamura, V.F. Veiga, A.C. Pinto, C.V. Nakamura, J. Med. Chem. 55 (2012) 2994e3001. [78] A.O. Santos, E. Izumi, T. Ueda-Nakamura, B.P. Dias-Filho, V.F. Veiga-Ju´nior, C.V. Nakamura, Mem. Inst. Oswaldo Cruz 108 (2013) 59e64. [79] T.M.A. Alves, P.P.G. Chaves, L.M.S.T. Santos, T.J. Nagem, S.M.F. Murta, I.P. Geravolo, A.J. Romanha, C.L. Zani, Planta Med. 61 (1995) 85e87. [80] M.M. Miranda, C. Panis, S.S. Da Silva, J.A. Macri, N.Y. Kawakami, T.H. Hayashida, B. Madeira, V.R. Acquaro Jr., S.L. Nixdorf, L. Pizzatti, S.R. Ambro´sio, R. Cecchini, N.S. Arakawa, W.A. Verri Jr., I.C. Costa, W.G. Pavanelli, Mediat. Inflamm. 2015 (2015) 1e10. [81] M.K. Langat, D.A. Mulholland, M.K. Langat, N.R. Crouch, D.A. Mulholland, N.R. Crouch, L. Pohjala, P. Tammela, L. Pohjala, P.J. Smith, Phytochem. Lett. 5 (2012) 414e418. [82] X.S. Mthembu, F.R. Van Herdeen, G. Fouche´, S. Afr, J. Bot. 76 (2010) 82e85. [83] F.S. Vargas, P.D.O. Almeida, E.S.P. Aranha, A.P.A. Boleti, P. Newton, M.C. Vasconcellos, V.F. Veiga Jr., E.S. Lima, Molecules 20 (2015) 6194e6210. [84] R. Slimestad, A. Marston, S. Mavi, K. Hostettmann, Planta Med. 61 (1995) 562e563. [85] J.M. Medina, J.L.B. Peixoto, A.A. Silva, S.K. Haraguchi, D.L.M. Falavigna, M.L.M. Zamuner, M.H. Sarragiotto, G.J. Vidotti, Braz. J. Pharmacogn. 19 (2009) 207e211. [86] K. Mori, M. Matsui, Tetrahedron 24 (1968) 3095e3111. [87] Y.J. Hong, D.J. Tantillo, J. Am. Chem. Soc. 132 (2010) 5375e5386. [88] J. Wang, S. Li, Z. Xiong, Y. Wang, Cell Res. 26 (2016) 258e261.

Chapter 4

Review of Patents Based on Triterpene Glycosides of Sea Cucumbers Dmitry L. Aminin,*, 1 Ekaterina S. Menchinskaya,* Evgeny A. Pislyagin,* Alexandra S. Silchenko,* Sergey A. Avilov,* Natalia I. Stadnichenko,* Peter D. Collinx, Vladimir I. Kalinin*

*G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Vladivostok, Russia; xCoastside Bio Resources, Deer Isle, ME, United States 1 Corresponding author: E-mail: [email protected]

Chapter Outline Introduction Methods of Triterpene Glycoside Isolation Methods for Producing an Extracts and Products Containing Triterpene Glycosides Methods for Isolating of Individual Triterpene Glycosides Quantification Methodologies and Modification of Triterpene Glycosides by Radioactive Isotopes

175 177

177

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Inclusion of Triterpene Glycosides in Functional Food and Other Products Means of Functional Food Medical Drinks Cosmetics Means for Disease Prophylaxis Immunostimulatory Means Sea Cucumber Glycosides and Cancer Conclusions Acknowledgments References

183 183 185 185 185 188 191 195 197 197

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INTRODUCTION Holothurians (or sea cucumbers) are marine invertebrates belonging to the phylum Echinodermata. They are inhabitants of all the oceans and seas except most part of Baltic Sea and Black Sea because of low salinity of their waters. Sea cucumbers contain a wide variety of biologically active compounds, but Studies in Natural Products Chemistry, Vol. 51. http://dx.doi.org/10.1016/B978-0-444-63932-5.00004-8 Copyright © 2016 Elsevier B.V. All rights reserved.

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176 Studies in Natural Products Chemistry 21

O

O 20

18 19

11

12

14 2 3

HO 31

1 4

10 5

9 6

17

13 15

22

24 23

26 25 27

16

8 7

30

32

FIGURE 4.1 Holostane, i.e., a lanostane derivative having 18(20)-lactone, the base structure for most of aglycones of sea cucumber triterpene glycosides.

the most characteristic secondary metabolites of sea cucumbers are triterpene glycosides of lanostane series preferably holostane derivatives having 18(20)lactone (Fig. 4.1) [1e3]. Sea cucumber triterpene glycosides have medically significant effects in established models of drug discovery. These compounds have a wide variety of medical benefits, including cytotoxicity, antifungal, immunomodulation, and antitumor effects [4e7]. The main biological role of the glycosides for sea cucumbers is chemical defense against predators. These substances also play a role in regulation of reproduction of these animals [4]. Although sea cucumbers are commercially harvested in China, Japan, Russia, Canada, the United States of America, Spain, Australia, and many other countries, the main consumers of these animals are in China, Japan, and countries of South-East Asia where the products from sea cucumbers are used as food delicacies and preparations for traditional folk medicine. The most part of harvested sea cucumbers is sold in China where the biggest sea cucumber (as dried material after processing) market is in Hong Kong. The sales in the Chinese market are more than 10000 tons of dried sea cucumbers and more than 50 millions US dollar. Only 40 species of sea cucumbers from a total of about 1500 are harvested [8]. The most expensive sea cucumber is Holothuria scabra. Its price in Hong Kong is 1668 US dollar per 1 kg while the price of Thelenota ananas is only 150 $ [9]. Sea cucumbers are objects of mariculture in China, Japan, Australia, and Canada. The cultivated sea cucumbers include H. scabra, Australostichopus mollis, and Apostichopus japonicus. The common laboratory procedure of isolation of triterpene glycosides from sea cucumbers includes extraction of fresh or dried animals with water ethanol or methanol, concentration of the extract in vacuo, redissolving the residue in water and chromatography on a hydrophobic resin using water for desalting and water/ethanol, water/methanol, or water/acetone for elution of glycoside fraction. The crude glycoside fraction is chromatographed on silica gel using chloroform/ethanol or methanol/water as the mobile phase. The individual components are separated commonly using HPLC (high performance liquid chromatography) procedures preferably on reverse-phase columns [10]. The determination of the glycosides in sea cucumbers preferably is carried out after the isolation of the glycosides by common laboratory procedure followed by analysis using HPLC technologies and spectral methods including

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NMR (nuclear magnetic resonance spectroscopy). Modern high performance liquid chromatographyemass spectrometry procedures are also applied for analysis of triterpene glycosides in sea cucumbers without isolation of individual compounds [11e13]. This method seems to be the most promised for standardization of glycoside-containing products from sea cucumbers. As a source of patent information over the last 30 years, the official government patent databases of Russia, the United States of America, Japan, China, and Korea were selected because most scientific and patenting activities concerning sea cucumber triterpene glycosides are concentrated in these countries. These reviewed patents cover such topics as methods for obtaining biologically active crude sea cucumber extracts, development of commercial products containing sea cucumber triterpene glycosides, methods for isolation of individual triterpene glycosides, methods of quantitative determination and modification of triterpene glycosides, means of production for functional foods, medical drinks, cosmetics, products for prophylaxis of various diseases, and agents having immunomodulatory and antitumor activity.

METHODS OF TRITERPENE GLYCOSIDE ISOLATION Methods for Producing an Extracts and Products Containing Triterpene Glycosides A procedure for isolation of glycosides from boiling water extracts of Far Eastern sea cucumber Cucumaria japonica has been patented by Stonik et al. for obtaining a preparation, “KD,” for use in veterinary medicine for immunodulation and biostimulation, prevention of various animal diseases, and reduction of mortality in animal livestock neonates. KD is the total monosulfated triterpene glycoside fraction of C. japonica obtained from industrial boiling water extracts. These glycosides are co-precipitated with a polysaccharideeprotein complex by acidification at pH 2 or by using a 1% solution of chitosan as a flocculant, followed by polar solvent precipitation. The resulting extract is purified by hydrophobic chromatography using Teflon powder Polychrom-1 or other hydrophobic sorbents followed by isolation of the target glycoside fraction by conventional chromatography on silica gel using chloroformeethanolewater (100:100:17) mixture as the mobile phase. An alternative procedure involves drying of the boiling water extract followed by extraction of glycosides using ethanol or a mixture of midpolar solvents. The extract is also purified by hydrophobic chromatography followed by chromatography on silica gel as described previously [14]. A procedure for isolation of fractions of carotenoids and triterpene glycosides from sea cucumber Cucumaria frondosa harvested in the North Atlantic has been patented by Lebskaya et al. The specimens are minced and extracted using a mixture of ethanol/chloroform/water (1:2:2) and (1:1:2) at room temperature, followed by extraction by ethanol under reflux. The dried

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residue may be used as a protein food additive. The extracts are combined and concentrated to dryness. The residue is then extracted by acetone to produce two products: (1) a carotenoid extract and (2) the triterpene glycosides which are obtained in the residue after further concentration, filtering and ethanolic extractions [15]. A method for obtaining biologically active fractions containing sea cucumber glycosides from body wall, tentacles, and epithelia of sea cucumbers was patented by Collin et al. The body walls or tentacles of the sea cucumber are boiled in water for 0.5 h and dried at low temperature. The dried fraction is used as a protein source or food product, or a component of biologically active products, or a starting material for isolation of active subfractions or single molecules. An epithelium can be obtained from sea cucumber body walls after heating the body wall in water at 60e80 C [16]. A method of isolation of triterpene glycoside fractions from boiling water extract after sea cucumber processing was patented by Yuan et al. The boiling water extract is filtered and diluted with ethanol, and the precipitate is centrifuged. The supernatant is concentrated in vacuo and subjected to hydrophobic chromatography on a column with macroporous resin and eluted with 60% ethanol. The eluate is concentrated and freeze dried [17]. A procedure for isolation of triterpene glycosides from Holothuria nobilis Selenka using the common extraction with ethanol followed by concentration in vacuo and submission to a column with DA201-B macroporous resin, with a subsequent eluting of glycosides with 50% ethanol was patented by Ping et al. [18]. A procedure for isolation of biologically active fractions including triterpene glycosides from sea cucumber boiling water extract was patented by Jang et al. The boiling water extracts are filtered including nanofiltration, enzymatic treatment (optionally), and then filtration followed by centrifugation. The supernatant is concentrated in resin, and the resin is washed with ethanol and kept approximately 12 h before centrifugation. The supernatant is diluted with ethanol and centrifuged for desalting. The supernatant is subsequently concentrated and pulverized to obtain a powder product [19]. A procedure for isolation of total saponins from T. ananas was patented by Jun et al. The patent describes a procedure for extraction of sea cucumbers with ethanol followed by concentration of the extract in vacuo and hydrophobic chromatography on a column with DA201-B macroporous resin, eluting the glycosides with 50% ethanol. The glycosides are redissolved with water and used for preparation of tablets for curing neoplastic diseases [20]. A method to obtain a hepatoprotective product of C. japonica triterpene glycosides was been patented by Stonik et al. The body walls of the animals are minced and extracted by hot ethanol. The ethanol is used to extract and separate triterpene glycosides, and the residue is first dried in open air followed by drying in vacuo. The residue is milled and strained through a sieve until the particles are 0.08 mm. The product is described as being hepatoprotective. It

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contains the following basic components (wt%): protein (no less than 70%), carbohydrates (4.5e4.9%), calcium (1.5e1.9%), sodium (0.9e1.3%), magnesium (0.5e0.9%), potassium (0.2e0.6%), alcohol (no more than 0.5%), moisture (no more than 10%), and ash (no more than 8%). The product is described as having a complete amino acid profile, beneficial food fibers, and being useful in prevention of toxic liver diseases [21]. A procedure for isolation of triterpene glycosides from dried sea cucumbers was patented by Wang et al. The dried sea cucumber body wall powder is refluxed with 60% ethanol. The extract is filtered, concentrated in vacuo, and subjected to hydrophobic chromatography on a macroporous resin column. The glycosides are eluted with 80% ethanol [22]. A procedure for obtaining products of acid hydrolysis of sea cucumber triterpene glycosides was patented by Zhang et al. An ethanolic extract of sea cucumbers is concentrated and applied to a chromatography column with DA201-B macroporous resin, eluted with 50% ethanol and concentrated to yield a total saponin fraction that is hydrolyzed with hydrochloric acid. The product is extracted with organic solvents and further refined for preparing therapeutic tablets. The cytotoxicity of the product is described as being low and able to decrease the level of uric acid in serum in vivo. The patent claims that this product may be useful for the development of medicinal treatment options for hyperuricemia [23]. A procedure for isolation of triterpene glycosides from sea cucumber coelomic fluid was patented by Liu et al. The coelomic fluid is filtered, concentrated to a clear solution with the addition of an appropriate amount of silica gel powder, and then dried. The powder is washed with petroleum ether followed by elution with ethanol. The eluate is then concentrated in vacuo and subjected to hydrophobic chromatography on macroporous resin column followed by elution with 60% ethanol. The eluate containing the total triterpene glycoside fraction finally concentrated to dryness [24]. A procedure for preparing modified sea cucumber triterpene glycosides from sea cucumber boiling water extract by enzymatic hydrolysis was patented by Lin et al. The resulting products are suitable for bioassay. The invention discloses a method for preparing secondary triterpene glycosides by enzymatic hydrolysis of sea cucumber total saponins. The patented method involved comprises centrifugation of boiling water extracts followed by hydrophobic chromatography and purification of the resulting glycosidic fractions by extraction with butanol and water. Butanol layers are concentrated, followed by enzymatic hydrolysis of the crude glycoside fraction with a snailase [25]. A procedure for isolation of biologically active substances including triterpene glycosides from sea cucumber viscera was patented by Yuan et al. The sea cucumber viscera is diluted with water and treated with protease, followed by alcohol precipitation. The medium is centrifuged, and the precipitates are used for obtaining polysaccharides. The supernatant is dissolved with a mixture of butanol and water. The butanol layer is evaporated and subjected to

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hydrophobic chromatography to yield a triterpene glycoside fraction. The water layer containing polypeptides then is dried. The polypeptides were described as possessing antioxidant activity [26]. A procedure of fermentation of sea cucumber body walls in order to obtain a water extract containing biological active substances including triterpene glycosides was patented by Chi et al. The sea cucumbers are washed, gutted, frozen and crushed and then heated with water for 20e35 min. High fructose corn syrup mix is added to medium, and a composition of bacteria was also added. After incubation the solution is filtered and dried. The process is applicable to healthcare product preparations [27]. A procedure for obtaining biologically active fractions containing triterpene glycosides from sea cucumber body walls was patented by Jiao et al. The body walls of sea cucumbers are cut and kept in an airtight container at 70e130 C for gelatinization for 1e20 h and then freeze-dried. The resulting powder is dissolved in water and treated with a proteinase. The supernatant is dried and pulverized into nanosize particles after proteinase deactivation. The product is described as having pharmacologically active beneficial complementary and synergistic effects [28].

Methods for Isolating of Individual Triterpene Glycosides Trivial procedure of isolation of triterpene glycosides from Holothuria pervicax resulting in new glycosides, pervicosides A, B, and C (Fig. 4.2), was patented by Kitagawa et al. The sea cucumber body wall is extracted with ethanol, concentrated, and submitted to column chromatography on a hydrophobic adsorbent, and the glycosides eluted with alcohol and separated using common silica gel chromatography to yield individual previcosides A, B, and C [29].

O

O

R

HO H

O

O

H

H

OH NaO3SO CH2OH O

O

O O

OCH3 HO

O O

OH

pervicoside A. R = pervicoside B. R = pervicoside C. R =

HO OH

CH3

CH2OH

OH

OH

FIGURE 4.2 Structures of pervicosides AeC.

OAc

Review of Patents Based on Triterpene Glycosides Chapter j 4

O

O

HO H

CH2OH O OCH3 HO

O

O

CH3 O

HO OH

O

CH2OH O

OH

O

H

H

OH

OH

OCH3 HO

O

HO

OH

CH2OH O

CH2OH O

O

181

bivittoside D

O

OH OH

FIGURE 4.3 Structure of bivittoside D.

A simple procedure for obtaining of bivittoside D (Fig. 4.3), a triterpene glycoside from the sea cucumber Bohadschia vitiensis having potent spermicidal and fungicidal activity, was patented by Lakshi et al. The procedure provides a process for isolation of bivittoside D from B. vitiensis. The process involves soaking B. vitiensis material first in a polar solvent (methanol, ethanol, propanol, butanol, water and any mixture thereof), filtering the material, and decanting the solvent followed by soaking the material in a second aqueous polar solvent, extracting the material by filtration, concentrating the extracted material under reduced pressure to obtain a thick viscous crude extract, and eluting the crude extract followed by crystallization to obtain a pure saponin bivittoside D [30]. A procedure for isolation of triterpene glycoside holotoxin A1 (Fig. 4.4) from boiling water extract after processing of the sea cucumber A. japonicus was patented by Liu et al. The boiling water extract is concentrated under vacuum and diluted with ethanol. The supernatant is concentrated and subjected to hydrophobic column chromatography on a macroporous resin column and eluted with 70% ethanol and subjected to chromatography on a silica gel column followed by HPLC [31].

Quantification Methodologies and Modification of Triterpene Glycosides by Radioactive Isotopes A procedure for determination of triterpene glycosides in food hydrolysate of sea cucumbers by a proteinase was patented by Blinov et al. A hydrolysate or boiling water extract of sea cucumbers is submitted to a column with Teflon

182 Studies in Natural Products Chemistry

O

O H

H O

CH2OH O

O

OCH3 HO

CH2OH O O

CH3 O O

OCH3 HO

HO OH

O

OH

O

OH

O

H

OH

HO

OH

CH2OH O

O

holotoxin A1

O

OH OH

FIGURE 4.4 Structure of holotoxin A1.

powder Polychrom-1 and washed with water. The glycosides are eluted with 50% ethanol, and the eluate is concentrated and rechromatographed on Teflon powder eluting with 96% ethanol. The analysis of the resulting glycosides is carried out by HPLC with detection at 220 nm [32]. A determination of sea cucumber glycosides by quantification of quinovose was patented by In et al. The glycosides are hydrolyzed with trifluoroacetic acid followed by derivatization of sugars by adding 1-phenyl3-methy-5-pyrazolone. The mixture of sugar derivatives is analyzed using HPLC [33]. A method of obtaining labeled sea cucumber glycosides for pharmacodynamic and pharmacokinetic studies was patented by Mjasoedov et al. The invention refers to production of new tritiated analogues of physiologically active compoundsdtriterpene glycosides from the sea cucumber C. japonica. A new tritiated analogue of the physiologically active compound, [3H]-cucumarioside A2-2 (Fig. 4.5), has been obtained after catalytic exchange of hydrogen atoms with gaseous tritium at Pd/C catalyst. The yield of labeled saturated triterpene glycoside reached 12%, molar radioactivityd71 Ci/mmol [34]. Thus the patented methods of isolation of fractions of biologically active triterpene glycosides from sea cucumbers include different variations of extraction with organic solvents, co-precipitation glycosides from sea cucumber boiling water with proteins with acids, centrifugation and nanofiltration of water extracts, enzymatic hydrolysis, and drying of animal tissues. Nevertheless, the key stage in obtaining of fractions with high contents of glycosides is almost always the chromatography on a hydrophobic resin for desalting and elimination of polar impurities as in most common laboratory procedures.

Review of Patents Based on Triterpene Glycosides Chapter j 4

O

183

O

H

H O

O

O

H

OH NaO3SO CH2OH O

O

O HO

OH

O O

OH

O

OR HO

CH3

CH2OH

OH

O

R = CH3 Cucumarioside A2-2 R = H Cucumarioside A4-2

O

OH HO

OH

FIGURE 4.5 Structure of cucumariosides A2-2 and A4-2.

The patented procedures of isolation of individual saponins really are only modifications of classic laboratory procedure including hydrophobic chromatography, chromatography on silica gel followed by isolation of individual glycosides using HPLC on reversed-phase columns. The procedure of isolation of bivittoside D is an exception because the authors used only different extractions and crystallization. It seems to be possible only for sea cucumber with extra rich saponin contents where one major component is predominant. The purity of final product also may be not high. The patented procedures of analysis of sea cucumber saponins include HPLC of crude glycoside fractions and determination of glycosides by specific quinovose monosaccharide residue. For control of pharmacodynamics of glycoside, the [3H]-labeled saponins were used.

INCLUSION OF TRITERPENE GLYCOSIDES IN FUNCTIONAL FOOD AND OTHER PRODUCTS Means of Functional Food A hydrolysate product comprised of the sea cucumber C. japonica, obtained by hydrochloric acid hydrolysis of sea cucumber tissues or by a protease containing triterpene glycosides was patented by Akulin et al. The patent describes a health supplement for people with high mental and physical stress or immune depletion. The invention is useful in the functional food

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industry and can be used as a fortifying food agent for the rehabilitation of patients [35]. The method of saturation of fish oil in concentrated extracts of different hydrobionts including sea cucumber was patented by Lebskaya et al. The concentrates are prepared from the internal organs of various marine animals, which were extracted with 96% ethanol, then evaporated to dryness and residues heated at 45e60 C with ethanol under stirring until complete dissolution of the concentrate. The alcohol is added in the ratio of the residue to alcohol of 1:10. Therapeutic and prophylactic effects caused by consumption of new biologically active additives containing the phospholipids, carotenoids, polyunsaturated fatty acids, vitamin E, phospholipideglycoside complex, and various glycosides are claimed. These natural products are claimed to enhance antioxidant, antimutagenic, immunostimulatory, and other properties in humans and/or animals [36]. A foodstuff from marine algae purified from crude starting materials with polar organic solvents was patented by Nekrasova et al. The purified algae contain alginic acid (about 55 dry wt% to about 0.25 dry wt%). The patent describes a foodstuff that includes certain amounts of sea cucumber triterpenoid glycosides [37]. A foodstuff, Akmar, as a product of complex utilization of the sea cucumbers A. japonicus and C. japonica, was patented by Timchishina et al. The body walls of sea cucumbers are boiled, dried, and used as a food. The tentacles and viscera are freeze dried and used as biologically active foodstuff enhancing the resistance of animals against infectious diseases. In addition, boiling water extracts from processing of body walls are dried. The resulting powder is the glycosidic foodstuff, Akmar, and may be used in tablets or capsulated form [38]. A probiotic food product based on soybean milk with the addition of mead, sea cucumber powder, and dried sea cucumber boiling water extract containing triterpene glycosides was patented by Senchenko et al. as a beneficial health food product. The mixture is fermented using a starter which is described as a “kefir fungi” or a standard yoghurt starter with subsequent ripening of the mixture at a temperature of 26e42 C for 5e8 h. The product is cooled and preserved at 5 C before packaging [39]. A mixed sea cucumber powder and a production method thereof were patented by Gao et al. for the creation of a foodstuff. The mixed sea cucumber powder containing triterpene glycosides uses sea cucumber powder as the main material with black fungus powder, red jujube powder, and lotus root starch as accessories. The mixed sea cucumber powder is described as having a good taste, high nutrition value, generating improved immunity, and a blood replenishing function [40]. A method for production of salt that contains triterpene glycosides from sea cucumbers was patented by Li et al. The sea cucumber was steamed and extracted with salt water. The salt water extract was filtered and dried to yield a salt that contains triterpene glycosides [41].

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Medical Drinks A special vodka Churin using a sea cucumber extract with triterpene glycosides was patented by Loenko et al. It is comprised of a waterealcohol liquid, incorporating an aqueous-alcoholic extract from dried sea cucumber as a glycoside-containing fraction, plus red pepper. The composition is claimed to have beneficial health effects [42]. A procedure of preparing a sea cucumber wine containing triterpene glycosides was patented by Jian et al. Grain wine (60% distilled alcohol obtained after grain fermentation followed by distillation) was combined with enzymatic hydrolysate of sea cucumber and Chinese herbal medicinal liquor. The product also contains traditional Chinese medicinal herbs. The components of the wine are described as having adaptogenic qualities [43]. A biological wine containing triterpene glycosides obtained from sea cucumber powder hydrolysate, followed by fermentation with a sugar media, was patented by Liu et al. The sea cucumber powder is dissolved in water and treated with a proteinase, the activity of the enzyme is terminated, and sugar is added to the media, and fermentation for 2e16 weeks. The product is mixed with traditional Chinese medicinal herbs and filtered to yield the finished product. The wine is claimed to have functions of antitumor, improved immunity, anticoagulation, antithrombotic effects, radioprotection, antivirus, liver protection, and cardiovascular benefits [44]. A health wine with extract of sea cucumbers containing triterpene glycosides and oysters was invented by Yi et al. The dried sea cucumbers and oysters raw material was mixed, milled, and dispersed in warm water and hydrolyzed with papain. The activity of the enzyme was stopped by boiling water. The extract was filtered and treated with chitosan to remove the animal smell and heavy metals. The extract and sediment were combined and diluted with ethanol by 50% concentration of ethanol and filtered. Other components traditional for Chinese health wines may be also added [45].

Cosmetics A method for manufacturing a cosmetic composition containing sea cucumber triterpene glycosides was patented by Lee et al. The sea cucumbers are steamed, and the liquid by-products are collected and desalted by osmotic membrane filtration [46].

Means for Disease Prophylaxis Slutskaya et al. patented certain food supplements, TINGOL-2 and Erogol, containing sea cucumber-derived triterpene glycosides. The patent describes improved motility of human and animal spermatozoids. The sea cucumber viscera are dried and milled and extracted with alcohol to yield an

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aqueous-alcoholic extract. The residue of sea cucumber viscera after extraction is dried and milled to yield a powder (Erogol), which is suitable for encapsulating. The biologically active supplement, TINGOl-2, is an aqueousalcoholic extract [47]. A method utilizing sea cucumber glycosides for increasing libido, stimulating spermatogenesis, number and mobility of sperm, was patented by Timchishina et al. The method comprises oral administration of biologically active additives derived from the viscera of the sea cucumber C. japonica [48]. A patent was obtained by Shapovalova et al. for health supplement products aimed at prevention or treatment of cardiovascular diseases. The patent describes a wide range of possible mixtures of marine organism extracts, including sea cucumber glycosides, various lipids, and extracts of starfish, herring, and sea urchins that increase the effects of fish oil and other similar products [49]. A therapeutic product, OSTEOMAKS EXTRA, is described in a patent by Kovalev et al. The composition is comprised of a proteineglycoside complex derived from sea cucumbers, glucosamine hydrochloride, and excipients, and further described as being therapeutic in osteoarthritis and other similar diseases [50]. Six individual triterpene glycosides holotoxins DeI (Fig. 4.6) isolated from the sea cucumber A. japonicus Selenka were patented as having antifungal activity by Liu et al. The in vitro antifungal effects of the glycosides are claimed to be active against Candida albicans SC5314, Cryptococcus neoformans BLS108, Candida tropicalis, Trichophyton rubrum, Mircrosporum gypseum, and fuming Aspergillus [51]. A composition of triterpene glycosides of sea cucumbers or individual triterpene glycosides was patented by Juan et al. as a means for preventing and improving or treating type II diabetes. The total glycosidic fraction of sea cucumbers or a sea cucumber glycoside is claimed to significantly reduce fasting blood glucose levels and significantly improve insulin resistance. The glycosides are isolated by common methods using ethanol extraction of dried sea cucumbers followed by hydrophobic chromatography [52]. A composition of triterpene glycosides of sea cucumbers or an individual triterpene glycoside and a sea cucumber polysaccharide was patented by In et al. for use in preventing and treating hyperuricemia. The glycosides are isolated by hot water/alcohol extraction, followed by evaporation and reextraction of the butanol/water mixture. The butanol layer is decanted and concentrated to yield a glycoside fraction. The polysaccharide fraction is isolated from another portion of sea cucumber after enzyme hydrolysis by a proteinase, followed by precipitation with ethanol, redissolving the precipitate in water with an acid, followed by dialysis and concentration to dryness. The patent claims a composition containing at least one sea cucumber triterpene glycoside and sea cucumber polysaccharides resulting in improvement of serum uric acid level of animals in vivo [53].

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11 9

B

A CH2OH O

O

8

D

H O

7

O

H

OH

O

OR3

E C

187

HO O

OH CH2OH O

R1 O

O O

R2 HO

HO OH

R1

OH

OH

R2

O

OH

E

R3

Holotoxin D CH 2OH OMe 3-O-Me- β - D - Glcp Holotoxin E

Me

OMe β - D - Glcp

Holotoxin F

Me

OMe 3-O-Me- β - D- Glcp

O

O

O

O

O

Me

OMe

Holotoxin H

Me

OMe H

Me

O

3-O-Me- β - D - Glcp

Holotoxin G

OMe H

9,11 7,8 OH

9,11

OH O

Holotoxin I

Δ

O

HO HO

O

9,11 9,11 9,11

FIGURE 4.6 Structure of holotoxins DeI from Apostichopus japonicus. The names of some glycosides are different from the names published in scientific journals by the same authors.

A sea cucumber extract containing more than 50% of sea cucumberederived triterpene sapogenins was patented by Li et al. The patent describes a pharmaceutical preparation for preventing and/or treating hyperuricemia through inhibition of xanthine oxidase and reduction of hematuria and serum uric acid levels in vivo [54]. Thus preparations containing triterpene glycosides from sea cucumbers have been patented as functional food and foodstuff protecting organisms against high mental and physical stress, immune depletion, and so forth. They may be used as compositions with marine algae and fish oil, fermented soya bean milk, salts, and traditional tablets and capsules. They also were patented as components of medical drinks including different wines and even cosmetics. Sea cucumber glycosides and glycoside-containing preparations were

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also patented as prophylaxis and treatments against disease, including increasing libido, cure and prevention of cardiovascular diseases, osteoarthritis, type II diabetes, hyperuricemia, and as antifungal preparations.

IMMUNOSTIMULATORY MEANS Useful properties of triterpene glycosides derived from the sea cucumber C. japonica are described in series of patents. These patents relate to veterinary medicine and specifically, the prophylaxis and treatment of Aleutian Disease in mink. These patents describe a product, Cucumarioside, produced from the total triterpene glycosides derived from the industrial processing waste products of the Far Eastern sea cucumber C. japonica. The drug is administered subcutaneously in 1 mL of physiological solution at a dose of 1 mg/kg of body weight, once during a treatment protocol of 2 weeks before the start of estrus and once again in the first half of pregnancy. For prevention of Aleutian disease in mink, the Cucumarioside is applied as a single subcutaneous dose of the same 1 mg/kg of body weight [55]. One of the first patents of the use of sea cucumber fractions utilizing triterpene glycosides as immunomodulatory agents was the patent by Collin et al. describing fractions of the sea cucumber, C. frondosa. The patent describes methods of production of fractions derived from epithelial layers and the tentacle portions of sea cucumber that significantly inhibit inflammation in laboratory animals and exert significant subjective benefit to humans with inflammation disorders such as arthritis [56]. Kovalevskaya et al. patented methods and compositions of matter relating to the field of radiation biology and medicine. The patent claims describe the use of triterpene glycosides, cucumariosides of the Far Eastern sea cucumber C. japonica for the treatment of radiation sickness. The claimed compositions increase the survival rate of irradiated animals and increase the resistance to exposure to ionizing radiation [57]. Two patents of Kovalevskaya et al. relate to medicinal pharmacology. The patents describe an active agent against a number of viruses such as vesicular stomatitis virus, mouse encephalomyocarditis, Coxsackie A7 and Coxsackie B7 viruses, poliomyelitis, herpes simplex, Newcastle disease and adenovirus type 7. The primary composition of matter is a mixture of triterpene glycosides from boiling water extract of the sea cucumber C. japonica which had been previously known as having immunostimulatory and adaptogenic effects. In addition, a new preventive and therapeutic agent active against tick-borne encephalitis viruses is described. The patented composition is a drug, KD, described as a mixture of triterpene glycosides of sea cucumber C. japonica, also being effective against a number of viruses [58]. A recent patent by Stonik et al. describes Cumaside, comprised of triterpene glycosides isolated from Far Eastern sea cucumber C. japonica as an immunomodulatory composition of matter. The patent describes a complex of

Review of Patents Based on Triterpene Glycosides Chapter j 4

O

H

189

O H OAc

O

O

H

OH NaO3SO CH2OH O

CH3 O

O O

OCH3 HO

O

OH

HO OH

O

OH

O

O

OH HO

OH

FIGURE 4.7 Structure of frondoside A.

monosulfated glycosides (mainly cucumarioside A2-2) (Fig. 4.5) with cholesterol in an approximate molar ratio of 1:2. This composition describes utility for the prevention and treatment of human immunodeficiency diseases. In addition, the patented composition is created through mixtures of sea cucumber glycosides from C. japonica and sterol solutions. The patent describes the useful sterols as being cholesterol and/or sitosterol. The patent also claims usefulness against cancer tumors in general [59]. A patent by Avilov et al. describes a triterpene glycoside from C. frondosa, frondoside A (Fig. 4.7), as being stimulatory of innate immunity in mammals. The patent describes the use of a chloroform/solvent mixture extraction at different solvent-to-feed ratios to isolate the compound. Following solvent extraction, the resulting mixture is evaporated and then extracted with ethyl acetate/water, followed by chromatography of the water phase on Teflon or other nonpolar resin and then silica gel column chromatography for recovering individual triterpene glycosides of high purity. The starting material of this patented process is the freeze-dried or spray-dried boiling water extract or dried powderized tissues of the industrially processed sea cucumber C. frondosa. The patent further claims that frondoside A stimulates lysosomal activity of peritoneal macrophages and phagocytosis and generates an oxidative burst in the macrophages at concentrations significantly less than for acute toxicity, hemolysis, and embryo toxicity [60]. Shnyrov et al. patented a sea cucumber triterpene glycoside complex as an immunostimulating composition and as a carrier for protein antigens. This complex is comprised of triterpene glycosides, cucumarioside A2-2 (Fig. 4.5),

190 Studies in Natural Products Chemistry

cholesterol, and monogalactosyl diacylglyceride (MGDG) polar lipid derived from sea macrophytes in mass ratio of 3:2:6. In addition, the complex is comprised of ultramicroscopic tubules having a diameter of approximately 40 nm. Antigen-containing lipid/saponin complexes with utility as a vaccine are also described [61]. Popov et al. have patented a carrier of antigens. It contains the triterpene glycoside holotoxin A1 (Fig. 4.4) from the sea cucumber A. japonicus, and MGDG from marine macrophytes taken in a weight ratio of 3 (holotoxin A1):2 (cholesterol):(2e6) (MGDG). The resulting glycoside cholesterolelipid carrier has an elongated filamentous-tubular structure. The patent claims that an antigen with the carrier enhances immunogenic activity of vaccines, as well as reducing or completely removing the hemolytic activity of holotoxin A1 and eliminating inflammation, pain, and toxic and hemolytic effects of vaccines [62]. A patent by Kim et al. describes a method and composition containing an A. (¼Stichopus) japonicus extract for anti-inflammation to suppress LPS (lipopolysaccharide)-induced iNOS and COX-1 (cyclooxygenase-1). A. japonicus is extracted with methanol; the extract is concentrated to dryness and redissolved in water followed by extraction with an organic solvent including, hexane, chloroform, ethyl acetate, or butanol [63]. One of the recent patents of Aminin et al. describes administration of triterpene glycosides of the holothurian Cucumaria okhotensis, chosen from a group consisting of frondoside A1, ochotoside B1, ochotoside A1-1, ochotoside A0-1, or cucumarioside A2-5 or their mixtures, as an agent stimulating cellmediated immunity in mammals [64] (Fig. 4.8).

O

H

O OH

NaO3SO CH2OH O

.R3

R4 O

O O

OCH3 HO

R2 OAc

O

O

H

OH R1 = O

OH

O OH HO

R1 H

O

HO OH

O

, R2 = H2, R3 = CH2OH, R4 = CH2OH Okhotoside A2- 1

R1 =

, R2 = O, R3 = CH3, R4 = CH2OH

Cucumarioside A2- 5

R1 =

, R2 = H2, R3 = CH3, R4 = H

Frondoside A1

R1 =

, R2 = H2, R3 = CH2OH, R4 = CH2OH Okhotoside B1

R1 =

, R2 = O, R3 = CH3, R4 = H

Okhotoside A1- 1

OH

FIGURE 4.8 Structure of okhotoside A2-1, cucumarioside A2-5, frondoside A1, okhotoside B1, and okhotoside A1-1.

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A patent by Kostetsky et al. describes a method and composition to regulate antigen immunogenicity including incorporation of an antigen into the immunostimulating composition (TI-complex). A porin from Yersinia pseudotuberculosis is used as the protein antigen. The carrier of the antigen is an immunostimulating complex having the form of ultramicroscopic tubules (TI-complex), which are comprised of the triterpene glycoside cucumarioside A2-2 (Fig. 4.5), cholesterol, and a polar lipid of MGDG from various marine macrophytes. The patent describes improved methods for prevention of pseudotuberculosis and other infectious diseases [65]. Thus some sea cucumber triterpene glycosides and preparations thereof were patented as immunomodulatory means. Glycosides from C. japonica were patented as veterinary preparations for prophylaxis of Aleutian disease in mink, as radioprotector and antiviral means. They were patented as part of immunostimulatory compositions of antigen-containingdlipiddsaponin complex as well as holotoxin A1 from A. japonicus possessing adjuvant properties. A complex of monosulfated triterpene glycosides from C. japonica and cholesterol was patented as immunostimulatory preparation. Frondoside A from C. frondosa was patented as immunomodulatory preparation stimulating cell immunity similar to glycosides from C. japonica. An anti-inflammatory fraction containing glycosides from C. frondosa was also patented. A series of glycosides from C. okhotensis was patented as stimulators of cell immunity. In conclusion, it should be noted that most patented immunomodulatory preparations preferably stimulators of cell immunity was created on the basis of glycosides of sea cucumbers belonging to the genus Cucumaria.

SEA CUCUMBER GLYCOSIDES AND CANCER Collin et al. have patented the use of sea cucumber fractions which include triterpene glycosides for the prevention and treatment of diseases in which angiogenesis contributes to the pathological condition. These patented methods describe means of inhibiting angiogenesis in a warm-blooded animal in need of such treatment through administration of therapeutically effective amounts of a composition comprising the isolated body wall of a sea cucumber, the isolated epithelial layer of the body wall of the sea cucumber, the tentacles of the sea cucumber, and their active derivatives or mixtures thereof. The patented preparations are claimed to be useful as therapeutic agents against malignant tumors and as preventives against various diseases, such as rheumatoid arthritis, caused by vascular hyperplasia. In addition, these patented fractions have shown therapeutic efficacy in clinically relevant surrogate biomarker assays designed to discover new cancer preventive and cancer treatment drug options [66]. An additional patent by Collin et al. relates to new classes of anticancer compounds. In particular, this patent provides triterpene glycosidic compounds from sea cucumbers as anticancer agents, alone, or in combination with other

192 Studies in Natural Products Chemistry

O

H

O H OAc

O

O

H

OH NaO3SO CH2OH O

O

O

OCH3 HO

CH3

CH2OSO3Na O

OH

HO OH

O O

OH

O

O

OH HO

OH

FIGURE 4.9 Structure of frondoside B.

anticancer agents or therapies. Specifically, the patent relates to the use of frondoside A (Fig. 4.7) and frondoside B (Fig. 4.9) from sea cucumbers as anticancer agents. The invention further provides a therapeutic composition comprising a frondoside compound (e.g., frondoside A and/or frondoside B from C. frondosa) configured by various means for administration to a subject having cancer [67]. Another patent concerning a class of anticancer agents based on triterpene glycosides of sea cucumber C. frondosa was patented by Collin et al. The patent describes multisolvent extracts derived from C. frondosa epithelial skin powder, subcomponents thereof, and related compositions for use in the treatment of cancer, including pancreatic cancer. The patented Frondanol A5 product is described as having the following activities: significant in vitro inhibition of pancreatic and prostate cancer cell proliferation as evidenced by inhibition of labeled thymidine incorporation, induction of apoptosis, inhibition of eicosanoid pathways, including 5-lipoxygenase, COX1 and COX-2, and antagonism of prostanoid receptor EP-1. It is further shown that extract Frondanol A5 has antitumor activity including in vivo antiproliferative activity in orthotopically transplanted tumors in immune competent hamsters. In some claimed examples, the patent describes Frondanol A5-CV, a multisolvent extract of dried C. frondosa epithelial skin powder. Frondanol A5-CV alters chemopreventive and treatment targets known to be involved in cancer processes. These include 5-lipoxygenase, COX-1 and COX-2, epoxidation of estrogen,

Review of Patents Based on Triterpene Glycosides Chapter j 4

O

O H OAc

H

CH2OH O

O

OCH3 HO

CH2OH O

R O

O O

HO OH

OH

Stichoposide C

O

OH

OCH3 HO

H R = CH3

HO

O

O

OH

O

OH

CH2OH O

O

193

R = CH2OH

Stichoposide D

OH OH

FIGURE 4.10 Structures of stichoposides C and D.

caspases, BCL (B-cell CLL/lymphoma 2), PPAR (peroxisome proliferator-activated receptor) gamma, and thymidine incorporation. The precipitate from the chloroform/methanol extraction, Frondanol A5-P, also may be used as an anticancer material. In some examples, the materials presented are provided in combination with agents which induce apoptosis, inhibit adenosine deaminase function, inhibit pyromidine biosynthesis, nucleotide interconversion, DNA, RNA and protein synthesis, and microtubule function [68]. Triterpene glycosides of the sea cucumbers are cucumarioside A2-2 or cucumarioside A4-2 (Fig. 4.5) or a mixture thereof, and stichoposide C or stichoposide D (Fig. 4.10) or a mixture thereof were patented by Fedorov et al. as a means to expand the arsenal of pharmaceutical compositions which can selectively stimulate apoptosis in leukemia cells and block them in the cell cycle. It is claimed in the patent that all the glycosides or mixtures thereof in noncytotoxic concentrations showed apoptosis-stimulating activity in several human leukemia cell lines, such as HL-60, THP-1, NB4, and K562. It was further confirmed by cytotoxicity assays, the study of apoptosis by flow cytometry, TUNEL (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling), and Western blot, and data on the effects upon cell cycle of cancer cells. Cucumariosides A2-2 and A4-2 are isolated from the commercially harvested edible sea cucumber C. japonica, and stichoposides C and D (Fig. 4.10) are isolated from the sea cucumber Thelenota anax [69]. Yi et al. have patented the use of echinoside A (Fig. 4.11), extracted from the sea cucumber H. nobilis Selenka, in preparing tumor topoisomerase II inhibitors. The patent describes distinct inhibitory effect of echinoside A on tumor topoisomerase II [70].

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O

O

HO OH

H

O

O

H

OH NaO3SO CH2OH O

O

O HO

OH

Echinoside A

O O

OH

O

OCH3 HO

CH3

CH2OH

OH

OH

FIGURE 4.11 Structure of echinoside A.

The individual triterpene glycoside griseaside A (Fig. 4.12) from the sea cucumber Holothuria grisea was patented by Sun et al. and described as a source of a lead compound for development of new antitumor drugs. The in vitro antitumor tests show that the compound has significant inhibiting effect upon four tumor cell lines of A-549 human gastric carcinoma cells,

OH O

O

HO H

CH2OH

O

O O

OH

Griseaside A O

OH

O O

OCH3 HO

HO OH

CH3

CH2OH O

H

OH

HO

CH2OH O

O

OH

O

OH OH

FIGURE 4.12 Structure of griseaside A.

H

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HL-60 human acute promyelocytic leukemia, Molt-4 human T lymphocyte leukemia cells, BEL-7402 human hepatoma cells, and so forth [71]. An individual triterpene glycoside, echinoside A, isolated from H. nobilis Selenka was patented by Liu et al. as a means of treating glioma and as a promising new anticancer drug. The patent describes significant inhibition of proliferation of glioma cancer cells in vivo by echinoside A [72]. A recent patent by Kalinin et al. describes the inhibition of multi-drug resistance (MDR) in tumor cells by frondoside A or a complex of frondoside A and cholesterol, and methods of preparing such a composition. The patent describes the frondoside A composition and its use as an expansion of the number and kinds of useful inhibitory agents now available against MDR in tumor cells [73]. Kim et al. patented pharmaceutical compositions and health supplements for the prevention of colon cancer comprising an A. (¼Stichopus) japonicus extract or its fractions. The extraction solvent may be 80% methanol or an alcohol having a carbon number 1 to 4, ethyl acetate, or any organic polar or nonpolar solvent such as hexane or dichloromethane, including mixed solvents including water, methanol, ethanol, and so forth [74]. An anticancer pharmaceutical or food supplement composition from a methanol extraction of A. (¼Stichopus) japonicus was patented by Kim et al. The methanol extract of the freeze-dried A. japonicus inhibits the cell growth more than 60% in a concentration of 60 mg/mL. A similar effect is described for the butanol fraction of the extract [75]. A functional dietary composition comprising an extract of A. (¼Stichopus) japonicus was patented by Choi et al. as a method to suppress prostatic hyperplasia. The patent provides a functional dietary composition for the prevention of benign prostatic hyperplasia by use of an extract of A. japonicus without toxicity and side effects. The extract is obtained by an alcohol having carbon numbers between 1 and 5, or a mixture using hexane, chloroform, dichloromethane, ethyl acetate, and butanol as the nonpolar solvents [76]. Thus a series of triterpene glycoside containing fractions from C. frondosa was patented as inhibitors of angiogenesis, cancer cell proliferation, eicosanoid pathways, and inductors of apoptosis in cancer cells. Extracts of A. japonicus and its fractions were patented as a means against colon cancer. Individual triterpene glycosides isolated from different species of sea cucumbers were patented as anticancer agents as individual substances and in combination with other anticancer preparations, cancer cells apoptotic stimulatory agents, inhibitors of tumor topoisomerase II, inhibitors of different tumor cells proliferation, and inhibitors of MDR of tumor cells.

CONCLUSIONS Sea cucumbers have been commercially harvested by hand for hundreds of years worldwide and recently by scuba diving and mechanized trawling. These

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marine invertebrates have been highly prized as food and for use in traditional medicines and health tonics, primarily in Southeast Asia. Harvesting pressures on the resources have increased worldwide in recent years, causing a decline in landings, and aquaculture operations have increased to supply the unmet needs of these traditional Asian markets, as well as the emerging health sector markets internationally. The efforts for the development of methods of sea cucumber cultivation and harvest are explained by their flavor and nutritional value. Over the years, a variety of sea cucumbers is credited with medicinal properties. It has been demonstrated that some of the products and supplements of sea cucumbers help prevent some diseases and have a pronounced therapeutic effect on certain ailments. In some cases, this therapeutic effect is due to the presence of triterpene glycosides, chemical compounds which are found in all orders of sea cucumbers. Historically, a majority of pharmaceutical drugs have had their origins in traditional medicines used over hundreds of years by indigenous populations. Recent patents, articles in peer-reviewed journals and drug discoveries give evidence of this same discovery and development model. In the last 20 years, there has been increased understanding of the biochemistry of traditional herbal medicines. The study of triterpene glycosides from ginseng is a good example of how drug discovery efforts closely follow the anecdotal reports of traditional healers. Sea cucumbers and ginseng contain significant amounts of triterpene glycosides which contribute to their highly researched health benefits. Similar to the rise of farmed cultivation of ginseng after global overharvesting of wild populations, sea cucumber cultivation is stimulated by a comparable overfishing of the available populations. The ginseng markets and the sea cucumber markets are supported by a sustained demand for the products-based food choices, but increasingly by the awareness in those markets of the pronounced health benefits enjoyed by the consumers. It is interesting to note that the traditional Chinese name for sea cucumber is “Hai Shen,” roughly translated as “ginseng of the sea.” This review of recent world patents covering sea cucumber triterpene glycosides describes emerging knowledge of specific biomedical and biochemical pathways and specific compositions of matter, useful in the allopathic and alternative healing arts. In addition, these recent patents describe specific individual glycosides and mixtures of glycosides that can now be manufactured and distributed as ethical and meaningful health food supplements and disease-specific medicines. Also included in this patent review are modifications of glycosides as well as their synergies with other useful compounds. The range of health benefits described in these patents is wide and includes immunopotentiating, immunomodulating, and adaptogenic medicines and foods, cancer preventives and anticancer health supplements and single molecule cancer medicines, products for support of mental health, protection from radiation, health restoratives, probiotic products, reproductive health supplements, medicines addressing type II diabetes, specific formulations

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against arthritic diseases, drugs for hyperuricemia and combating fungal infections, and various cosmetics to address dermatological conditions. Some of the mentioned medical properties are due to combined and/or synergic effect of triterpene glycosides and other biologically active compounds present in some sea cucumbers, such as certain peptides, amino acids, polysaccharides, lipids, vitamins, and so forth. But primarily, the pronounced health benefits from sea cucumber result directly from triterpene glycosides being incorporated into human and animal diets. There is a critical mass of medical research and patents that now point to the efficacy of this class of medical drugs and nutraceutical food supplements based on sea cucumber triterpene glycoside compounds. It is hoped that these new drugs, foods, main, and auxiliary means will be further developed and made available worldwide for the prevention and treatment of these many disease conditions.

ACKNOWLEDGMENTS This study was supported by the grants of RFBR Nos 14-04-01822-a, 16-04-00010 and the grant of President of Russian Federation MK-4329.2015.4. The authors are very appreciative to Professor John M. Lawrence (University of South Florida, Tampa, USA) for correction and useful discussion of the manuscript.

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Chapter 5

Bioactive Dietary Compounds Regulate Mitochondrial Apoptosis Signaling in Ambivalent Way to Function as Neuroprotective or Antitumor Agents Makoto Naoi,1 Yuqiu Wu, Masayo Shamoto-Nagai, Wakako Maruyama Aichi Gakuin University, Nisshin, Japan 1 Corresponding author: E-mail: [email protected]

Chapter Outline Introduction Mitochondria Regulate Cell Survival and Death Mitochondrial Permeability Transition: Structure of Pore Regulation of Mitochondrial Permeability Transition Mitochondrial Superoxide Flash and Ca2þ Efflux as Indicators of Transient and Persistent Pore Formation Phytochemicals Suppress and Promote MPT in Apoptosis Dietary Components Protect Cells by Regulation of Mitochondrial Apoptosis Signaling

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Dietary Components Enhance Apoptosis Signaling in Cancer Cells Molecular Mechanism Behind Ambivalent Functions of Phytochemicals Phytochemicals Regulate MTP at the IMM Mechanism Behind the Regulation of MPT by Phytochemicals: Involvement of Oxidative Stress and Membrane Lipid Fluidity Conclusion Abbreviations Acknowledgment References

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INTRODUCTION In aging and age-related neurodegenerative disorders, loss of neuronal cells induces the decline in cognitive, motor and perceptual activity, and neuroprotection to prevent, delay, or even reverse the cell death has been proposed as antiaging and disease-modifying therapy. Loss of distinct neurons and accumulation of denatured proteins are commonly observed pathological features in the brain of aging and neurodegenerative disorders. The etiology of Parkinson’s and Alzheimer’s disease remains enigmatic, whereas the cell death is caused by oxidative stress, mitochondrial dysfunction, impaired ubiquitin-proteasome and autophagy system, endoplasmic reticulum stress, neurotoxins, excitotoxicity, and neuroinflammation. In the brain, programmed cell death, especially in the form of apoptosis, is often detected, which is induced either by receptor-mediated extrinsic or mitochondria-associated intrinsic apoptosis pathway. Apoptosis cascade initiated in mitochondria is a well-conserved system and processes through mitochondrial membrane permeability transition (MPT), namely sudden increased permeability of mitochondrial membrane, release of apoptogenic protein, such as cytochrome c, Smac/Diablo, apoptosis inducing factor and endonuclease G, into the cytoplasm, activation of caspases, and fragmentation and condensation of nuclear DNA to form typical cellular features of apoptosis [1e5]. Neuroprotection has been confirmed in cellular and animal models of Parkinson’s and Alzheimer’s diseases using various lines of agents. Molecular mechanism has been clarified mainly by the use of inhibitors of type B monoamine oxidase (MAO-B), such as selegiline [()deprenyl, (2R)-Nmethyl-1-phenyl-N-prop-2-ynyl-propan-2-amine] and rasagiline [(R)-N2-prop-2-ynyl-2,3-dihydro-1H-inden- amine]. Selegiline and rasagiline inhibit MAO-B to reduce oxidative synthesis of hydrogen peroxide but also protect neuronal cells against apoptosis and necrosis through regulation of MPT and induction of genes, including antiapoptotic Bcl-2 and prosurvival neurotrophic factors, such as neurotrophins [brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3] and glial cell lineederived neurotrophic factors (GDNFs), and antioxidant enzyme (catalase, superoxide dismutase) [6e11]. Epidemiological studies reveal that dietary habits and bioactive food factors, including green tea catechins, Ginkgo biloba, u-3 fatty acid, and polyphenols, prevent ageing-related decline in cognitive and motor performance and depression. Dietary compounds improve impaired cognitive function in humans and animal models, the mechanism of which have been proposed to be the cell membrane, energy metabolism, BDNF levels, and synaptic plasticity, in addition to antioxidative and antiinflammatory function [12e15]. EGb761, an extract of Ginkgo biloba [16], flavonoid-rich orange juice [17] have been reported to improve cognitive function, but the results from clinical studies are

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still controversial and the conclusion of the beneficial effects of food factors requires further investigation [18e21]. Recently we established a cellular model of apoptosis in human catecholaminergic SH-SY5Y cells by use of PK11195 [1-(2-chlorophenyl)-Nmethyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide], a ligand of the outer membrane translocator protein 18 kDa (TSPO, also called as peripheral benzodiazepine receptor) [22,23]. PK11195 induced MPT with burst of superoxide called “superoxide flash” [24,25] and release of calcium (Ca2þ) from mitochondrial pool, followed by cytochrome c release into the cytoplasm, caspase activation, and nuclear DNA fragmentation. Rasagiline and selegiline prevented the MPT by PK11195 and following activation of apoptosis [22,23,26]. These results indicate the MPT as the initial signal in mitochondrial apoptosis and its regulation as the vital point to decide the neuronal fate. On the other hand, ambivalent functions of dietary compounds are shown to be either prosurvival or cytotoxic in neurons and cancer cells [27]. The different redox potency of dietary factors has been proposed to contribute the controversial functions, but the cellular mechanism should be further clarified. We investigated the effects of dietary compounds on MPT, using our established cellular model in order to clarify the structureeactivity relationship to the MPT suppressive or enhancing activity. In this review, we concentrate our subject on molecular mechanism how natural food factors regulate MTP and mitochondrial apoptosis signal pathway in neurons and cancer cells to prevent or promote cell death. The results are discussed in relation to novel function of bioactive natural products as antiaging neuroprotective agents and also as a possible therapeutic strategy against cancer.

MITOCHONDRIA REGULATE CELL SURVIVAL AND DEATH Mitochondria arose more than a billion years ago after primitive bacteria invaded a single-cell anaerobic organism of an Archea-type and established a symbiotic relationship through the evolutional development as a selfregulating organelle with high efficiency to use oxygen and substrates (glucose and pyruvate) to generate ATP [28e31]. Thirteen proteins in the electron transport chain (ETC) are encoded in mitochondria genes out of more than 1000 mitochondrial proteins, whereas others are coded in nuclear genes. The role of mitochondria in age-associated neuronal degeneration has been mainly discussed in relation to production of ROS and reactive nitrogen species (RNS), leading to oxidative stress, impaired cellular function, energy crisis, disturbed calcium homeostasis, and cell death. Furthermore, programmed cell death may have evolved with the endosymbiotic incorporation of the aerobic a-proteobacteria, a group of obligate intracellular parasites [32]. The structure of mitochondria and the regulation of cell death

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are quite similar from lower eukaryotes (yeast) to human [33,34], suggesting that mitochondria play a more direct role in cellular fate. This session discusses the basal death machinery, the regulation and possible targets in mitochondria for the neuroprotective agents or anticancer agents.

Mitochondrial Permeability Transition: Structure of Pore Under physiological conditions, mitochondrial membrane permeability is tightly regulated, and mitochondria reserve an electrochemical gradient across the inner mitochondrial membrane (IMM), created through ETC and exclusion of Hþ from the matrix to the intermembrane space. The intact mitochondrial membrane potential, DJm, is essential required for the mitochondrial physiological activity, energy synthesis, Ca2þ and pH homeostasis in cells, and also sequencing caspase activators. In apoptosis and necrosis, initially the membrane permeability increases at the IMM with DJm collapse. Under mild stimulus, transient and reversible pore is formed, which allows entry of water and solutes with molecular mass up to 980 Da, metabolites and inorganic ions into the matrix. Cyclophilin D (Cyp-D, a peptidyl-prolyl cis-trans isomerase) in the matrix binds to adenine nucleotide translocator (ANT) at the IMM and the pore is formed. Cyclosporin A (CysA) binds to Cyp-D and inhibits Cyp-D binding to ANT and suppresses the pore formation. More intense insults make the IMM pore irreversible, and a nonselective mega channel, called permeability transition pore (mPTP), opens fully, which increases the membrane permeability to solutes with molecular mass up to 1500 Da, and influx of solutes causes expansion of the matrix and rupture of the outer mitochondrial membrane (OMM). Cytochrome c and other caspase activator proteins released from the matrix into the cytoplasm activate caspase and finally apoptosis, whereas necrosis is induced when ATP levels decrease abruptly to less than 50% [35]. The mPTP is a pore with c.3-nm diameter and formed by assembly of proteins, but the exact composition and regulatory mechanism are still matter of debate [36e38]. The major proposed proteins include ANT at the IMM, voltage-dependent anion channel (VDAC, porin) at the OMM, Cyp-D at the matrix. TSPO, the Bcl-2 protein family, the hexokinase bound to VDAC at the OMM and the creatinine kinase in the intermembrane space are also bound to the mPTP and associated with the regulation. Recently, the mitochondrial phosphate carrier, ubiquinol-cytochrome c-reductase core protein II, has been proposed as the real regulator of the mPTP through binding to Cyp-D [39]. The mPTP opening is the point of “no return” in most apoptosis. In addition to Cyp-D or phosphate carrier, Bcl-2 protein family regulates the pore formation at the OMM, either in preventing (Bcl-2, Bcl-xL, Mcl-1, and Bcl-w), or promoting way (Bax, Bak, and Bad). Bcl-2 protein functions primarily during the initiation of apoptosis, and under physiological condition, these antiapoptotic and proapoptotic species form the heterodimer and

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antagonizes each other, whereas in apoptosis Bcl-2 proteins are activated or displaced with either species and form neuroprotective or apoptogenic homodimers. A pore called mitochondrial apoptosis-inducing channel is formed by homodimerization of Bax and Bak at the OMM [40].

Regulation of Mitochondrial Permeability Transition Mitochondria function not only as the sole powerhouse producing ATP in cells, but also they are the major site of free radical generation and initiation of oxidative stress. Excess production of ROS and RNS induces either a loss or a gain of function or a switch to a different function, suggesting the pathogenic roles in neurodegenerative disorders, cancer, and other diseases. Vice versa mitochondria are also damaged by free radicals produced in situ. Oxidative stress induces MPT by direct oxidative modification of mitochondrial protein and pyridine nucleotides [41]. NAD(P) redox state regulates MPT by the reductive effects for glutathione (GSH) and thioredoxin to remove H2O2 and O 2 in mitochondria. In addition, NADPH redox state maintains DJm as higher level and prevents its collapse by controlling NADP transhydrogenase sensitive to DJm [42]. This NADPH redox state maintains GSH level and mitochondrial protein thiol redox state [43]. MPT is regulated by thiol state in mitochondrial protein; thiol reductants (dithiothreitol) prevent MPT, whereas thiol oxidants (diamide, phenylarsine oxide, and 4,40 -diisothiocyanato-stilbene-2,20 - disulfonic acid) promote MPT [44]. Oxidative stress decreases the binding of adenine nucleotides (ADP and ATP) to ANT, or increases Cyp-D binding [45,46]. Oxidation of a critical cysteine residue (Cys56) of ANT enforces mPTP opening and apoptosis [47]. ROS and phenylarsine oxide cross-link two thiol groups between Cys169 and Cys257 on the matrix surface of ANT, affect ADP- and Cyp-D- binding, and stimulate pore opening [48]. The mPTP opening is modulated by specific ligands, such as carboxyatractyloside (CAT) and bogkretic acid (BKA). CAT induces the “c” conformation of ANT and sensitizes pore opening to Ca2þ, whereas BKA enhances “m” conformation and inhibits pore opening [39,45,49]. However, the detailed structure of these “c” and “m” conformation has not been characterized. Ca2þ and phosphate also activate mitochondrial pore opening. Mitochondria are the sites of intracellular Ca2þ signaling and storage and maintain the Ca2þ gradient across the IMM. Ca2þ in mitochondria activates the oxidative phosphorylation, tricarboxylic acid cycle dehydrogenase, and the ATP synthesis [50,51]. Ca2þ homeostasis in cells and mitochondria is strictly regulated by Ca2þ pumps, channel and buffering protein [52,53]. Ca2þ accumulation in mitochondrial matrix through the ion-impermeable IMM is mainly carried out by the mitochondrial Ca2þ uniporter, which in counteracted by mitochondrial Naþ/Ca2þ exchangers (mNCX). Ca2þ homeostasis is

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maintained by DJm coupled with Hþ translocation across the IMM through ATP synthesis in the ETC. The OMM is permeable to nonelectrolytic (without charge) solutes with molecular mass smaller than 5000 Da, and the role of the OMM and VDAC in Ca2þ accumulation may be limited. Ca2þ-involved necrosis is observed in excitotoxicity of neurons and ischemia reperfusion of the heart. Ca2þ overload in mitochondria increases ROS generation and opens the mPTP, rapid DJm collapse, cytochrome c release, and ATP depletion, leading to necrosis in cardiomyocytes [54]. In excitotoxicity, activation of Nmethyl-a-aspartate receptors by glutamate allows extracellular Ca2þ into the cytoplasm and further causes Ca2þ overload in mitochondria [55]. Excess Ca2þ interacts with the anionic head of cardiolipin, alters the lipid organization at the IMM, and increases ROS production. Ca2þ binds to “c” state of ANT-surrounding cardiolipin, weakens the interaction of ANT with cardiolipin, and enhances the mobility of Cys56 of ANT to be oxidized, resulting in the mPTP opening [56]. In apoptosis, Ca2þ is an important trigger for the mPTP opening. Ca2þ synergically activates subthreshold apoptosis signal (mild oxidative stress, C2 ceramide production), and induces morphological modification of mitochondria, and cytochrome c release, mitochondrial fission, and directly activates caspases. Recently, MPT is proposed to mediate the ROS production by Ca2þ, suggesting again that the MPT regulation may be the main target for mitochondria-targeting therapy [57,58]. Mitochondrial drugs are designed as antioxidants for therapy against aging and neurodegenerative disorders, as inducers of apoptosis in cancer therapy, or as uncouplers of the ETC in obesity and diabetes. The targets of mitochondria therapy include Bcl-2 protein family, TSPO, and the ETC, in addition to ANT, Cyp-D, and VDAC [59,60]. Bioactive natural products may be one of the most promising candidates because of their ambivalent functions [27].

Mitochondrial Superoxide Flash and Ca2D Efflux as Indicators of Transient and Persistent Pore Formation The step-wise increase of membrane permeability is clearly shown in our apoptosis model prepared with PK11195 (Fig. 5.1) [22,23,26]. By addition of PK11195, sudden transitional production of superoxide ðO2  Þ called “superoxide flashing” is observed for less than 2 s, followed by gradual increase of Ca2þ in the cytoplasm (Fig. 5.1). Increased O2  and Ca2þ are simultaneously quantified by use of a chemiluminescence probe for O2 , MCLA [2-methyl6-(4-methoxyphenyl)-3,7-dihydro-imidazo-(1,2-a)-pyrazin-3-one-HCl], and Fluo 3-AM, a cell-permeable Ca2þ fluorescence indicator, in a fluorescenceluminescence spectrophotometer, PMX-6100 (Hamamatsu Photonics, Hamamatsu, Japan) [61,62]. Pretreatment of CysA prevented superoxide flash and Ca2þ efflux, whereas Blc-2 overexpression suppressed Ca2þ efflux but did not suppress O2  flash.

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O2.- flash

207

Ca2+ efflux Ca2+ (units)

O2• − (units)

120000 14000 90000

+ PK11195 11000

+ PK11195

8000

Control

Control

60000 30000 0

5000

0

250 500 Time (sec)

0

250 500 Time (sec)

FIGURE 5.1 PK11195 opened the pore at the inner mitochondrial membrane and O2  flash was observed, followed by Ca2þ efflux into the cytoplasm. CysA treatment prevented O2  flashing, whereas Bcl-2 overexpression inhibited Ca2þ efflux.

These results indicate that the pore formation occurs at the IMM and advances to open mPTP across the OMM, IMM to matrix. O2  flash will be a marker of the transient MPT at the IMM and Ca2þ of the persistent formation of mPTP. 2þ Rasagiline, an antiapoptotic MAO-B inhibitor, could inhibit O 2 flash, Ca efflux, cytochrome c release, caspase 3 activation, and apoptosis. Regulation of the MPT at the IMM should be the decisive point for the antiapoptotic function [22,23,26]. O2  flashes are transient, intermittent, qunatal massive, bursts of O2  production lasting less than 10 s long in the matrix [24,25]. Suddenly, all-ornone O2  production is initiated by flickering pore opening by metabolic stress and increased ROS or Ca2þ and transient DJm depolarization [63e65]. O2  flashes have been detected in neurons, astrocytes, cardiomyocytes, skeletal muscle myotubes and fibers, and many types of cancer cells [66]. Physiological roles of O2  flashes are the participation in early developmental signaling, and regulation of the differentiation of cortical neuronal progenitor cells [67,68], but this issue remains to be further clarified. Ca2þ is released from mitochondria by the mPTP activation, which is prevented by CysA treatment and Bcl-2 overexpression [23,26]. SH-SY5Y ells are treated with a cell-permeable Ca2þ chelator, 1,2-bis(2-aminophenoxy)-ethane-N,N,N0 ,N0 -tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA-AM), in order to chelate Ca2þ selectively in the cytoplasm and mitochondria by warm and cold treatment [69]. Ca2þ depletion from mitochondrial pool reduced Ca2þ efflux by PK11195 but did not affect O2  flashing. These results indicate that PK11195 induces the initial transient pore opening, which is sensitive to CysA, but independent of mitochondrial Ca2þ, followed by the persistent mPTP opening and the release of Ca2þ and apoptosis-inducing proteins from the matrix, which is regulated by Bcl-2. Fig. 5.2 summarizes the two steps of pore formation by PK11195.

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Cytoplasm

Bax Bcl-2 TSPO

PK11195

OMM

Phytochemicals Rasagiline, selegiline

VDAC IMM

Matrix

ANT

Cyp-D

CysA

O2.- flash, ΔΨ m decline, water entry, mitochondrial swelling

Cytoplasm

VDAC

Bcl-2

OMM

Apoptosis IMM

Matrix

ANT

mPTP

Ca2+ efflux, Cyt c release, ROS production FIGURE 5.2 PK11195 induces transient pore formation at the IMM, which CysA prevents. O2  flashes and entry of water into the matrix cause DJm decline, ETC dysfunction, and swelling of mitochondria, leading to the persistent mPTP opening, which Bcl-2 suppresses. The mPTP allows the release of cytochrome c and activates apoptosis cascade.

PHYTOCHEMICALS SUPPRESS AND PROMOTE MPT IN APOPTOSIS Phytochemicals are bioactive secondary metabolites derived from plants containing polyphenols, carotenoids, glucosinolates, amines, or alkaloids, and their activities attribute disease-preventive and health beneficial function. Protective effects of phytochemicals are recognized against infectious and degenerative disorders, such as aging, Alzheimer’s and Parkinson’s disease, cardiovascular disease, and cancer [70]. In vivo and in vitro experiments have proved antioxidative activity of phytochemicals as the major player of beneficial effects, but the results from clinical trials are controversial, indicating that the effects of dietary compounds depend on complex interactions within human body; direct and indirect effects on oxidative stress, mitochondrial function, and gene induction. Therefore, we will focus our topic mainly on the regulation of MPT by phytochemicals in neurons and tumor cells.

Dietary Components Protect Cells by Regulation of Mitochondrial Apoptosis Signaling Aging is associated with mitochondrial dysfunction and vulnerability to oxidative stress, impaired Ca2þ homeostasis, and other insults. The lower

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DJm was observed in aged or senescent cells, including neurons, lymphocytes, hepatocytes, and cardiac myocytes [71e73]. The threshold to Ca2þinduced, CysA sensitive Ca2þ release was significantly lower in brain and liver mitochondria from aging mice [74,75], and the ratio between Cyp-D and ANT increased [76]. Age-dependent increased oxidative stress modifies and deforms the mPTP components, Cyp-D, ANT, and cardiolipin, changes Bcl-2 levels, and depletes u-3 polyunsaturated fatty acids, which may contribute to sensitize mPTP in aging brain [77,78]. Neuroprotection targeting the MPT by phytochemicals has been proved in the brain of old rats: EGb761 prevented age-related morphological changes in mitochondria [79], and curcumin decreased mitochondrial dysfunction in the fast-aging senescence-associated mouse-prone 8, improved DJm and ATP, and restored mitochondrial fusion [80]. The mitochondria therapy using berberine, quercetin, and chalcones, the precursors of flavonoids and isoflavonoids, showed beneficial effects in animal and cellular models of ischemia-perfusion damage of the cardiomyocytes and neurons, inflammatory diseases, diabetes, and neurotoxins [81e85]. The molecular mechanism of the protective, antiapoptotic function is ascribed to the scavenging of ROS-RNS, preservation of the ETC activity, inhibition of cytotoxic signals (a transcription factor nuclear factor erythroid-2 related factor 1/2 [Nrf1/2], and extracellular signal-regulated protein kinase [ERK1/2]), activation of protective phosphatidylinositol-3-kinase (PI3K)/Akt pathway, attenuation of Ca2þ overload, chelation of toxic metals, induction of pro-survival genes (Bcl-2, Bcl-xL, superoxide dismutase, catalase) and the suppression of apoptogenic genes (Bax, Bad, cytochrome c, caspase-3, -9 and -12) [20]. However, the direct regulation of the mPTP by phytochemicals has not been reported.

Dietary Components Enhance Apoptosis Signaling in Cancer Cells Most of tumor cells are resistant to apoptosis, and mitochondria are also involved in tumorigenesis and tumor progression. Correlation has been reported between the mutations and oxidation of mitochondrial DNA and tumorigenesis [86,87]. The mPTP-targeting anticancer agents are designed to trigger the pore opening by stimulating ROS generation and increasing intracellular Ca2þ concentrations or decreasing endogenous inhibitors of mPTP opening, such as glucose, creatine phosphate, ATP, and glutathione [36]. Synthetic compounds were reported as anticancer drugs targeting ANT, TSPO, hexokinase, and ROS overproduction [88]. Epidemiological studies indicate that diet habits, such as the Mediterranean diet may protect humans against several kinds of cancer, but at present, the clinical and epidemiological studies cannot present direct evidences for the prevention by bioactive diet compounds, whereas some dietary compounds, such as foods rich in fat increase the incidence of breast cancer [89]. However,

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in cellular models, the molecular mechanism has been intensively investigated to establish the rational basis for developing antitumor agents. Natural antiproliferative compounds, such as derivatives of pyridothiopyranopyrimidine, and 1,4-dihydrobenzothiopyrano[4,3-c]pyrazole, and 3a-hydroxy-masticadienonic acid were reported to inhibit mitochondria and promote cell death [90e92]. Curcumin [1,7-bis(4-hydroxy-3-methoxphenyl)-1,6-heptadiene-3,5-dione] shows antioxidant but also cytotoxic activity in vivo and in vitro [93e95]. Curcumin induced the CysA-sensitive opening of mPTP and apoptosis in WM-115 melanoma cells [96], increased ROS generation, and downregulated Bcl-2, Bcl-xL, and inhibitor of apoptosis protein in human renal Caki cell line [97]. In human hepatoma G2 [98] and colon cancer Colo 205 cells [99], curcumin increased O2  production and caused mitochondrial DNA damage, transient DJm elevation followed by cytochrome c release, DJm collapse, and apoptosis.

MOLECULAR MECHANISM BEHIND AMBIVALENT FUNCTIONS OF PHYTOCHEMICALS Phytochemicals regulate mitochondrial apoptosis machinery either in a preventing or enhancing way, through the effects on oxidative stress in mitochondria. Redox state of phytochemicals is proposed as the most critical factor in decision to suppress or induce the mPTP activation, which is often observed as the biphasic concentration activity relationship. Fig. 5.3 shows polyphenol functions either antioxidant, or prooxidant. A novel aspect on cellular mechanism of MPT regulation by phytochemicals is presented from our recent results.

OH OH OH

. OH

O

H2O

OH

OH OH OH OH

O

+ H2O2

H2O + . OH

OH

OH

FIGURE 5.3 Scavenging and formation of polyphenol derivatives. In the presence of ion, H2O2 produces OH radical by the Fenton reaction.

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Phytochemicals Regulate MTP at the IMM As discussed previously, phytochemicals regulate the MPT in diverse ways. Our established assay method could demonstrate the structure-dependent effects of phytochemicals on the initial transitional pore opening at the IMM and the following persistent mega channel formation at the contact site between the IMM and OMM. Ferulic acid [(E)-3-(4-hydroxy-3-methoxy-phenyl)prop-2-enoic acid] derivatives, sesame lignans (sesamin, sesamolin, and sesaminol) and astaxanthin (Ast, 3,30 -dihydroxy-b-carotene-4,40 -dione) were investigated for their structure-activity relationship on the MPT regulation. Ferulic acid is synthesized in plants by the conversion of 4-hydroxycinnamic acid via caffeic acid, and the daily intake of caffeic and ferulic acid is about 500e1000 mg in humans [100e102]. Ferulic acid shows a strong radical scavenging activity toward hydroxyl and superoxide radicals, and peroxynitrite. 4-Hydroxy and 3-methoxy groups on the benzene ring are associated with antioxidant function by formation of a resonance stabilized peroxyl radical intermediate [103,104] (Fig. 5.4). The carboxylic acid group acts as a lipid anchor and protects membrane against lipid peroxide [102]. The antioxidant function may verify therapeutic potency against Alzheimer’s disease [105] and Parkinson’s disease [105e107], several acute and chronic disorders including ischemia, and cardiovascular diseases [108]. The discrepant antitumor function is also recognized among ferulic acid derivatives [109,110]. Ferulic acid derivatives suppressed or enhanced the mPTP opening, Ca2þ release into the cytoplasm and the constituent O 2 production in control SH-SY5Y cells. The inhibitory potency was dependent on the polarity of the side chain: suppression of Ca2þ efflux was most potent by the derivative with OH group (coniferyl alcohol), followed by with CHO (coniferyl aldehyde), whereas the effects other derivatives were not so significant. The basal ROS production was most markedly decreased by the aldehyde derivative and less by other derivatives except ferulic acid itself. In the mPTP opening induced by PK11195, coniferyl aldehyde, and alcohol inhibited O 2 flash and the basal ROS production markedly, whereas ferulic acid itself increased and the ethyl 3HC

O

R

HO R= COOH CHO OH

Hydrophobicity Ferulic acid Coniferyl aldehyde Coniferyl alcohol

CH3 Isoeugenol COOCH2CH3 Ethyl ferulate

FIGURE 5.4 Chemical structure of ferulic acid derivatives. They share the common structure of 4-hydroxy-3-methoxy-phenyl and are different in the side chain with distinct hydrophobicity.

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ester and the CH3 derivative did not affect. The alcohol and aldehyde derivatives decreased Ca2þ efflux most markedly, followed by ferulic acid and the CH3 derivative, as in the case with the suppression of O2  flash. On the other hand, the ethyl ester synergistically increased O2  flash, Ca2þ efflux, and the basal ROS production in PK11195-treated cells (Wu et al., in preparation). Sesame lignans prepared from sesame seeds are reported to exhibit promoting effects on human health, including cholesterol-lowering and blood pressureelowering capacity, protection against ethanol-induced liver injury and hyperglycemia-induced b cell apoptosis, neuroprotection, and antitumor function in vivo and in vitro [111e114]. Sesamin is the major lignin constituent in sesame seed (>98%) and its potent antioxidant capacity contributes the effects against hypertension and hyperlipidemia [115e117]. In addition, induction of antiapoptotic Bcl-2 and genes of proteins regulating fatty acid metabolism have been proposed to attribute the bioactivity [114,118]. Fig. 5.5 presents structure of sesamin, sesamolin, and sesaminol. Sesamin protected PC12 cells against the cytotoxicity of dopamine and L-DOPA, through inhibition of ROS production, induction of extracellular signaleregulated kinase (ERK1/2), and Bcl-2 expression and inhibition of caspase 3 activation [119]. Sesamin and sesaminol suppressed inflammatory reactions, such as increased expression of cyclooxygenase 2, inducible nitric oxide synthase, and toxic cytokines (IL-6 and TNFea) to protect cells [120e122]. We confirmed that sesame lignans suppressed or promoted the mPTP opening according to the structure. In control cells, sesame lignans increased Ca2þ efflux, but suppressed O2  flash. Sesamin and sesaminol suppressed constituent ROS production, but sesaminol increased it. Sesamin was the most potent to increase Ca2þ efflux in control cells, and only sesamin synergistically enhanced PK11195-induced Ca2þ and O2  flashes. Sesaminol and sesamolin decreased PK11195-induced O2  flashes and constituent ROS production and Ca2þ efflux.

O

O O

H

O

H

O

O

O

H H O O

Sesamin

O H

O O

O

HO H

O O

O

O

O O

Sesamolin

Sesaminol

FIGURE 5.5 Lipophilic sesamin and sesamolin or hydrophilic sesaminol are isolated from polarsoluble or water-soluble fractions of sesame seeds.

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Astaxanthin (Ast) is a member of the caroteneoid family like b-carotene and has quite high antioxidant activity and the beneficial effects for heath were shown clinically, such as reduction of oxidative stress in obese subjects and smokers, oxidative DNA damage and inflammation markers C-reactive protein, and increase of serum HDL-cholesterol and adiponectin in subjects with hyperlipidemia [123e125]. Preliminary small-scale study showed Ast improved cognition in aged subjects [126]. The presence of hydroxyl and keto endings on each ionone rings of Ast contributes to its unique higher antioxidant activity and more polar configuration than other caroteneoids (Fig. 5.6). It accepts or donates electrons without being destroyed or becoming prooxidant in the process. Ast has been proposed to scavenge ROS at the surface and inside of membrane, increase the membrane rigidity, prevent the mPTP opening, and to protect cells, as shown in a natural and an artificial membrane model, liposome [127,128]. Neuroprotective activity of Ast has been reported against cell death induced in vitro by 6-hydroxdopamine and docosahexaenoic acid hydroperoxide [129], and in vitro and in vivo by a dopaminergic neurotoxin, 1-methyl4-phenyl-1,2,3,6-tetra-hydro-pyridine [130]. Antioxidant and Ca2þ chelating activities have been proposed as a major mechanism of the protection. Ast forms a complex with Ca2þ in 1:2 stoichiometry and reduces the Ca2þ toxicity [131]. Ast of concentrations higher than 0.1 mM inhibited O2  flashes, Ca2þ efflux, and following apoptosis in PK11195-activated mPTP opening. This potency did not directly depend on the Ca2þ-chelating and antioxidant function, suggesting the primary interaction of Ast with the MPT-inducing factor. Ast did not synergistically enhance PK11195-induced O2  flashes, which might be relevant with the fact that Ast cannot function as a prooxidant. In some types of cancer cells, such as rat hepatocellular carcinoma CGRH (chonic gonadotrophin-release hormone)-7919 cells, Ast induced apoptosis with DJm collapse, impaired ETC function, and reduction of antiapoptotic Bcl-2, but the molecular mechanism was not clarified [132].

O OH

HO O FIGURE 5.6 Chemical structure of astaxanthin.

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Mechanism Behind the Regulation of MPT by Phytochemicals: Involvement of Oxidative Stress and Membrane Lipid Fluidity Bioactive natural compounds, including phytochemicals and fatty acids, function as either antioxidants or prooxidants and contribute the health maintenance [133e135]. Polyphenolic phytochemicals, including hydrocinnamic acid, chalone, and flavonoids, function as antioxidants and prooxidants, which may be associated with their ambivalent bioactivity observed in cellular and animal models [136e138]. The discrepant results may be due to used experimental conditions, such as cell types, the concentrations of compounds, high pH, and presence of active transition metal ions and oxygen. However, the different redox potency of phytochemicals attribute to their biological properties. Flavonoids are biosynthesized through flavanones and flavonols, and the basic structure is a 15-carbon skeleton consisting of two benzene rings (A and B) liked through a heterocyclic pyrane ring (C) (Fig. 5.7). Polyphenols contain a meta-5,7-dihydroxy group in the A ring and an orthodiol or trihydroxyl group in the B ring. The diol group scavenges catalytic ions and prevents ROS production, and the hydroxyl group reacts with free radicals to form a stable compound and protect cells from cytotoxic oxidative stress (Fig. 5.7). At high doses and in the presence of metal ions, polyphenols function as prooxidants and induce apoptosis in tumor cells, and the cytotoxicity is associated with single electron oxidation [139]. Curcumin shows antioxidant and free radical scavenging activities, protects cells from oxidative stress, and in vivo and in vitro cytoprotective activity of curcumin has been reported [140,141]. As discussed previously, it also shows chemo-preventing properties against human malignancies and also in animals, inhibits the tumor initiation by carcinogenesis [142e147]. Curcumin induces the mPTP by thiol oxidation of mitochondrial membrane protein, maybe by its prooxidant activity at higher concentrations [148]. The dual function of curcumin as antioxidant and prooxidant is involved in these controversial effects on neuronal and tumor cells. Studies on the structure activity of curcumin derivatives reveal phenol and methoxy groups promote the mPTP opening by oxidation of thiol groups, whereas hydrogenation increases radical scavenging and antioxidant potency [95]. In addition to antioxidant function, curcumin 3’ 2’ 8

1

O 7

A

C

6

1’ 2

B

4’ 5’

6’

3 5

4

FIGURE 5.7 Basal structure of polyphenol.

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exhibits antiinflammatory, immune-modulating, and antiatherogenic activities, directly reduces the toxicity of amyloid-b-peptide toxicity [97], and activates protective or cytotoxic genes, and signal pathways [149]. These results suggest that bioactivity of curcumin should be discussed further in respect to its multiple function. Some phytochemicals are both lipophilic and hydrophilic, dissolved at the interface between plasma membrane and aqueous layer. They quench the propagation of free radicals in lipid peroxidation, whereas they oxidize a-tocopherol in lipid membrane, and ascorbic acid and glutathione in the aqueous layer. Their hydrophobicity is correlated with cytotoxicity [150]. Increase in mitochondrial membrane fluidity induces MPT, as in the case with free fatty acids. Saturated free fatty acids with 12 to 18 carbon chain length induce CysA-insensitive swelling of mitochondria, whereas unsaturated fatty acids open mPTP [151]. In mitochondria enriched in cholesterol, CysA-sensitive MPT was impaired in a dose-dependent way to cholesterol due to decreased membrane fluidity [152]. Vice versa, MPT increased mitochondrial membrane fluidity, which may be due to conformational change of mPTP components, especially CysA-sensitive ANT-Cyp-D complex [153]. MPT induced by mastoparan peptide, a tetrad-peptide (INLKALAALAAKKIL-NH2) was sensitive to CysA at the lower concentration, but insensitive at the higher concentration. This peptide regulates MTP via the effects of mitochondrial membrane fluidity [154], as shown in plasma membrane of cells undergoing apoptosis [155]. We focused our discussion on the regulation of MPT, but the health beneficial effects of phytochemicals are also attributed to their effects on signal mechanism and epigenetic modification. Polyphenols are known to modify the intracellular signal pathway associated with cell growth and differentiation and induce expression of genes encoding antioxidant enzymes SOD (superoxide dismutase), catalase, glutathione reductase and peroxidase, and others), Bcl-2 protein family and neurotrophic factors (NGF, BDNF, GDNF). ()Epicatechin activates PI3K, antioxidant response element (ARE), Nrf1/2 and upregulates glutathione and antioxidant enzyme (glutathione-cysteine ligase, MnSOD, heme oxygenase) [156,157]. The redox-sensitive regulating system, ARE/Nrf1/2/Kelch-like ECH-associated protein 1 (Keap1) may be a major target of phytochemicals, in addition thiol residues in mitochondria [134,158]. Tumor growth is associated with epigenetic and genetic aberrations leading to altered gene expression. Epigenetic deregulation occurs during early phase of neoplastic development and most common epigenetic modifications are changes in the DNA methylation pattern, posttranslational histone modification, and the varied expression of noncoding microRNA [159,160]. DNA hypermethylation is associated with gene inactivation of tumor suppressor genes, and DNA hypomethylation with chromosomal instability. ()Epigallocatechin-3-gallate (EGCG), the most abundant flavonoid in green tea inhibits DNA methyltansferase (DNMT), reduces DNA methylation in human

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cancer cell lines, esophageal, colon, prostate, and breast cancer [161,162]. EGCG inhibits cellular histone acetyltransferase activity, histone acetylation and alters chromatin structure. Green tea inhibited mRNA and protein expression of 5-cytosine DNA methyltransferase in human prostate cancer xenografted in mice and reduced tumor volume, which antioxidative enzymes reactivated [163]. DNA methylation is also associated with the longevity by calorie restriction through the effects on distinct gene loci [164]. In addition, the activity of SIRT1, an important histone deacetylase in aging process, is activated by calorie restriction and life span elongation [165e167]. These results indicate that the molecular mechanism of the biological activity of phytochemicals should be further investigated including genetic and epigenetic regulation of gene expression to maintain health and lead to longevity.

CONCLUSION In our cellular model of MPT induced by PK11195, two-step formation of pore at the IMM and OMM was confirmed. Phytochemicals prevented or enhanced CysA-sensitive O2  flashes corresponding to pore formation at the IMM and also Ca2þ efflux by mPTP formation regulated by Bcl-2. Considering the quite different structure, these phytochemicals may not target specific proteins in mitochondrial membrane, but interact with phospholipids in the IMM, reduce the space between adjunct head groups, increase the interaction between the neighboring lipid tails, and suppress penetration of water among the heads, whereas proapoptotic compounds decreased membrane lipid rigidity. The potency of ferulic acid derivatives on the pore formation at the IMM was closely related to the hydrophobicity of the side chain, not to the oxidativeereductive activity due to 4- and 3-methoxy group of the benzene ring. Ast prevented MPT by PK11195 at the concentration quite lower than that for scavenging ROS and Ca2þ. Phytochemicals may regulate the membrane fluidity not only by the redox function to suppress or promote the oxidative modification of the mPTP components but also by their own dipolar properties to affect the membrane lipid characteristics.

ABBREVIATIONS ANT Ast CysA Cyp-D DJm ETC IMM MAO-B MPT

adenine nucleotide translocator astaxanthin cyclosporin A cyclophilin D membrane potential electron transport system inner mitochondrial membrane type B monoamine oxidase membrane permeability transition

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mitochondrial permeability transition pore outer mitochondrial membrane outer membrane translocator protein 18 kDa

ACKNOWLEDGMENT This work was supported by the Research Grant for Longevity Science (21A-13) from the Ministry of Health, Labor and Welfare, Japan (W.M, M. N., Y.W.). Conflict of Interest The authors declare that there are no competing financial interests in relation to the work described.

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Chapter 6

Dietary Carotenoids for Reduction of Cancer Risk Jose´ M. Lorenzo*, 1, Paulo E. Munekatax

*Centro Tecnolo´gico de la Carne de Galicia, Ourense, Spain; xUniversity of Sa˜o Paulo, Pirassununga, Sa˜o Paulo, Brazil 1 Corresponding author: E-mail: [email protected]

Chapter Outline Introduction Classification, Sources, and Metabolism of Dietary Carotenoids Epidemiologic Studies Oxidative Cleavage Reactions Enzymatic Formation of Apocarotenoids Chemical Formation of Apocarotenoids Effect on Cancer Cells In Vitro Reduction of Cell Viability, Arrest of Cycle Progression, and Activation of Apoptosis Modulation of Insulin-Like Growth Factor System

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Activation of Antioxidant Responsive Elements Nuclear Factor Kappa B Regulation of Peroxisome Proliferator-Activated Receptors Regulation of Retinoid Acid Receptors/Retinoid-X Receptors Reduction of Cancer Development in Animal Models Dietary Interventional Studies With Carotenoids Conclusion Remarks References

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INTRODUCTION Cancer, a complex and multistage disease, is a major worldwide public health problem. In the United States, more than 1.6 million were estimated in 2014, wherein prostate and breast cancer were the most frequent cases in men and women, respectively. Cancer in lung/bronchus and colorectal was also very common registered cases in both sexes between 1995 and 2010 in the Studies in Natural Products Chemistry, Vol. 51. http://dx.doi.org/10.1016/B978-0-444-63932-5.00006-1 Copyright © 2016 Elsevier B.V. All rights reserved.

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United States [1]. In European countries, 1.3 million cancer deaths in 2014 were estimated. Lung cancer was the main cause of death in men, followed by colorectal and prostate, whereas breast cancer was the most common cause of death in women, followed by lung and colorectal [2]. Due to the large number of cases and deaths, several researchers have been investigating which favorable and unfavorable factors are associated to cancer incidence. The knowledge about these factors led to elaboration of preventive strategies against cancer development, since genetic disorders are associated to 5e10% of all cancer cases and 90e95% of cancer cases are associated to environment and lifestyle factors. This information has great impact for general population, since many important changes in daily routine can reduce cancer risk [3]. Cancer prevention can be divided in three major sequential strategies: (1) reduce and avoid exposure to carcinogens as tobacco, UV radiation, or inadequate diet; (2) attenuate or inhibit the effect of carcinogens and prevent first steps of carcinogenesis after exposure to carcinogens; and (3) identification and removal of preneoplastic lesions, which is an aggressive but efficient strategy to reduce cancer development if both previous strategies were ineffective [4]. It is important to note that second strategy is of great interest to general population, since changes in life style as control of body weight [5,6], proper dietary choices [7], and regular physical activity [8] are part of the recommendations to reduce cancer risk. Regarding to food choices, vegetables in general, including roots, fruits, and green leafy vegetables, are considered as “low calorie” and rich in bioactive macronutrients and micronutrients that must be consumed instead of food classified as “calorie-dense foods,” which includes deep fried food, sweets, and sugar-sweetened beverages. Once the consumption of calorie-dense foods is reduced, the nutritional recommendation is the consumption of 2.5 cups of fruits and vegetables per day in all meals [9]. This recommendation is supported by epidemiologic studies that advise that food rich in specific components as polyphenols, carotenoids, vitamins, cereal fiber, and other bioactive compounds is related to reduced cancer risk [7,10,11]. Among the diversity of bioactive compounds in food, dietary carotenoids are important natural antioxidants [12] and colorants [13] found in fruits and vegetables with potential to promote beneficial effects against cancer development. Several studies indicated the effect of carotenoids on prevention of cancer development by many pathways with important changes in cancer cells as induction of cell cycle arrest, reduction of viable cells, and activation of apoptosis mechanism. In this context, suppress the activity of upregulated molecules and/or activate mechanism downregulated during cancer development are interesting strategies to understand beneficial effects of carotenoids. Some carotenoids can undergo oxidative cleavage reactions and form several bioactive products by enzymes or chemical reactions, known as apocarotenoids. The products generated from these reactions have been associated

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with pathways preferred for electrophilic compounds than intact carotenoids, which provide additional information about the effect in cancer cells [14]. The molecular mechanism provided by specific culture cells is also observed in animal test, complementing the information about the effects of dietary carotenoids in prevention of cancer. In similar way, interventional studies have been showing promising results in cancer patients, but additional attention is necessary to minimize adverse effects [15,16]. This review will focus in recent studies of carotenoids and apocarotenoids sources, important reactions, and mechanism associated to cancer development, both in cellular and animal models. Brief comments in relation to recent dietary interventional studies and future perspectives are also included.

CLASSIFICATION, SOURCES, AND METABOLISM OF DIETARY CAROTENOIDS Carotenoids are lipophilic pigments with C-40ebased isoprenoid structure responsible for yellow, orange, red, or dark green color. These compounds naturally occur in fruits, vegetables, and microorganism. Although animals do not synthesize carotenoids, these compounds are observed in food of animal origin such as eggs, milk, and cheese [17]. Carotenoids include more than 700 compounds that can be initially divided in carotenes (hydrocarbon carotenoids) and xanthophylls (oxygenated carotenoids) [18]. Despite the large number of compounds, around 50 carotenoids in human diet were associated to biological activity. Only b-carotene, b-cryptoxanthin, a-carotene, lycopene, lutein, and zeaxanthin (Fig. 6.1) have been reported in human plasma and seem to be promising bioactive compounds in cancer prevention [17,19]. Additionally, the provitamin A activity is the most wide studied property of carotenoids due to severe impact of vitamin A deficiency cause in human body, especially in pregnant women and young children. However, few carotenoids, mainly b-carotene, can be converted in retinol or vitamin A [20]. a- and b-carotene are geometric isomers and are the principal carotenoids found in carrot, which are considered one of the main sources of carotenoids in diet of the Western countries. This root vegetable is a good source of important nutrients, including dietary fibers, vitamins, carbohydrates, and minerals [21]. In carrots, the a-carotene content ranges between 2538 and 8100 mg/100 g and b-carotene from 5977 to 12,700 mg/100 g [22,23]. Other good dietary sources of a- and b-carotene are banana and green leafy vegetables, respectively. Lycopene is the major carotenoid found in tomato and products elaborated from tomato. Tomato is widely consumed as raw or processed product (e.g., canned, puree, or sauce) and can provide 85% of dairy lycopene intake. Tomato contains several bioactive compounds [24]. Concentration of lycopene in raw tomato ranges between 32 and 27,100 mg/100 g of fresh weight. b-Carotene is also found, achieving 14,600 mg/100 g [25e27]. It is worth noting that lycopene absorption is enhanced in tomato products due to increase

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FIGURE 6.1 Chemical structures of selected carotenes and xanthophylls.

in softness and change in isomerization from cis to trans in lycopene structure [24,28]. Other sources of dietary lycopene are guava and papaya [29,30]. b-Cryptoxanthin is one of the xanthophylls found in fruits and vegetables. Papaya is an important source of carotenoids due to b-Cryptoxanthin content in the range between 295 and 1034 mg/100 g. Consumption of papaya also

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provides another advantage related to carotenoid content, due to the elevated content of lycopene, between 1674 and 3674 mg/100 g [31]. Lutein and zeaxanthin are isomers belonging to xanthophyll class in composition of several fruits and vegetables. Lutein is found in large concentration in green leafy vegetables, such as lettuce (between 171 and 3824 mg/100 g), basil (from 3650 to 8270 mg/100 g), parsley (4326 mg/100 g), garden rocket (7440 mg/100 g), and cilantro (7703 mg/100 g). Likewise papaya, these vegetables also provide elevated amount of b-carotene [26,32,33]. Zeaxanthin is usually observed in lower concentration compared to other dietary carotenoids cited above and is also reported in fewer vegetables and fruits compared to lutein, although pepper and scallions display elevate concentration of zeaxanthin (1665 and 2488 mg/100 g, respectively) [26]. Food of animal origin contains lower content of carotenoids compared to fruits and vegetables. Eggs have relevant content of lycopene (336 mg/100 g) and zeaxanthin (328 mg/100 g). Similar content of b-carotene is observed in butter in the range of 296e431 mg/100 g [26,30]. Regarding the absorption and metabolism of carotenoids, these molecules share similar process as known for fat. Food composition and physicalechemical characteristics influence the release of carotenoids from food matrix during digestion. Thermal, physical, or enzymatic disruption of fruits and vegetables generally increases release of carotenoids and dispersion during digestion [34]. Then, carotenoids are dispersed in intestinal lumen, and in this condition, bile salt micelles facilitate the transport to intestine mucosa. Once carotenoids reach intestinal mucosa, these compounds are absorbed by enterocytes and transported to blood by lymphatic chylomicrons. To achieve other tissues, carotenoids are transported by lipoproteins in plasma. The structure of carotenes and xanthophylls influences the type of lipoprotein [35]. b-Carotene can be metabolized in enterocytes to produce vitamin A; however, for xanthophylls carotenoids, their metabolism remains not fully elucidated. It is believed secondary hydroxyl group in xanthophylls undergoes enzymatic oxidative reactions and forms ketocarotenoids in mammals [36]. Due to structural features of carotenoids related with oxygenated b-ionone ring, low-density lipoproteins transport carotenes (a-carotene, b-carotene, and lycopene), whereas high-density lipoproteins circulate xanthophylls (b-cryptoxanthin, lutein, and zeaxanthin) in blood stream [37]. Once lipoproteins reach tissues, cellular receptors induce the absorption of carotenoids and promote degradation of lipoproteins.

EPIDEMIOLOGIC STUDIES The general recommendation for daily consumption for fruits and vegetable (main sources of carotenoids) is worldwide known due to positive effects in general health. This indication can also have another advantage, since studies have been associating the consumption of bioactive compounds to reduce the risk of chronic disease development in different countries. Food consumption

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(e.g., frequency and amount), diet, lifestyle, metabolic, and environmental factors and the occurrence of diseases are usually considered in this context. In this sense, dietary carotenoids have great importance due to the impact on development of several types of cancer. In China, the personal and medical information of 845 colorectal cancer cases was compared to 845 health people (controls) of similar age range and mixed gender; the consumption of a-carotene, b-carotene, b-cryptoxanthin, and lycopene was inversely associated with colorectal cancer risk [38]. Similar results were observed for nonHodgkin lymphoma in the study performed by National Cancer Institute between 1998 and 2000. In this study, the comparison of 1321 cases with 1057 controls indicated reduced non-Hodgkin lymphoma risk for high consumption of vegetables, green leafy vegetables, lutein, and zeaxanthin [39]. However, this approach can be improved with evaluation of carotenoid content in blood samples of subjects, which indicates biological content of carotenoids. In this approach, liquid chromatography analyses of blood samples are evaluated for total and individual carotenoid content along with medical records of each subject. The Nurses’ Health Study is an ongoing large and long-term epidemiological study focus in the health of women that started in 1976 with 121,700 registered female nurses aged 30e55 years. The evaluation of breast cancer association with plasma carotenoids used blood samples collected 10 apart between 1989 (32,826 women) and 2000 (18,743 of these women donated blood again) resulting in the association of high carotenoid content (individual and total) with 18e28% reduction on breast cancer risk. Additionally, an interesting outcome from this study is the inverse association of a-carotene, b-carotene, and total carotenoids content in blood samples with cancer development, but for lycopene, the inverse association to cancer was only suggestive [40]. On the other hand, another study performed between 1998 and 2007 also evaluated the relationship of plasma carotenoids and breast cancer risk. Although the study considered 496 cases of invasive cancer among 21,956 women in the United States, only high a-carotene concentration in plasma was associated with reduction of invasive breast cancer. Other carotenoids and total carotenoid content in plasma were not associated with reduction of breast cancer risk [41]. The European Prospective Investigation into Cancer and Nutrition (EPIC) is a wide study about the relation of several factors as food consumption, nutritional status, lifestyle, metabolic, and environmental factors, with the incidence of cancer and other chronic diseases in 10 European countries (e.g., Greece, Spain, the Netherlands, Norway, and the United Kingdom). Evaluation of data regarding the association of food consumption and serum levels of carotenoids indicated that root vegetables, carrots, and tomato products are good predictors for b-cryptoxanthin, a-carotene, and lycopene concentration in plasma, respectively. Besides the confirmation about the impact of consumption of carotenoid-rich food, habits showed influence in the concentration

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of carotenoids in blood. Smoking habit was related with reduced blood level of lutein, b-cryptoxanthin, and a- and b-carotene in both actual and previous smokers. Alcohol consumption and increase of body mass index were inversely associated to carotenoid content in blood. Additionally, total carotenoid content in plasma ranged between 1.91 and 1.98 mM for men and from 2.27 to 2.42 mM for women [42]. The EPIC study also assessed the relation between intake of b-carotene and cancer cases. Generally, men and women had similar consumption, for all main cities of Europe combined (2760 and 2887 mg/day, respectively). An interesting feature to note was the higher intake of b-carotene in population of central European countries (3057.6 mg/day) than southern countries (2743.0 mg/day) and northern countries (2283.4 mg/day). The consumption of b-carotene also had little variation throughout the year, for men and women. However, some countries as Spain, Italy, Germany, and Sweden seem to intake more b-carotene in summer [43]. Regarding pancreatic cancer in EPIC study, evaluation of 446 cases of this cancer indicated b-carotene and zeaxanthin content in plasma were inversely related to number of cases [44]. Bladder cancer was also investigated in EPIC study, wherein a total of 856 cases of urothelial cell carcinoma were observed. The total carotenoid content in plasma showed inverse association with bladder cancer. b-Carotene displayed positive effect against aggressive urothelial cell carcinoma, and lutein was inversed related to nonaggressive urothelial cell carcinoma [45]. Colorectal cancer data were also evaluated in EPIC study. A total of 1550 cases were reported, and the reduced incidence of this category of cancer was associated with prediagnostic plasma retinol and b-carotene concentration in blood [46]. Despite the inconsistency among results of recent studies, the present information available in literature strongly suggests the importance of total and individual dietary carotenoids on cancer prevention. In addition to these important information, the protective effect of carotenoids in vitro and in vivo against cancer provides better understanding in how each one of the dietary carotenoids can impact different types of cancer and the suggested mechanism involved. Since carotenoids are metabolized inside the body, their metabolites are also involved in important pathways altered in cancer cells.

OXIDATIVE CLEAVAGE REACTIONS Along with carotenoids, products formed through oxidative reactions in carotenoids have received great attention due to biological activity similar or higher than precursor molecules. The products of oxidative cleavage of carotenoids are denominated as apocarotenoids which are produced by chemical and enzymatic reactions, either in plant tissue, food, or human body cells. This group of compounds is composed by a wide range of structures. In these reactions, cleavage of double bounds between carbons in main carbon

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backbone promotes the formation of acids, ketones, epoxies, and aldehydes [47]. The nomenclature of carotenoid oxidation products includes the term apo-, the position of substitutes in carbon chain, name of carotenoid, and type of oxidized group. In this system, the product generated from lycopene with one aldehyde (-al) at the carbon 15 is named as apo-15-lycopenal. The same basic nomenclature system is applied for acids, ketones (-one) and epoxides (-epoxide) products [14].

Enzymatic Formation of Apocarotenoids Enzymatic cleavage of carotenoids has great biological importance, especially for provitamin A carotenoids. In humans, liver cells are responsible for 70% of total carotenoid content in body, where b,b-carotene-15,150 -oxygenase (BCO1) and b,b-carotene-9,100 -oxygenase (BCO2) are expressed. These enzymes are also found in intestine cells (Fig. 6.2). The reaction catalyzed by BCO1 is responsible for symmetrically cleavage of b-carotene in retinal and consequently conversion to retinal (vitamin A). This enzyme is localized in the cytoplasm and catalyzes the formation of compounds with vitamin A activity from other carotenoids with b-ionone ring structure. a-Carotene and b-cryptoxanthin are important alternative precursor for vitamin A production. The reaction catalyzed by BCO1 is currently considered as main pathway to produce vitamin A from carotenoids [47e49]. Differently than BCO1 that has only produces retinal, BCO2 catalyzes the formation of asymmetric oxidation products (apocarotenoids and retinoids). This enzyme is expressed in mitochondria and can promote the formation of apo-100 -carotenal and b-ionone when b-carotene is the substrate, although other asymmetric products are also produced. This enzyme was previously reported in ferret and mouse [47e49]. The cleavage of provitamin A carotenoids has great dependency of BCO1 activity. This effect is supported by accumulation of b-carotene (main provitamin A carotenoid) accumulation and vitamin A deficiency on BCO1 knockout mice. BCO2 oxidative cleavage of provitamin A carotenoids is an alternative via for retinoid production and consequent undergoes a esterification reaction leading to vitamin A production. However, in this condition, affinity and reaction kinetics are reduced [50].

Chemical Formation of Apocarotenoids Carotenoids can undergo chemical cleavage and form several products, which are of natural occurrence in food and plant tissue. In this sense, some carotenoids are subjected to chemical cleavage, as reported for lycopene in several studies. When this carotenoid is in the presence of potassium permanganate, a wide range of products are formed (Fig. 6.3). The reaction of lycopene with

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FIGURE 6.2 Apocarotenoids formed by enzymatic cleavage of b-carotene.

KMnO4 methylene chloride/toluene medium with cetyltrimethylammonium bromide formed 8 apolycopenals (e.g., apo-60 -lycopenal and apo-80 -lycopenal), 6 diapolycopenals (e.g., diapocarotene-6-100 -dial), and 3 apolycopenones (e.g., apo-13-lycopene) [51]. The suggested mechanism of apolycopenals formation involves isomerization of (E)-lycopene in (Z)-lycopene as first step. Then, oxygen is inserted in double bound forming epoxide intermediate, leading to the cleavage of carbon chain and formation of lycopenals. In this reaction, several products can be formed at the same time throughout the reaction time, due to the different sites of double bond. Additionally, lycopenals and lycopenones with large carbon chain can undergo another oxidative cleavage and form smaller molecules [51].

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FIGURE 6.3 Chemical structures of lycopene and apocarotenoids formed by chemical reaction.

The importance of chemical cleavage is based on synthetic production of apocarotenoids of natural occurrence in food and plat tissues. Studies of lycopene oxidation products have characterized the presence of apo-60 lycopenal (0.023e19 mg/100 g), apo-80 -lycopenal (0.027e34 mg/100 g), apo-100 -lycopenal (0.022e3.7 mg/100 g), apo-120 -lycopenal (0.047e16 mg/ 100 g), and apo-140 -lycopenal (0.11e0.69 mg/100 g) in lower concentration in tomato than its products. However, the values are usually at least 800-fold lower than lycopene concentration. This study also reported the presence of apolycopenals in human plasma, wherein seven human subjects consumed high amount of tomato juice for 8 weeks. Blood plasma analysis revealed the presence of apo-60 -, apo-80 -, apo-100 -, apo-120 -, and apo-140 -lycopenal (0.12, 0.63, 0.28, 0.73, and 0.12 nmol/L, respectively) [52]. Formation of stable lycopene-epoxide derivative can be formed by reaction with m-chloroperbenzoic acid in dichloromethane. In this condition, cleavage products were not observed; however, eight compounds were identified which included 2,6-cyclolycopene-1,5-epoxide, lycopene-5,6-epoxide, and lycopene1,2-epoxide as the main products (11.2%, 15.8%, and 18.5%, respectively). Additionally, some of the compounds formed in this reaction were also observed in tomato juice, paste, and puree [53].

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EFFECT ON CANCER CELLS IN VITRO Fruit and vegetable consumption and serum content of carotenoids, described in previous section, are related to lower cancer risk, but several mechanisms are involved to promote this effect. The knowledge from several events and mechanism of carotenoid activity in cancer cells known so far can be attributed to experiments with cancer cell lines. Cell lines are of special interest due to preservation of similar characteristics (genotype and phenotype) from precursor tumor in the moment of biopsy. The production of cell lines starts with the primary culture, which is the production of new cancer cells from tumor tissue removed from a patient with cancer. After the proper growth in primary culture, the new cells are transferred to other medium and named as specific cell line. The proliferative activity keeps cancer cells in steady growth condition until the normal activity is no longer maintained and senescence occurs. Experiments with cell lines allow researchers to prevent variations from different individuals, avoid formalities and ethical concerns related to animal and human experiments, facilitate general experiment manipulation, and provide detailed information about the mechanism and their effects in cells [54]. Several studies in vitro have been providing better understand about the role of carotenoids and their oxidation products on modulation of genes expression, promotion of cell cycle arrest, induction of apoptotic mechanism, and modulation of nuclear receptors activity and other mechanisms. It is worth noting that apocarotenoids are responsible for activation/deactivation of specific mechanism that was attributed to intact carotenoids and was recently elucidated [55,56], as described in the section for antioxidant responsive elements (AREs). Studies with apocarotenoids demand the isolation of specific or a mixture of target compounds or use of commercial standards [55,57]. Several compounds can be formed and studied when chemical cleavage of carotenoids is performed before the in vitro experiment, but demands additional analysis to confirm their presence. Commercial standards may be preferred to facilitate the experiment, but also are usually more expensive compared to perform chemical synthesis.

Reduction of Cell Viability, Arrest of Cycle Progression, and Activation of Apoptosis In normal conditions, cell cycle involves several events, molecules, and reactions related to DNA synthesis, replication, and segregation, divided in four sequential steps, and denominated G1, S, G2, and M. In the S phase, DNA is replicated and in M phase, cell division takes place and two daughter cells are formed. Between these two steps, the cell is in one of the gap phases (G1 and G2). In G1 phase, cell is susceptible to growth factors, either to stay in this phase or move forward next phase. The checking process is characteristic in

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this step, verifying if cell structures and molecules are ready for DNA replication on S phase. After DNA replication, cell enters G2 phase when the cell prepares for mitoses and checks process. Additionally to cell cycle phases, G0 phase is the quiescence condition, when cell stop the dividing process due to lack of stimulating signals [58]. Carotenoids can arrest a significant number of cancer cells in one of the gap phases of cell cycle, reducing the number of cells before DNA replication (arrest in G0/G1 phase) or the amount of cells before mitosis initiation (arrest in G2 phase). In the case of lycopene in the range between 1 and 5 mM, colon adenocarcinoma (HT-29), MCF-7, lung carcinoma (A-549), and DU145 cells were arrested in G0/G1 phase, whereas T84 cells were arrest at G2/M [59]. Prevention of irregularities in DNA synthesis and chromosome segregation is followed up by checkpoints. When defects are identified, these checkpoints are activated and inhibit cyclin-dependent kinases (CDKs) activity and promote cell cycle arrest. These enzymes express activity when linked to cyclin subunits. In this condition, defects are repaired, avoiding the generation of new cells with damaged DNA. Each one of the phases uses specific CDKs to control the progression through cell cycle. In some cases, DNA damage is beyond the repairing mechanism, which lead cells to enter senescence condition or active apoptosis mechanism. However, in cancer cells, DNA mutations usually deregulate CDKs activity, causing persistent proliferation or nonexpected cell cycle initiation [60,61]. Once cancer cells have irregularities in DNA, carotenoids reduce CDKs activity and cyclin levels and modulate of CDK inhibitors. In a study with mammary cancer cell lines (MCF-7 and T-47D) and endometrial cancer cells (ECC-1) lines, lycopene caused cycle arrest at G1 phase in all cell lines tested, which inhibited phosphorylation of retinoblastoma protein and related pocket proteins. Regarding to this inhibition, cdk4 and cdk2 activity were reduced to around 40% of control cells activity for these cell lines, due to lycopene activity. Besides the reduction of CDKs activity, cyclin levels were also affected by lycopene exposure, wherein cyclin D1 level displayed 20% of control samples response in ECC-1 cells. The same effect is observed in T-47D cells, but lycopene effect on MCF-7 showed the same level of cyclins than control cells. Lycopene also modulated p27 (CDK inhibitor) in cyclin Eecdk2 complex of G1 phase, causing the cycle arrest in this phase [62]. Similar effect of cell cycle arrest was observed for lycopene in androgenresponsive human prostate carcinoma cells (LNCaP) and androgenindependent benign prostate PC3 cells. Lycopene treatments at 400 and 800 nM prevented the G1/S transition, which was also a dose-dependent effect. Additionally, lycopene at 100 nM reduced cyclin D1, cyclin E, and CDK4 levels and suppressed retinoblastoma phosphorylation. In this condition, lycopene was associated to cytostatic and cytotoxic activity to induce cell cycle arrest at G0/G1 phase [63].

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Lycopene at 5 and 10 mM reduced the number of viable malignant prostate cancer (DU-145) cells by 15% and 25%, respectively. However, lycopene at higher concentration (20 mM) was effective to reduce by 15% the number of viable benign prostate hyperplasia (PC-3) cells [64]. The reduction of viable cells seems to be dose dependent since for higher concentrations. When 20 or 50 mM were include in medium with DU-145 cells, reduction of 39% and 55% in viable cells was observed, respectively. In the same concentrations, the number of PC-3 viable cells was reduced by 36% and 49%, respectively [65]. Cell type dependency seems to be an important characteristic for dietary carotenoids observed in different mammary cancer cells (MCF-7, MDA-MB-231, and MDA-MB-235). Reductions of 20% (MCF-7 cells), 30% (MDA-MB-231 cells), and 75% (MDA-MB-235 cells) on viable cells were reported for lycopene at 10, 0.5, and 0.5 mM, respectively. In the same way, b-carotene promoted reduction of viable cells by 40% (MCF-7 cells), 30% (MDA-MB-231 cells), and 70% (MDA-MB-235 cells) at 1, 1, and 0.5 mM, respectively [66]. The apoptotic mechanism is a group of events activated in cell at normal conditions to maintain the balance of new and stressed/injured cells or when DNA is too damaged. In this condition, crucial events occur in cell as the induction of caspases (cysteine proteases), membrane permeabilization in mitochondria, nuclear and DNA fragmentation, condensation of chromatin, cell shrinkage, and membrane blebbing [67,68]. Intracellular and extracellular mechanisms are involved in apoptosis, wherein caspases have major role and work as mediators and executioners. In extracellular pathway, death membrane receptors are activated by death ligands and bind with adapter proteins forming the ligand-receptor-adaptor protein complex, leading to caspase-8 activation. After caspase-8 induction, a series of events in cascade induce cleavage of caspase-3 and cause cell death. Apoptosis through internal pathways occurs by mitochondrial pathway, which is mediated by Bcl-2 proteins, which include antiapoptotic (e.g., Bcl-2 and Bcl-xL), proapoptotic (e.g., Bax and Bak), and initiators of apoptosis proteins (e.g., Bad and Bik). When antiapoptotic and proapoptotic proteins levels are favorable for apoptosis initiation, mitochondrial membrane loses the capacity to retain cytochrome C. Once cytochrome C achieves the cytoplasm, caspase-9 is activated and consequently activates caspase-3, which results in cell death [69,70]. The treatment with b-Carotene caused damage in DNA of hepatocellular carcinoma cells (HepG2) and induced apoptosis and necrosis of cancer cells [71]. b-Carotene induced apoptosis in gastric cancer AGS cells. In this case, the increase of reactive oxygen species and caspase-3 activity caused reduction of Ku proteins (Ku70 and Ku80) levels. The importance of Ku proteins in apoptosis is related to their involvement in DNA-dependent protein kinase expression, responsible for DNA repair. When this protein

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kinase activity is inhibited, the repair process of DNA is not performed leading to apoptosis [72]. Induction of apoptosis by zeaxanthin in melanoma cells (SP6.5 and C918) was related to Bcl-2 proteins mechanism. Zeaxanthin at 30 mM displayed similar effect in both cell lines: reduction on Bcl-xL and Bcl-2 expression, increase of Bak protein expression in SP6.5 cells, decrease of Bcl-xL expression, and increased expression Bak protein in C918 cells [69]. Additionally, another effect indicated the apoptotic activity of carotenoids in cancer cells: the exposure of colon adenocarcinoma Caco-2 cells to b-cryptoxanthin at 3 mM reduced cell viability and induced apoptosis by changes in cell composition as elevation of intracellular Ca2þ level (which is one of the events before apoptosis), increasing intracellular reactive oxygen and nitrogen species level, arrest of cell cycle in sub-G1 phase, and reduction of mitochondrial transmembrane potential [67].

Modulation of Insulin-Like Growth Factor System The insulin-like growth factor (IGF) system has great importance in normal cells due to regulation of tissue growth, antiapoptotic activity, and cell division. This system consists of IGFs (IGF-I and IGF-II), IGF receptors (IGF-IR and IGF-IIR), and IGF binding proteins (six IGFBP structures). In cancer cells, IGF activity is altered and may promote aberrant growth and proliferation in different types of cancer. IGF-I and IGF-II are polypeptides arranged in a single chain with homologous structure to insulin. IGFs have essential role in human growth and development throughout life acting inside the cell (autocrine), surrounding cells (paracrine), and distant cells (endocrine). An interesting characteristic is the difference in IGF-I and IGF-II circulatory levels in adults: IGF-II level is significant higher than IGF-I [73,74]. The IGF-I and IGF-II activities are regulated by glycoprotein receptors located in cell membrane: IGF receptor type I (IGF-IR) and type II (IGF-IIR). Both growth factors interact with IGF-IR that has two extracellular subunits (denominated a) responsible for binding to IGFs and other two intracellular subunits (named b) with tyrosine kinase to regulate cellular growth, differentiation, RNA and DNA synthesis, proliferation, and other effects associated to cell survival. On the other side, the IGF-IIR structure is formed by one polypeptide chain of three cell domains: a large extracellular segment, transmembrane section, and a small intracellular fraction. However, IGF-IIR structure does not possess tyrosine kinase activity, which suggests this receptor is specific for IGF-II presence and consequently alters IGF-II level outside the cellular membrane [73,74]. The transport of IGFs in circulatory system is controlled by IGFBP that are homologous proteins with different characteristics and biological distribution. These binding proteins are responsible for IGFs transport and proper deliver and protect IGFs from degradation. IGFBP is divided into two groups

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according to their IGF affinity. Six IGFBPs (IGFBP-1 to IGFBP-6) have high affinity for IGFs, whereas IGFBP-related proteins (four structures: IGFBP-rp1 to IGFBP-rp4) have low affinity. Among binding proteins, IGFBP-3 is the major circulatory protein in humans [73,74]. Carotenoid can influence IGF-IR expression in cancer cells, which is observed for lycopene in liver adenocarcinoma cells (SK-Hep-1). This carotenoid reduces IGF-IR expression at 2.5 and 5 mM at dose-dependent manner, wherein 5 mM displayed the higher capacity [75]. The impact of carotenoids in IGF system on cancer cells is related to increase of IGFBPs levels, since these proteins bind specifically with IGFs and reduce cell proliferation, cell turnover, and susceptibility of malignant potential. In prostate cancer cells (PC-3), lycopene reduced cell viability and induced DNA fragmentation and apoptosis. In fact, this positive outcome may be related to enhanced IGFBP-3 level in both extracellular and intracellular medium and the unaltered concentration of IGF-I. This effect indicated lycopene interacted with IGFBP-3 and not with IGF-I. This result is also supported by significant higher IGFBP-3 level when lycopene (at 40 and 60 mM) and additional IGF-I (50 ng/mL) were tested in PC-3 cells. Thus, indicating the increase IGFBP-3 level in PC-3 cells was associated to lycopene-induced apoptosis [76]. As previously described, carotenoids induce cell cycle arrest in cancer cells, but the involvement of IGF in cell cycle arrest may involve cyclin modulation. In an experiment with human breast (MCF-7) and endometrial (ECC-1) cancer, cells were arrested at G0/G1 phase and stimulated only by IGF-I to progress to S phase. In this condition, lycopene and all-trans retinoic acid prevented the progression of cell cycle. Along with this result, cyclin D1 levels were reduced, indicating the involvement of cyclin proteins in cell cycle progress by lycopene and all-trans retinoic acid activity. This assumption was tested with MCF-7.7D1.13 cells that are treat cells to express cyclin D1 by Zninducible metallothionein promoter (ectopic expression). In this experiment, the hypothesis was based in the reduction of cyclin D1 by lycopene and alltrans retinoic acid had influence of cyclin D1 ectopic expression to arrest cell cycle and could be able to inhibit lycopene and all-trans retinoic acid activity. Since the MCF-7.7D1.13 cells showed sufficient cyclin D1 expression to avoided cell cycle arrest by lycopene and all-trans retinoic acid, the mechanism proposed was supported. In another words, lycopene and all-trans retinoic acid induce cell cycle arrest by reduction of cyclin D1 expression, which is involved in reduction of IGF-I activity [77].

Activation of Antioxidant Responsive Elements Activation of phase II detoxification enzymes is another important mechanism related to reduction of cancer risk, due to inverse association between tissue levels of these enzymes and resistance against chemical

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carcinogenesis. Induction of phase II detoxification enzymes occurs in the presence of harmful compound, which releases of transcription nuclear factor E2-related factor 2 (Nrf2) from Keap1 (inhibitor protein of Nrf2). Once Nrf2 translocate form cytoplasm to the nucleus, this factor induces antioxidant and detoxifying genes of promoter or enhancer regions, known as ARE. Thus, phase II detoxification enzymes are induced and promote the conversion of harmful compounds in water-soluble metabolites that can be quickly excreted [78,79]. In a study with hepatocellular carcinoma cells (HepG2), lycopene and b-carotene were capable to induce ARE system, although lycopene displayed higher capacity to induce the ARE system than b-carotene. An interesting hypothesis was considered in this study: Oxidation products of lycopene may be the effective compounds involved in ARE activation. Oxidation derivatived compounds of lycopene were separated from intact lycopene by ethanolic extraction and tested for induction of ARE. Results with the oxidation products from lycopene for ARE test showed similar capacity to induce this biological system, strongly indicating that lycopene oxidation products are responsible for ARE transactivation. According to these results, it is reasonable to consider the role of carotenoids oxidation derivatives in cancer prevention [78]. Following this evidence, a novel approach was designed to add knowledge in the role of carotenoids, by the activity of their metabolites, in reduction of cancer risk. This hypothesis was bases in the assumption that carotenoids, lipophilic colorants, do not interact with electrophilic molecules, particularly electrophilic modulators with cysteine sulfhydryl groups on ARE system. The involvement of intact carotenoids with such molecules is improbable. Such context seems reasonable explained by interaction of apocarotenoids from lycopene as dialdehyde derivatives [55]. Specific compounds as 10,100 -diapocarotene-10,100 -dial, theoretically produced by enzymatic reaction from lycopene, transactivated the ARE system in prostate cancer cells (LNCaP) and human mammary cancer cells (MCF-7) resulting in expression of phase II enzyme NQO1. Since compounds of different classes and structures can be formed in oxidative cleavage reaction, it seems reasonable to consider the hypothesis that these characteristics have different effects on induction of ARE system. Comparison between apo100 -lycopenal and apo-100 -lycopenoic acid to induce in LNCaP and MCF-7 cells indicated the greater effect of the aldehyde molecule than the acid structure on induction of ARE system. Similar result was observed when LNCaP and MCF-7 cell were exposed to 8,15-diapocarotene-8,15-dial and 8,15-diapocarotene-8-al-15-acid, indicating again the greater capacity of aldehyde derivative to induce ARE system. Another important outcome was considered to compare these apocarotenoids: the number of chemical groups. A comparative analysis indicated dialdehydes derivatives were more effective to induce ARE system than monoaldehydes derivatives [55].

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Another important characteristic of aldehyde derivatives is the relative location of the first methyl group from the aldehyde end. Carotenoid derivatives with distant methyl groups as gamma or delta locations have greater activity compared to carotenoid derivatives with close positions. The backbone length also has importance on induction of the ARE system: A diapocarotene dial with 12 carbons had greater capacity than similar structure with 8 or 16 carbons in main chain. This outcome indicated 12 carbons as the optimal length for dialdehydes [50]. The interference in redox cell signaling pathways and transcription factors, especially Nrf2, has been showing promising results. Despite the few cancer types with natural Nrf2 induction, the increase of Nrf2 level is a safe and effective strategy for cancer prevention [80,81].

Nuclear Factor Kappa B The nuclear factors-kappa B (Nf-kB) are formed by dimers of Rel protein family. This group includes p50 (Nf-kB1), p52 (Nf-kB2), Rel-A (p65), c-Rel, and Rel-B that are involved in adequate response of immune system. The NfkB activity promotes inflammation and tumor development, which makes the regulation of these proteins a delicate process, since cancer is considered an inflammatory disease. Nf-kB proteins are mediated by inhibitor proteins belonging to IkB family. In normal conditions, IkB is linked to Nf-kB in cytoplasm preventing the migration of Nf-kB to the nucleus. In response to stimuli, IkB protein is phosphorylate and undergoes a degradation process and release Nf-kB protein. These proteins accumulate inside the nucleus and induce expression of specific genes associated to cellular growth, invasion, and angiogenesis [82e84]. Due to the importance of this system, several studies were conducted to understand how carotenoids and their oxidation cleavage products modulate Nf-kB. The treatment of human prostate carcinoma cells (LNCaP) with lycopene reduced the translocation and binding capacity of p65 subunit to DNA within 24 h, whereas for control cells, p65 translocation and consequent DNA binding were observed in the same incubation time [85]. The effect of electrophilic products of lycopene oxidation on Nf-kB transcription system indicated apocarotenoids as active compounds instead of precursor carotenoid in bone cancer cells [56], which is similar to activation of ARE system by carotenoid oxidation derivatives [55]. In another words, only the oxidized products caused 30% reduction of Nf-kB activity, whereas absence of inhibition was observed for intact lycopene even at high concentration (17 mM) in human mammary cancer cell T47D. The inhibition of Nf-kB displayed positive correlation with apocarotenoids (10,100 diapocarotene-10,100 -dial and 6,140 -diapocarotene-6,140 -dial) concentration, indicating a dose-dependent behavior. This activity was also greater than exhibited by curcumin, which is a well-known Nf-kB inhibitor. This effect is partially explained by two elements of Nf-kB pathway: direct interaction with p65 (which avoid the bind to DNA) and attenuation of IkB kinases

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activity (inhibiting the release of Nf-kB and consequent translocation of NfkB to the nucleus) [56]. Despite the conflict information about lycopene and Nf-kB, this carotenoid still have great importance for cancer prevention, also observed in animal tests.

Regulation of Peroxisome Proliferator-Activated Receptors Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor transcription factors included in nuclear hormone receptor superfamily. PPARs group is composed by three substructures (PPARa, PPARb/d, and PPARg) that heterodimerize with retinoid X receptor (RXR) and bind to specific genes. The activity of PPARs is related to lipid metabolism as sensors and modulates cell growth, differentiation, and homeostasis regulation, also leading to inhibition of cell proliferation and apoptosis [86,87]. Each PPAR subtype has important biological effects, modulates several processes, and is also related to fatty acids metabolism. PPARa is widely expressed in different tissues as heart, small intestine, liver, pancreas, adrenal gland, kidney, muscles, and brown adipose tissue. The PPARa activation is due to hypolipidemic drugs, long-chain unsaturated fatty acids, and eicosanoids (products of fatty acids with 20 carbons that work as molecular signals). The activation of PPARa for long periods may induce hepatocarcinomas in rodents. PPARb/d is expressed in virtually all tissues and is associated to macrophages response to very low-density lipoprotein, wound healing process, keratinocyte differentiation, and fatty acid oxidation. In cancer cells, its activity is related to modulation of cell proliferation and differentiation that may lead to apoptosis. In contrast, PPARg is expressed in few tissues, including intestinal epithelium, lymphoid organs, brown white adiposities, retina cells, and muscle. The PPARg activity is associated to reduction of proliferation and differentiation processes and proapoptotic effect [87,88]. Carotenoids can induce the expression of PPARg. Expression of PPARg was modulated by b-carotene and other carotenoids (astaxanthin, capsanthin, and bixin) in leukemia cells (K562). Exposure of K562 cells to b-carotene at 5 mM or higher concentrations induced the expression of PPARg and inhibited cell growth. Additionally, astaxanthin, capsanthin, and bixin showed similar effect on upregulation of PPARg expression and antiproliferative effect [89]. This outcome is observed when androgen-dependent human prostate cancer cells (LNCaP) [86] and androgen-independent prostate cancer cells (DU145) [90] were exposed to lycopene. In LNCaP cells, lycopene (range of 2.5e10 mM) increased protein and mRNA expression of PPARg along with liver X receptor alpha (LXRa) and ATP-binding cassette transporter 1 (ABCA1), which resulted in inhibition of cancer cell proliferation. This effect suggests PPARg-LXRa-ABCA1 pathway as one of the lycopene antiproliferative mechanism. This hypothesis is supported by inhibitory effect of PPARg and LXRa antagonist restored the normal proliferative activity of

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LNCaP cells even in the presence of lycopene. In similar fashion, proliferative activity of DU145 cells was reduced by lycopene (10 mM) resulting in increased PPARg, LXRa, and ABCA1 protein and mRNA levels. Proliferative activity was also recovered by PPARg and LXRa antagonists. Furthermore, the involvement of PPARg and LXRa in lycopene antiproliferative activity was due to efflux of cellular cholesterol to culture medium in LNCaP and DU145 cells. Particularly for DU145 cells, lycopene and T0901317 (LXRa agonist) promoted synergist effect reducing cell proliferation and increasing protein expression of PPARg, LXRa, and ABCA1. The proliferative activity of cancer cells is reduced in the presence of natural or artificial PPARg agonists and is enhanced when carotenoids are included in cellular culture medium. The PPAR agonists are compounds that regulate glucose homeostasis and lipid metabolism and are associated to positive effects against cancer development. In hormone-refractory human prostate cancer (PC-3) cells [91], the presence of natural ligand 15d-PGJ2 at 25 mM and synthetic ligand pioglitazone at 25 mM decreased proliferation of PC-3 cells by 56% and 35%, respectively. This effect was enhanced in the presence of lycopene at 25 mM, which decrease PC-3 cells proliferation in 15d-PGJ2 treatment (25 mM) by 78% and pioglitazone treatment (25 mM) by 82%. The apoptotic mechanism was also induced by PPAR agonists and enhanced by lycopene, since 25 mM 15d-PGJ2 and pioglitazone caused 15% and 5% apoptosis, respectively. However, when 25 mM lycopene was included in medium, apoptosis was increased to 22% on 15d-PGJ2 treatments and 11% on pioglitazone treatment.

Regulation of Retinoid Acid Receptors/Retinoid-X Receptors Retinoic acid receptors (RAR) and RXR are the two groups of receptors of nuclear receptor that mediate the bioactivity of retinoic acid. These receptors have six different structures: RARa, RARb, and RARg for RAR group and RXRa, RXRb, and RXRg for RXR, which belong to steroid/thyroid hormone receptor superfamily and are involved in cell growth, cell differentiation, metabolism, reproduction, and morphogenesis [92,93]. In the presence of a ligand (e.g., retinoic acid), the heterodimer RAReRXR binds to retinoic acid response elements (RAREs), which regulate retinoic acid activity on target genes. However, when RAReRXR is in unliganded state, this heterodimer binds to nuclear corepressors and the transcription is inhibited. The transcriptional mechanism is affected in the early events of carcinogenesis, suggesting tumor demands the reduction of retinoid signaling to develop, even with normal ingestion of vitamin A. Additionally, retinoid signaling is associated with cellular differentiation and inhibition of cell proliferation, which involves mainly RARb expression [92,93]. Carotenoids and apocarotenoids may induce RAReRXR system, since the provitamin A or the oxidation cleavage products from provitamin A

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carotenoids can be converted in retinoids (homologues of vitamin A). The biochemical conversion of retinoids to retinoic acid can induce the RAReRXR system and promote beneficial effects against cancer development, thus, indicating an indirect effect of carotenoids in RAReRXR system induction [94]. The experiment with human bronchial epithelial (NHBE) cells tested the effect of b-carotene, apo-140 -carotenoic acid, and benzo[a]pyrene (lung carcinogen of cigarette smoke). Results demonstrated that RARb levels were reduced in lung cancer cells, whereas in lung cells treated with b-carotene and apo-140 -carotenoic acid RARb level increased even in the presence of benzo [a]pyrene. However, this effect was associated to conversion of both carotenoids to retinoic acid, which is associated to induction of RARb expression and consequently growth inhibition [95]. A study conducted with breast cancer cells (MCF-7, Hs578T, and MDA-MB-231) and retinoids resulted in inhibition of MCF-7 cells growth by all-trans, 9-cis, and 13-cis-retinoic acid and inhibition of Hs578T cells growth by all-trans-retinoic. A further experiment with all-trans-retinoic acid was conducted in this study to evaluate the inhibitory effect. However, RARa and RARg levels in MCF-7 and RARa, RARb, and RARg levels were not affected which suggested retinoids induced growth inhibitory effect by other mechanism than RAReRXR system in breast cancer cells [96]. The inhibitory growth activity of acyclo-retinoic acid (aliphatic retinoic acid homologue) was compared to retinoic acid in breast cancer cells (MCF-7). Both compounds tested had similar activities to reduce cell growth, although the effect of acyclo-retinoic acid was 100-fold lower than retinoic acid to activate RAReRXR system. This outcome indicates the acyclo-retinoic acid inhibitory activity did not influence RAReRXR system in breast cancer cells [97]. A recent study of apocarotenals, apocarotenones, and retinoids indicated negative impact in RAReRXR system. These compounds at 10 mM failed to active RAReRXR system in kidney fibroblast-like cells (Cos-1), and apo-140 carotenal, apo-140 -carotenoic acid, and apo-13-carotenone were antagonists to retinoic acid in transactivation of RARs by direct competition [98]. On the other side, an experiment with in colon cancer cells (HCT116), b-ionone at 40 and 60 mM (a product of provitamin A carotenoids asymmetric cleavage), upregulated RXRa mRNA level in a dose-dependent manner which may induce apoptosis. However, b-ionone had no significant effect in RXRb mRNA level [99]. The effect of carotenoids and apocarotenoids in this RAReRXR system demands more studies, due to the controversial results [100].

REDUCTION OF CANCER DEVELOPMENT IN ANIMAL MODELS Experiments designed to evaluate the effect of dietary carotenoids in animal model with induced cancer provide important evidence of their protective

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effect against cancer development in live animals, since several important events occur with carotenoids inside the animal model. One of the important considerations is the supraphysiologic concentration used in some culture cell experiments that may not show similar conditions in vivo. Epidemiologic studies reported carotenoid daily consumption in the range of 7.5e16.1 mg/ day of total carotenoid in health subjects [38,101]. However, at plasma level, total carotenoid contented can be reduced to values between 1.37 and 1.53 mmol/L (0.68 and 0.82 mg/L, respectively) [44,45], which is lower than reported in some in vitro studies. Additionally, supplementary information can be obtained, such as differences in uptake, effect of matrix (incorporation of pure carotenoid in diet or from food in diet), or methods of administration (intraperitoneal injection or diet). However, the optimal dose, interaction with other components dietary fat (especially fat soluble compounds), and the extrapolation of animal model to humans should be consider in animal experiments [15]. Carotenoids and apocarotenoids have positive influence against the development of several types of cancer cell lines modulating many molecular mechanisms and also possess preventive activity in animal tests. Tomato powder supplementation inhibited initial signals of adenocarcinoma development in induced colorectal cancer of Wistar rats. Inclusion of tomato powder in diet reduced the number of animals with adenocarcinoma and lowered the incidence of precancerous aberrant crypt foci lesions (tube-like glands in colorectal tissue). The molecular mechanism involved can be explained by inhibition of Nf-kB activity and consequently reduction on cyclooxygenase-2 expression, which is an enzyme involved in metabolism of arachidonic acid. Increase on caspase-3 protein level (involved in apoptotic mechanism) was induced in animals feed with tomato powder [102]. In female Wistar rats with induced mammary cancer, lycopene supplementation (20 mg/kg) reduced by 30% cancer occurrence, decreased Bcl-2 expression (inhibitor of cell death), and partially restored caspase-3 and caspase-9 levels. It is worth noting that lycopene can also act synergistically with genistein (an isoflavone isolated from soybean) to inhibit cancer development [103]. Lutein has protective effect against expression of proliferative related genes in colon cancer. In colon cancer, when the expression of K-ras, b-catenin, and the protein kinase B (PKB) genes are affected, an abnormal growth is usually observed. Inclusion of lutein at 0.002% in diet of male SpragueeDawley rats treated with dimethylhydrazine reduced the incidence of tumors by 55% and downregulated the expression of K-ras, b-catenin, and PKB (25%, 28%, and 32% of reduction, respectively). Additionally, lutein supplementation reduced by 32% colon cancer incidence and expression of K-ras, b-catenin, and PKB genes (39%, 26%, and 26%, respectively). This indicates the involvement of lutein in expression of growth-related genes reducing the risk of colon cancer either for prevention or treatment condition [104]. The influence of lutein/zeaxanthin is also associated with reduction of

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photoaging and photocarcinogenesis caused by UVB radiation in female Skh-1 hairless mice. Inclusion of lutein/zeaxanthin at 0.4% in diet reduced skin fold thickness and the number of infiltrating mast cells in mice exposed to photoaging UVB radiation level (16,000 mJ/cm2). In photocarcinogenesis condition (30,200 mJ/cm2) the diet with carotenoids was associated with reduced number and total area of tumors. In this condition, lutein/zeaxanthin may display tumor suppressant activity, since these carotenoids reduced the number of invasive squamous carcinomas cells and increased the number of actinic keratosis [105]. It is well known that nicotine exposure cause lung cancer. Supplementation of b-cryptoxanthin on diet of A/J male mouse with nicotine reduced tumor and showed positive effects on reduction of tumor volume and multiplicity. Additionally, this supplementation at 10 and 20 mg/kg diet restored the levels of lung Sirtuin 1 (SIRT1), tumor inhibitor p53, RAR-b expression, and increased survival probability. These results support the long-term prospective evidence of b-cryptoxanthin preventive effect on lung cancer [106]. The effect of b-cryptoxanthin against lung cancer biological effects induced for cigarette smoke showed positive results in male ferrets. In this experiment, b-cryptoxanthin at low (7.5 mg/kg) and high (37.5 mg/kg) levels reduce lung squamous metaplasia and inflammation. Another important effect is the increase of Nf-kB level by cigarette smoke exposure, although b-cryptoxanthin at both doses reduces Nf-kB level in dose-dependent manner of bronchial and bronchial serous/mucous glands epithelial cells. It was suggested that the NfkB mechanism was involved in reduction of lung inflammation and squamous metaplasia by b-cryptoxanthin [107]. Apocarotenoid supplementation can also decrease incidence of cancer and restore or inhibit the expression of target molecules. Inclusion of apo-100 lycopenoic acid at 10, 40, and 120 mg/kg in diet of A/J mouse model, with induced lung cancer, reduced the number of tumors by 32.7%, 53.6%, and 65.4%, respectively. This effect was attributed to cell cycle arrest in G1 phase by inhibition cyclin E expression and induction of p21 and p27 protein levels, giving strong evidence apo-100 -lycopenoic acid inhibit cell proliferation [108]. Similar effect was observed for b-ionone in diet of male F344 rats with induced colon cancer. The treatment with azoxymethane induces formation of aberrant crypt foci, which is a lesion observed in primary stages of colon cancer. Results indicated b-ionone at 0.1% and 0.2% reduced aberrant crypt foci formation by 34e38%, respectively [99].

DIETARY INTERVENTIONAL STUDIES WITH CAROTENOIDS Consumption of carotenoid-rich vegetables shows health benefits for cancer patient in ongoing treatment and cancer survivors, which may increase general health and well-being. In some cases, cancer treatment reduces plasma carotenoids and additional intake of fruit and vegetables may be advantageous

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[109]. Previous studies indicated lycopene consumption may be beneficial, since reduction of tumor size and induction of apoptosis in prostate cancer patients after 3 weeks of increased lycopene diet were reported [110,111]. The protective effect of dietary carotenoids was also reported in prevention of DNA damage in clinical trial. A study with 37 healthy postmenopausal women (aged 50e70 years) assessed the effects of daily consumption of selected carotenoids (b-carotene, lutein, or lycopene) for 56 days in lymphocyte DNA. The experiment divided subjects into groups: control, mix of 12 g of the combination of the carotenoids (4 mg each), and 12 g of single carotenoid. After the experiment period, all groups with supplemented diet displayed significant reduction of DNA damage, compared to control group. Additionally, carotenoid mixed group and b-carotene group showed significant less DNA damage after 15 days. Such results suggest a protective effect of carotenoids against lymphoma [112]. The biological effects of increased vegetable daily servings in diet were evaluated in noninvasive bladder cancer patients. The experiment was performed with 48 patients who consumed at least two portions of cruciferous vegetables among seven daily portions of vegetables for 6 months. Results indicated the consumption of vegetables, reported by patients, caused significant increase of plasma a-carotene. Other recommendations for cancer prevention were also achieved in this study: reduction of energy intake and fat ingestion. This therapeutic diet promoted biological changes with potential to prevent recurrent and progressive bladder cancer [113]. Cancer survivors are considered as risk group to develop secondary cancer and other diseases. In this sense, inclusion of carotenoids in diet, by fruits and vegetables, may promote health changes associated with lower cancer incidence observed in previous studies. The access to information is also an important to improve intake of carotenoids by increasing portions fruits and vegetables, which are rich in carotenoids [114]. This outcome was observed in an intervention study with 489 breast and prostate cancer survivor followed-up for 2 years. The tailored mailed print material was prepared to induce high consumption of fruits and vegetables and reduce total and saturated fat ingestion and/or stimulating exercise for 10 months. After 2 years, patients reported increased daily amount of fruits and vegetables servings and overall diet quality, suggesting mailed information produced long-term healthier dietary changes in cancer survivors [115]. Self-report in dietary interventional studies could demand careful preparation and evaluation. Adequate information about portion size and previous knowledge of dietary intervention must be considered to avoid measurement and systematic errors [116]. In some studies, supplemented diet did not promote positive effects related with cancer prevent, but are associated to increase general health. Tomato juice was used as source of lycopene for an interventional study about tolerance and acceptance of daily consumption of 4, 8, and 12 oz. in 20 men with prostate cancer during radiotherapy treatment. All levels of tomato juice consumption

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were tolerated and accepted by patients, and adverse gastrointestinal effects were not observed. Serum lycopene levels significantly increased in 8 and 12 oz. of tomato juice treatments, but serum levels were not correlated to tomato juice consumption. Another important result was the correlation of serum lycopene with weight and body mass index, suggesting attention for weight gain in therapeutic diet with lycopene in future studies [117]. However, increase in cancer risk may also be promoted by carotenoid consumption. This outcome was reported in dietary intervention with b-carotene and vitamin A in lung cancer patients. Authors indicated that this combination may increase the incidence risk and death due to lung cancer [118]. Another study with a-tocopherol and b-carotene also indicated similar result, indicating the interaction of carotenoids and cancer may be influenced by other factors [119]. Such results provide valuable information for future interventional studies, particularly for increase of dietary carotenoid consumption in diet of cancer patients. However, the relationship of carotenoids with some factors as adequate food source, interactions of physiological conditions, and environmental factors are not fully elucidated in cancer patients and demands more studies.

CONCLUSION REMARKS This review focused in recent studies about the mechanisms modulated by dietary carotenoids that are associated with reduced risk of cancer by arresting cell cycle, inducing apoptosis, modulating nuclear receptors, and other pathways in both isolated cell lines and animal model. Vast and supportive information provided by these studies explains, at least in part, how the consumption of carotenoids and the related plasma level can be associated with reduced risk of cancer in many tissues. Dietary Interventional studies have been showing promising results, particularly to increase plasma carotenoids and general health in cancer patients, but adverse effects due to interaction of carotenoids intake and cancer development must be considered, as reported for b-carotene consumption and lung cancer patients. Nonrelated effects to carotenoids consumption as lifestyle, environmental factors, and increase of body weight must be considered, as well as other anthropometric measures. The main concern is to avoid negative interactions with ongoing treatments that would increase cancer development or reduce drug activity and ongoing treatment efficiency. Due to recent advances in PPAR system, future studies should evaluate the effect of intact carotenoids on this signaling pathway in other cell lines and in animal model. Apocarotenoids are formed by enzymatic or chemical reactions on carotenoids (e.g., vitamin A and apo-100 -lycopenal) and show potential activity against cancer development. However, the role of such compounds against cancer still partially understood. More studies are necessary to characterize the apocarotenoids (particularly dialdehydes), optimize the formation of specific

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products with high activity, and evaluate the influence on cancer cells, especially for ARE system and Nf-kB activity. Future studies should evaluate xanthophylls metabolites produced in human body with special focus in elucidating their structure and biological activity against cancer. Other aspects as interaction of carotenoids/apocarotenoids with drugs and treatments also deserve attention.

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Chapter 7

Dihydrochalcones: Occurrence in the Plant Kingdom, Chemistry and Biological Activities Ce´line Rivie`re Univ. Lille, INRA, ISA, Univ. Artois, Univ. Littoral Coˆte d’Opale, EA 7394 e ICV, Institut Charles Viollette, F-59000 Lille, France E-mail: [email protected]

Chapter Outline Introduction Occurrence in the Plant Kingdom Chemistry Dihydrochalcones With Simple Patterns of O-Substitution Monoterpene, Prenylated, and Geranylated Dihydrochalcones C-Benzylated Dihydrochalcones Dihydrochalcone Lignans Dihydrochalcone Dimers Dihydrochalcone Glycosides Biological Activities

253 254 282

283 302 319 319 324 327 341

Dihydrochalcones With Simple Patterns of O-Substitution Prenylated Dihydrochalcones C-Benzylated Dihydrochalcones Dihydrochalcone Lignans Dihydrochalcone Dimers Dihydrochalcone Glycosides Bioavailability of Dihydrochalcones Conclusion Abbreviations References

365 367 368 369 369 369 371 372 372 373

INTRODUCTION Dihydrochalcones (DHCs) are a class of minor flavonoids, structurally characterized by the presence of a benzylacetophenone skeleton, derived from the phenylpropanoid and polyketide biosynthetic pathways. DHCs are defined by the presence of two C6 rings joined by a C3 bridge, but the double bond is Studies in Natural Products Chemistry, Vol. 51. http://dx.doi.org/10.1016/B978-0-444-63932-5.00007-3 Copyright © 2016 Elsevier B.V. All rights reserved.

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reduced in comparison with chalcones. DHCs are biosynthetically close to other minor flavonoids such as flavanones, flavanonols, chalcones, and retrochalcones; chalcones and DHCs are open-ring derivatives of flavones and flavanones, respectively. DHCs can be simple, but they can also be glycosylated, sometimes C-glycosylated (such as aspalathin, which is isolated from rooibos, Aspalathus linearis), or substituted by different groups, for example, C-benzylated or prenylated. DHCs are known as a class of compounds found in apple trees (Malus x domestica Borkh., Malus sp., Rosaceae) along with hydroxycinnamic acids, flavanols, procyanidins, flavonols, and anthocyanins. These natural products are rarely encountered in other edible plants but have been isolated from many medicinal plants belonging to different botanical families, with a fairly heterogeneous distribution within the plant kingdom. This chapter will focus on the distribution of DHCs in the plant kingdom, as well as their chemistry. Finally, it will summarize the latest research concerning the biological activities of DHCs, as well as the current state of knowledge about their bioavailability. DHCs are of special interest because of their potentially valuable health effects. Indeed, DHCs have demonstrated a wide range of biological and pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial, cytotoxic, and antispasmodic effects. To close, DHCs will be reviewed for their well-known use as additives in the food industry. In fact, some DHCs are known to be intense artificial sweeteners, such as neohesperidin DHC, obtained by hydrogenation of neohesperidin.

OCCURRENCE IN THE PLANT KINGDOM To date, approximately 256 DHCs are known to be formed in over 46 plant families (Fig. 7.1 and Tables 7.1e7.8). The distribution of DHCs is quite heterogeneous in the plant kingdom since they are found in species that are very distant taxonomically: DHCs have been isolated both from the

FIGURE 7.1 Distribution of dihydrochalcones in botanical families (number of genera and species containing DHCs).

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Pteridophyta division (Polypodiales order) and from the Magnoliophyta division or Angiosperms (Magnoliids, Monocots, and Eudicots) (Table 7.1). In the Pteridophyta division, DHCs are particularly encountered in the Polypodiales order, in three families (Pteridaceae, Thelypteridaceae, and Woodsiaceae), as simple DHCs or DHC-flavonol dimers such as trianguletins in Pentagramma species [2]. DHCs are most widely distributed in the Magnoliid clade, in the Laurales, Magnoliales, and Piperales orders (Fig. 7.2). The Magnoliales order produces many DHCs, in particular in nine genera of the Annonaceae family and two genera of the Myristicaceae family (Fig. 7.2). Uvaria species have long been known to produce C-benzylated DHCs [21e39], but studies have shown that other genera of Annonaceae (Cyathostemma, Melodorum, and Xylopia) also produce this type of DHCs [13,18,40e43] (Table 7.1). In Myristicaceae family, original DHC-lignans, Iryantherins, are encountered in Iryanthera species [45,49], whereas in the Piperales order, Piper species produce monoterpene and prenylated DHCs [60e61,63]. In Monocots, the distribution of DHCs is heterogeneous. DHCs are encountered in the Alismatales, Asparagales, Dioscoreales, Liliales, and Arecales orders. Dracaena species (Asparagaceae) produce simple hydroxylated and methoxylated DHCs [72e81], whereas recent studies have highlighted the presence of cytotoxic retrodihydrochalcones in Tacca species (Dioscoreaceae) [83e85]. In the Zingiberaceae family, several species from different genera biosynthesize DHCs, including original prenylated DHCs such as etlinglittarolin, recently isolated from Etlingera littoralis [91]. In Eudicots, DHCs are mainly represented in the Rosid clade, in particular in Fabids, in the Fabales and Rosales orders. The Fabaceae family contains a lot of species that produce simple DHCs (including the specific a- and b-hydroxy or methoxy-DHCs) [101,107e108,110e111], prenylated DHCs and DHC glycosides (O- and C-glycosides), such as aspalathin, a DHC C-glycoside isolated from rooibos [95]. New prenylated DHCs have recently been isolated from species belonging to the Fabaceae family, such as Eriosema [99] and Flemingia [102]. Moraceae and Rosaceae are other families known for their DHCs. Artocarpus species, in the Moraceae family, produce prenylated and geranylated DHCs with interesting biological activities [131e139]. In the Rosaceae family, the famous domesticated apple, Malus x domestica Borkh., a complex interspecific hybrid, is an edible plant that possesses DHCs. These metabolites, mainly phloridzin, represent a small amount of the total polyphenols (around 3% of the total content) in apple fruit, but they are the major flavonoid subgroup in apple green tissues. Malus species produce high levels of DHCs in young leaves (200 mg/g of leaf dry weight (DW)) and immature fruits [197]. The genus Malus is native to the temperate zones of the northern hemisphere and is comprised of about 30e35 species of small deciduous trees or shrubs. The main ancestor is thought to be Malus sieversii M. Roem, and other ancestors include Malus sylvestris Mill., Malus Mill. and Malus dasyphylla Borkh [144]. Other DHCs, mainly derivatives (sieboldin, trilobatin, phloretin, and 3-hydroxyphloretin), have been isolated or detected in Malus x

TABLE 7.1 Distribution of Dihydrochalcones in the Embryophyta Division Family

Genus

Species

Type of Dihydrochalcones

Refs.

Pentagramma triangularis (Kaulf.) Yatsk., Windham and E. Wollenw. ssp. triangularis

Frond exudate: Trianguletin (208)

[1]

P. triangularis (Kaulf.) Yatsk., Windham, and E. Wollenw

Frond exudate: 4,2ʹ,6ʹ-trihydroxy-4ʹmethoxy-3,5-dimethyl-dihydrochalcone (58), trianguletin (208), trianguletin “B” (209)

[2]

Frond exudate: Trianguletin “C” (210), trianguletin “D” (211), trianguletin “E” (212)

[3]

Pityrogramma calomelanos (L.) link

Frond exudate: 2ʹ,6ʹ-dihydroxy-4ʹmethoxy-dihydro-chalcone (23)

[4]

Pityrogramma tartarea (Cav.) Maxon

Frond exudate: 2ʹ,6ʹ-dihydroxy-4ʹmethoxy-dihydro-chalcone (23), 2ʹ,6ʹdihydroxy-4,4ʹ-dimethoxydihydrochalcone (47), 20 ,60 -dihydroxy3,4,40 -trimethoxy-dihydrochalcone (74)

[4,5]

Euphyllophytes-Monilophytes-Polypodopsidia Polypodiales

Pteridaceae

Pentagramma

Pityrogramma

Thelypteridaceae

Abacopteris

Abacopteris penangiana (Hook.) Ching

Rhizomes: Abacopterin L (254)

[6]

Woodsiaceae

Woodsia

Woodsia scopulina D.C. Eaton

Fronds: 4ʹ-hydroxy-2ʹ,6ʹ-dimethoxydihydrochalcone (13), 2ʹ,4ʹ,6ʹtrimethoxy-dihydrochalcone (28)

[7]

256 Studies in Natural Products Chemistry

Order

Spermatophytes-Angiosperms-Magnoliids Laurales

Annonaceae

Lindera

Lindera erythrocarpa Makino

Leaves: Dihydropashanone (48) Wood: Dihydropashanone (48), 20 hydroxy-3ʹ,40 ,50 ,60 -tetramethoxydihydrochalcone (65)

[8]

Lindera lucida Boerl.

Twigs: 20 -hydroxy-3ʹ,40 ,50 ,60 tetramethoxy-dihydrochalcone (65), 3ʹ,50 dihydroxy-20 ,40 ,60 -trimethoxydihydrochalcone (76)

[9]

Lindera umbellata Thunb.

Leaves: 20 ,60 -dihydroxy-40 -methoxydihydrochalcone (23), 20 ,40 ,60 trihydroxy-dihydrochalcone (28)

[10]

L. umbellata Thunb. var. lancea

Fresh leaves: 20 ,60 -dihydroxy-40 methoxy-dihydrochalcone (23), 20 ,40 ,60 trihydroxy-dihydrochalcone (28), linderatin (98)

[11]

Leaves: ()-Methyllinderatin (99)

[12]

Cyathostemma argenteum (Blume) J. Sinclair

Leaves and twigs: 40 ,60 -dihydroxy20 ,4-dimethoxy-dihydrochalcone (49), 40 ,60 -dihydroxy-20 ,4-dimethoxy-50 -(200 hydroxy-benzyl)-dihydrochalcone (181)

[13]

Desmos

Desmos dunalii (Hook. f. & Thomson) Saff.

Leaves: 20 ,4-dihydroxy-40 ,60 -dimethoxydihydrochalcone (40), 20 ,4-dihydroxy40 ,60 -dimethoxy-50 -methyl-dihydrochalcone (41), 20 ,4-dihydroxy-40 ,60 dimethoxy-30 ,50 -dimethyldihydrochalcone (42), 20 ,4-dihydroxy-40 ,50 ,60 trimethoxy-dihydrochalcone (70)

[14]

257

Cyathostemma

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

Magnoliales

Lauraceae

Continued

Order

Family

Genus

Species

Type of Dihydrochalcones

Refs.

Fissistigma

Fissistigma bracteolatum Chatterjee

Leaves: 2-hydroxy-3,4,6-trimethoxydihydrochalcone (32), 20 -hydroxy-30 ,40 , 60 -trimethoxy-dihydrochalcone (34)

[15]

Fissistigma lanuginosum (Hook. f. & Thomson) Merr.

Leaves: 2ʹ,5ʹ-dihydroxy-30 ,40 ,60 trimethoxy-dihydrochalcone (73)

[16]

Goniothalamus

Goniothalamus gardneri Hook. f. & Thomson

Aerial parts: 20 -hydroxy-4,4ʹ,60 trimethoxy-dihydrochalcone (35), 20 ,40 dihydroxy-4,60 -dimethoxydihydrochalcone (45), 4,20 ,40 -trihydroxy60 -methoxy-dihydrochalcone (55), (rel)1b,2a-di-(2,4-dihydroxy6-methoxybenzoyl)-3b,4a-di(4-methoxyphenyl)-cyclobutane (214)

[17]

Melodorum

Melodorum siamense (Scheff.) Baˆn (syn. Rauwenhoffia siamensis Scheff.)

Leaves: 20 ,40 -dihydroxy-4,60 dimethoxydihydrochalcone (45), 4,20 ,40 trihydroxy-60 -methoxydihydrochalcone (54), 20 ,40 -dihydroxy-4,60 -dimethoxy30 (200 -hydroxybenzyl)-dihydrochalcone (180), 4,20 ,40 -trihydroxy-60 -methoxy30 (200 -hydroxybenzyl) dihydrochalcone (182), 30 ,300 -bis-20 ,40 ,60 -trihydroxy4-methoxydihydrochalcone (202)

[18]

Miliusa

Miliusa balansae Finet & Gagnep.

Leaves and branches: 2ʹ,6ʹ-dihydroxy-4ʹmethoxy-dihydrochalcone (23), dihydropashanone (48)

[19]

258 Studies in Natural Products Chemistry

TABLE 7.1 Distribution of Dihydrochalcones in the Embryophyta Divisiondcont’d

Stem bark: 20 ,60 -dihydroxy-40 methoxy-dihydrochalcone (23), ()-neolinderatin (91), ()linderatin (92)

[20]

Uvaria

Uvaria acuminata Oliv.

Roots: Uvangoletin (19), uvaretin (165), isouvaretin (168), diuvaretin (169), isochamuvaritin (178), acumitin (179)

[21,22]

Uvaria angolensis Welw. ex Oliv.

Roots: Uvangoletin (19), angoletin (21), uvaretin (165), isouvaretin (168)

[23]

Roots: Angoluvarin (167)

[24]

Roots: Anguvetin (166), dihydroflavokawin B (8)

[25]

Stem bark: Uvaretin (165), diuvaretin (169), chamuvaritin (177)

[26]

Stem bark: Uvaretin (165), isouvaretin (168)

[27]

Roots: Chamuvaritin (177)

[28]

Root bark: Uvaretin (165), isouvaretin (168), diuvaretin (169)

[29]

Uvaria dulcis Dunal (syn. Anomianthus dulcis (Dunal) James Sinclair)

Leaves: 2ʹ,3ʹ-dihydroxy-4ʹ,6ʹ-methoxydihydrochalcone (43)

[30,31]

Uvaria kirkii Oliv. ex Hook. f.

Root bark: Uvaretin (165), diuvaretin (169)

[32,33]

Uvaria chamae P. Beauv.

259

Mitrella kentii Miq.

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

Mitrella

Continued

TABLE 7.1 Distribution of Dihydrochalcones in the Embryophyta Divisiondcont’d Family

Genus

Xylopia

Species

Type of Dihydrochalcones

Refs.

Uvaria leptoclados Oliv.

Root bark: Uvaretin (165), angoluvarin (167), isouvaretin (168), diuvaretin (169), triuvaretin (170), isotriuvaretin (171),

[34]

Uvaria lucida Bojer ex Benth.

Root bark: Uvaretin (165), diuvaretin (169), chamuvaretin (177)

[35]

Uvaria mocoli de wild. & T. Dur.

Stem bark: 2-Hydroxy-4,5,6-trimethoxydihydrochalcone (33)

[36]

Uvaria puguensis D.M. Johnson

Stem bark: Uvaretin (165), isoangoletin (¼anguvetin) (166), diuvaretin (169), chamuvaritin (177), a mixture of triuvaretin, and isotriuvaretin (170-171)

[37]

Uvaria scheffleri Diels

Root bark: Uvaretin (165), diuvaretin (169)

[38]

Uvaria tanzaniae Verdc.

Root bark: Uvaretin (165), diuvaretin (169), isotriuvaretin (170) chamuvaretin (177)

[39]

Xylopia africana (Benth.) Oliv.

Roots: Triuvaretin (170), isotriuvaretin (171), 20 ,40 -dihydroxy-60 -methoxy-30 (2-hydroxy-benzyl)-50 -(3  2-hydroxybenzyl)-dihydrochalcone (172), 20 ,40 dihydroxy-60 -methoxy-30 -(3  2-hydroxybenzyl)-50 -(2-hydroxy-benzyl)dihydrochalcone (173), 20 ,40 -dihydroxy60 -methoxy-30 -(2-hydroxy-benzyl)-50 (4  2-hydroxy-benzyl)-dihydrochalcone

[40e43]

260 Studies in Natural Products Chemistry

Order

Myristicaceae

Iryanthera

Iryanthera grandis Ducke

Iryanthera laevis Markgr.

Iryanthera lancifolia Ducke

Fruits: 20 ,40 -dihydroxy-4,60 -dimethoxydihydro-chalcone (45)

[44]

Fruits: Iryantherins G-J(189-192)

[45]

0

0

0

Bark: 2 ,4 -dihydroxy-4,6 -dimethoxydihydrochalcone (45), 20 ,40 -dihydroxy3,4,60 -trimethoxy-dihydrochalcone (68), 20 ,40 -dihydroxy-60 -methoxy3,4-methylene-dioxy-dihydrochalcone (69)

[46]

Trunk wood: 20 ,40 -dihydroxy-4,60 dimethoxy-dihydrochalcone (45)

[47]

Fruits: 20 ,40 -dihydroxy-4,60 -dimethoxydihydrochalcone (45), 20 ,40 ,60 -trihydroxy4-methoxy-dihydrochalcone (61), iryantherin A (183)

[48]

Fruits: Iryantherins B-E (184-187)

[49]

0

0

0

Pericarps: 2 ,4 -dihydroxy-4,6 dimethoxy-dihydrochalcone (39), 20 ,4-dihydroxy-40 ,60 - dimethoxy-dihydro-

[50]

261

Continued

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

(174), 20 ,40 -dihydroxy-60 -methoxy-30 (4  2-hydroxy-benzyl)-50 -(2-hydroxybenzyl)-dihydrochalcone (175), 20 ,60 dihydroxy-40 -methoxy-30 -(2-hydroxybenzyl)-dihydrochalcone (176)

Order

Family

Genus

Species

Type of Dihydrochalcones

Refs.

chalcone (45), iryantherin K (193), iryantherin L (194) Iryanthera paraensis Huber

Bark: 20 ,40 -dihydroxy-4,60 -dimethoxydihydrochalcone (45), iryantherin F (188)

[49]

Iryanthera polyneura Ducke

Trunk wood: 4,2ʹ,4ʹ-trihydroxy3-methoxy-dihydrochalcone (52)

[51]

Iryanthera sagotiana (Benth.) Warb.

Bark: 20 ,40 -dihydroxy-4,60 -dimethoxydihydrochalcone (45), 20 ,40 -dihydroxy-60 methoxy-3,4-methylene-dioxydihydrochalcone (69)

[52]

Inflorescences: 20 ,40 -dihydroxy-4,60 dimethoxy-dihydrochalcone (45), 4,20 ,40 trihydroxy-60 -methoxy-dihydrochalcone (54), 20 ,40 ,60 trihydroxy-4-methoxy-dihydrochalcone (61), 40 ,60 -dihydroxy-4-methoxydihydrochalcone- 20 -O-b-Dglucopyranoside (234)

[53]

Leaves: 20 ,40 -dihydroxy-4,60 -dimethoxydihydrochalcone (45), 4,2ʹ,40 -trihydroxy60 -methoxy-dihydrochalcone (54), 30 ,3ʹʹ-

[53]

262 Studies in Natural Products Chemistry

TABLE 7.1 Distribution of Dihydrochalcones in the Embryophyta Divisiondcont’d

bis-20 ,40 ,60 -trihydroxy-4-methoxydihydrochalcone (202) [49]

Bark: 20 ,40 -dihydroxy-3,4,60 -trimethoxydihydrochalcone (68)

[54]

Trunk wood: 20 ,40 -dihydroxy-4,60 dimethoxy-dihydrochalcone (45)

[54]

Virola

Virola calophylloidea Markgr.

Trunk wood: ()-a,2ʹ-dihydroxy-4,4ʹdimethoxy-dihydrochalcone (84)

[55]

Virola carinata (Benth.) Warb

Bark: ()-a,2ʹ-dihydroxy-4,4ʹ-dimethoxydihydrochalcone (84)

[56]

Virola surinamensis (rol. ex Rottb.) Warb.

Twigs and roots: ()-a,2ʹ-dihydroxy-4,4ʹdimethoxy-dihydrochalcone (84)

[57,58]

Piperales

Piperaceae

Piper

Piper aduncum L.

Leaves: 2ʹ,6ʹ-dihydroxy-4ʹ-methoxydihydrochalcone (23), asebogenin (57), piperaduncins A-B (102-103), piperaduncin C (203)

[59]

Leaves: ()-Methyl-linderatin (99), adunctins A-E (105-109),

[60]

Leaves: adunchalcone (101)

[61]

Leaves: 2ʹ,6ʹ-dihydroxy-4ʹ-methoxydihydrochalcone (23), asebogenin (57)

[62]

Piper carpunya Ruiz & Pav.

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

Bark: 20 ,40 -dihydroxy-4,60 -dimethoxydihydrochalcone (45), iryantherin B (184), iryantherins D-F (186-188)

Iryanthera ulei Warb.

263 Continued

Order

Family

Genus

Species

Type of Dihydrochalcones

Refs.

Piper dennisii Trel.

Leaves: 20 ,60 -dihydroxy-40 methoxydihydrochalcone (23), asebogenin (57), dennisic acid A (110), dennisic acid B (148), piperaduncin C (203)

[63]

Piper elongatum Vahl

Aerial parts: 2ʹ,6ʹ-dihydroxy-4ʹ-methoxydihydrochalcone (23), asebogenin (57)

[64]

Piper hostmannianum (Miq.) C. DC. var. berbicense

Leaves: 20 ,60 -dihydroxy-40 methoxydihydrochalcone (23), ()-methyl-linderatin (99), adunctin E (109), hostmanins A-D (111-114)

[65]

Piper longicaudatum Trel. & Yunck.

Leaves and twigs: 20 ,60 -dihydroxy-40 methoxydihydrochalcone (23), asebogenin (57), piperaduncin B (103), longicaudatin (104)

[66]

Piper mollicomum Kunth

Leaves: 20 ,60 -dihydroxy-40 methoxydihydrochalcone (23)

[67]

Spermatophytes-Angiosperms-Monocots Alismatales

Cymodoceaceae

Thalassodendron

Thalassodendron ciliatum (Forssk.) Hartog

Plant: Thalassodendrone (224), asebotin (225)

[68]

Zosteraceae

Zostera

Zostera sp.

Plant: Zosterin (256)

[69]

264 Studies in Natural Products Chemistry

TABLE 7.1 Distribution of Dihydrochalcones in the Embryophyta Divisiondcont’d

Asparagales

Amaryllidaceae

Agapanthus africanus

Roots: rel-(1b,2a)-di-(2,4-dihydroxy benzoyl)-rel-(3b,4a)-di(4-hydroxyphenyl)-cyclobutane (217)

[70]

Crinum

Crinum bulbispermum (Burm. f.) Milne-Redh. & Schweick.

Bulbs: 4-Hydroxy-20 ,40 -dimethoxydihydrochalcone (6)

[71]

Dracaena

Dracaena cinnabari Balf. f.

Resin: 4-Hydroxy-2-methoxy-dihydrochalcone (2), loureirin C (16)

[72]

Resin: Cinnabarone (206)

[73]

Dracaena cochinchinensis (Lour.) S.C. Chen

0

0

Resin (Chinese dragon s blood): 4 hydroxy-2,6-dimethoxy-dihydrochalcone (11), loureirin B (36)

[74]

Resin: Loureirin C (16), 2,4,40 -trihydroxydihydrochalcone (26), loureirin D (50), cochinchinenin (207)

[75]

Fresh stems: Loureirin C (16)

[76]

0

0

[77]

Resin: 4-Hydroxy-2,40 -dimethoxydihydrochalcone (7), loureirin A (10), loureirin C (16), 2,4,40 -trihydroxydihydrochalcone (26), loureirin B (36), 2,40 -dihydroxy-4,6-dimethoxy dihydrochalcone (37), loureirin D (50), 3,40 -dihydroxy-2,4,6-trimethoxydihydrochalcone (75)

[78]

265

Resin: 4 -Hydroxy-4,2 -dimethoxydihydrochalcone (12)

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

Asparagaceae

Agapanthus

Continued

Order

Dioscoreales

Liliales

Family

Genus

Species

Type of Dihydrochalcones

Refs.

Dracaena draco (L.) L.

Resin: 2,4,40 -trihydroxy-dihydrochalcone (26)

[79]

Dracaena loureiroi (Lour.) Gagnep. (syn. D. cochinchinensis)

Stems: Loureirin A (10), loureirin C (16), loureirin B (36), loureirin D (50)

[80]

Stem wood: Loureirin B (36), 2,4ʹdihydroxy-4,6-dimethoxydihydrochalcone (37), 4,40 -dihydroxy2,6-dimethoxy-dihydrochalcone (38), 4ʹ,4,6-trihydroxy-2-methoxy-dihydrochalcone (60)

[81]

Orchidaceae

Luisia

Luisia volucris Lindl.

Whole plant: Lusianin (44)

[82]

Dioscoreaceae

Tacca

Tacca chantrieri Andre´

Roots and rhizomes: Taccabulin A (66), taccabulin D (67), taccabulin C (71), taccabulin E (72), taccabulin B (82), evelynins A-B (80-81)

[83e85]

Tacca integrifolia Ker Gawl.

Roots and rhizomes: Taccabulin A (66), taccabulin D (67), taccabulin C (71), taccabulin E (72), taccabulin B (82), evelynins A-B (80-81)

[84,85]

Ledebouria ovatifolia (Baker) Jessop

Bulbs: 4,4ʹ-dihydroxy-2ʹ,6ʹ-dimethoxydihydrochalcone (39)

[86]

Liliaceae

Ledebouria

266 Studies in Natural Products Chemistry

TABLE 7.1 Distribution of Dihydrochalcones in the Embryophyta Divisiondcont’d

Spermatophytes-Angiosperms-Monocots-Commelinids Arecaceae

Daemonorops

Daemonorops draco (Willd.) Blume

Resin: Daemonorol F (14), 4,6-dihydroxy-2- methoxy-3-methyldihydrochalcone (15)

[87,88]

Zingiberales

Zingiberaceae

Alpinia

Alpinia speciosa (Blume) D. Dietr.

Rhizomes: Dihydroflavokawin B (8)

[89]

Boesenbergia

Boesenbergia pandurata (Roxb.) Schltr.

Rhizomes: Uvangoletin (19), 2ʹ,4ʹ,6ʹtrihydroxy-dihydrochalcone (28)

[90]

Etlingera

Etlingera littoralis (J. Koenig) Giseke

Rhizomes: 20 ,60 -dihydroxy-40 -methoxydihydrochalcone (23), 20 ,40 ,60 -trihydroxydihydrochalcone (28), asebogenin (57), (L)-methyllinderatin (99), adunctin E (109), etlinglittarolin (115)

[91]

Renealmia

Renealmia nicolaioides Loes.

Roots: ()-nicolaioidesins A-C (116-118)

[92]

Coptis

Coptis chinensis Franch Coptis deltoidea C.Y. Cheng et Hsiao. Coptis teetoides C.Y. Cheng (syn. Coptis teeta Wall.)

Rhizomes: Dihydrochalcone (1)

[93]

Corylopsis pauciflora siebold & Zucc.

Leaves: Phloretin 4ʹ-O-glucoside, phloretin 4ʹ-O-galloylglucosidea

[94]

Spermatophytes-Angiosperms-Eudicots Ranunculales

Ranunculaceae

Spermatophytes-Angiosperms-Eudicots-Core eudicots Saxifragales

Hamamelidaceae

Corylopsis

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

Arecales

267 Continued

TABLE 7.1 Distribution of Dihydrochalcones in the Embryophyta Divisiondcont’d Family

Genus

Species

Type of Dihydrochalcones

Refs.

Spermatophytes-Angiosperms-Eudicots-Core Eudicots-Rosids-Fabids Fabales

Fabaceae

Aspalathus

Aspalathus linearis (Burm.f.) Dahlg.

Leaves (rooibos): Aspalathin (257), nothofagin (258)

[95]

Cyclopia

Cyclopia subternata Vogel

Stems and leaves: Phloretin-30 ,50 -di-C-bglucoside, 3-hydroxyphloretin-30 ,50 -di-Chexosideb

[96]

Crotalaria

Crotalaria ramosissima Roxb.

Plant: Crotaramosmin (93)

[97]

Plant: Crotaramin (94), crotin (126)

[98]

Eriosema

Eriosema glomeratum (Guill. & Perr.) Hook. f.

Whole plant: Erioschalcone B (90), erioschalcone A (95)

[99]

Eysenhardtia

Eysenhardtia polystachya (Ortega) Sarg.

Trunk wood: Coatline A (259), coatline B (260)

[100]

Bark and trunks: (aR)-a,3,4,2ʹ,4ʹpentahydroxy-dihydrochalcone (83), (aR)-3ʹ-O-b-D-xylopyranosyl- a,3,4,2ʹ,4ʹpentahydroxy-dihydrochalcone (232), coatline B (260), (aR)-3ʹ-C-b-Dxylopyranosyl- a,3,4,2ʹ,4ʹ-pentahydroxydihydrochalcone (261)

[101]

Flemingia

Flemingia philippinensis Merr. & Rolfe

Roots: Fleminchalcone B (96), fleminchalcone A (127), fleminchalcone C (128)

[102]

Glycyrrhiza

Glycyrrhiza glabra L.

Underground parts: Kanzanol Y (129)

[103]

Glycyrrhiza pallidiflora maxim.

Hairy roots culture: Licoagroside F (231)

[104]

268 Studies in Natural Products Chemistry

Order

Leptoderris fasciculata (Benth.) Dunn

Leaves: Dihydrochalcone (1)

[105]

Lonchocarpus

Lonchocarpus subglaucescens Mart. ex Benth.

Roots: 3,4-Methylenedioxy-20 -methoxy[200 ,3“:40 ,30 ]-furanodihydrochalcone (130)

[106]

Millettia

Millettia hemsleyana Prain

Stem bark: Dihydromilletenone methyl ether (88), dihydroisomilletenone methyl ether (89)

[107]

Millettia leucantha Kurz

Stem bark: 2ʹ,4ʹ,6ʹ -trimethoxy3,4-methylene-dioxy-dihydrochalcone (77), dihydromilletenone methyl ether (88)

[108]

Millettia usaramensis Taub. Subsp. usaramensis

Stem bark: 40 -geranyloxy-a,4,20 -trihydroxy-dihydrochalcone (131)

[109]

Oxytropis

Oxytropis falcate Bunge

Whole plant: 20 ,40 -dihydroxychalcone (5), 20 ,40 ,b-trihydroxy-dihydrochalcone (85)

[110]

Pongamia

Pongamia pinnata (L.) Pierre

Root bark: Ponganone VII (46), ponganone IX (163), ponganone VIII (164), ovalitenin B (97), dihydromilletenone methyl ether (88)

[111]

Pterocarpus

Pterocarpus marsupium Roxb.

Roots and heartwood: 3ʹ-C-b-Dglucopyranosyl-20 ,4,40 ,b-tetra-hydroxydihydrochalcone (262)

[112,113]

Heartwood: 3ʹ-C-b-D-glucopyranosyla-hydroxy-dihydrochaIcone (263)

[114]

Corylus

Corylus avellana L.

Fruit: Phloretin-20 -O-glucoside (phloridzin)c

[115,116]

Fagaceae

Lithocarpus

Lithocarpus litseifolius (Hance) Chun

Leaves: Phloridzin (240), trilobatin (241)

[117]

Continued

269

Betulaceae

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

Fagales

Leptoderris

TABLE 7.1 Distribution of Dihydrochalcones in the Embryophyta Divisiondcont’d Family

Myricaceae

Malpighiales

Euphorbiaceae

Genus

Myrica

Species

Type of Dihydrochalcones

Refs.

Lithocarpus pachycarpus (Hickel & A. Camus) A. Camus

Leaves: Phloridzin (240), trilobatin (241), trilobatin 2ʹʹ-acetate (233)

[118]

Lithocarpus polystachyus (Wall. ex ADC.) Rehder

Leaves: Trilobatin (241)

[119,120]

Myrica gale L.

Fruits: Myrigalone H (20), myrigalone G (24)

[121]

Fruit exudate: Myrigalone E (9), myrigalone H (20), angoletin (21), myrigalone G (24), myrigalone B (25), myrigalones A (31)

[122]

Seeds: Uvangoletin (19), myrigalone H (20), angoletin (21), myrigalone G (24), myrigalone B (25), myrigalone A (31), ceratiolin (64)

[123]

Euphorbia

Euphorbia portlandica

Whole plant: Davidigenin (27)

[124]

Macaranga

Macaranga trichocarpa (Rchb. f. & Zoll.) Mu¨ll. Arg.

Leaves: Macatrichocarpins C-D (122-123)

[125]

Leaves: Oxymacatrichocarpin C (124), iso-macatrichocarpin C (125)

[126]

Ochnaceae

Brackenridgea

Brackenridgea zanguebarica Oliv

Bark from stems and roots: Brackenin (199)

[127]

Salicaceae

Populus

Populus balsamifera L.

Buds: 2ʹ,6ʹ-dihydroxy-4ʹ-methoxydihydrochalcone (23), 2ʹ,4ʹ,6ʹ-trihydroxy-

[128]

270 Studies in Natural Products Chemistry

Order

dihydrochalcone (28), balsacone C (30), 2ʹ,6ʹ-dihydroxy-4,4ʹ-dimethoxydihydrochalcone (47), asebogenin (57), balsacone A (59), 2ʹ,4ʹ,6ʹ-trihydroxy4-methoxy-dihydrochalcone (61), balsacone B (62) [129]

Humulus

Humulus lupulus L.

Cones: a,b-dihydroxanthohumol (120)

[130]

Moraceae

Artocarpus

Artocarpus altilis (Parkinson) Fosberg (syn. ¼ A. communis J.R. Forst. & G. Forst.)

Leaves and stems: 1-(2,4-Dihydroxy phenyl)-3-[8-hydroxy-2-methyl-2(4-methyl-3-pentenyl)-2H-1-benzopyran5-yl]-1-propanone ¼ CG901 (132)

[131]

Leaves: CG901 (132), 2-geranyl-20 ,3,4,40 tetrahydroxy-dihydrochalcone (133), 1(2,4-dihydroxyphenyl)-3-{4-hydroxy6,6,9-trimethyl-6a,7,8, 10a-tetrahydro6H-dibenzo[b,d]pyran-5-yl}-1-propanone (134), 1-(2,4-dihydroxy-phenyl)-3[3,4-dihydro-3,8-dihydroxy-2-methyl-2(4-methyl-3-pentenyl)-2H-1-benzopyran5-yl]-1-propanone (135), 1(2,4-dihydroxy-phenyl)-3-[8-hydroxy2-methyl-2-(3,4-epoxy-4-methyl1-pentenyl)-2H-1-benzopyran-5-yl]1-propanone (136), 1-(2,4-dihydroxyphenyl)-3-[8-hydroxy-2-methyl-2(4-hydroxy-4-methyl-2-pentenyl)-2H1-benzopyran-5-yl]-1-propanone (137), 2-[6-hydroxy-3,7-dimethylocta2(E),7-dienyl]-20 ,3,4,40 -tetrahydroxy dihydrochalcone (138), cycloaltilisin 6 (201)

[132]

271

Cannabaceae

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

Rosales

Buds: Iryantherin D (186), balsacones J-M (195-198)

Continued

TABLE 7.1 Distribution of Dihydrochalcones in the Embryophyta Divisiondcont’d Family

Genus

Species

Type of Dihydrochalcones

Refs.

Leaves: 2-Geranyl-20 ,3,4,40 -tetrahydroxydihydrochalcone (133)

[133]

Leaves: CG901 (132), 2-geranyl-20 ,3,4,40 tetra- hydroxy-dihydrochalcone (133), 1(2,4-dihydroxy-phenyl)-3-[3,4-dihydro3,8-dihydroxy-2-methyl-2-(4-methylpent-3-enyl)-2H-1-benzopyran-5-yl] propan-1-one (135), sakenins A-H (139146), cycloaltilisin 6 (201) Buds: 2-Geranyl-20 ,3,4,40 -tetrahydroxydihydrochalcone (133), cycloaltilisin 6 (201),

[135]

Flowers (seeded variety): CG901 (132), 2-geranyl-20 ,3,4,40 -tetrahydroxydihydrochalcone (133)

[136]

Leaves (variety breadfruit): CG901 (132) Leaves (variety chataigne): CG901 (132), 2-geranyl-20 ,3,4,40 -tetrahydroxydihydrochalcone (133)

[137]

Leaves: CG901 (132)

[138]

Artocarpus elasticus Reinw. ex Blume

Leaves: Elastichalcone A (100), elastichalcone B (147)

[139]

Fragaria

Fragaria  ananassa Duchesne ex Rozier

Fruits: Phloridzinc

[140]

Malus

Malus x domestica Borkh.

Fruits and immature fruits: Phloridzin (240)d

[141]

Leaves: Phloretin (23)

[142]

Artocarpus communis J.R. Forst. & G. Forst. (syn. ¼ A. altilis (Parkinson) Fosberg)

Rosaceae

[134]

272 Studies in Natural Products Chemistry

Order

Leaves: Phloretin (23), phloridzin (240), 3-hydroxyphloridzin. 40 ,60 dihydroxy-dihydrochalcone20 -O-b-D-gluco-pyranosidee 3-Hydroxyphloretin, trilobatin, 4-Omethylphloretin, phloretin-20 -O-(b-Dxylopyranosyl-(1 / 6)-b-Dglucopyranoside), phloretin-20 -O-b-Dxylopyranoside, 3,5-dihydroxyphloretin-20 -O-b-D-gluco-pyranoside (3,5-dihydroxyphloridzin), 3,5-dihydroxyphloretin-40 -O-b-D-glucopyranoside (3,5-dihydroxy-trilobatin), methyl3,5-dihydroxy-phloridzinf

[143]

Wild Malus Rare red Italian wild apple “Pelingo”

Fruit: phloridzin (240), phloretin-20 O-xyloglucoside (251)g

[144]

Malus hupehensis (Pamp.) Rehder

Root skins, stems, tender leaves, fruits: Phloridzin (240)

[145]

Malus pumila Mill.

Leaves, bark, roots: Phloridzin (240)

[146]

Malus sieboldii (Regel) Rehder

Leaves: Sieboldin (243)

[146]

Malus trilobata C.K. Schneid

Leaves: Trilobatin (241)

[146]

Rosa cymosa Tratt.

Roots: Rocymosin B (252)

[147]

273

Continued

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

Rosa

Malus doumeri (Bois) A. Chev.

Order

Family

Genus

Species

Type of Dihydrochalcones

Refs.

Polygonum odoratum (Mill.) Druce

Rhizomes: Polygonatone D (56)

[148]

Polygonum salicifolium Brouss. ex Willd.

Aerial parts: Salicifolioside A (239)

[149]

Spermatophytes-Angiosperms-Eudicots-Core Eudicots-Rosids-Malvids Caryophyllales

Polygonaceae

Polygonum

Geraniales

Melianthaceae

Greyia

Greyia flanaganii Bolus

Leaves: 2ʹ,6ʹ-dihydroxy-4ʹmethoxydihydrochalcone (23), 2ʹ,4ʹ,6ʹtriihydroxy-dihydrochalcone (28), 2ʹ,6ʹdihydroxy -4ʹ,4-dimethoxy dihydrochalcone (47), asebogenin (57)

[150]

Malvales

Muntingiaceae

Muntingia

Muntingia calabura L.

Stem wood: (R)-20 ,b-dihydroxy-30 ,40 dimethoxy-dihydrochalcone (86)

[151]

Leaves: 4,20 ,40 -trihydroxy-30 -methoxydihydrochalcone (53), 2,3-dihydroxy4,30 ,40 ,50 -tetramethoxy-dihydrochalcone (79)

[152]

Aerial parts: rel-1b-(4,6-dihydroxy2-methoxy)-benzoyl -rel-2a(2,6-dimethoxy-4-hydroxy)-benzoyl-rel(3b,4a)-diphenyl-cyclobutane (215), rel(1a,2b)-di-(2,6-dimethoxy-4-hydroxy)benzoyl- rel-(3a,4b)-diphenylcyclobutane (216)

[153]

Myrtales

Combretaceae

Combretum

Combretum albopunctatum

274 Studies in Natural Products Chemistry

TABLE 7.1 Distribution of Dihydrochalcones in the Embryophyta Divisiondcont’d

Diplectaria beccariana Kuntzeh

Leaves: 4ʹ-O-methyl-davidigenin (17), 2ʹ,4ʹ-dihydroxy-4-methoxydihydrochalcone (18)

[154]

Myrtaceae

Calythropsis

Calythropsis aurea C.A. Gardner

Plant: Dihydrocalythropsin (51)

[155]

Eucalyptus

Eucalyptus citriodora Hook.

Leaves: Rhodomyrtosone E (213)

[156]

Leptospermum

Leptospermum recurvum Hook. f.

Foliage: 20 ,40 ,60 -trihydroxy-30 methyldihydrochalcone (29)

[157]

Syzygium

Syzygium jambos (L.) Alston

Leaves: 20 ,60 -dihydroxy-40 methoxydihydrochalcone (23), myrigalone G (24), myrigalone B (25)

[158]

Syzygium samarangense (Blume) Merr. & L.M. Perry

Leaves: Myrigalone H (20)

[159]

Balanophora harlandii Hook. f.

Rhizomes: 3-Hydroxyphloretin (78), trilobatin (241), sieboldin (243), 3-hydroxy-phloretin 40 -(6ʹʹ-O-galloyl-bD-glucoside) (244), 3-hydroxyphloretin 40 -[4ʹʹ,6ʹʹ-di-O-(S)-HHDP-b-D -glucoside] (247), 3-hydroxyphloretin 4ʹ-O-[3ʹʹ-Ogalloyl-4ʹʹ,6ʹʹ-di-O-(S))-HHDP-bD-glucoside] (248), hesperetin dihydrochalcone 40 -b-D-glucoside (250)

[160]

Balanophora involucrata Hook. f.

Whole plant: Sieboldin (243), 3-hydroxyphloretin 4ʹ-O-(6ʹʹ-O-galloyl)b-D-glucoside) (244), 3-hydroxyphloretin 40 -O-[40 ʹ,60 ʹ-diO-(S)-HHDP]-bD-glucoside (247)

[161]

Balanophoraceae

Balanophora

275

Diplectaria

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

Santalales

Melastomataceae

Continued

Order

Family

Schoepfiaceae

Genus

Species

Type of Dihydrochalcones

Refs.

Balanophora tobiracola Makino

Aerial parts: 3-Hydroxyphloretin (78), trilobatin (241), phloretin 4ʹ-O-[3ʹ-Ogalloyl-4ʹ,6ʹ-O-(S)- HHDP]-b-D-glucoside (242), sieboldin (243), 3-hydroxyphloretin 4ʹ-O-(6ʹʹ-O-galloyl)-b-D-glucoside (244), 3-hydroxyphloretin 4ʹ-O-(3ʹʹ,4ʹʹ-di-Ogalloyl)-b-D-glucoside (245), 3-hydroxyphloretin 4ʹ-O-(4ʹʹ,6ʹʹ-di-Ogalloyl)-b-D-glucoside (246), 3-hydroxyphloretin 4ʹ-O-[4ʹ,6ʹʹ-O-(S)HHDP]-b-D-glucoside (247), 3-hydroxyphloretin 4ʹ-O-[3ʹʹ-O-galloyl4ʹʹ,6ʹʹ-O-(S)-HHDP]-b-D-glucoside (248), 3-hydroxyphloretin 4ʹ-[3ʹʹ-O-caffeoyl4ʹʹ,6ʹʹ-O-(S)-HHDP] -b-D-glucoside (249)

[161e163]

Thonningia

Thonningia sanguinea Vahl

Roots: Thonningianins A-B (222-223)

[164]

Schoepfia

Schoepfia chinensis Gardner & Champ.

Bark: Schoepfins A-B (265-266), nothofagin (258)

[165]

Schoepfia jasminodora siebold & Zucc.

Branches: Schoepfin B (266), schoepfiajasmin D (253), schoepfiajasmins A-C (267-269)

[166]

276 Studies in Natural Products Chemistry

TABLE 7.1 Distribution of Dihydrochalcones in the Embryophyta Divisiondcont’d

Sapindales

Rutaceae

Boronia

[167]

Boronia pinnata Sm.

Aerial parts: Bipinnatones A-B (151-152)

[168]

Citrus aurantium L.

Leaves: neohesperidin dihydrochalcone (255)

[169]

Citrus hystrix DC.

Fruits: Phloretin-3ʹ,5ʹ-di-C-bglucopyranoside (264)

[170]

Citrus microcarpa Bunge

Fruits: Phloretin-3ʹ,5ʹ-di-C-bglucopyranoside (264)

[170]

Esenbeckia grandiflora subsp. brevipetiolata Kaastra

Leaves: Dihydrochalcone M-1 (153), dihydrochalcone M-2 (154)

[171]

E. grandiflora subsp. grandiflora

Leaves: 20 ,40 ,6ʹ,3,4epentahydroxy3ʹ,5-diprenyl-dihydrochalcone (158), 20 ,40 ,6ʹ,3,4epentahydroxy-3ʹ-geranyl5-prenyldihydrochalcone (159), 20 ,40 ,6ʹ,3-tetra-hydroxy-3ʹ-geranyl-6ʹʹ,6ʹʹdimethylpyrano [2ʹʹ,3ʹʹ:4,5]dihydrochalcone (160)

[172]

Fortunella

Fortunella sp.

Fruits and leaves: Phloretin-3ʹ,5ʹ-di-C-bglucopyranoside (264)

[173]

Metrodorea

Metrodorea nigra A. St.Hil.

Fresh fruits: 20 ,3,40 ,60 -tetra hydroxy4-methoxy-30 ,5-di-(3,3- dimethylallyl)dihydrochalcone (161), 20 ,3,60 trihydroxy-4-methoxy-5(3,3-dimethyallyl)-30 ,40 -(2ʹʹ,2ʹʹ-dimethyl dihydropyran)-dihydrochalcone (162)

[174]

Citrus

Esenbeckia

277

Aerial parts: 2ʹ,4,4ʹ,6ʹ-tetra-hydroxy-5-(E3,7dimethylocta-2,6-dienyl)-3(3-methyl-but-2-enyl)-dihydrochalcone (149), 2ʹ,4,4ʹ,6ʹ-tetrahydroxy3,5-di(3-methylbut-2- enyl)-dihydrochalcone (150)

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

Boronia inconspicua Benth.

Continued

Order

Family

Genus

Species

Type of Dihydrochalcones

Refs.

Metrodorea stipularis Mart.

Stems: Dihydrochalcone M-2 (154), 1(5,7-di-hydroxy-2,2-dimethyl-chroman6-yl)-3-(2,2-di-methyl-chroman-6-yl) propan-1-one (155), 1-(5,7-dihydroxy2,2-dimethylchroman-6-yl)-3-[4-hydroxy -3-(3-methylbut-2-en-1-yl)-phenyl]propan-1-one (156), 1-(5,7-dihydroxy2,2-dimethyl- chroman-6-yl)-3-(1,1,4atrimethyl-2,3,4,4a,9a-hexahydro-1Hxanthen-7-yl)propan-1-one (157)

[175]

Ceratiola

Ceratiola ericoides

Aerial parts: 20 ,40 edihydroxydihydrochalcone (5), angoletin (21), 20 ,60 dihydroxy-4-methoxy-30 ,50 dimethyldihydrochalcone (22), ceratiolin (64)

[176]

Empetrum

Empetrum nigrum L.

Aerial parts: 20 -hydroxy-40 -methoxydihydrochalcone (3), 40 -hydroxy-20 methoxy-dihydrochalcone (4), 20 ,40 dihydroxydihydrochalcone (5), dihydroflavokawin-B (8), uvangoletin (19)

[177]

Aerial parts: 2ʹ-methoxy-4ʹ-hydroxy-a,bdihydrochalcone (4), 2ʹ,4ʹ-dihydroxy-a,bdihydrochalcone (5)

[178]

Spermatophytes-Angiosperms-Eudicots-Core Eudicots-Asterids Ericales

Ericaceae

278 Studies in Natural Products Chemistry

TABLE 7.1 Distribution of Dihydrochalcones in the Embryophyta Divisiondcont’d

Loiseleuria procumbens (L.) Desv.

Whole plant: Phloretin (63), asebotin (225) 6ʹʹ-acetylphloridzosid (230), phloridzosid (240)

[179]

Pieris

Pieris japonica (Thunb.) D. Don ex G. Don

Leaves: Asebogenin (57), phloretin (63), pierotin B (121), pierotin A (200), asebotin (225), 3-hydroxyasebotin (226), asebogenin 20 -O-b-D-ribohexo3-ulopyranoside (227), 200 -acetyl-asebotin (228), 30 ,4,50 -trihydroxy-40 -methoxydihydrochalcone 30 ,50 -di-O-bglucopyranoside (229), phlorizin (240)

[180]

Pentaphylacaceae

Anneslea

Anneslea fragrans var. lanceolata Hayata

Roots: Davidigenin (27), davidioside (218), 4ʹ-O-methyl-davidioside (219), davidigenin-2ʹ-O-(6ʹʹ-O-4ʹʹʹ-hydroxybenzoyl)-b-glucoside (235), davidigenin2ʹ-O-(2ʹʹ-O-4ʹʹʹ-hydroxy-benzoyl)-bglucoside (236), davidigenin-2ʹ-O-(3ʹʹ-O4ʹʹʹ-hydroxy-benzoyl)-b-glucoside (237), davidigenin-2ʹ-O-(6ʹʹ-O-syrin-goyl)-bglucoside (238)

[181]

Symplocaceae

Symplocos

Symplocos lancifolia siebold and Zucc.

Leaves: Phlorizin (240)

[182]

Symplocos microcalyx Hayata

Leaves: Trilobatin (241)

[182]

Symplocos spicata Roxb.

Leaves: Phlorizin (240)

[182]

279

Continued

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

Loiseleuria

Order

Family

Genus

Species

Type of Dihydrochalcones

Refs.

Spermatophytes-Angiosperms-Eudicots-Core Eudicots-Asterids-Lamiids Gentianales

Apocynaceae

Mascarenhasia

Mascarenhasia arborescens ADC.

Leaves and stems: Davidigenin (27)

[183]

Lamiales

Lamiaceae

Vitex

Vitex leptobotrys Hallier f.

Aerial parts: 4,20 ,40 ,b-tetrahydroxy-60 methoxy-a,b-dihydrochalcone (87)

[184]

Verbenaceae

Verbena

Verbena litoralis Kunth

Aerial parts: Verbenachalcone (204), littorachalcone (205)

[185,186]

Viburnum davidii Franch.

Leaves: 40 -O-methyldavidigenin (17), davidigenin (27), davidioside (218)

[187,188]

Viburnum lantanoides Michx.

Leaves: Davidioside (218), 40 -O-methyldavidioside (219)

[188]

Spermatophytes-Angiosperms-Eudicots-Core Eudicots-Asterids-Campanulids Dipsacales

Adoxaceae

Viburnum

Apiales

Apiaceae

Ducrosia

Ducrosia ismaelis Asch.

Aerial parts: Ismaeloside A (220)

[189]

Asterales

Asteraceae

Artemisia

Artemisia dracunculus L.

Shoots: 20 ,40 -dihydroxy-4-methoxydihydrochalcone (18), davidigenin (27)

[190]

Artemisia palustris L.

Plant: 2ʹ,4-dihydroxy-40 -methoxydihydro-chalcone (17), 2ʹ,40 -dihydroxy4-methoxy-dihydrochalcone (18), davidigenin (27)

[191]

280 Studies in Natural Products Chemistry

TABLE 7.1 Distribution of Dihydrochalcones in the Embryophyta Divisiondcont’d

Bidens pinnata L.

Aerial parts: Bidenoside B (221)

[192]

Helichrysum

Helichrysum aphelexioides DC.

Leaves and stems: 30 -prenyl-4,60 dihydroxy-30 -methoxy-20 oxodihydrochalcone (119)

[193]

Helichrysum tenuifolium Killick

Aerials parts and roots: 20 ,40 ,60 trihydroxy-dihydrochalcone (28)

[194]

Helichrysum splendidum (Thunb.) less.

Plant: Dihydronaringenin (63)

[195]

Lactuca sativa L.

Fresh leaves: Phloridzin (240)i

[196]

Lactuca a,b,c,d,e,h

Compounds identified by LC-UV-MS or LC-DAD-MS/MS, not isolated. Four major dihydrochalcones isolated by High Speed counter current Chromatograhy (HSCCC) and preparative High Performance Liquid Chromatography (HPLC). Minor dihydrochalcones tentatively identified by HPLCeDADeQTOF-MS/MS, not isolated. h Unresolved name. i Phloridzin detected by HPLC-DAD and comparison with standard, not isolated. f

g

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

Bidens

281

282 Studies in Natural Products Chemistry

FIGURE 7.2 Distribution of dihydrochalcones in botanical orders (number of species containing DHCs per order).

domestica and in other species, such as Malus doumeri or Malus pumila [143,146]. A recent study has identified the main bioactive compounds, including DHCs, of a broad apple germplasm collection, composed of 247 accessions of wild (97) and domesticated (150) species [141]. In some wild apple species and cultivars, the concentration of phloridzin in fruits can reach 10% [141,198]. Several recent studies are interested in polyphenol content, including DHCs, in a number of old apple cultivars [199e200]. DHCs are also encountered to a lesser extent in other eudicots, in Malvids and in the Asterid clade. Simple methylated DHCs are found in Myrtaceae, whereas Balanophoraceae produce galloyl, caffeoyl, and (S)-hexahydroxydiphenoyl (HHDP) esters of dihydrochalcone glucosides [160e163]. Several new prenylated DHCs have been recently isolated from different species of the Rutaceae family [168,171,175]. In the Asterid clade, species belonging to the Ericaceae family produce different types of DHCs, from simple forms to more complex structures such pierotin A, a newly isolated dimer [180]. Asteraceae species produce rather simple forms or O-glycosides.

CHEMISTRY Like chalcones, dihydrochalcones are biosynthesized via both the shikimate and acetate-malonate pathways, often in response to biotic and abiotic stresses.

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

283

However, biosynthesis of DHCs requires the conversion of p-coumaroyl-CoA, the main precursor of chalcones obtained via the shikimate pathway, into p-dihydrocoumaroyl-CoA by an NADPH (reduced form of nicotinamide adenine dinucleotide phosphate)-dependent dehydrogenase. It is thought that the chalcone synthase will then be able to catalyze the addition of three molecules of malonyl-CoA, obtained via the polyketide pathway, to one molecule of p-dihydrocoumaroyl-CoA [201]. The A-ring on the left linked directly to the C-carbonyl system is thus formed via the polyketide pathway, while the B-ring is determined by the phenylpropanoid pathway. DHCs may be named under their trivial name, semisystematic name or IUPAC-approved systematic name. For example, phloretin can also be called 2ʹ,4,4ʹ,6ʹ-dihydrochalcone or (E)-1-(2,4,6-trihydroxyphenyl)-3-(4-hydroxyphenyl)2-propan-1-one [201]. The general structure of DHCs, using the example of phloretin, is shown in Fig. 7.3. The substitution pattern and the type of substituent in DHCs can lead to a great structural diversity. Depending on the species, as we have just seen, DHCs can be hydroxylated, methylated, methoxylated, prenylated, geranylated, or glycosylated. From a biosynthetic point of view, like chalcones, some DHCs may have their aromatic rings reversed to normal flavonoids. In this case, the A-ring is formed via shikimate pathway, while the B-ring is determined by the acetate-malonate pathway. These compounds are named retrodihydrochalcones [202]. This chapter focuses on newly purified compounds discovered from 2004 onwards. For dihydrochalcones reported from 1992 to 2003, the structures can be found in the chapter by N.C. Veitch and R.J. Grayer [69].

Dihydrochalcones With Simple Patterns of O-Substitution Dihydrochalcones with simple patterns of O-subtitution are listed in Table 7.2, and the structures of the new dihydrochalcones reported in the literature from 2004 to 2015 (in bold in Table 7.2) are presented in Fig. 7.4. Dragon’s blood is the vernacular name of a deep red resin obtained from different plant sources including some species belonging to the genera Daemonorops (Arecaceae), Dracaena (asparagaceae), Pterocarpus (Fabaceae), and Croton (Euphorbiaceae). Each species potentially responsible for this resin produces pigments of dracorhodin, dracoflavylium, santalin A, and procyanidin B1, respectively, which unequivocally allows the species to be identified [87]. In traditional Chinese medicine, this resin, in particular obtained from Dracaena cochinchinensis (“Chinese dragon’s blood”) is widely used for different purposes. OH

O β β

A HO

OH

α

2 3

B

4

OH

FIGURE 7.3 Ring labeling and atom numbering for dihydrochalcones [201] phloretin ¼ 2ʹ,4,4ʹ,6ʹ-dihydrochalcone or (E)-1-(2,4,6-trihydroxyphenyl)-3-(4-hydroxyphenyl)2-propan-1-one.

TABLE 7.2 Dihydrochalcones With Simple Patterns of O-Substitution

N

Semisystematic or IUPAC-Approved Systematic Name

1

Dihydrochalcone

Trivial Name

Source

Family

Part of Plant

Refs.

Leptoderris fasciculata

Fabaceae

Leaves

[105]

Coptis rhizoma (C. chinensis, C. deltoidea, C. teetoides)

Ranunculaceae

Rhizome

[93]

Di O-Substituted 2

4-Hydroxy-2-methoxy dihydrochalcone

Dracaena cinnabari

Asparagaceae

Resin

[72]

3

20 -hydroxy-40 -methoxydihydrochalcone

Empetrum nigrum

Ericaceae

Aerial parts

[177]

4

40 -hydroxy-20 -methoxydihydrochalcone

E. nigrum

Ericaceae

Aerial parts

[177,178]

5

20 ,40 -dihydroxydihydrochalcone

Ceratiola ericoides

Ericaceae

Aerial parts

[176]

Empetrum nigrum

Ericaceae

Aerial parts

[177,178]

Oxytropis falcate

Fabaceae

Whole plant

[110]

Crinum bulbispermum

Amaryllidaceae

Bulbs

[71]

Tri O-Substituted 6

4-Hydroxy-20 ,40 -dimethoxydihydrochalcone

7

4-Hydroxy-2,40 -dimethoxydihydrochalcone

8

20 -hydroxy-40 ,60 -dimethoxydihydrochalcone

Dihydro-flavokawin B ¼ uvangoletin 40 -methylether

Dracaena cochinchinensis

Asparagaceae

Resin

[78]

Alpinia speciosa

Zingiberaceae

Rhizome

[89]

Empetrum nigrum

Ericaceae

Aerial parts

[177]

Uvaria angolensis

Annonaceae

Roots

[25]

9

20 -hydroxy-40 ,60 -dimethoxy-3ʹmethyl-dihydrochalcone

Myrigalone E

Myrica gale

Myricaceae

Fruit exudate

[122]

10

4ʹ-hydroxy-2,4-dimethoxydihydrochalcone

Loureirin A

Dracaena loureiroi

Asparagaceae

Stems

[80]

Dracaena cochinchinensis

Asparagaceae

Resin

[78]

0

11

4 -hydroxy-2,6-dimethoxydihydrochalcone

D. cochinchinensis

Asparagaceae

Resin

[74]

12

40 -Hydroxy-4,20 -dimethoxydihydrochalcone

D. cochinchinensis

Asparagaceae

Resin

[77]

13

40 -hydroxy-20 ,60 -dimethoxye dihydrochalcone

Woodsia scopulina

Woodsiaceae

Fronds

[7]

14

2,4-Dihydroxy-6-methoxy3-methyl-dihydrochalcone

Daemonorops draco

Arecaceae

Resin

[87]

15

4,6-Dihydroxy-2- methoxy3-methyl-dihydrochalcone

D. draco

Arecaceae

Resin

[88]

16

4,40 -dihydroxy-2-methoxydihydrochalcone

Dracaena cinnabari

Asparagaceae

Resin

[72]

D. loureiroi

Asparagaceae

Stems

[80]

D. cochinchinensis

Asparagaceae

Fresh stems

[76]

Resin

[75,78]

Daemonorol F

Loureirin C

Continued

TABLE 7.2 Dihydrochalcones With Simple Patterns of O-Substitutiondcont’d

N 17

18

19

20

Semisystematic or IUPAC-Approved Systematic Name 20 ,4-dihydroxy-40 -methoxydihydrochalcone

Trivial Name

Source

Family

Part of Plant

Refs.

40 -O-methyl davidigenin

Viburnum davidii

Adoxaceae

Leaves

[188]

Artemisia palustris

Asteraceae

Plant

[191]

Diplectaria beccariana

Melastomataceae

Leaves

[154]

Artemisia dracunculus

Asteraceae

Shoots

[190]

A. palustris

Asteraceae

Plant

[191]

Diplectaria beccariana

Melastomataceae

Leaves

[154]

Uvaria acuminata

Annonaceae

Roots

[22]

U. angolensis

Annonaceae

Roots

[23]

Empetrum nigrum

Ericaceae

Aerial parts

[177]

Myrica gale

Myrtaceae

Seeds

[123]

Boesenbergia pandurata

Zingiberaceae

Rhizomes

[90]

Myrica gale

Myricaceae

Fruits Fruit exudate Seeds

[121e123]

Syzygium samarangense

Myrtaceae

Leaves

[159]

20 ,40 -dihydroxy-4-methoxydihydrochalcone

20 ,40 -dihydroxy-60 -methoxydihydrochalcone

0

0

0

Uvangoletin

0

2 ,4 -dihydroxy-6 -methoxy-3 methyl-dihydrochalcone

Myrigalone H

21

20 ,40 -dihydroxy-60 -methoxy30 ,50 -dimethyldihydrochalcone

22

20 ,60 -dihydroxy-4-methoxy30 ,50 -dimethyldihydrochalcone

23

2ʹ,6ʹ-dihydroxy-4ʹ-methoxydihydrochalcone

Angoletin Myrigalone D

Phloretin 40 -O-methyl ether

Uvaria angolensis

Annonaceae

Roots

[23]

Ceratiola ericoides

Ericaceae

Aerial parts

[176]

Myrica gale

Myricaceae

Fruit exudate Seeds

[122,123]

Ceratiola ericoides

Ericaceae

Aerial parts

[176]

Miliusa balansae

Annonaceae

Leaves and branches

[19]

Mitrella kentii

Annonaceae

Stem bark

[20]

Lindera umbellata

Lauraceae

Leaves

[10]

L. umbellata Thunb. var. lancea

Lauraceae

Fresh leaves

[11]

Greyia flanaganii

Melianthaceae

Leaves

[150]

Syzygium jambos

Myrtaceae

Leaves

[158]

Piper aduncum

Piperaceae

Leaves

[59]

Piper carpunya

Piperaceae

Leaves

[62]

Piper dennisii

Piperaceae

Leaves

[63]

Piper elongatum

Piperaceae

Aerial parts

[64]

Piper hostmannianum var. barbicense

Piperaceae

Leaves

[65]

Continued

TABLE 7.2 Dihydrochalcones With Simple Patterns of O-Substitutiondcont’d

N

24

25

Semisystematic or IUPAC-Approved Systematic Name

0

0

0

0

0

0

Trivial Name

0

2 ,6 -dihydroxy-4 -methoxy-3 methyl-dihydrochalcone

2 ,6 -dihydroxy-4 -methoxy30 ,5ʹ-dimethyldihydrochalcone

Myrigalone G

Myrigalone B

Part of Plant

Source

Family

Refs.

Piper longicaudatum

Piperaceae

Leaves and twigs

[66]

Piper mollicomum

Piperaceae

Leaves

[67]

Pityrogramma calomelanos

Pteridaceae

Frond exudate

[4]

P. tartarea

Pteridaceae

Frond exudate

[5]

Malus x domestica

Rosaceae

Leaves

[142]

Populus balsamifera

Salicaceae

Buds

[128]

Etlingera littoralis

Zingiberaceae

Rhizomes

[91]

Myrica gale

Myricaceae

Fruits Fruit exudate Seeds

[121e123]

Syzygium jambos

Myrtaceae

Leaves

[158]

M. gale

Myrtaceae

Fruit exudate Seeds

[122,123]

S. jambos

Myrtaceae

Leaves

[158]

26

27

28

2,4,40 -trihydroxydihydrochalcone 0

0

2 ,4,4 -trihydroxydihydrochalcone

2ʹ,4ʹ,6ʹ-trihydroxydihydrochalcone

Davidigenin Dihydroisoliquiritigenin

Draceana draco

Asparagaceae

Resin

[79]

D. cochinchinensis

Asparagaceae

Resin

[75,78]

Viburnum davidii

Adoxaceae

Leaves

[188]

Mascarenhasia arborescens

Apocynaceae

Leaves and stems

[183]

Artemisia palustris

Asteraceae

Plant

[191]

A. dracunculus

Asteraceae

Shoots

[190]

Euphorbia portlandica

Euphorbiaceae

Whole plant

[124]

Anneslea fragrans var. lanceolata

Pentaphylacaceae

Roots

[181]

Helichrysum tenuifolium

Asteraceae

Aerial parts and roots

[194]

Lindera umbellata

Lauraceae

Leaves

[10]

L. umbellata var. lancea

Lauraceae

Fresh leaves

[11]

Greyia flanaganii

Melianthaceae

Leaves

[150]

Populus balsamifera

Salicaceae

Buds

[128]

Woodsia scopulina

Woodsiaceae

Fronds

[7]

Boesenbergia pandurata

Zingiberaceae

Rhizomes

[90]

Etlingera littoralis

Zingiberaceae

Rhizomes

[91] Continued

TABLE 7.2 Dihydrochalcones With Simple Patterns of O-Substitutiondcont’d

N

Semisystematic or IUPAC-Approved Systematic Name

Trivial Name

Source

Family

Part of Plant

Refs.

Leptospermum recurvum

Myrtaceae

Foliage

[157]

29

20 ,40 ,60 -trihydroxy-30 -methyldihydrochalcone

30

2ʹʹ,4ʹʹ,6ʹʹ-trihydroxy-3ʹʹ-(4ʹʹʹhydroxycinnamyl)dihydrochalcone

Balsacone C

Populus balsamifera

Salicaceae

Buds

[128]

31

3-(ß-phenyl-propionyl)5-methyl filicinic acid ¼ 4,4,6-trimethyl-2(3-phenylpropionyl)cylohexane-l,3,5- trione

Myrigalone A

Myrica gale

Myrtaceae

Fruit exudate Seeds

[122,123]

Tetra O-Substituted 32

2-Hydroxy-3,4,6-trimethoxydihydrochalcone

Fissistigma bracteolatum

Annonaceae

Leaves

[15]

33

2-Hydroxy-4,5,6-trimethoxydihydrochalcone

Uvaria mocoli

Annonaceae

Stem bark

[36]

34

20 -hydroxy-30 ,40 ,60 -trimethoxydihydrochalcone

F. bracteolatum

Annonaceae

Leaves

[15]

35

20 -hydroxy-4,4ʹ,60 -trimethoxydihydrochalcone

36

40 -hydroxy-2,4,6-trimethoxydihydrochalcone

Goniothalamus gardneri

Annonaceae

Aerial parts

[17]

Dracaena cochinchinensis

Asparagaceae

Resin

[74]

D. cochinchinensis

Asparagaceae

Resin

[78]

D. loureiroi

Asparagaceae

Stems

[80]

D. loureiroi

Asparagaceae

Stem wood

[81]

2,40 -dihydroxy-4,6-dimethoxydihydrochalcone

D. loureiroi

Asparagaceae

Stem wood

[81]

D. cochinchinensis

Asparagaceae

Resin

[78]

38

4,40 -dihydroxy-2,6-dimethoxydihydrochalcone

D. loureiroi

Asparagaceae

Stem wood

[81]

39

4,4
-dihydroxy-2ʹʹ,6ʹʹ -dimethoxy-dihydrochalcone

Ledebouria ovatifolia

Liliaceae

Bulbs

[86]

40

20 ,4-dihydroxy-40 ,60 dimethoxy-dihydrochalcone

Iryanthera lancifolia

Myristicaceae

Pericarps

[50]

Desmos dunalii

Annonaceae

Leaves

[14]

41

20 ,4-dihydroxy-40 ,60 dimethoxy-50 -methyldihydrochalcone

D. dunalii

Annonaceae

Leaves

[14]

42

20 ,4-dihydroxy-40 ,60 dimethoxy-30 ,50 -dimethyldihydrochalcone

D. dunalii

Annonaceae

Leaves

[14]

43

2ʹ,3ʹ-dihydroxy-4ʹ,6ʹdimethoxy-dihydrochalcone

Uvaria dulcis (syn. Anomianthus dulcis)

Annonaceae

Leaves

[30,31]

44

2ʹ,4ʹ-dihydroxy3ʹ,4-dimethoxydihydrochalcone

Luisia volucris

Orchidaceae

Whole plant

[82]

37

Loureirin B

Lusianin

Continued

TABLE 7.2 Dihydrochalcones With Simple Patterns of O-Substitutiondcont’d

N 45

Semisystematic or IUPAC-Approved Systematic Name 20 ,4ʹ-dihydroxy-4,60 dimethoxy-dihydrochalcone

Trivial Name

Source

Family

Part of Plant

Refs.

Iryanthera grandis

Myristicaceae

Fruits

[44]

Iryanthera laevis

Myristicaceae

Bark

[46]

Trunk wood

[47]

Fruits

[48]

I. lancifolia

Myristicaceae

Pericarps

[50]

I. paraensis

Myristicaceae

Bark

[49]

I. sagotiana

Myristicaceae

Bark Leaves Inflorescence

[52,53]

I. ulei

Myristicaceae

Bark

[49]

Trunk wood

[54]

Goniothalamus gardneri

Annonaceae

Aerial parts

[17]

Melodorum siamense (¼Rauwenhoffia siamensis)

Annonaceae

Leaves

[18]

46

2ʹ,4ʹ-dimethoxy3,4-methylenedioxydihydrochalcone

47

2ʹ,6ʹ-dihydroxy-4,4ʹdimethoxy-dihydrochalcone

48

20 ,6ʹ-hydroxy-40 ,50 -dimethoxydihydrochalcone

Ponganone VII

Dihydro-pashanone

Pongamia pinnata

Fabaceae

Root bark

[111]

Greyia flanaganii

Melianthaceae

Leaves

[150]

Pityrogramma tartarea

Pteridaceae

Frond exudate

[5]

Populus balsamifera

Salicaceae

Buds

[128]

Lindera erythrocarpa

Lauraceae

Leaves, wood

[8]

Miliusa balansae

Annonaceae

Leaves and branches

[19]

Cyathostemma argenteum

Annonaceae

Leaves and twigs

[13]

Dracaena cochinchinensis

Asparagaceae

Resin

[75,78]

D. loureiroi

Asparagaceae

Stems

[80]

Calythropsis aurea

Myrtaceae

Plant

[155]

49

4ʹ,60 -dihydroxy20 ,4-dimethoxydihydrochalcone

50

2,4,40 -trihydroxy-6-methoxydihydrochalcone

Loureirin D

51

3,4,20 -trihydroxy-40 -methoxydihydrochalcone

Dihydrocalythropsin

52

4,2ʹ,4ʹ-trihydroxy-3-methoxydihydrochalcone

Iryanthera polyneura

Myristicaceae

Trunk wood

[51]

53

4,20 ,40 -trihydroxy-30 -methoxydihydrochalcone

Muntingia calabura

Muntingiaceae

Leaves

[152]

Continued

TABLE 7.2 Dihydrochalcones With Simple Patterns of O-Substitutiondcont’d

N 54

Semisystematic or IUPAC-Approved Systematic Name

Trivial Name

4,20 ,40 -trihydroxy-60 -methoxydihydrochalcone

Source

Family

Part of Plant

Refs.

Iryanthera sagotiana

Myristicaceae

Inflorescence

[53]

Leaves

[53]

Melodorum siamense (¼Rauwenhoffia siamensis)

Annonaceae

Leaves

[18]

Goniothalamus gardneri

Annonaceae

Aerial parts

[17]

55

4,20 ,40 -trihydroxy-60 -methoxydihydrochalcone

56

4,20 ,40 -trihydroxy-60 -methoxy30 -methyl-dihydrochalcone

Polygonatone D

Polygonum odoratum

Polygonaceae

Rhizome

[148]

57

4,2ʹ,6ʹ-trihydroxy-4ʹ-methoxydihydrochalcone

Asebogenin

Pieris japonica

Ericaceae

Leaves

[180]

Greyia flanaganii

Melianthaceae

Leaves

[150]

Piper aduncum

Piperaceae

Leaves

[59]

P. carpunya

Piperaceae

Leaves

[62]

P. dennisii

Piperaceae

Leaves

[63]

P. elongatum

Piperaceae

Aerial parts

[64]

P. longicaudatum

Piperaceae

Leaves and twigs

[66]

Populus balsamifera

Salicaceae

Buds

[128]

Etlingera littoralis

Zingiberaceae

Rhizomes

[91]

58

4,2ʹ,6ʹ-trihydroxy-4ʹ-methoxy3,5-dimethyl-dihydrochalcone

Pentagramma triangularis

Pteridaceae

Frond exudate

[2]

59

4,2ʹʹ,6ʹʹ-trihydroxy-3ʹʹ-(4ʹʹʹ -hydroxycinnamyl)-4ʹʹmethoxydihydro-chalcone

Populus balsamifera

Salicaceae

Buds

[128]

60

40 ,4,6-trihydroxy-2-methoxydihydrochalcone

Dracaena loureiroi

Asparagaceae

Stem wood

[81]

61

20 ,40 ,60 -trihydroxy-4-methoxydihydrochalcone

Iryanthera laevis

Myristicaceae

Fruits

[48]

I. sagotiana

Myristicaceae

Inflorescence

[53]

Populus balsamifera

Salicaceae

Buds

[128]

Balsacone A

62

2ʹʹ,4ʹʹ,6ʹʹ-trihydroxy-3ʹʹ-(4ʹʹʹhydroxycinnamyl) -4-methoxydihydro-chalcone

Balsacone B

P. balsamifera

Salicaceae

Buds

[128]

63

4,20 ,40 ,60 -tetrahydroxydihydrochalcone

Phloretin Dihydronaringenin

Helichrysum splendidum

Asteraceae

Plant

[195]

Loiseleuria procumbens

Ericaceae

Whole plant

[179]

Pieris japonica

Ericaceae

Leaves

[180]

Malus x domestica

Rosaceae

Leaves

[142]

Ceratiola ericoides

Ericaceae

Aerial parts

[176]

Myrica gale

Mrytaceae

Seeds

[123]

64

Ceratiolin

Continued

TABLE 7.2 Dihydrochalcones With Simple Patterns of O-Substitutiondcont’d

N

Semisystematic or IUPAC-Approved Systematic Name

Trivial Name

Source

Family

Part of Plant

Refs.

Dihydro-kanakugiol

Lindera erythrocarpa

Lauraceae

Leaves

[8]

L. lucida

Lauraceae

Twigs

[9]

Tacca chantrieri

Dioscoreaceae

Roots and rhizomes

[84,85]

T. integrifolia

Dioscoreaceae

Roots and rhizomes

[84,85]

T. chantrieri

Dioscoreaceae

Roots and rhizomes

[84,85]

T. integrifolia

Dioscoreaceae

Roots and rhizomes

[84,85]

Iryanthera laevis

Myristicaceae

Bark

[46]

I. ulei

Myristicaceae

Trunk wood

[54]

2 ,4 -dihydroxy-6 -methoxy3,4- methylenedioxydihydrochalcone

I. laevis

Myristicaceae

Bark

[46]

I. sagotiana

Myristicaceae

Bark

[52]

20 ,4-dihydroxy-40 ,50 ,60 trimethoxy-dihydrochalcone

Desmos dunalii

Annonaceae

Leaves

[14]

Penta O-Substituted 65

66

67

68

69

70

20 -hydroxy-3ʹ,40 ,50 ,60 tetramethoxy- dihydrochalcone 0

0

3-hydroxy-4,2ʹʹ,4 ,6 tetramethoxy-dihydrochalcone

4-hydroxy-3,2ʹʹ,40 ,60 tetramethoxy-dihydrochalcone

20 ,40 -dihydroxy-3,4,60 trimethoxy-dihydro-chalcone 0

0

0

Taccabulin A

Taccabulin D

71

72

2ʹʹ,4-dihydro-3,40 ,60 trimethoxy-dihydrochalcone

Taccabulin C

Tacca chantrieri

Dioscoreaceae

Roots and rhizomes

[84,85]

T. integrifolia

Dioscoreaceae

Roots and rhizomes

[84,85]

T. chantrieri

Dioscoreaceae

Roots and rhizomes

[84,85]

T. integrifolia

Dioscoreaceae

Roots and rhizomes

[84,85]

Fissistigma lanuginosum

Annonaceae

Leaves

[16]

1-(benzo[d][1,3]dioxol-5-yl)-3(2,4,6- trimethoxyphenyl) propan-1-ol

Taccabulin E

73

2ʹ,5ʹ-dihydroxy-30 ,40 ,60 trimethoxy-dihydrochalcone

Dihydro-pedicin

74

20 ,60 -dihydroxy-3,4,40 trimethoxy-dihydrochalcone

Pityrogramma tartarea

Pteridaceae

Frond exudate

[5]

75

3,40 -dihydroxy2,4,6-trimethoxydihydrochalcone

Dracaena cochinchinensis

Asparagaceae

Resin

[78]

76

3ʹ,50 -dihydroxy-20 ,40 ,60 trimethoxydihydrochalcone

Lindera lucida

Lauraceae

Twigs

[9]

77

2ʹ,4ʹ,6ʹ-trimethoxy3,4-methylenedioxydihydrochalcone

Millettia leucantha

Fabaceae

Stem bark

[108]

78

3,4,2ʹ,4ʹ,6ʹ-pentahydroxydihydrochalcone

Balanophora harlandii

Balanophoraceae

Rhizomes

[160]

B. tobiracola

Balanophoraceae

Whole plant

[162]

3-Hydroxy-phloretin

Continued

TABLE 7.2 Dihydrochalcones With Simple Patterns of O-Substitutiondcont’d

N

Semisystematic or IUPAC-Approved Systematic Name

Trivial Name

Source

Family

Part of Plant

Refs.

Muntingia calabura

Muntingiaceae

Leaves

[152]

Tacca chantrieri

Dioscoreaeae

Roots and rhizomes

[83e85]

T. integrifolia

Dioscoreaceae

Roots and rhizomes

[84,85]

T. chantrieri

Dioscoreaceae

Roots and rhizomes

[84,85]

T. integrifolia

Dioscoreaceae

Roots and rhizomes

[84,85]

T. chantrieri

Dioscoreaceae

Roots and rhizomes

[84,85]

T. integrifolia

Dioscoreaceae

Roots and rhizomes

[84,85]

Hexa O-Substitued 79

2,3-Dihydroxy-4,30 ,40 ,50 tetramethoxy-dihydrochalcone

80

2ʹʹ,4ʹʹ,3,4-tetramethoxy-3ʹʹ,6ʹʹdioxo-dihydrochalcone

81

82

Evelynin A

2ʹʹ,4ʹʹ-dimethoxy3,4-methylene-dioxy-3ʹʹ,6ʹʹ– dioxo-dihydrochalcone

Evelynin B

3,4,2ʹʹ,30 ,40 ,60 -hexamethoxydihydrochalcone

Taccabulin B

a-Hydroxy-Substituted 83

(aR)-a,3,4,2ʹ,4ʹ-pentahydroxydihydrochalcone

Eysenhardtia polystachya

Fabaceae

Bark and trunks

[101]

84

()-a,2ʹ-dihydroxy-4,4ʹdimethoxydihydro-chalcone

Virola calophylloidea

Myristicaceae

Trunk wood

[55]

V. carinata

Myristicaceae

Bark

[56]

V. surinamensis

Myristicaceae

Twigs

[57]

V. surinamensis

Myristicaceae

Roots

[58]

b-Hydroxy-Substituted 85

20 ,40 ,b-trihydroxydihydrochalcone

Oxytropis falcate

Fabaceae

Whole plant

[110]

86

(R)-20 ,b-dihydroxy-30 ,40 dimethoxy-dihydrochalcone

Muntingia calabura

Muntingiaceae

Stem wood

[151]

87

4,20 ,40 ,b-tetrahydroxy-60 methoxy-a,b-dihydrochalcone

Vitex leptobotrys

Lamiaceae

Aerial parts

[184]

Millettia hemsleyana

Fabaceae

Root bark

[107]

M. leucantha

Fabaceae

Stem bark

[108]

Pongamia pinnata

Fabaceae

Root bark

[111]

M. hemsleyana

Fabaceae

Root bark

[107]

b-Methoxy-Substituted 88

89

20 ,40 ,b-trimethoxy3,4-methylenedioxydihydrochalcone 2,4,b-trimethoxy-3ʹ,4ʹmethylenedioxydihydrochalcone

Dihydro-milletenone methyl ether

Dihydroiso-milletenone methyl ether

300 Studies in Natural Products Chemistry

Modern pharmacological studies have shown that this resinous medicine has antibacterial, antispasmodic, anti-inflammatory, analgesic, antidiabetic, and antitumor activities [203]. Dihydrochalcones are abundant in dragon’s blood. Recently, two new dihydrochalcones tri O-substituted 4-hydroxy-2,40 -dimethoxydihydrochalcone (7) and penta O-substituted 3,40 -dihydroxy2,4,6-trimethoxydihydrochalcone (75), were isolated from the red resin of D. cochinchinensis, along with 13 other dihydrochalcones and homoisoflavones [78]. These new compounds have original substitutions. In general, most of the dihydrochalcones isolated from D. cochinchinensis are substituted in the 4,40 -position. Some are substituted in the 2,6-position, and a few are substituted in the 2,4,6-position [151]. From dragon’s blood from OH

H3CO

OH

HO

4

4

H3CO

OCH 3

O

O

7

14

OH

H3CO

HO

HO

4

OH

4'

OH

OH

O

O

30

15 4

HO

OH

4

OH

HO

OCH 3

H3CO OH

OCH 3 O

O 53

39 4

OH

H3CO

HO

HO

OH

4

OH

OCH 3

OH

OH

O

O 59

56

HO

HO

OCH 3

OH 4 3'

OH

O

62

FIGURE 7.4 New dihydrochalcones with simple patterns of O-substitution isolated from 2004 to 2015.

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

H3CO

OCH 3

OCH 3

H3CO

OCH 3

301

OH 4

3

OCH 3

OH

OCH 3

O

OCH 3

O

66

H3CO

67

OH

OH

4

3

OCH 3

H3CO

OCH 3

4

3

OCH 3

OCH 3

O

O

O

OH 72

71

OH

OH H3CO

4

OCH 3

HO

HO

4

OCH 3

H3CO OCH 3

H3CO O

OCH 3 O

75

79

O H3CO

3'

O OCH 3

4

3

6'

O

OCH 3

H3CO

3'

OCH 3

O

OCH 3

6'

O

4

O

3

O

O 81

80

OCH 3 H3CO

OCH 3

4

OCH 3

H3CO

HO β

4'

3

OCH 3

OCH 3

O

H3CO OH

82

O 86

FIGURE 7.4 Cont’d

Daemonorops draco (Arecaceae), two new methylated dihydrochalcones, 2,4-dihydroxy-6-methoxy-3-methyl-dihydrochalcone (daemonorol F) (14) [87] and 4,6-dihydroxy-2-methoxy-3-methyl-dihydrochalcone (15) [88], were isolated. Continuing with Monocots species, 4,4ʹ-dihydroxy-2ʹ,6ʹ-dimethoxydihydrochalcone (39) was obtained from the bulbs of Ledebouria ovatifolia [86]. Seven new retrodihydrochalcones, named evelynins A-B (80-81) and taccabulins A (66), B (82), C (71), D (67), and E (72), were isolated from the

302 Studies in Natural Products Chemistry

roots and rhizomes of two Tacca species (Dioscoreaceae): Tacca chantrieri and Tacca integrifolia. Evelynins A (80) and B (81) are rare benzoquinonetype retrodihydrochalcones. Some of these retrodihydrochalcones, in particular evelynin B (81) and taccabulin A (66), have shown promising antiproliferative and microtubule-depolymerizing activities [84]. As with D. cochinchinensis, the rhizomes of Polygonatum odoratum are also listed in the Chinese pharmacopoeia. From this traditional Chinese medicine, a new methylated dihydrochalcone named polygonatone D (4,20 ,40 -trihydroxy-60 methoxy-30 -methyl-dihydrochalcone) (56) and six homoisoflavonoids were isolated [148]. Fifteen compounds, including a new dihydrochalcone, (R)-20 ,bdihydroxy-30 ,40 -dimethoxy-dihydrochalcone (86), were isolated from the stem wood of Muntingia calabura [151]. The b-hydroxydihydrochalcones are relatively rare but have been found in some genera of Fabaceae [110] and previously isolated from Vitex leptobotrys [184]. Two new dihydrochalcones, 4,20 ,40 -trihydroxy-30 -methoxydihydrochalcone (53) and 2,3-dihydroxy4,30 ,40 ,50 -tetramethoxydihydrochalcone (79) were also isolated from the leaves of M. calabura [152]. Three original dihydrochalcone derivatives, substituted by a cinnamic acid, balsacones A (59), B (62) and C (30), along with five known dihydrochalcones, were isolated from the buds of Populus balsamifera from the Salicaceae family, a tree of North America. The biosynthesis of balsacones A-C could be explained by cinnamylation reactions of compounds 2ʹ,4,6ʹ-trihydroxy-4ʹ-methoxydihydrochalcone, 2ʹ,4ʹ,6ʹ-trihydroxy4-methoxydihydrochalcone and 2ʹ,4ʹ,6ʹ-trihydroxydihydro-chalcone [128]. In addition, 2ʹ,4ʹ-dihydroxy-4-methoxy-dihydrochalcone was reported for the first time in Diplectria beccariana [154] and in Artemisia dracunculus [190], but it had been reported previously in another species of Artemisia, Artemisia palustris [191]. Its chemical synthesis is known [204].

Monoterpene, Prenylated, and Geranylated Dihydrochalcones Prenylated and geranylated dihydrochalcones are listed in Table 7.3 and the structures of the new dihydrochalcones reported in the literature from 2004 to 2015 (in bold in Table 7.3) are presented in Fig. 7.5. After an ethanolic extract from the leaves of Piper aduncum displayed antileishmanial activity, bioactivity-guided fractionation of the active extract yielded a new prenylated dihydrochalcone named adunchalcone (101). This polyphenol may biogenetically result from enzymatic prenylation of 40 -methoxy-20 ,60 -dihydroxydihydrochalcone, followed by oxidation of C-100 and connection of a methyl protocatechuate unit [61]. The bioassay-guided purification of an apolar extract from the leaves of Piper hostmannianum var. berbicense led to the isolation of four monoterpene or prenyl-substituted dihydrochalcones named hostmanins A-D (111-114), along with ()-methyllinderatin, which showed the best antiplasmodial activity confirmed in-vivo [65]. Two new dihydrochalcones, dennisic acid A (110) and B (148), as well as piperaduncin C and 40 -methoxy-20 ,60 -dihydroxydihydrochalcone,

TABLE 7.3 Monoterpene, Prenylated, and Geranylated Dihydrochalcones N

Semisystematic or IUPAC-Approved Systematic Name

Source

Family

Part of Plant

Refs.

Erioschalcone B

Eriosema glomerata

Fabaceae

Plant

[99]

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

Trivial Name

Di-O-Substituted 90

20 ,40 -dihydroxy-30 -(g,g)dimethylallyl)dihydrochalcone

Tri-O-Substituted (300 R,400 S)-(3000 R,4000 S)20 ,40 ,60 -trihydroxy-30 ,50 -bis(4-isopropyl1-methylcyclohex-1-en3-yl)-dihydrochalcone

()-Neolinderatin.

Mitrella kentii

Annonaceae

Stem bark

[20]

92

(300 R,400 S)-20 ,40 ,60 trihydroxy-30 -(4-isopropyl-1-methyl-cyclohex1-en-3-yl)dihydrochalcone

()-Linderatin

M. kentii

Annonaceae

Stem bark

[20]

93

1-(5-Hydroxy-2,2-dimethyl-2H-chromen-6-yl)-3(4-hydroxyphenyl)-propanone

Crotaramosmin

Crotalaria ramosissima

Fabaceae

Plant

[97]

94

1-(5-Hydroxy2,2-dimethyl-2H1-benzopyran-6-yl)-3(4-methoxyphenyl)1-propanone

Crotaramin

C. ramosissima

Fabaceae

Plant

[98]

303

91

Continued

95

20 ,40 -dihydroxy4-methoxy-30 -(g,g)dimethylallyl)-dihydrochalcone

Erioschalcone A

Eriosema glomerata

Fabaceae

Plant

[99]

96

1-(3,5-Dihydroxy2,2-dimethyl-chroman6-yl)-3-(4-methoxyphenyl) propan-1-one

Fleminchalcone B

Flemingia philippinensis

Fabaceae

Roots

[102]

97

2,b-dimethoxy-furano [200 ,3”: 40 ,30 ] dihydrochalcone

Ovalitenin B

Pongamia pinnata

Fabaceae

Root bark

[111]

98

Linderatin

Lindera umbellata var. lancea

Lauraceae

Fresh leaves

[11]

99

()-Methyllinderatin

L. umbellata var. lancea

Lauraceae

Leaves

[12]

Piper aduncum

Piperaceae

Leaves

[60]

Piper hostmannianum var. berbicense

Piperaceae

Leaves

[65]

Etlingera littoralis

Zingiberaceae

Rhizomes

[91]

Elastichalcone A

Artocarpus elasticus

Moraceae

Leaves

[139]

Adunchalcone

Piper aduncum

Piperaceae

Leaves

[61]

100

101

20 ,4-dihydroxy-40 ,50 (2,2-dimethyl-chromen)30 -prenyldihydrochalcone

304 Studies in Natural Products Chemistry

TABLE 7.3 Monoterpene, Prenylated, and Geranylated Dihydrochalconesdcont’d

piperaduncin A

Piper aduncum

Piperaceae

Leaves

[59]

103

piperaduncin B

P. aduncum

Piperaceae

Leaves

[59]

P. longicaudatum

Piperaceae

Leaves and twigs

[66]

20 -hydroxy-40 -methoxy-2”[2-hydroxy-5-methoxycarbonyl- phenyl]-furano [400 ,5”:50 ,60 ]dihydrochalcone

Longicaudatin

P. longicaudatum

Piperaceae

Leaves and twigs

[66]

105

((100 S)-l-{20 -hydroxy-4methoxy-60 -[400 -methy1100 -(1000 -methylethyl) cyclohex-300 -en-100 -yloxy] phenyl}-3-phenylpropan-Lone

Adunctin A

P. aduncum

Piperaceae

Leaves

[60]

106

(5aR*, 8R*,9aR*)3-phenyl-1-[50 a,80 ,90 ,90 atetrahydro-30 -hydroxy- 10 methoxy-80 -(100 methylethyl)-50 a-methyldibenzo-[b,d]furan-40 -yl] propan-1-one

Adunctin B

P. aduncum

Piperaceae

Leaves

[60]

107

(20 R*,4S*)-1-{600 ydroxy-40 rnethoxy-4-(100 -methyl ethyl)spiro[benzo[b]furan-20 (30 H), 100 -cyclohex200 -en]-70 -yl}3-phenylpropan-1-one

Adunctin C

P. aduncum

Piperaceae

Leaves

[60]

305

104

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

102

Continued

108

(20 R*,4R*)-1-{600 ydroxy-40 rnethoxy-4-(100 -methyl ethyl)spiro[benzo[b]furan-20 (30 H), 100 -cyclohex200 -en]-70 -yl} 3-phenylpropan-1-one

Adunctin D

P. aduncum

Piperaceae

Leaves

[60]

109

(50 aR*,6S*,90 R*,90 aS*)-1[50 a,6,70 ,80 ,90 a-hexahydro30 ,6-dihydroxy-l0 -methoxy -6-methyl-90 -(100 -methyl ethyl)dibenzo[b,d]- furan40 -yl]-3-phenyIpropan1-one

Adunctin E

P. aduncum

Piperaceae

Leaves

[60]

P. hostmannianum var. barbicense

Piperaceae

Leaves

[65]

Etlingera littoralis

Zingiberaceae

Rhizomes

[91]

110

Dennisic acid A

Piper dennisii

Piperaceae

Leaves

[63]

111

Hostmanin A

P. hostmannianum var. barbicense

Piperaceae

Leaves

[65]

112

Hostmanin B

P. hostmannianum var. barbicense

Piperaceae

Leaves

[65]

113

Hostmanin C

P. hostmannianum var. barbicense

Piperaceae

Leaves

[65]

114

Hostmanin D

P. hostmannianum var. barbicense

Piperaceae

Leaves

[65]

115

etlinglittarolin

Etlingera littoralis

Zingiberaceae

Rhizomes

[91]

306 Studies in Natural Products Chemistry

TABLE 7.3 Monoterpene, Prenylated, and Geranylated Dihydrochalconesdcont’d

116

Nicolaioidesin A

Renealmia nicolaioides

Zingiberaceae

Roots

[92]

117

Nicolaioidesin B

R. nicolaioides

Zingiberaceae

Roots

[92]

118

Nicolaioidesin C

R. nicolaioides

Zingiberaceae

Roots

[92]

Helichrysum aphelexiodes

Asteraceae

Leaves and stems

[193]

a,b-dihydro xanthohumol

Humulus lupulus

Cannabaceae

Cones

[130]

pierotin B

Pieris japonica

Ericaceae

Leaves

[180]

122

Macatrichocarpin C

Macaranga trichocarpa

Euphorbiaceae

Leaves

[125]

123

Macatrichocarpin D

M. trichocarpa

Euphorbiaceae

Leaves

[125]

119

30 -prenyl- 4,60 -dihydroxy30 -methoxy-20 oxodihydrochalcone

120 121

1-Methoxy3,7,8-trihydroxy-4-[3(4-hydroxy-phenyl)-1-propanoyl]dibenzo-furan

1-(2,4,6-trihydroxyphenyl)-3-[4-methoxy3-(2-hy- droxy3-methylbut-3-enyl) phenyl]propan-1-one

Oxymacatrichocarpin C

M. trichocarpa

Euphorbiaceae

Leaves

[126]

125

1-(2,6-Dihydroxy4-methoxyphenyl)-3-[4hydroxy-3-(3-methylbut2-enyl)phenyl]propan1-one

Isomacatrichocarpin C

M. trichocarpa

Euphorbiaceae

Leaves

[126]

307

124

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

Tetra O-Substituted

Continued

126

1-(5-Hydroxy2,2-dimethyl-2H1-benzopyran-6-yl)-3(3,4-dihydroxyphenyl)1-propanone

Crotin

Crotalaria ramosissima

Fabaceae

Plant

[98]

127

1-(5-Hydroxy2,2-dimethyl-3,4-dihydro2H chroman-8-yl)-3(4-methoxyphenyl)propan-1-one

Fleminchalcone A

Flemingia philippinensis

Fabaceae

Roots

[102]

128

1-(5-Hydroxy-8(2-hydroxypropan-2-yl)2,2-dimethyl-7,8-dihydro2H-furo[2,3-h]chromen6-yl)-3-(4-methoxyphenyl)propan-1-one

Fleminchalcone C

F. philippinensis

Fabaceae

Roots

[102]

129

3,50 -diprenyl-20 ,4,40 ,a -tetrahydroxydihydrochalcone

Kanzanol Y

Glycyrrhiza glabra L.

Fabaceae

Roots

[103]

130

3,4-Methylenedioxy-20 methoxy-[200 ,3“:40 ,30 ]furanodihydrochalcone

Lonchocarpus subglaucesceens

Fabaceae

Roots

[106]

131

40 -geranyloxy-a,4,20 -trihydroxy- dihydrochalcone

Millettia usaramensis Taub. subsp. usaramensis

Fabaceae

Stem bark

[109]

308 Studies in Natural Products Chemistry

TABLE 7.3 Monoterpene, Prenylated, and Geranylated Dihydrochalconesdcont’d

132

CG901

2-Geranyl- 20 ,3,4,40 tetrahydroxydihydrochalcone

AC-5-1

Artocarpus altilis

Moraceae

Leaves and stems Leaves

[131,132,134]

A. communis

Moraceae

Flower (seeded var.) Leaves (var. Breafruit and chataigne) Leaves

[136e138]

A. altilis

Moraceae

Leaves

[133,134]

A. communis

Moraceae

Flower (seeded var.) Leaves (var. Chataigne)

[136,137]

1-(2,4-dihydroxyphenyl)3-{4-hydroxy6,6,9-trimethyl6a,7,8,10a-tetrahydro6H-dibenzo[b,d]pyran5-yl}-1-propanone

A. altilis

Moraceae

Leaves

[132]

135

1-(2,4-Dihydroxy-phenyl)3-[3,4-dihydro3,8-dihydroxy-2-methyl-2(4-methyl-3-pentenyl)2H-1-benzopyran-5-yl]1-propanone

A. altilis

Moraceae

Leaves

[132,134]

136

1-(2,4-dihydroxyphenyl)3-[8-hydroxy-2-methyl-2(3,4-epoxy-4-methyl1-pentenyl)-2H1-benzopyran-5-yl]1-propanone

A. altilis

Moraceae

Leaves

[132]

309

134

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

133

1-(2,4-dihydroxyphenyl)3-[8-hydroxy-2- methyl-2(4-methyl-3-pentenyl)-2H1-benzopyran-5-yl]propan-1-one

Continued

137

1-(2,4-Dihydroxy-phenyl)3-[8-hydroxy-2-methyl-2(4-hydroxy-4-methyl2-pentenyl)-2H1-benzopyran-5-yl]1-propanone

Artocarpus altilis

Moraceae

Leaves

[132]

138

2-[6-Hydroxy3,7-dimethylocta2(E),7-dienyl]-20 ,3,4,40 tetrahydroxy dihydrochalcone

A. altilis

Moraceae

Leaves

[132]

139

2-[7-Hydroxy3,7-dimethyl-2(E)octenyl]20 ,40 ,3,4-tetrahydroxydihydrochalcone

Sakenin A

A. altilis

Moraceae

Leaves

[134]

140

2-[6,7-Dihydroxy3,7-dimethyl-2(E)octenyl]20 ,40 ,3,4-tetrahydroxydihydrochalcone

Sakenin B

A. altilis

Moraceae

Leaves

[134]

141

2-[2-Hydroxy-7-methyl3-methyleneoct-6-enyl]20 ,40 ,3,4-tetrahydroxydihydrochalcone

Sakenin C

A. altilis

Moraceae

Leaves

[134]

142

Sakenin D

A. altilis

Moraceae

Leaves

[134]

143

Sakenin E

A. altilis

Moraceae

Leaves

[134]

310 Studies in Natural Products Chemistry

TABLE 7.3 Monoterpene, Prenylated, and Geranylated Dihydrochalconesdcont’d

1-(2,4-dihydroxyphenyl)3-(7-hydroxybenzo- furan4-yl) propan-1-one

Sakenin F

Artocarpus altilis

Moraceae

Leaves

[134]

145

1-(2,4-Dihydroxy-phenyl)3-(7-hydroxybenzo- furan4-yl)propan-1-one

Sakenin G

A. altilis

Moraceae

Leaves

[134]

146

1-(2,4-Dihydroxy-phenyl)3-(7-hydroxy-2-methoxy2,3-dihydro- benzofuran4-yl)propan-1-one

Sakenin H

A. altilis

Moraceae

Leaves

[134]

147

20 ,3,40 -trihydroxy-4,5(2,2-dimethylchromen)2-prenyl-dihydrochalcone

Elastichalcone B

A. elasticus

Moraceae

Leaves

[139]

Dennisic acid B

Piper dennisii

Piperaceae

Leaves

[63]

148 2ʹ,4,4ʹ,6ʹ-tetrahydroxy-5(E-3,7-dimethylocta2,6-dienyl)-3(3-methylbut-2-enyl)dihydrochalcone

Boronia inconspicua

Rutaceae

Aerial parts

[167]

150

2ʹ,4,4ʹ,6ʹ-tetrahydroxy3,5-di(3-methylbut-2enyl)-dihydrochalcone

B. inconspicua

Rutaceae

Aerial parts

[167]

Bipinnatone A

Boronia pinnata

Rutaceae

Aerial parts

[168]

Bipinnatone B

B. pinnata

Rutaceae

Aerial parts

[168]

Dihydrochalcone M-1

Esenbeckia grandiflora subsp. brevipetiolata

Rutaceae

Leaves

[171]

151 152 153

0

0

0

0

2 ,4 ,6 ,4-tetrahydroxy-3 geranyl-3-prenyldihydrochalcone

311

149

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

144

Continued

154

20 ,40 ,60 ,4-tetrahydroxy-30 geranyl-dihydrochalcone

Dihydrochalcone M-2

Esenbeckia grandiflora subsp. brevipetiolata

Rutaceae

Leaves

[171]

Metrodorea stipularis

Rutaceae

Stems

[175]

155

1-(5,7-Di-hydroxy2,2-dimethyl-chroman6-yl)-3-(2,2-di-methylchroman-6-yl)propan1-one

M. stipularis

Rutaceae

Stems

[175]

156

1-(5,7-Dihydroxy2,2-dimethylchroman6-yl)-3-[4-hydroxy -3(3-methylbut-2- en-1-yl)phenyl]-propan-1-one

M. stipularis

Rutaceae

Stems

[175]

157

1-(5,7-Dihydroxy2,2-dimethyl-chroman6-yl)-3-(1,1,4a-trimethyl2,3,4,4a,9a-hexahydro1H-xanthen-7-yl) propan1-one

M. stipularis

Rutaceae

Stems

[175]

Penta eO-Substituted 158

20 ,40 ,6ʹ,3,4epentahydroxy3ʹ,5-diprenyldihydrochalcone

Esenbeckia grandiflora subsp. grandiflora

Rutaceae

Leaves

[172]

159

20 ,40 ,6ʹ,3,4epentahydroxy-3ʹ-geranyl5-prenyl-dihydrochalcone

E. grandiflora subsp. grandiflora

Rutaceae

Leaves

[172]

312 Studies in Natural Products Chemistry

TABLE 7.3 Monoterpene, Prenylated, and Geranylated Dihydrochalconesdcont’d

20 ,40 ,6ʹ,3-tetra-hydroxy-3ʹgeranyl-6ʹʹ,6ʹʹdimethylpyrano [2ʹʹ,3ʹʹ:4,5]dihydrochalcone

Esenbeckia grandiflora subsp. grandiflora

Rutaceae

Leaves

[172]

161

20 ,3,40 ,60 -tetra hydroxy4-methoxy-30 ,5-di-(3,3dimethylallyl)dihydrochalcone

Metrodorea nigra

Rutaceae

Fresh fruits

[174]

162

20 ,3,60 -trihydroxy4-methoxy-5(3,3-dimethyallyl)-30 ,40 -(2ʹʹ,2ʹʹ-dimethyl dihydropyran)dihydrochalcone

M. nigra

Rutaceae

Fresh fruits

[174]

163

2-b-dimethoxy3,4-methylenedioxyfurano [200 ,3”: 40 ,30 ]dihydrochalcone

Ponganone IX

Pongamia pinnata

Fabaceae

Root bark

[111]

Ponganone VIII

P. pinnata

Fabaceae

Root bark

[111]

Hexa-O-Substituted 164

20 ,50 ,b-trimethoxy3,4-methylenedioxy-6ʹʹ,6ʹʹdimethylpyrano [200 ,3”:40 ,30 ]dihydrochalcone

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

160

313

314 Studies in Natural Products Chemistry

FIGURE 7.5 New monoterpene, prenylated, and geranylated dihydrochalcones isolated between 2004 and 2015.

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7 OCH 3

OCH 3

OH

HO

OH

HO

O

O

118

117

OH

HO

O

H3CO

OH

O

OH

121

OCH 3

R2 R1

HO

OH

OH

HO

OH

OH

O 122 : R1 = OH, R2 = OCH 123 : R1 = OCH , R2 = OCH 125 : R1 = OCH , R2 = OH

O 124

OH

OH

OCH 3 O

OH

OCH 3

O

OH

O

O

OH

O 128

127

OH

OH

O

O

HO

HO

H

OH

OH

O

HO

O H 134

135

FIGURE 7.5 Cont’d

315

316 Studies in Natural Products Chemistry O

OH

O

OH

HO HO

OH OH

O O HO

O

136

137

O

OH

HO

OH

OH

HO

OH

O OH

OH OH 139

HO

OH

OH

138

OH OH

HO

O

OH

OH 141

OH OH

O HO

OH

O

OH

140

HO

OH

O

OH

H

OH 142

OH

O OH

O

HO

H

HO

OH

H HO

O

143

OH

HO

O

OH

O OH

HO

144

HO

OH

O 145

O OH

O 146

FIGURE 7.5 Cont’d

OCH3

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7 O

OH

HO O OH 147

HO

OH

OH

O

OH

151

HO

OH

OH

O

OH

152

HO

HO

OH

OH

OH

OH

OH

O 153

O 154

OH

O

OH

OH

O

OH

O

OH

OH

O

O 156

155

O OH

O

H

OH

O 157

FIGURE 7.5 Cont’d

317

318 Studies in Natural Products Chemistry

were isolated from the leaves of Piper dennisii Trel., using bioassay-guided fractionation to determine their antileishmanial potential. Piperaduncin C was isolated for the second time from a Piper species, whereas 40 -methoxy-20 ,60 -dihydroxydihydrochalcone is very common in the Piper genus and could be a chemotaxonomic marker for this genus [63]. Etlinglittarolin (115), a monoterpene-substituted hydroperoxy dihydrochalcone, together with five known dihydrochacones also found in the Piper genus (namely 20 ,60 -dihydroxy-40 -methoxydihydrochalcone, 20 ,40 ,60 -trihydroxydihydrochalcone, 20 ,60 ,4-trihydroxy-40 -methoxydihydrochalcone, ()-methyllinderatin, and adunctin E), was isolated from the rhizomes of a Zingiberaceae, Etlingera littoralis [91]. Three new prenylated dihydrochalcones, ()-nicolaioidesins A-C 116e118) were also obtained from another Zingiberaceae, Renealmia nicolaioides, which mainly grows in the forests of the western part of tropical South America [92]. Flemingia philippinensis is used as an edible plant or medicinal plant in the tropical regions of China. Activity-guided isolation of this plant yielded six polyphenols including three new dihydrochalcones named fleminchalcones A (127), B (96), and C (128) [102]. Five new geranyl dihydrochalcones, 1-(2,4-dihydroxyphenyl)-3-{4-hydroxy-6,6,9trimethyl-6a,7,8,10a-tetrahydro-6H-dibenzo[b,d]pyran-5-yl}-1-propanone (134), 1-(2,4-dihydroxyphenyl)-3-[3,4-dihydro-3,8-dihydroxy-2-methyl- 2-(4-methyl-3pentenyl)-2H-1-benzopyran-5-yl]-1-propanone (135), 1-(2,4-dihydroxyphenyl)-3[8-hydroxy-2-methyl-2-(3,4-epoxy-4-methyl-1-pente-nyl)-2H-1-benzopyran5-yl]-1-propanone (136), 1-(2,4-dihydroxyphenyl)-3-[8-hydroxy-2-methyl-2(4-hydroxy-4-methyl-2-pentenyl)-2H-1-benzopyran-5-yl]-1-propanone (137), and 2-[6-hydroxy-3,7-dimethylocta-2(E),7-dienyl]-2ʹ,3,4,4ʹ-tetrahydroxydihydrochalcone (138), along with four known geranyl flavonoids, were isolated from the leaves of Artocarpus altilis. From a biogenetic point of view, the precursor of these various compounds could be 2ʹ,3,4,4ʹ-tetra-hydroxychalcone [132]. A recent investigation of this species led to the isolation of eight new geranylated dihydrochalcones named sakenins A-H (139-146) [134]. Artocarpus elasticus is another species of Artocarpus used in traditional medicine in Malaysia. From the leaves, two new geranyl dihydrochalcones were purified, elastichalcone A (100) and elastichalcone B (147) [139]. Two new geranyl dihydrochalcones were isolated from the leaves of Esenbeckia grandiflora subsp. brevipetiolata, dihydrochalcone M-1 (153) and M-2 (154). Dihydrochalcones from E. grandiflora subsp. grandiflora possess more oxygen than those from E. grandiflora subsp. brevipetiolata [171]. Two new active prenylated chalcones, bipinnatones A (151) and B (152), were isolated from aerial parts of Boronia bipinnata following high-throughput screening of plants and marine invertebrates extracts to search for new natural products that inhibit the malarial parasite enzyme target hemoglobinase II [168]. Two new dihydrochalcones with antimicrobial properties, named erioschalcones A (95) and B (90), were isolated from a Cameroonian medicinal plant, Eriosema glomerata [99]. Two major prenylated dihydrochalcones, trivially named macatrichocarpins C-D (122e123), were obtained from the leaves of Macaranga trichocarpa from the Euphorbiaceae family [125]. More recently, two minor additional

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

319

dihydrochalcones derivatives, trivially named oxymacatrichocarpin C (124) and isomacatrichocarpin C (125), were also isolated from the same part of the species [126]. Pierotin B (121) is a dihydrochalcone, containing a dibenzofuran moiety, isolated from Pieris japonica (Ericaceae), together with a dimer and dihydrochalcone glycosides [180].

C-Benzylated Dihydrochalcones C-benzylated dihydrochalcones are listed in Table 7.4, and the structures of the new dihydrochalcones reported in the literature from 2004 to 2015 (in bold in Table 7.4) are presented in Fig. 7.6. From a chemotaxonomic point of view, the Annonaceae family specifically, and in particular the genus Uvaria, produces C-benzylated dihydrochalcones (Table 7.4). Two new C-benzylated dihydrochalcones, isochamuvaritin (178) and acumitin (179), have been isolated from the African medicinal plant Uvaria acuminata, together with uvaretin, isouvaretin, diuvaretin, and uvangoletin, which have previously been reported in several other Uvaria species [22]. The first total synthesis of angoluvarin (161), isolated from Uvaria angolensis [24] and Uvaria leptoclados [34], has been reported. Starting with 2-bromophenol, the synthesis was accomplished in eight steps with an overall yield of 2% [205]. A new C-benzyldihydrochalcone derivative, 40 ,60 -dihydroxy-20 ,4-dimethoxy-50 -(200 -hydroxybenzyl)-dihydrochalcone (181), together with one known dihydrochalcone, 40 ,60 -dihydroxy20 ,4-dimethoxy-dihydrochalcone, was isolated from the leaves and twigs of another Annonaceae, Cyathostemma argenteum [13]. Two new C-benzylated dihydrochalcone derivatives, 20 ,40 -dihydroxy-4,60 -dimethoxy-30 (200 -hydroxybenzyl)dihydrochalcone (180) and 4,20 ,40 -trihydroxy-60 -methoxy-30 (200 hydroxybenzyl)dihydrochalcone (182) were isolated from the leaves of Melodorum siamense (accepted name Rauwenhoffia siamensis) [18], together with the known dimer 30 ,300 -bis-20 ,40 ,60 -trihydroxy-4-methoxydihydrochalcone previously isolated from Iryanthera sagotiana [53].

Dihydrochalcone Lignans Dihydrochalcone lignans are listed in Table 7.5 and the structures of the new dihydrochalcones reported in the literature from 2004 to 2015 (in bold in Table 7.5) are presented in Fig. 7.7. A phytochemical study of buds from Populus balsamifera, a tree used in traditional medicine by Canada’s native people, led to the isolation of six new cinnamoylated dihydrochalcones as pairs of racemates balsacones J-L (195e197) and one as a racemic mixture balsacone M (198) along with the known compound iryantherin-D (186). The absolute configuration of this compound previously isolated from Iryanthera laevis was unambiguously determined for the first time via X-ray diffraction analyses and electron circular dichroism spectroscopic data, as was the absolute configuration of isolated enantiomers of balsacones J-K. A plausible biosynthetic pathway for these hydroxycinnamoylated dihydrochalcones is proposed by the authors [129].

N

Semisystematic or IUPAC-Approved Systematic Name

Trivial Name

Source

Family

Part of Plant

Refs.

Uvaretin

Uvaria acuminata

Annonaceae

Roots

[21,22]

U. angolensis

Annonaceae

Roots

[23]

Stem bark

[26]

Stem bark

[27]

Root bark

[29]

Tri-O-Substituted 165

20 ,40 -dihydroxy-60 -methoxy-30 (2-hydroxy-benzyl)-dihydrochalcone

U. chamae

166

0

0

0

0

0

2 ,4 -dihydroxy-6 -methoxy-5 -methyl-3 (2-hydroxy-benzyl)- dihydrochalcone

Annonaceae

U. kirkii

Annonaceae

Root bark

[32]

U. leptoclados

Annonaceae

Root bark

[34]

U. lucida

Annonaceae

Root bark

[35]

U. puguensis

Annonaceae

Stem bark

[37]

U. scheffleri

Annonaceae

Root bark

[38]

U. tanzaniae

Annonaceae

Root bark

[38,39]

Anguvetin

U. angolensis

Annonaceae

Roots

[25,206]

Isoangoletin (¼anguvetin)

U. puguensis

Annonaceae

Stem bark

[37,206]

320 Studies in Natural Products Chemistry

TABLE 7.4 C-Benzylated Dihydrochalcones

167

169

170

Angoluvarin

20 ,40 -dihydroxy-60 -methoxy-50 (2-hydroxy-benzyl)-dihydrochalcone

Isouvaretin

20 ,40 -dihydroxy-60 -methoxy-30 (2-hydroxy-benzyl)-50 -(2-hydroxybenzyl)-dihydrochalcone

0

0

0

0

2 ,4 -dihydroxy-6 -methoxy-3 (2-hydroxy-benzyl)-50 -(2  2-hydroxybenzyl)- dihydrochalcone

Diuvaretin

Triuvaretin

Uvaria angolensis

Annonaceae

Roots

[24]

U. leptoclados

Annonaceae

Root bark

[34]

U. acuminata

Annonaceae

Roots

[22]

U. angolensis

Annonaceae

Roots

[23]

U. chamae

Annonaceae

Stem bark

[27]

Root bark

[29]

U. leptoclados

Annonaceae

Root bark

[34]

U. acuminata

Annonaceae

Roots

[22]

U. angolensis

Annonaceae

Stem bark

[26]

U. chamae

Annonaceae

Root bark

[29]

U. kirkii

Annonaceae

Root bark

[33]

U. leptoclados

Annonaceae

Root bark

[34]

U. lucida

Annonaceae

Root bark

[35]

U. scheffleri

Annonaceae

Root bark

[38]

U. tanzaniae

Annonaceae

Root bark

[38,39]

U. leptoclados

Annonaceae

Root bark

[34]

U. puguensis

Annonaceae

Stem bark

[37]

Xylopia africana

Annonaceae

Roots

[40]

321

Continued

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

168

20 ,40 -dihydroxy-60 -methoxy-30 (2  2-hydroxy-benzyl)dihydrochalcone

N 171

Semisystematic or IUPAC-Approved Systematic Name 20 ,40 -dihydroxy-60 -methoxy-30 (2  2-hydroxy-benzyl)- 50 -(2-hydroxybenzyl)- dihydrochalcone

0

0

0

0

Trivial Name

Source

Family

Part of Plant

Refs.

Isotriuvaretin

Uvaria leptoclados

Annonaceae

Root bark

[34]

U. puguensis

Annonaceae

Stem bark

[37]

U. tanzaniae

Annonaceae

Root bark

[38,39]

Xylopia africana

Annonaceae

Roots

[34]

172

2 ,4 -dihydroxy-6 -methoxy-3 (2-hydroxy-benzyl)-50 -(3  2-hydroxybenzyl)- dihydrochalcone

X. africana

Annonaceae

Roots

[43]

173

20 ,40 -dihydroxy-60 -methoxy-30 (3  2-hydroxy-benzyl)-50 -(2-hydroxybenzyl)- dihydrochalcone

X. africana

Annonaceae

Roots

[43]

174

20 ,40 -dihydroxy-60 -methoxy-30 (2-hydroxy-benzyl)-50 -(4  2-hydroxybenzyl)- dihydrochalcone

X. africana

Annonaceae

Roots

[42]

175

20 ,40 -dihydroxy-60 -methoxy-30 (4  2-hydroxy-benzyl)-50 -(2-hydroxybenzyl)- dihydrochalcone

X. africana

Annonaceae

Roots

[42]

322 Studies in Natural Products Chemistry

TABLE 7.4 C-Benzylated Dihydrochalconesdcont’d

176

20 ,60 -dihydroxy-40 -methoxy-30 (2-hydroxy-benzyl)-dihydrochalcone

177

Chamuvaritin

Annonaceae

Roots

[41]

Uvaria angolensis

Annonaceae

Stem bark

[26]

U. chamae

Annonaceae

Roots

[28]

U. lucida

Annonaceae

Root bark

[35]

U. tanzaniae

Annonaceae

Root bark

[39]

178

1-[1,3-dihydroxy-2- [(2-hydroxyphenyl)methyl]-9H-xanthen-4-yl]-3-phenyl1-propanone

Iso-chamuvaritin

U. acuminata

Annonaceae

Roots

[22]

179

[1,3-dihydroxy-2-[(2-hydroxy-phenyl) methyl]-9H-xanthen-9-one-4-yl]3-phenyl-1-propanone

Acumitin

U. acuminata

Annonaceae

Roots

[22]

Tetra-O-Substituted 180

20 ,40 -dihydroxy-4,60 -dimethoxy-30 (200 hydroxybenzyl)-dihydrochalcone

Melodorum siamense (¼ Rauwenhoffia siamensis)

Annonaceae

Leaves

[18]

181

40 ,60 -dihydroxy-20 ,4-dimethoxy-50 -(200 hydroxybenzyl)-dihydrochalcone

Cyathostemma argenteum

Annonaceae

Leaves and twigs

[13]

182

4,20 ,40 -trihydroxy-60 -methoxy-30 (200 hydroxybenzyl)-dihydrochalcone

Melodorum siamense (¼ Rauwenhoffia siamensis)

Annonaceae

Leaves

[18]

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

Xylopia africana

323

324 Studies in Natural Products Chemistry

O HO

OH

O

HO

O

OH

O

OH

O

OH

178

179 OCH 3

HO HO

OH OH

OCH 3

OCH 3

OCH 3

OH

O

OH

O

181

180

OH HO

OH

OCH 3

OH

O

182

FIGURE 7.6 New C-benzylated dihydrochalcones isolated between 2004 and 2015.

Dihydrochalcone Dimers Dihydrochalcone dimers are listed in Table 7.6, and the structures of the new dihydrochalcones reported in the literature from 2004 to 2015 (in bold in Table 7.6) are presented in Fig. 7.8. Dihydrochalcones are a less common variation of the chalcone skeleton which may rarely occur as dimers. Pierotin A (200) is a dihydrochalcone dimer with a methylene bridge, like piperaduncin C, obtained from the leaves of P. japonica (Ericaceae) [180]. Rhodomyrtosone E (213), a racemic mixture, was isolated from the leaves of Eucalyptus citriodora. This compound possesses a b-triketoneedihydrochalcone conjugate skeleton. Other similar natural products include rhodomyrtone and rhodomyrtosones B and C [156]. Four dimers based on a cyclobutane ring are present in the Annonaceae family, (rel)-1b,2a-di-(2,4-dihydroxy6-methoxybenzoyl)-3b,4a-di-(4-methoxyphenyl)-cyclobutane (214) [17], Combretaceae family, rel-1b-(4,6-dihydroxy-2-methoxy)-benzoyl-rel-2a(2,6-dimethoxy-4-hydroxy)-benzoyl-rel-3b,4a)-diphenyl-cyclobutane (215) and rel-(1a,2b)-di-(2,6-dimethoxy-4-hydroxy)-benzoyl-rel-(3a,4b)-diphenylcyclobutane (216) [153], and the Amaryllidaceae family, rel-(1b,2a)-di(2,4-dihydroxybenzoyl)-rel-(3b,4a)-di-(4-hydroxyphenyl)-cyclobutane (217) [70]. In this last case, the chalcone isoliquiritigenin would be its precursor [70].

TABLE 7.5 Dihydrochalcone Lignans Trivial Name

Source

Family

Part of Plant

Refs.

Iryantherin A

Iryanthera laevis

Myristicaceae

Fruits

[48]

Iryantherin B

I. laevis

Myristicaceae

Fruits

[49]

I. ulei

Myristicaceae

Bark

[49]

189

Iryantherin G

I. grandis

Myristicaceae

Fruits

[45]

190

Iryantherin H

I. grandis

Myristicaceae

Fruits

[45]

191

Iryantherin I

I. grandis

Myristicaceae

Fruits

[45] Continued

325

Semisystematic or IUPAC-Approved Systematic Name

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

N 183 184

0

00

0

0

00

3 -(7 -allylphenyl)-2 ,4 ,4 -trihydroxy4,60 dimethoxydihydrochalcone

185

Iryantherin C

I. laevis

Myristicaceae

Fruits

[49]

186

Iryantherin D

I. laevis

Myristicaceae

Fruits

[49]

I. ulei

Myristicaceae

Bark

[49]

Populus balsamifera

Salicaceae

Buds

[129]

Iryanthera laevis

Myristicaceae

Fruits

[49]

I. ulei

Myristicaceae

Bark

[49]

I. paraensis

Myristicaceae

Bark

[49]

I. ulei

Myristicaceae

Bark

[49]

187

188

Iryantherin E

Iryantherin F

N

Semisystematic or IUPAC-Approved Systematic Name

192

Trivial Name

Source

Family

Part of Plant

Refs.

Iryantherin J

Iryanthera grandis

Myristicaceae

Fruits

[45]

193

(100 R*,200 S*,300 R*)-30 -(100 ,400 -di-p-hydroxyphenyl200 ,300 -dimethylbutyl)-20 ,40 -dihydroxy-4,60 -dimethoxy-dihydrochalcone

Iryantherin K

I. lancifolia

Myristicaceae

Fruits (pericarps)

[50]

194

(100 S*,200 S*,300 R*)-30 -(100 ,400 -di-p-hydroxy-phenyl200 ,300 -dimethy-lbutyl)-20 ,40 -dihydroxy-4,60 dimethoxydihydrochalcone

Iryantherin L

I. lancifolia

Myristicaceae

Fruits (pericarps)

[50]

195

Balsacone J

Populus balsamifera

Salicaceae

Buds

[129]

196

Balsacone K

P. balsamifera

Salicaceae

Buds

[129]

197

Balsacone L

P. balsamifera

Salicaceae

Buds

[129]

198

Balsacone M

P. balsamifera

Salicaceae

Buds

[129]

326 Studies in Natural Products Chemistry

TABLE 7.5 Dihydrochalcone Lignansdcont’d

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

327

FIGURE 7.7 New dihydrochalcone lignans isolated between 2004 and 2015.

Dihydrochalcone Glycosides Dihydrochalcone glycosides are listed in Table 7.7, and the structures of the new dihydrochalcones reported in the literature from 2004 to 2015 (in bold in Table 7.7) are presented in Fig. 7.9. A new dihydrochalcone O-glycoside, ismaeloside A (220), was isolated together with 14 other compounds from the methanol extract of the aerial parts of Ducrosia ismaelis. The absolute configuration was determined as a-R by CD (circular dichroism) spectral analysis where a positive cotton effect at 292.4 nm was observed. This glycoside does not show significant antiosteoporotic or antioxidant activities [189]. From the Egyptian seagrass Thalassodendron ciliatum, a glycoside of asebogenin, thalassodendrone (224), was obtained [68]. Four other new glycosides of asebogenin, 3-hydroxyasebotin (226), asebogenin 20 -O-b-D-ribohexo-3-ulopyranoside (227), 200 -acetyl-asebotin (228), and 30 ,4,50 -trihydroxy-40 -methoxy-dihydrochalcone 30 ,50 -di-O-b-glucopyranoside (229), as well as pierotins A (200) and B (121) cited previously, were isolated from the leaves of Pieris japonica (Ericaceae), a wellknown poisonous plant, distributed mainly in south and southwest China and used in folk medicine [180]. Bioassay-guided fractionation of the roots of Anneslea fragrans var. lanceolata led to the isolation of four

TABLE 7.6 Dihydrochalcone Dimers

Trivial Name

Source

Family

Part of Plant

Refs.

DihydrochalconeeDihydrochalcone Carbon-to-Carbon Link Between the Two a-Carbon Atoms 199

Brackenin

Brackenridgea zanguebarica

Ochnaceae

Bark from stems and roots

[127]

Pierotin A

Pieris japonica

Ericaceae

Leaves

[180]

Cycloaltisin 6

Artocarpus altilis

Moraceae

Buds

[135]

Leaves

[132,134]

DihydrochalconeeDihydrochalcone 200

bis[20 ,4,60 -trihydroxy-40 -methoxy-dihydrochalcone-50 yl]methane

201

202

30 ,300 -bis-20 ,40 ,60 -trihydroxy4-methoxydihydrochalcone

203

Piperaduncin C

0

0

000

000

Iryanthera sagotiana

Myristicaceae

Leaves

[53]

Melodorum siamense (¼ Rauwenhoffia siamensis)

Annonaceae

Leaves

[18]

Piper aduncum

Piperaceae

Leaves

[59]

P. dennisii

Piperaceae

Leaves

[63]

204

4,2 ,4 ,2 ,4 -penta-hydroxy300 -methoxy -3-O-4ʹʹ-tetrahydrobichalcone

Verbenachalcone

Verbena litoralis

Verbenaceae

Aerial parts

[185]

205

20 ,40 ,300 ,2000 ,4000 -penta-hydroxy4- O-400 -tetra-hydrobichalcone

Littorachalcone

V. litoralis

Verbenaceae

Aerial parts

[186]

Cinnabarone

Dracaena cinnabari

Asparagaceae

Resin

[73]

Dihydrochalcone-Deoxotetrahydrochalcone 206

328 Studies in Natural Products Chemistry

N

Semisystematic or IUPAC-Approved Systematic Name

207

1-[5-(2,4,40 trihydroxydihydrochalconyl)]-1(p-hydroxyphenyl)-3(2-methoxy-4-hydroxy-phenyl)propane

Cochinchinenin

Dracaena cochinchinensis

Asparagaceae

Resin

[75]

Trianguletin

Pentagramma triangularis spp. triangularis

Pteridaceae

Frond exudate

[1]

P. triangularis

Pteridaceae

Frond exudate

[2]

Trianguletin “B”

P. triangularis

Pteridaceae

Frond exudate

[2]

Dihydrochalcone-Flavonol

209 8-[2,4-Dihydroxy-6-methoxy5-methyl- 3-{1-oxo-3(4-hydroxy-phenyl-propyl)} phenyl]methyl-ene3,5,7-trihydroxy-2(4-methoxyphenyl)-4H1-benzopyran-4-one

Trianguletin “C”

P. triangularis

Pteridaceae

Frond exudate

[3]

211

8-[2,4-Dihydroxy-6-methoxy5-methyl- 3-{1-oxo-3(4-hydroxy-phenyl-propyl)} phenyl]methyl-ene5,7-dihydroxy -3-methoxy-2(4-methoxyphenyl)-4H1-benzopyran-4-one

Trianguletin “D”

P. triangularis

Pteridaceae

Frond exudate

[3]

212

8-[2,4-Dihydroxy-6-methoxy5-methyl- 3-{1-oxo-3(4-hydroxy-phenyl-propyl)} phenyl]methyl-ene5,7-dihydroxy -3-methoxy2-phenyl)-4H-1-benzopyran4-one

Trianguletin “E”

P. triangularis

Pteridacee

Frond exudate

[3]

329

210

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

208

Continued

TABLE 7.6 Dihydrochalcone Dimersdcont’d

Trivial Name

Source

Family

Part of Plant

Refs.

Rhodomyrtosone E

Eucalyptus citriodora

Myrtaceae

Leaves

[156]

b-TriketoneeDihydrochalcone 213

(˘) 6,8-dihydroxy-9-isobutyl2,2,4,4- tetramethyl-7(3-phenylpropanoyl)4,9-dihydro-1 H-xanthene1,3(2H)-dione

Cyclobutane-Dihydrochalcone 214

(rel)-1b,2a-di-(2,4-dihydroxy6-methoxybenzoyl)-3b,4a-di(4-methoxyphenyl)cyclobutane

Goniothalamus gardneri

Annonaceae

Aerial parts

[17]

215

rel-1b-(4,6-dihydroxy2-methoxy)-benzoyl-rel-2a(2,6-dimethoxy-4-hydroxy)benzoyl-rel-(3b,4a)-diphenylcyclobutane

Combretum albopunctatum

Combretaceae

Aerial parts

[153]

216

rel-(1a,2b)-di-(2,6-dimethoxy4-hydroxy)-benzoyl- rel(3a,4b)-diphenyl-cyclobutane

C. albopunctatum

Combretaceae

Aerial parts

[153]

217

rel-(1b,2a)-di-(2,4-dihydroxy benzoyl)-rel-(3b,4a)-di(4-hydroxyphenyl)-cyclobutane

Agapanthus africanus

Amaryllidaceae

Roots

[70]

330 Studies in Natural Products Chemistry

N

Semisystematic or IUPAC-Approved Systematic Name

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

331

FIGURE 7.8 New dihydrochalcone dimers isolated between 2004 and 2015.

davidigenin glycosides, davidigenin-2ʹ-O-(6ʹʹ-O-4ʹʹʹ-hydroxybenzoyl)-b-glucoside (235), davidigenin-2ʹ-O-(2ʹʹ-O-4ʹʹʹ-hydroxy-benzoyl)-b-glucoside (236), davidigenin-2ʹ-O-(3ʹʹ-O-4ʹʹʹ-hydroxy-benzoyl)-b-glucoside (237), and davidigenin-2ʹ-O-(6ʹʹ-O-syringoyl)-b-glucoside (238) plus 13 known compounds including davidigenin, davidioside, and 40 -O-methyldavidioside [181]. Seven galloyl, caffeoyl, and HHDP esters of dihydrochalcone glucosides were isolated from the aerial parts of Balanophora tobiracola: phloretin 4ʹ-O-[3ʹO-galloyl-4ʹ,6ʹ-O-(S)-HHDP]-b-D-glucoside (242), 3-hydroxyphloretin 4ʹ-O-(6ʹʹ-O-galloyl)-b-D-glucoside (244), 3-hydroxyphloretin 4ʹ-O-(3ʹʹ,4ʹʹ-di-Ogalloyl)-b-D-glucoside (245), 3-hydroxyphloretin 4ʹ-O-(4ʹʹ,6ʹʹ-di-O-galloyl)-bD-glucoside (246), 3-hydroxyphloretin 4ʹ-O-[4ʹ,6ʹʹ-O-(S)-HHDP]-b-D-glucoside (247), 3-hydroxyphloretin 4ʹ-O-[3ʹʹ-O-galloyl-4ʹʹ,6ʹʹ-O-(S)-HHDP]-bD-glucoside (248), and 3-hydroxyphloretin 4ʹ-[3ʹʹ-O-caffeoyl-4ʹʹ,6ʹʹ-O-(S)HHDP]-b-D-glucoside (249) [163]. Some of these compounds (243, 244, 247e248) were also isolated from the rhizomes of Balanophora harlandii [160] and from the whole plant of Balanophora involucrata (244, 247) [161]. From the branches of Schoepfia jasminodora, a species growing wild in Japan, three new dihydrochalcone C-glycosides, schoepfiajasmins AeC (267e269), and one new O-glycoside, schoepfiajasmin D (253), were isolated, together with schoepfin B (266) [166]. This C-glycoside was previously obtained from Schoepfia chinensis

N

Semisystematic or IUPAC-Approved Systematic Name

Trivial Name

Source

Family

Part of Plant

Refs.

Davidioside

Viburnum davidii

Adoxaceae

Leaves

[188]

V. lantanoides

Adoxaceae

Leaves

[188]

Anneslea fragrans var. lanceolata

Pentaphylacaceae

Roots

[181]

40 -Omethyldavidioside

Viburnum lantanoides

Adoxaceae

Leaves

[188]

Anneslea fragrans var. lanceolata

Pentaphylacaceae

Roots

[181]

Ismaeloside A

Ducrosia ismaelis

Apiaceae

Aerial parts

[189]

O-Glycosides 218

Davidigenin-20 -O-glucoside

219

220 0

0

0

221

2 ,4 ,6 -trimethoxy-4-O-b-Dglucopyranosyl-dihydrochalcone

Bidenoside B

Bidens pinnata

Asteraceae

Aerial parts

[192]

222

40 -O-(300 -O-Galloyl-400 ,600 -O,Ohexa-hydroxydiphenoylglucoside)-20 ,40 ,60 -trihydroxydihydrochalcone

Thonningianin A

Thonningia sanguinea

Balanophoraceae

Roots

[164]

223

40 -O-(400 ,600 -O,Ohexahydroxydiphenoylglucoside) -20 ,40 ,60 -trihydroxydihydrochalcone

Thonningianin B

T. sanguinea

Balanophoraceae

Roots

[164]

332 Studies in Natural Products Chemistry

TABLE 7.7 Dihydrochalcone Glycosides

60 -O-rhamnosyl-(1000 / 600 )glucopyranosyl asebogenin

Thalassodendrone

Thalassodendron ciliatum

Cymodo-ceaceae

Plant

[68]

225

20 -O-gluco-pyranosyl-40 methoxy-4,60 - dihydroxydihydrochalcone

Asebotin

Loiseleuria procumbens

Ericaceae

Whole plant

[179]

Pieris japonica

Ericaceae

Leaves

[180]

Thalassodendron ciliatum

Cymodoceaceae

Plant

[68]

226

3-Hydroxyasebotin

Pieris japonica

Ericaceae

Leaves

[180]

227

Asebogenin 20 -O-bD-ribohexo-3-ulopyranoside

P. japonica

Ericaceae

Leaves

[180]

228

200 -acetyl-asebotin

P. japonica

Ericaceae

Leaves

[180]

P. japonica

Ericaceae

Leaves

[180]

30 ,4,50 -trihydroxy-40 -methoxydihydrochalcone 30 ,50 -di-O-b-glucopyranoside

230

20 -O-(6ʹʹ-O-acetylglucopyranosyl)-4,40 ,60 trihydroxy-dihydrochalcone

6ʹʹ-acetylphloridzosid

Loiseleuria procumbens

Ericaceae

Whole plant

[179]

231

a-R,a-O-b-D-glucopyranosyl4,4ʹ,7ʹ-trihydroxydihydrochalcone

Licoagroside F

Glycyrrhiza pallidiflora

Fabaceae

Hairy roots

[104]

232

(aR)-3ʹ-O-b-D- xylopyranosyla,3,4,2ʹ,4ʹ-pentahydroxydihydrochalcone

Eysenhardtia polystachya

Fabaceae

Bark and trunks

[101]

333

229

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

224

Continued

N

Semisystematic or IUPAC-Approved Systematic Name

233

Trivial Name

Source

Family

Part of Plant

Refs.

Trilobatin-2ʹʹacetate

Lithocarpus pachyphyllus

Fagaceae

Leaves

[118]

234

40 ,60 -dihydroxy-4-methoxydihydrochalcone- 20 -O-b-Dglucopyranoside

Iryanthera sagotiana

Myristicaceae

Inflorescences

[53]

235

Davidigenin-2ʹʹ-O-(6ʹʹʹ-O-4ʹʹʹʹhydroxybenzoyl)- b-glucoside

Anneslea fragrans var. lanceolata

Pentaphylacaceae

Roots

[181]

236

Davidigenin-2ʹʹ-O-(2ʹʹʹ-O-4ʹʹʹʹhydroxy-benzoyl)-b-glucoside

A. fragrans var. lanceolata

Pentaphylacaceae

Roots

[181]

237

Davidigenin-2ʹʹ-O-(3ʹʹʹ-O-4ʹʹʹʹhydroxy-benzoyl)-b-glucoside

A. fragrans var. lanceolata

Pentaphylacaceae

Roots

[181]

238

Davidigenin-2ʹʹ-O-(6ʹʹʹ-Osyringoyl)-b-glucoside

A. fragrans var. lanceolata

Pentaphylacaceae

Roots

[181]

239

Diglycoside 40 -O- [b-Dlucopyranosyl -(1 / 6)-glucopyranosyl]-oxy-20 -hydroxy-30 ,60 dimethoxy-dihydrochalcone

Polygonum salicifolium

Polygonaceae

Aerial parts

[149]

Salicifolioside A

334 Studies in Natural Products Chemistry

TABLE 7.7 Dihydrochalcone Glycosidesdcont’d

240

20 -O-gluco-pyranosyl-4,40 ,60 trihydroxy-dihydrochalcone

Asteraceae

Fresh leaves

[196]

Corylus avellana

Betulaceae

Fruits

[115,116]

Loiseleuria procumbens

Ericaceae

Whole plant

[179]

Pieris japonica

Ericaceae

Leaves

[180]

Lithocarpus litseifolius

Fagaceae

Leaves

[117]

L. pachyphyllus

Fagaceae

Leaves

[118]

Malus x domestica

Rosaceae

Leaves immature fruits

[141]

Malus hupehensis

Rosaceae

Root skins, stems, leaves, fruits

[145]

Malus pumila Mill.

Rosaceae

Leaves, bark, roots

[146]

Wild Malus

Rosaceae

Fruits

[141]

Wild malus (rare red Italian wild apple “Pelingo”)

Rosaceae

Fruits

[144]

Fragaria  ananassa

Rosaceae

Fruits

[140]

Symplocos lancifolia

Symplocaceae

Leaves

[182]

Symplocos spicata

Symplocaceae

Leaves

[182] Continued

335

Lactuca sativa

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

Phlorizin, phloridzin, phloridzosid, phloretin-20 -Oglucoside

TABLE 7.7 Dihydrochalcone Glycosidesdcont’d

241

0

0

0

4 -O-gluco-pyranosyl-(2,2 ,6 triydroxy-dihydrochalcone)

242

Phloretin 4ʹʹ-O-[3ʹʹ -O-galloyl4ʹʹ,6ʹʹ-O -(S)- HHDP]-bD-glucoside

243

3-Hydroxyphloretin 4ʹ-O-bD-glucoside

Trivial Name

Source

Family

Part of Plant

Refs.

Trilobatin phloretin40 -O-glucoside

Balanophora harlandii

Balanophoraceae

Rhizomes

[160]

B. tobiracola

Balanophoraceae

Aerial parts

[163]

Lithocarpus litseifolius

Fagaceae

Leaves

[117]

L. pachyphyllus

Fagaceae

Leaves

[118]

L. polystachyus

Fagaceae

Leaves

[119,120]

Corylopsis pauciflora

Hamamelidaceae

Leaves

[94]

Malus trilobata

Rosaceae

Leaves

[146]

Symplocos microcalyx

Symplocaceae

Leaves

[182]

Balanophora tobiracola

Balanophoraceae

Aerial parts

[163]

B. harlandii

Balanophoraceae

Rhizomes

[160]

B. involucrata

Balanophoraceae

Whole plant

[161]

B. tobiracola

Balanophoraceae

Aerial parts

[162,163]

Malus sieboldii

Rosaceae

Leaves

[146]

Sieboldin

336 Studies in Natural Products Chemistry

N

Semisystematic or IUPAC-Approved Systematic Name

244

3-Hydroxyphloretin 4ʹʹ-O-(6ʹʹʹ-Ogalloyl)- b-D-glucoside

Balanophora harlandii

Balanophoraceae

Rhizomes

[160]

B. involucrata

Balanophoraceae

Whole plant

[161]

B. tobiracola

Balanophoraceae

Aerial parts

[163]

B. tobiracola

Balanophoraceae

Aerial parts

[163]

246

3-Hydroxyphloretin 4ʹʹ-O-(4ʹʹʹ,6ʹʹʹdi-O-galloyl)-b-D-glucoside

B. tobiracola

Balanophoraceae

Aerial parts

[163]

247

3-Hydroxyphloretin 4ʹʹ-O-[4ʹʹʹ,6ʹʹʹdi-O-(S)-HHDP]-b-D-glucoside

B. harlandii

Balanophoraceae

Rhizomes

[160]

B. involucrata

Balanophoraceae

Whole plant

[161]

B. tobiracola

Balanophoraceae

Aerial parts

[163]

3-Hydroxyphloretin 4ʹʹ-O-[3ʹʹʹ-Ogalloyl-4ʹʹʹ,6ʹʹʹ-di-O-(S)-HHDP]-bD -glucoside

B. harlandii

Balanophoraceae

Rhizomes

[160]

B. tobiracola

Balanophoraceae

Aerial parts

[163]

249

3-Hydroxyphloretin 4ʹʹ-[3ʹʹʹ-Ocaffeoyl-4ʹʹʹ,6ʹʹʹ-di-O-(S)-HHDP] -b-D-glucoside

B. tobiracola

Balanophoraceae

Aerial parts

[163]

250

Hesperetin dihydrochalcone 40 b-D-glucoside

B. harlandii

Balanophoraceae

Rhizomes

[160]

251

Phloretin-20 -O-xyloglucoside

Wild Malus (rare red Italian wild apple “Pelingo”)

Rosaceae

Fruits

[144]

252

20 -O-b-D-glucopyranosyl4,40 ,b-trihydroxydihydrochalcone

Rosa cymosa

Rosaceae

Roots

[147]

248

Rocymosin B

337

3-Hydroxyphloretin 4ʹʹ-O-(3ʹʹʹ,4ʹʹʹdi-O-galloyl)-b-D-glucoside

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

245

Continued

N

Semisystematic or IUPAC-Approved Systematic Name

Trivial Name

Source

Family

Part of Plant

Refs.

253

2ʹʹ,4ʹʹ,6ʹʹ-trihydroxydihydrochalcone 2ʹʹ,4ʹʹ-di-O-b-Dglucopyranoside

Schoepfiajasmin D

Schoepfia jasminodora

Schoepfiaceae

Branches

[166]

254

a,b-dihydro-2,4,6-trihydroxy-40 methoxy-3,5-dime- thylchalcone 2-(6- O-acetyl-b-D -glucopyranoside)

Abacopterin L

Abacopteris penangiana

Thelypteridaceae

Rhizomes

[6]

Neohesperidin dihydro-chalcone

Citrus aurantium

Rutaceae

Leaves

[169]

Zosterin

Zostera

Zosteraceae

Plant

[69]

255 256

20 ,4-dihydroxy-40 ,60 -diacetoxydihydrochalcone- 20 -O-glucoside

C-Glycosides 257

20 ,3,4,40 ,60 -pentahydroxy-30 -C-bD-glucopyranosyldihydrochalcone

Aspalathin

Aspalathus linearis

Fabaceae

Leaves

[95]

258

20 ,4,40 ,60 -tetrahydroxy-30 -C-b-Dglucopyranosyl- dihydrochalcone

Nothofagin

A. linearis

Fabaceae

Leaves

[95]

Schoepfia chinensis

Schoepfiaceae

Bark

[165]

(aR)-3ʹ-C-b-D-glucopyranosyla,4,2ʹ,4ʹ-tetrahydroxydihydrochalcone

Coatline A

Eysenhardtia polystachya

Fabaceae

Trunk wood

[100]

259

338 Studies in Natural Products Chemistry

TABLE 7.7 Dihydrochalcone Glycosidesdcont’d

(aR)-3ʹ-C-b-D-glucopyranosyla,3,4,2ʹ,4ʹ-pentahydroxydihydrochalcone

261

(aR)-3ʹ-C-b-D- xylopyranosyla,3,4,2ʹ,4ʹ-pentahydroxydihydrochalcone

262

30 -C-b-D-glucopyranosyl20 ,4,40 ,b- tetrahydroxydihydrochalcone

263 264

Coatline B

Eysenhardtia polystachya

Fabaceae

Trunk wood Bark and trunks

[100,101]

E. polystachya

Fabaceae

Bark and trunks

[101]

Pterocarpus marsupium

Fabaceae

Roots Heartwood

[112,113]

30 -C-b-D-glucopyranosyla-hydroxy-dihydrochaIcone

P. marsupium

Fabaceae

Heartwood

[114]

Phloretin-3ʹ,5ʹ-di-C-bglucopyranoside

Citrus hystrix

Rutaceae

Fruits

[170]

Citrus microcarpa

Rutaceae

Fruits

[170]

Fortunella sp.

Rutaceae

Fruits and leaves

[173]

Pterosupin 30 -glucosylb-hydroxydavidigenin

265

4,2ʹʹ,4ʹʹ-trihydroxy-3ʹʹ-Ceb-Dglucosyl-dihydrochalcone

Schoepfin A

Schoepfia chinensis

Schoepfiaceae

Bark

[165]

266

2ʹʹ,4ʹʹ-dihydroxy-3ʹʹ-Ceb-Dglucosyl-dihydrochalcone

Schoepfin B

S. chinensis

Schoepfiaceae

Bark

[165]

S. jasminodora

Schoepfiaceae

Branches

[166]

Schoepfiajasmin A

S. jasminodora

Schoepfiaceae

Branches

[166]

268

Schoepfiajasmin B

S. jasminodora

Schoepfiaceae

Branches

[166]

269

Schoepfiajasmin C

S. jasminodora

Schoepfiaceae

Branches

[166]

339

267

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

260

340 Studies in Natural Products Chemistry

FIGURE 7.9 New dihydrochalcone glycosides isolated between 2004 and 2015.

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

341

FIGURE 7.9 Cont’d

with schoepfin A (265) and nothofagin (258) [165]. This last C-glycoside dihydrochalcone is encountered in the famous herbal tea, rooibos, Aspalathus linearis (Fabaceae), together with aspalathin (257). Phlorizin was converted into nothofagin using a direct O- to C-glucoside rearrangement in two catalytic steps in 2014 [207]. A new dihydrochalcone glycoside, abacopterin L (254), was isolated from the rhizomes of Abacopteris penangiana [6]. Other glycosides dihydrochalcones have not been isolated but have been tentatively identified by LC-MS2, such as phloretin 4ʹ-O-galloylglucoside in the leaves of Corylopsis pauciflora (Hamamelidaceae), together with a major dihydrochalcone, phloretin 4ʹ-O-glucoside [94]. Similarly, phloretin-30 ,50 -diC-b-glucoside and 3-hydroxyphloretin-30 ,50 -di-C-hexoside have been tentatively identified from the leaves and stems of Cyclopia subternata, a South African herbal tea known as honeybush [96].

BIOLOGICAL ACTIVITIES In this part, I describe biological activities for dihydrochalcones identified in the last 10 years. For other dihydrochalcones described more than 10 years ago, biological activities are only given in Table 7.8. It is worth specifying that this chapter deals with the biological activities of DHCs purified from plant extracts, not of crude plant extracts containing these metabolites. Indeed, activities can fluctuate significantly between purified compounds and crude plant extracts because of several factors: synergy, antagonism, and concentration. Also, most studies presented in this part relate to the demonstration of biological activities in vitro which does not, of course, necessarily reflect the activity in vivo and in humans. Many parameters concerning DHCs, including

TABLE 7.8 Biological Activities of Dihydrochalcones Name of Dihydrochalcone

Class

Source

Biological Activity

Other Use

Refs.

Dihydrochalcones With Simple Patterns of O-Substitution 1

Dihydrochalcone

No substitution

Coptis rhizoma (C. chinensis, C. deltoidea, C. teetoides)

Potential agonist of a7nAChR (alpha7 nicotinic acetylcholine receptor)

[93]

18

20 ,40 -dihydroxy4-methoxydihydrochalcone

Tri-O-substituted

Artemisia dracunculus

Aldose reductase (ALR2) inhibitor

[190]

23

20 ,60 -dihydroxy-40 methoxydihydrochalcone

Tri-O-substituted

Piper aduncum

Molluscicidal and antimicrobial activities

[59]

Piper dennisii

Antiplasmodial activity (IC50 ¼ 12.69 mM) against both chloroquine- sensitive and resistant strains of Plasmodium falciparum (F32,FcB1)

[63]

Piper elongatum

In vitro antileishmanial activity against promastigote forms of L. (V.) braziliensis. (IC50 ¼ 27.04 mg/mL). Antileishmanial activity against L. (L.) tropica and L.(L.) infantum.

[64]

Piper elongatum

Radical scavenging effect

[209]

Piper mollicomum

Antifungal activity against Cladosporium sp.

[67]

342 Studies in Natural Products Chemistry

N

Tri-O-substituted

28

2ʹ,4ʹ,6ʹ-trihydroxydihydrochalcone

30

Aldose reductase (ALR2) inhibitor

[190]

Mascarenhasia arborescens

Antispasmodic activity

[183]

Tri-O-substituted

Greyia flanaganii

Antityrosinase activity (IC50 ¼ 69.15 mM) Low toxicity of the cells with reduction of melanin content of the cells. Antiradical activity scavenging activity.

[150]

Balsacone C

Tri-Osubstituted þ cinnamoyl

Populus balsamifera

Antibacterial activity against S. aureus (MIC ¼ 3.1 mM) Moderate cytotoxic activity on human skin fibroblasts, WS1 (IC50 ¼ 23.6 mM)

[128]

49

40 ,60 -dihydroxy-20 ,4dimethoxydihydrochalcone

Tetra-O-substituted

Cyathostemma argenteum

Anti-inflammatory activity of both tested compounds in the acute phase of inflammation, by inhibition of the release or synthesis of various inflammatory mediators

[13]

50

Loureirin D

Tetra O-substituted

Dracaena cochinchinensis

Mild inhibitory activity against NO production (IC50 ¼ 50.3 mM) No significant cytotoxicity with LPS treatment for 24 h.

[78]

56

4,20 ,40 -trihydroxy-60 methoxy-30 -methyldihydrochalcone (poygonatone D)

Tetra-O-substituted

Polygonum odoratum

Significant promotive effects on the phosphorylation of AMPK and AC

[148]

343

Artemisia dracunculus

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

20 ,4,40 -trihydroxydihydrochalcone (davidigenin)

27

Continued

N 57

59

Name of Dihydrochalcone 4,2ʹ,6ʹ-trihydroxy-4ʹmethoxydihydrochalcone (asebogenin)

Balsacone A

Class

Source

Biological Activity

Tetra O-substituted

Piper aduncum

Molluscicidal and antimicrobial activities

[59]

P. elongatum

In vitro antileishmanial activity against promastigote forms of L. (V.) braziliensis. (IC50 ¼ 28.47 mg/ml). Antileishmanial activity against L. (L.) tropica and L. (L.) infantum.

[64]

P. elongatum

Radical scavenging effect Inhibition effect on the activation of hyaluronidase Antityrosinase activity

[209]

P. longicaudatum

Antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) (IC50 ¼ 10 and 4.5 mg/mL)

[66]

Pieris japonica

Inhibition of the proliferation of murine B

[180]

Populus balsamifera

Antibacterial activity against S. aureus (MIC ¼ 6.3 mM) Moderate cytotoxic activity on human skin fibroblasts, WS1 (IC50 ¼ 25 mM)

[128]

Tetra O-substituted þ cinnamoyl

Other Use

Refs.

344 Studies in Natural Products Chemistry

TABLE 7.8 Biological Activities of Dihydrochalconesdcont’d

Balsacone B

Tetra O-substituted þ cinnamoyl

Populus balsamifera

Antibacterial activity against S. aureus (MIC ¼ 6.3 mM) No cytotoxic activity on human skin fibroblasts.

[128]

63

Phloretin

Tetra O-substituted

Malus x domestica.

Promotes osteoclast apoptosis in murine macrophages inhibits estrogen deficiency-induced osteoporosis in mice

[142]

Neuroprotective effects via attenuated neuronal oxidative stress in cerebral ischemia/reperfusion rats.

[217]

Antibacterial activity against Gram positive and Gram negative bacteria. MICs against S. aureus ATCC 6538 and MRSA between 7.81 and 125 mg/mL. Decrease enzymatic activity of catalase, lactate and isocitrate dehydrogenase

[218]

Promotes adipocyte differentiation in vitro and improves glucose homeostasis in vivo

[216]

Phytoestrogen

[145]

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

62

345 Continued

TABLE 7.8 Biological Activities of Dihydrochalconesdcont’d Name of Dihydrochalcone

Class

Source

Biological Activity

Other Use

Refs.

Pieris japonica

Inhibition of the proliferation of murine B cells

[180]

66

Taccabulin A

Penta O-substituted

Tacca chantrieri, T. integrifolia

Cytotoxic activity Microtubule destabilizing effects

[84]

72

Taccabulin E

Penta O-substituted

T. chantrieri, T. integrifolia

Cytotoxic activity

[84]

77

20 ,40 ,60 -trimethoxy3,4-methylenedioxydihydrochalcone

Penta O-substituted

Millettia leucantha

Anti-HSV activity (IC50 ¼ 15.5  3 HSV-1, IC50 ¼ 17.0  1 HSV-2)

[108]

78

3-Hydroxy-phloretin

Penta O-substituted

Balanophora harlandii

Antiradical activity (SC50 ¼ 18 mM)

[160]

79

2,3-Dihydroxy4,30 ,40 ,50 tetramethoxydihydrochalcone

Hexa O-substituted

Muntingia calabura

Anti-platelet aggregation activity in vitro

[152]

80

Evelynin A

Hexa O-substituted

Tacca chantrieri

Cytotoxicity against four human cancer cell lines, MDA-MB-435 melanoma, MDA-MB-231 breast, PC-3 prostate, and HeLa cervical carcinoma cells (IC50 values of 4.1, 3.9, 4.7, 6.3 mM)

[83]

346 Studies in Natural Products Chemistry

N

Evelynin B

Hexa O-substituted

Tacca chantrieri, T. integrifolia

Cytotoxic activity Microtubule destabilizing effects

[85]

84

()-a,20 -dihydroxy4,40 -dimethoxydihydrochalcone

a-hydroxy-substituted

Virola surinamensis

Antifungal activity against Cladosporium cladosporioides

[58]

88

Dihydromilletenone methyl ether

b-methoxy-substituted

Millettia leucantha

Anti-HSV activity (IC50 ¼ 17.0  2 HSV-1)

[108]

Prenylated Dihydrochalcones 90

Erioschalcone B

Di O-substituted

Eriosema glomerata

Antimicrobial activity against Bacillus megaterium, Escherichia coli, Chlorella fusca, Microbotryum violaceum

[99]

92

()-Linderatin

Tri-O-substituted

Mitrella kentii

Cytotoxic activity against a non-small-cell bronchopulmonary lung carcinoma (IC50 ¼ 3.8 mg/ mL)

[20]

95

Erioschalcone A

Tri O-substituted

Eriosema glomerata

Antimicrobial activity against B. megaterium, E. coli, C. fusca, M. violaceum

[99]

96

Fleminchalcone B

Tri O-substituted

Flemingia philippinensis

Tyrosinase inhibitor

[102]

347

Continued

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

81

N

Name of Dihydrochalcone

Class

Source

Biological Activity

99

()-Methyllinderatin

Tri O-substituted

Piper aduncum

Cytotoxic activity toward KB nasopharyngeal carcinoma cells (ED50 ¼ 6.1 mg/mL) Antibacterial effects toward Micrococcus luteus (MIC ¼ 2.5 mg/mL)

[60]

P. dennisii

Antiplasmodial activity (IC50 ¼ 5.64 mM) against both chloroquine- sensitive and resistant strains of Plasmodium falciparum (F32,FcB1) Antiplasmodial activity in vivo against Plasmodium vinckei petteri in mice (80% of reduction of parasitaemia) at a dose of 20 mg/kg/day

[63]

P. aduncum

Antileishmanial activity against promastigote forms of L. (L.) amazonensis and L. (V.) shawi, (EC50 ¼ 11.03  2.11 and 11.26  4.24 mM)

[61]

101

Adunchalcone

Tri-O-substituted

Other Use

Refs.

348 Studies in Natural Products Chemistry

TABLE 7.8 Biological Activities of Dihydrochalconesdcont’d

L. (L.) chagasi was more resistant to adunchalcone. Tri-O-substituted

Piper aduncum

Antibacterial activity toward Bacillus subtilis and Micrococcus luteus Cytotoxic activity toward a KB nasopharyngeal carcinoma cell line.

[59]

103

Piperaduncin B

Tri-O-substituted

P. aduncum

Antibacterial activity toward Bacillus subtilis and Micrococcus luteus Cytotoxic activity toward a KB nasopharyngeal carcinoma cell line.

[59]

106

Adunctin B

Tri O-substituted

P. aduncum

Antibacterial effects toward Micrococcus luteus (MIC ¼ 3.5 mg/mL)

[60]

107

Adunctin C

Tri O-substituted

P. aduncum

Antibacterial effects toward Micrococcus luteus (MIC ¼ 2.4 mg/mL)

[60]

108

Adunctin D

Tri O-substituted

P. aduncum

Antibacterial effects toward Micrococcus luteus (MIC ¼ 2.9 mg/mL)

[60]

121

Pierotin B

Tetra O-substituted

Pieris japonica

Inhibition of the proliferation of murine B and T cells

[180]

122

Macatrichocarpin C

Tetra O-substituted

Macaranga trichocarpa

Moderate antibacterial activity

[126]

Continued

349

Piperaduncin A

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

102

TABLE 7.8 Biological Activities of Dihydrochalconesdcont’d Name of Dihydrochalcone

Class

Source

Biological Activity

123

Macatrichocarpin D

Tetra O-substituted

Macaranga trichocarpa

Moderate antibacterial activity

[126]

124

Oxymacatrichocarpin C

Tetra O-substituted

M. trichocarpa

Moderate antibacterial activity

[126]

125

Isomacatrichocarpin C

Tetra O-substituted

M. trichocarpa

Moderate antibacterial activity

[126]

127

Fleminchalcone A

Tetra O-substituted

Flemingia philippinensis

Tyrosinase inhibitor; simple reversible slow-binding inhibition against monophenolase

[102]

128

Fleminchalcone C

Tetra O-substituted

F. philippinensis

Tyrosinase inhibitor; most potent inhibitor: Significant inhibitions against both the monophenolase (IC50 ¼ 1.28 mM) and diphenolase (IC50 ¼ 5.22 mM) activities of tyrosinase

[102]

132

1-(2,4-Di hydroxyphenyl)-3[8-hydroxy-2-methyl2-(4-methyl-3-pentenyl)-2H1-benzopyran-5-yl]1-propanone (CG901)

Tetra O-substituted

Artocarpus altilis

Potential lead molecule for developing novel therapeutics against STAT3-related diseases, including cancer and inflammation.

[131]

Artocarpus communis

Cytotoxic activity against murine P-388 leukaemia cells IC50 ¼ 6.7 mg/mL

[138]

Other Use

Refs.

350 Studies in Natural Products Chemistry

N

133

2-Geranyl- 20 ,3,4,40 -tetrahydroxydihydrochalcone (AC5-1)

Tetra O-substituted

Inhibitor of 5-lipoxygenase

[136]

A. altilis

Inhibitor of cathepsin K (cysteine protease implicated in osteoporosis) IC50 ¼ 170 nM

[135]

A. altilis

Inhibitor of 5-a-reductase

[133]

1-(2,4-dihydroxyphenyl)-3-{4-hydroxy6,6,9-trimethyl-6a,7, 8,10a-tetrahydro-6Hdibenzo[b,d]pyran-5yl}-1-propanone

Tetra O-substituted

A. altilis

Moderate cytotoxicity against SPC-A-1, SW-480, and SMMC-7721 human cancer cells (IC50 ¼ 28.14, 34.62 and 49.86 mM respectively)

[132]

135

1-(2,4-dihydroxyphenyl)-3[3,4-dihydro3,8-dihydroxy2-methyl-2-(4-methyl3-pentenyl)-2H1-benzopyran-5-yl]1-propanone

Tetra O-substituted

A. altilis

Moderate cytotoxicity against SPC-A-1, SW-480, and SMMC-7721 human cancer cells

[132]

138

2-[6-Hydroxy3,7-dimethylocta2(E),7-dienyl]20 ,3,4,40 -tetrahydroxydihydrochalcone

Tetra O-substituted

A. altilis

Moderate cytotoxicity against SPC-A-1, SW-480, and SMMC-7721 human cancer cells

[132]

351

134

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

Artocarpus communis (¼ A. altilis)

Continued

N

Name of Dihydrochalcone

Class

Source

Biological Activity

144

sakenin F

Tetra O-substituted

Artocarpus altilis

Cytotoxic activity against a PANC-1 human pancreatic cancer cell line PC50 ¼ 8.0 mM

[134]

146

Sakenin H

Tetra O-substituted

A. altilis

Cytotoxic activity against a PANC-1 human pancreatic cancer cell line PC50 ¼ 11.1 mM

[134]

147

Elastichalcone B

Tetra O-substituted

A. elasticus

Free radical scavenging Activity (IC50 ¼ 11.30 mg/ mL)

[139]

151

Bipinnatone A

Tetra O-substituted

Boronia pinnata

Antiplasmodial activity Inhibition of the enzyme haemoglobinase II (IC50 ¼ 64 mM)

[168]

152

Bipinnatone B

Tetra O-substituted

B. pinnata

Antiplasmodial activity Inhibition of the enzyme haemoglobinase II (IC50 ¼ 51 mM)

[168]

Other Use

Refs.

352 Studies in Natural Products Chemistry

TABLE 7.8 Biological Activities of Dihydrochalconesdcont’d

C-Benzylated Dihydrochalcones 165

Uvaretin

Tri O-substituted

[21]

U. acuminata

Cytotoxic activity against human promyelocytic leukemia HL-60 cells (IC50 ¼ 9.3 mM), by induction of apoptosis

[22,219]

Uvaria chamae

Cytotoxic activity against cells derived from human carcinoma of the nasopharynx (KB)

[27]

U. chamae

Antibacterial activity against Staphylococcus aureus, Bacillus subtilis, and Mycobacterium smegmatis

[27]

U. leptoclados

Antibacterial activity against Bacillus subtilis

[34]

U. scheffleri

Antimalarial activity In vitro activity against the multidrug resistant Kl strain of Plasmodium falciparum (IC50 ¼ 3.49, mg/ml)

[38]

U. tanzaniae

Antimalarial activity Growth inhibition of Plasmodium falciparum in vitro (IC50 ¼ 3.49 mg/mL)

[39]

353

Cytotoxic activity against the P-388 (3 PS) lymphocytic leukemia

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

Uvaria acuminata

Continued

N

Name of Dihydrochalcone

Class

Source

Biological Activity

166

Anguvetin

Di O-substituted

Uvaria angolensis

Antibacterial activity: active against S. aureus (MIC ¼ 1.5 mg/mL), Bacillus subtilis (MIC ¼ 0.2 mg/mL), Mycobacterium smegmatis (MIC ¼ 1.5 mg/mL).

[25]

167

Angoluvarin

Tri O-substituted

U. leptoclados

Antibacterial activity against Bacillus subtilis

[34]

U. angolensis

Antibacterial activity MIC values ¼ 0.78 mg/mL (Bacillus subtilis), 1.56 mg/ mL (S. aureus), 3.12 mg/mL (Mycobacterium smegmatis)

[24]

U. chamae

In vitro activity against cells derived from human carcinoma of the nasopharynx (KB)

[27]

U. acuminata

Cytotoxic activity against human promyelocytic leukemia HL-60 cells (IC50 ¼ 24.7 mM), by induction of apoptosis

[22,219]

U. leptoclados

Antibacterial activity against Bacillus subtilis

[34]

168

Isouvaretin

Tri O-substituted

Other Use

Refs.

354 Studies in Natural Products Chemistry

TABLE 7.8 Biological Activities of Dihydrochalconesdcont’d

169

Diuvaretin

Tri O-substituted

In vitro activity against the multidrug resistant Kl strain of Plasmodium falciparum (IC50 ¼ 4.20 mg/mL)

[38]

U. acuminata

Cytotoxic activity against human promyelocytic leukemia HL-60 cells (IC50 ¼ 6.1 mM), by induction of apoptosis

[22,219]

U. leptoclados

Antibacterial activity against Bacillus subtilis

[34]

U. tanzaniae

Antimalarial activity Growth inhibition of Plasmodium falciparum in vitro (IC50 ¼ 4.20 mg/mL)

[39]

170

Triuvaretin

U. leptoclados

Antibacterial activity against Bacillus subtilis

[34]

171

Isotriuvaretin

U. leptoclados

Antibacterial activity against Bacillus subtilis

[34]

U. tanzaniae

Antimalarial activity Growth inhibition of Plasmodium falciparum in vitro (IC50 ¼ 20.85 mg/ mL)

[39]

355

Continued

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

Uvaria scheffleri

N

Name of Dihydrochalcone

Class

Source

Biological Activity

Other Use

Refs.

172

20 ,40 -dihydroxy-60 methoxy-30 (2-hydroxy-benzyl)-50 (3  2-hydroxybenzyl)dihydrochalcone

Tri O-substituted

Xylopia africana

Antibacterial activity

[43]

173

20 ,40 -dihydroxy-60 methoxy-30 (3  2-hydroxybenzyl)-50 -(2-hydroxybenzyl)dihydrochalcone

Tri O-substituted

X. africana

Antibacterial activity

[43]

174

20 ,40 -dihydroxy-60 methoxy-30 (2-hydroxy-benzyl)-50 (4  2-hydroxybenzyl)dihydrochalcone

Tri O-substituted

X. africana

Antibacterial activity

[42]

175

20 ,40 -dihydroxy-60 methoxy-30 (4  2-hydroxybenzyl)-50 -(2-hydroxybenzyl)dihydrochalcone

Tri O-substituted

X. africana

Antibacterial activity

[42]

356 Studies in Natural Products Chemistry

TABLE 7.8 Biological Activities of Dihydrochalconesdcont’d

Tri O-substituted

Uvaria tanzaniae

Antimalarial activity Growth inhibition of Plasmodium falciparum in vitro (IC50 ¼ 8.31 mg/mL)

[39]

178

Isochamuvaretin

Tri O-substituted

U. acuminata

Cytotoxic activity against human promyelocytic leukemia HL-60 cells (IC50 ¼ 8.2 mM)

[22]

179

Acumitin

Tri O-substituted

U. acuminata

Cytotoxic activity against human promyelocytic leukemia HL-60 cells (IC50 ¼ 4.1 mM)

[22]

180

20 ,40 -dihydroxy-4,60 dimethoxy-30 (200 hydroxy-benzyl) dihydrochalcone

Tetra O-substituted

Melodorum siamensis

Strong cytotoxicity against human tumor cell lines KB and NCI-H187, with IC50 values in the range of 0.66e7.16 mg/mL. Inactive for antimalarial activity and for antimycobacterial activity against Mycobacterium tuberculosis (H37Ra)

[18]

181

40 ,60 -dihydroxy20 ,4-dimethoxy-50 -(200 hydroxy-benzyl)dihydrochalcone

Tetra-O-substituted

Cyathostemma argenteum

Anti-inflammatory activity in the acute phase of inflammation, by inhibition of the release or synthesis of various inflammatory mediators

[13]

357

Chamuvaretin

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

177

Continued

N 182

Name of Dihydrochalcone 4,20 ,40 -trihydroxy-60 methoxy-30 (200 hydroxybenzyl)dihydrochalcone

Class

Source

Biological Activity

Other Use

Refs.

Tetra O-substituted

Melodorum siamensis

Strong cytotoxicity in the NCI-H187 cell line (IC50 ¼ 3.66 mg/mL) Moderate activity in KB and MCF7 cell line (IC50 ¼ 7.16 and 14.86 mg/mL) Inactive for antimalarial activity and for antimycobacterial activity against M. tuberculosis (H37Ra)

[18]

Dihydrochalcones-Lignans 186

Iryantherin D

Populus balsamifera

Antibacterial activity against S. aureus

[129]

195

Balsacone J

P. balsamifera

Antibacterial activity against S. aureus

[129]

196

Balsacone K

P. balsamifera

Antibacterial activity against S. aureus

[129]

197

Balsacone L

P. balsamifera

Antibacterial activity against S. aureus

[129]

198

Balsacone M

P. balsamifera

Antibacterial activity against S. aureus

[129]

358 Studies in Natural Products Chemistry

TABLE 7.8 Biological Activities of Dihydrochalconesdcont’d

Dimeric Dihydrochalcones Pierotin A

DHCeDHC

Pieris japonica

Inhibition of the proliferation of murine B cells

[180]

201

Cycloaltisin 6

DHCeDHC

Artocarpus altilis

Inhibitor of cathepsin K (cysteine protease implicated in osteoporosis) IC50 ¼ 98 nM

[135]

204

Verbenachalcone

DHCeDHC

Verbena litoralis

Significant enhancement of nerve growth factormediated neurite outgrowth from PC12D cells

[185]

205

Littorachalcone

DHCeDHC

V. litoralis

Significant enhancement of nerve growth factormediated neurite outgrowth from PC12D cells

[186]

Dihydrochalcones Glycosides 222

Thonningianin A

O-glycoside ellagitannins

Thonningia sanguinea

Antiradical activity (DPPH) IC50 ¼ 8 mM

[164]

223

Thonningianin B

O-glycoside ellagitannins

T. sanguinea

Antiradical activity (DPPH) IC50 ¼ 21 mM

[164]

224

60 -O-rhamnosyl(1000 / 600 )-glucopyranosyl asebogenin (thalassodendrone)

O-glycoside

Thalassodendron ciliatum

Anti-influenza A virus activity (IC50 ¼ 1.96 mg/mL) Cytotoxic activity (CC50 ¼ 3.14 mg/mL)

[68]

359

Continued

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

200

N

Name of Dihydrochalcone

Class

Source

Biological Activity

225

Asebotin

O-glycoside

Pieris japonica

Inhibition of proliferation of murine B cells

[180]

O-glycoside

Thalassodendron ciliatum

Anti-influenza A virus activity (IC50 ¼ 2.00 mg/mL) Cytotoxic activity (CC50 ¼ 3.36 mg/mL)

[68]

Other Use

Refs.

226

3-Hydroxyasebotin

O-glycoside

Pieris japonica

Inhibition of proliferation of murine B and murine T cells

[180]

228

200 -acetylasebotin

O-glycoside

P. japonica

Inhibition of proliferation of murine B cells

[180]

229

30 ,4,50 -trihydroxy-40 methoxydihydrochalcone 30 ,50 di-O-b-glucopyranoside

O-glycoside

P. japonica

Inhibition of proliferation of murine B cells

[180]

232

(aR)-30 -O-b-Dxylopyranosyla,3,4,20 ,40 pentahydroxydihydrochalcone

O-glycoside and a-hydroxy-substituted

Eysenhardtia polystachya

Insecticidal activity

[101]

233

Trilobatin-2ʹʹ-acetate

O-glycoside

Lithocarpus pachyphyllus

Sweet agent

[118]

360 Studies in Natural Products Chemistry

TABLE 7.8 Biological Activities of Dihydrochalconesdcont’d

Davidigenin-2ʹʹ-O-(6ʹʹʹO-syringoyl)- bglucoside

O-glycoside

Anneslea fragrans var. lanceolata

ABTS cation radical scavenging activity, with SC50 ¼ 52.6  5.5 mg/mL

[181]

240

Phloridzin

O-glycoside

Malus x domestica, wild Malus, Corylus avellana

Strong inhibitor of lipid peroxidation, improve insulin sensitivity by lowering blood sugar

[220]

Produce renal glycosuria and block intestinal glucose absorption through inhibition of the sodiumglucose symporters

[221]

Protection against ovariectomy-induced osteopenia under inflammation conditions by improving inflammation markers and bone resorption.

[222]

Antioxidant agent

[223]

Phytoestrogen

[145]

Lithocarpus pachyphyllus

Sweet agent

[118]

Continued

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

235

361

N

Name of Dihydrochalcone

Class

Source

Biological Activity

241

Trilobatin

O-glycoside

Lithocarpus polystachyus

Inhibition of the activities of a-glucosidase and a-amylase linked to type 2 diabetes

[119]

Inhibition of the LPS-induced inflammatory response by suppressing the NF-kB signaling pathway.

[120]

Antioxidant activity

[223]

L. pachyphyllus

Other Use

Sweet agent

Refs.

[118]

242

Phloretin 4ʹʹ-O-[3ʹʹ-Ogalloyl-4ʹʹ,6ʹʹ-O-(S)HHDP]-b-D-glucoside

O-glycoside

Balanophora tobiracola

Inhibitor of a-glucosidase (IC50 ¼ 0.8 mg/mL)

[163]

243

3-Hydroxyphloretin 40 O-b-D-glucoside (sieboldin)

O-glycoside

B. harlandii

Antiradical activity (SC50 ¼ 23.6 mM)

[160]

B. involucrata

BACE1 inhibitory activities

[161]

Malus sieboldii

Antioxidant agent Prevention of vasoconstriction and inhibition of AGEs formation

[223]

362 Studies in Natural Products Chemistry

TABLE 7.8 Biological Activities of Dihydrochalconesdcont’d

244

O-glycoside

246

3-Hydroxyphloretin 4ʹʹ-O-(4ʹʹʹ,6ʹʹʹ-di-Ogalloyl)-b-D-glucoside

247

Balanophora harlandii

Antiradical activity (SC50 ¼ 9.2 mM)

[160]

B. involucrata

BACE1 inhibitory activities

[161]

O-glycoside

B. tobiracola

Inhibitor of a-glucosidase (IC50 ¼ 1.8 mg/mL)

[163]

3-Hydroxyphloretin 4ʹʹ-O-[4ʹʹ,6ʹʹʹ-di-O-(S)HHDP]-b-D-glucoside

O-glycoside

B. harlandii

Antiradical activity (SC50 ¼ 10.3 mM)

[160]

B. tobiracola

Inhibitor of a-glucosidase (IC50 ¼ 1.6 mg/mL)

[163]

3-Hydroxyphloretin 4ʹʹ-O-[3ʹʹʹ-O-galloyl4ʹʹʹ,6ʹʹʹ-O-(S)-HHDP]-bD-glucoside

O-glycoside

B. harlandii

Antiradical activity (SC50 ¼ 8.2 mM)

[160]

B. tobiracola

Inhibitor of a-glucosidase (IC50 ¼ 0.4 mg/mL)

[163]

249

3-Hydroxyphloretin 4ʹʹ-[3ʹʹʹ-O-caffeoyl4ʹʹʹ,6ʹʹʹ-O-(S)-HHDP]b-D-glucoside

O-glycoside

B. tobiracola

Inhibitor of a-glucosidase (IC50 ¼ 1.1 mg/mL)

[163]

255

Neohesperidin dihydrochalcone

O-glycoside

Citrus aurantium

Anti-oxidative and antiinflammatory capacities. Hepatoprotective agent against CCl4-induced oxidative damage via direct free radical scavenging and indirect Nrf2/ARE signaling pathway.

[224,225]

248

Artificial sweetener

[226]

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

3-Hydroxyphloretin 40 -O-(600 -O-galloyl-bD-glucoside)

363 Continued

N

Name of Dihydrochalcone

Class

Source

Biological Activity

257

Aspalathin

C-glycoside

Aspalathus linearis

Blockade of HG-induced vascular inflammation via inhibition of NF-kB in primary human endothelial cells.

[95]

Powerful plasma sugarlowering properties

[228]

Anti-diabetic effect (in-vivo model) Hypoglycaemic effect related to increased GLUT4 translocation to plasma membrane via AMPK activation Reduction of gene expression of hepatic enzymes related to glucose production and lipogenesis.

[229]

Blockade of HG-induced vascular inflammation via inhibition of NF-kB in primary human endothelial cells.

[95]

258

Nothofagin

C-glycoside

A. linearis

Other Use

Refs.

364 Studies in Natural Products Chemistry

TABLE 7.8 Biological Activities of Dihydrochalconesdcont’d

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

365

bioavailability and biotransformation in the body, will have a role to play in the real activity found in animals and humans. As we will see at the end of this part, until now, there have been few reports in the literature on the bioavailability of dihydrochalcones, with the main exception of the known metabolites found in some edible plants: phloretin and its main glycoside conjugates found in apples, phloretin-2ʹ-O-glucoside (phloridzin) and phloretin 2ʹ-O-(2ʹʹ-Oxylosyl)glucoside, and the dihydrochalcone C-glycosides, aspalathin and nothofagin, found in rooibos [208].

Dihydrochalcones With Simple Patterns of O-Substitution Dihydrochalcone (1), isolated from Coptidis rhizoma in the Chinese pharmacopoeia, may act as a potential agonist of the alpha7 nicotinic acetylcholine receptor, considered to be a candidate in Alzheimer’s disease [93]. This traditional Chinese medicine includes three Coptis species (Ranunculaceae family). Dihydrochalcone was previously isolated in the plant kingdom from Leptoderris fasciculata [105] but also from a mushroom, Phallus impudicus and from a marine species, the wrinkled star (Pteraster militaris) [206]. 2ʹ,6ʹdihydroxy-4ʹ-methoxy-dihydrochalcone (23) was isolated recently from Piper dennisii and showed antiplasmodial activity against both chloroquine-sensitive and resistant strains of Plasmodium falciparum, with an IC50 (half maximal inhibitory concentration) equal to 12.69 mM [63]. This dihydrochalcone, isolated in several other Piper species, has also demonstrated molluscicidal, antimicrobial [59], and antileishmanial activities [64] and a radical scavenging effect like asebogenin (57) [209] (Table 7.8). 2ʹ,4ʹ,6ʹ-trihydroxy-dihydrochalcone (28) isolated from the leaves of Greyia flanaganii, with three other simple dihydrochalcones, exhibited significant antityrosinase activity with an IC50 value of 69.15 mM, low-cell toxicity and reduction of melanin content in the cells. Tyrosinase is known to be the key enzyme in melanin production. An overproduction of melatonin can lead to hyperpigmentation of the skin, a common problem in middle-aged and elderly people [150]. An ethanolic extract of Artemisia dracunculus demonstrating antidiabetic activity was examined as a possible inhibitor of aldose reductase (ALR2), a key enzyme involved in diabetic complications. Four natural products with ALR2 inhibitory activity were identified, among them 2ʹ,4ʹ-dihydroxy-4-methoxydihydrochalcone (18) and davidigenin (DG) (27) [190]. This last compound has been isolated and identified in other species such as Viburnum davidii (Adoxaceae) [188], Mascarenhasia arborescens (Apocynaceae) [183], Euphorbia portlandica (Euphorbiaceae) [124], and Anneslea fragrans var. lanceolata (Pentaphylaceae) [181]. This compound has also been chemically synthesized [210]. DG (27) is known to have various activities. It induces apoptosis in human lung fibroblasts [211] and shows antispasmodic activity on guinea pig ileum and rat duodenum [183]. DG is a reductive metabolite formed via hydrogenative cleavage of the liquiritigenin C-ring by intestinal

366 Studies in Natural Products Chemistry

bacterial flora at the absorption stage [212]. This conversion of liquiritigenin, a flavanone, into davidigenin occurs in the lower gastrointestinal tract in guinea pigs [213]. A study suggests excellent absorption of liquiritigenin and davidigenin through the human intestinal epithelial cell line Caco-2 [214]. Moreover, DG would be a minor metabolite resulting from the metabolism of isoliquiritigenin, a chalcone, by human liver microsomes [215]. The cinnamoyl-dihydrochalcones, balsacones A (59), B (62) and C (30), isolated from the buds of P. balsamifera, were found to be significantly active against Staphylococcus aureus with MIC values of 6.3, 6.3, and 3.1 mM. The presence of the 4-hydroxycinnamyl group at position 3ʹ of ring A of balsacones seems to be important in obtaining significant biological activity. Balsacone B (62) possesses antibacterial properties without cytotoxicity on WS1 cells [128]. Compounds isolated from Dracaena cochinchinensis were evaluated for their inhibitory effects on NO production in LPS (lipopolysaccharide)-stimulated RAW 264.7 macrophages using the Griess assay. Loureirin D (50) showed mild inhibitory activity against NO production with an IC50 value of 50.3 mM compared with the positive control of quercetin. Loureirin D (up to 80 mM) did not show significant cytotoxicity with LPS treatment for 24 h [78]. Phloretin (63) is a dihydrochalcone encountered in apple tree leaves, in particular Malus x domestica, which has many interesting biological properties in vitro. The list of its effects in this section is not exhaustive. Some of these activities have been demonstrated in vivo, but the potential benefits of phloretin in human health need more investigation. Some effects can be mentioned here; for example, phloretin has been shown to reduce the risk of major chronic diseases, such as diabetes, through its crucial effect on adipogenesis and lipolysis in adipocytes [216]. Phloretin abrogated estrogen deficiency induced osteoporosis and promoted apoptosis in mature osteoclasts. Therefore, from a clinical point of view, phloretin may serve as a modulator against postmenopausal osteoporosis and pathological osteoresorptive disorders [142]. Moreover, phloretin might serve as a promising therapeutic agent for the treatment of ischemic stroke; it produced neuroprotective effects by attenuating neuronal oxidative stress in cerebral ischemia/reperfusion rats. The mechanisms underlying the protection exhibited by phloretin involve activation of the Nrf2 defense pathway [217]. Phloretin has also shown antibacterial activity against Gram-positive bacteria, in particular against Listeria monocytogenes strains and methicillin-resistant S. aureus clinical strains, and against the Gram-negative bacteria Salmonella typhimurium. Phloretin decreases the enzymatic activity of catalase, lactate, and isocitrate dehydrogenase, and structure/activity relationships have highlighted that the presence of a glycosyl moiety bound to the chalcone structure dramatically decreases the antimicrobial activity of phloretin [218]. Several new retrodihydrochalcones have been isolated from the roots and rhizomes of Tacca species (Dioscoreaceae), in particular T. chantrieri and T. integrifolia [85]. Evelynin A (80) was the first compound isolated from this series. This benzoquinone-type

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7

367

retrodihydrochalcone was found to have antiproliferative activity against a range of cancer cells at low micromolar concentrations [83]. Taccabulin A (66) was identified more recently via bioassay-guided fractionation and was found to have antiproliferative activity against multiple cancer cell lines at nanomolar concentrations. Its mechanism of action was found to be similar to that of colchicine. It had an unexpected microtubule destabilizing effect and had synergistic effects when combined with the taccalonolides, a terpenic class of microtubule stabilizers also found in Tacca species [84]. A new investigation of Tacca species led to the isolation of other active retrodihydrochalcones, including taccabulin E (72) and evelynin B (81). Like taccabulin A, evelynin B inhibits tubulin polymerization [85].

Prenylated Dihydrochalcones The two new dihydrochalcones, named erioschalcones A (95) and B (90), isolated from E. glomerata, have demonstrated significant antimicrobial activity against the strains Bacillus megaterium, Escherichia coli, Chlorella fusca, and Microbotryum violaceum [99]. Adunchalcone (101) isolated from the leaves of Piper aduncum was evaluated against promastigote forms of Leishmania (L.) amazonensis, L. (V.) braziliensis, L. (V.) shawi, and L. (L.) chagasi and displayed half maximal effective concentrations (EC50) of 11.03, 26.70, 11.26, and 107.31 mM, as well as selectivity indexes (SI) of 4.86, 2.01, 4.76, and 0.50, respectively. In this study, SI corresponds to a ratio between adunchalcone’s cytotoxic effect on peritoneal macrophages and its antileishmanial effect. In peritoneal macrophages incubated with adunchalcone, the CC50 (50% cytotoxic concentration) was determined as 53.71 mM. This compound was also tested against amastigotes of L. (L.) amazonensis, displaying weak activity, in comparison to the reference drug amphotericin B [61]. Flemingia philippinensis roots are rich in potent tyrosinase inhibitors. Tyrosinase may contribute to neurodegeneration associated with Parkinson’s disease. Fleminchalcones A (127) and C (128) were at least 10 times more effective against the monophenolase activity of tyrosinase than the positive control, kojic acid (IC50 ¼ 12.3 mM). Fleminchalcone A (127) was found to be a simple reversible slow-binding inhibitor of monophenolase. Fleminchalcone C (128) was the most potent inhibitor. This finding is unusual because a literature survey revealed that dihydrochalcones are not typically associated with tyrosinase inhibition [102]. The geranyl dihydrochalcone CG901 isolated from different species of Artocarpus including A. altilis, downregulated the expression of STAT3 target genes, induced apoptosis in DU145 prostate cancer cells via caspase-3 and PARP (poly ADP (adenosine diphosphate) ribose polymerase) degradation, and inhibited tumor growth in a human prostate tumor (DU145) xenograft initiation model [131]. This dihydrochalcone had previously shown significant cytotoxicity against murine P-388 leukemia cells with IC50 ¼ 6.7 mg/mL [138]. Three geranyl dihydrochalcones isolated from

368 Studies in Natural Products Chemistry

A. altilis leaves, 1-(2,4-dihydroxyphenyl)-3-{4-hydroxy-6,6,9-trimethyl6a,7,8,10a-tetrahydro-6H-dibenzo[b,d]pyran-5-yl}-1-propanone (134), 1-(2, 4-dihydroxyphenyl)-3-[3,4-dihydro-3,8-dihydroxy-2-methyl-2-(4-methyl-3-pentenyl)-2H-1-benzopyran-5-yl]-1-propanone (135), and 2-[6-hydroxy3,7-dimethylocta-2(E),7-dienyl]-20 ,3,4,40 -tetrahydroxy-dihydrochalcone (138), showed moderate cytotoxicity against SPC-A-1, SW-480, and SMMC-7721 human cancer cells at 80 mM. Among the tested compounds, compound (134) was the most potent against the SPC-A-1 and SW-480 cells (IC50 ¼ 28.14 and 34.62 mM, respectively) and was found to be relatively more active than standard fluorouracil [132]. Other dihydrochalcones obtained from A. altilis were tested for their cytotoxic activity against a PANC-1 human pancreatic cancer cell line utilizing an antiausterity strategy. Sakenins F (144) and H (146) displayed the most potent preferential cytotoxic activity with PC50 (concentration to achieve 50% cell mortality) values of 8.0 mM and 11.1 mM, respectively [134]. Bipinnatones A (151) and B (152) isolated from Boronia pinnata showed antiplasmodial activity. They inhibited the malarial parasite enzyme hemoglobinase II, with IC50 values of 64 and 52 mM, respectively [168].

C-Benzylated Dihydrochalcones C-benzylated dihydrochalcones are encountered particularly in the Annonaceae family and were first isolated from Uvaria species. In most cases, these specific dihydrochalcones show strong cytotoxic activity. Dihydrochalcones isolated from U. acuminata were evaluated for their cytotoxic activity against human promyelocytic leukemia HL-60 cells by WST-8 assay. C-Benzylated dihydrochalcones, especially the new isochamuvaritin (178) and acumitin (179), together with the known uvaretin (165) and diuvaretin (169), exhibited considerable cytotoxicity. Acumitin showed stronger cytotoxic activity than uvaretin and diuvaretin, which were previously reported to have cytotoxicity against other cells. Uvangoletin, which lacks a benzyl group, was not cytotoxic. The structure of the 2-hydroxybenzylated group appeared to play an important role in the cytotoxicity against HL-60 cells [22]. The mechanism of the cytotoxicity of uvaretin, diuvaretin, and isouvaretin (168) was examined by Nakatani et al. [219]. These C-benzylated dihydrochalcones appeared to induce apoptosis against HL-60 cells. The cytotoxicity of uvaretin and diuvaretin was stronger than that of isouvaretin, which suggests that the 5ʹ-substitution of the 2-hydroxybenzyl group increased the cytotoxicity (Fig. 7.10) [219]. More recently, new C-benzylated dihydrochalcones were also found in other Annonaceae genera, in particular Melodorum siamense and Cyathostemma argenteum. The two new compounds, 20 ,40 -dihydroxy-4,60 dimethoxy-30 (200 -hydroxybenzyl)dihydrochalcone (180) and 4,20 ,40 -trihydroxy60 -methoxy-30 (200 -hydroxybenzyl)-dihydrochalcone (182), showed strong cytotoxic activity against some human tumor cell lines [18]. Bioactivity results highlighted that the C-benzylated substituent on ring A of these two natural

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7 HO

4

A

369

OCH 3

B

5'

OH

OH

2-hydroxybenzyl group in particular in position 5' on ring A is important for cytotoxicity

O

methoxy group on ring B, in particular in position 4, is important for cytotoxicity against KB and NCI-H187 cells

FIGURE 7.10 Structure-activities relationship between C-benzylated dihydrochalcones and cytotoxic activities.

products appears to be an important moiety for cytotoxic activity, while the presence of methoxy on ring B of compound (180) is essential for cytotoxicity against both KB (a subline of the ubiquitous keratin-forming tumor cell line HeLa) and NCI-H187 (NCI-lung cancer cell line) cells (Fig. 7.10). By contrast, these two compounds were inactive for antimalarial activity and for antibacterial activity against Mycobacterium tuberculosis. The new C-benzylated dihydrochalcone, 40 ,60 -dihydroxy-20 ,4-dimethoxy-50 -(200 -hydroxybenzyl)-dihydrochalcone (181), isolated from leaves and twigs of Cyathostemma argenteum, displayed anti-inflammatory activity, in particular a significant inhibitory effect on edema formation, with similar intensity to phenylbutazone [13].

Dihydrochalcone Lignans The antibacterial activity of enantiomers isolated from Populus balsamifera, iryantherin D (186) and balsacones J-L (195e197), as well as racemic balsacone M (198), was evaluated in vitro. They demonstrated antibacterial activity against Staphylococcus aureus with IC50 values ranging from 0.61 to 6 mM. The most active compound was the ()-enantiomer of balsacone L with an IC50 value of 0.61  0.02 mM. A comparison of the IC50 values for each pair of enantiomers showed that the ()-enantiomers were significantly more active than the (þ)-enantiomers. Interestingly, the isolated compounds were not cytotoxic (>10 mM) against healthy cells (WS1) [128].

Dihydrochalcone Dimers Pierotin A (200), a dihydrochalcone dimer with a methylene bridge isolated from Pieris japonica, inhibited the proliferation of murine B cells significantly in vitro [180].

Dihydrochalcone Glycosides 60 -O-rhamnosyl-(1000 / 600 )-glucopyranosyl asebogenin (thalassodendrone) (224) isolated from the Egyptian seagrass, Thalassodendron ciliatum, as well as

370 Studies in Natural Products Chemistry

the known compound asebotin (225), revealed anti-influenza A virus activity [68]. Asebotin was also encountered in Pieris japonica, with other dihydrochalcone glycosides (226, 228 and 229), demonstrating inhibition of proliferation of murine B cells. 3-hydroxy-asebotin (226) was also shown to inhibit murine T cells proliferation. Davidigenin-2ʹ-O-(6ʹʹʹ-O-syringoyl)-b-glucoside (238), a davidigenin glucoside isolated recently from Anneslea fragrans var. lanceolata, showed ABTS [2,2ʹ-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)] cation radical scavenging activity, with an SC50 value (concentration required to inhibit radical formation by 50%) of 52.6  5.5 mg/mL [181]. Phloridzin (240), the major dihydrochalcone glycoside found in leaves and immature fruits of the apple tree, has been widely studied in vitro and in vivo for its effects on various diseases, in particular diabetes. This compound is a strong inhibitor of lipid peroxidation and improves insulin sensitivity by lowering blood sugar [220]. It produces renal glycosuria and blocks intestinal glucose absorption through inhibition of the sodium-glucose symporters [221]. Phloridzin was also effective on bone resorption in an ovariectomized rat model with chronic inflammation due to its phytoestrogenic, anti-inflammatory, and antioxidant activities [222]. It played the role of a phytoestrogen, as did phloretin [145]. Phloridzin acts as a functional antioxidant in the resistance of Malus leaves to oxidative stress, together with trilobatin (241) and sieboldin (243). Sieboldin (243) is a powerful multipotent antioxidant agent, effective at preventing vasoconstriction and inhibiting advanced glycation end-products [223]. Trilobatin (241), which is also obtained from the Chinese traditional sweet tea Lithocarpus polystachyus significantly attenuates LPS-induced proinflammatory cytokine secretion in both in vitro and in vivo studies, possibly by suppressing the NF-kB signaling pathway [120]. Trilobatin also inhibits the activities of a-glucosidase and a-amylase linked to type 2 diabetes [119]. Phloretin 4ʹ-O-[3ʹ-O-galloyl-4ʹ,6ʹ-O-(S)-HHDP]-b-D-glucoside (242), 3-hydroxyphloretin 4ʹ-O-(4ʹʹ,6ʹʹ-di-O-galloyl)-b-D-glucoside (246), 3-hydroxyphloretin 4ʹ-O-[4ʹ,6ʹʹ-di-O-(S)-HHDP]-b-D-glucoside (247), 3-hydroxyphloretin 4ʹ-O-[3ʹʹ-O-galloyl-4ʹʹ,6ʹʹ-di-O-(S)-HHDP]-b-D-glucoside (248), and 3-hydroxyphloretin 4ʹ-[3ʹʹ-O-caffeoyl-4ʹʹ,6ʹʹ-di-O-(S)-HHDP]-bD-glucoside (249), dihydrochalcones glycosides isolated from Balanophora tobiracola, inhibited a-glucosidase with IC50 values of 0.8, 1.8, 1.6, 0.4, and 1.1 mg/mL, respectively, corresponding to lower concentrations than epigallocatechin-3-O-gallate, the main catechin in green tea which is known to have moderate inhibitory activity. Compounds with the 3-O-galloyl-4,6-OHHDP-glucose structure were the most potent inhibitors [163]. Some of these compounds, including 3-hydroxyphloretin 4ʹ-O-[4ʹ,6ʹʹ-di-O-(S)-HHDP]-bD-glucoside (247) and 3-hydroxyphloretin 4ʹ-O-[3ʹʹ-O-galloyl-4ʹʹ,6ʹʹ-di-O-(S)HHDP]-b-D-glucoside (248), together with 3-hydroxyphloretin 4ʹ-O-(6ʹʹ-Ogalloyl-b-D-glucoside) (244) and 3-hydroxyphloretin with its 4ʹ-b-D-glucoside (243), isolated from Balanophora harlandii, exhibited higher radical scavenging activities than ascorbic acid. These compounds have a catechol moiety as

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ring B [160]. 3-hydroxyphloretin 40 -O-b-D-glucopyranose (243) and 3-hydroxyphloretin 4ʹ-O-(6ʹʹ-O-galloyl-b-D-glucoside) (244) isolated from B. involucrata showed Beta secretase 1 (BACE 1, also known as beta-site amyloid precursor protein cleaving enzyme 1) inhibitory activities [161]. The aqueous extract made from the leaves of Citrus aurantium exhibits anticonvulsant properties with a mechanism involving N-methyl-D-aspartate and mGluRs I and II. The analysis revealed that the extract contained 0.00125 mg/mL neohesperidin dihydrochalcone (NHDC) (255) [169]. NHDC shows several biological activities. It appears to have promising antioxidative and anti-inflammatory capacities and could be used as a hepatoprotective agent. It has shown its protective antioxidant effect against CCl4-induced oxidative damage in vivo and in vitro via the direct free-radical scavenging and indirect Nrf2/ARE signaling pathway [224e225]. NHDC is also well known as an artificial sweetener [226], as are trilobatin, trilobatin 2ʹʹ-acetate (233), and phloridzin (240) [118]. NHDC is approximately 1500 times sweeter than sucrose, and trilobatin is 300 times sweeter than sugar. Stability studies have demonstrated that NHDC was stable during food processing and storage conditions [227]. Aspalathin (257) and nothofagin (258), C-glycoside dihydrochalcones occurring in rooibos tea, which is manufactured by fermenting the leaves of Aspalathus linearis, have significant therapeutic benefits against diabetic complications and atherosclerosis, by blockade of high glucose-induced vascular inflammation via inhibition of NF-kB in primary human endothelial cells [95]. Aspalathin exhibits powerful plasma sugar-lowering properties [228]. Recent in vivo assays in several diabetic model mice (obese diabetic model ob/ob mice and type 2 diabetic model KK-Ay mice) have demonstrated the potential antidiabetic effect of green rooibos extract and its metabolite aspalathin. The latter improves hyperglycemia and glucose intolerance in obese model ob/ob mice [229]. The antidiabetic effect of rooibos extract would be mediated through multiple modes of action [230]. Because of the low content of aspalathin in rooibos and its possible use in the treatment of diabetes, its synthesis has been considered [228]. A recent human bioavailability study conducted on aspalathin showed that C-glycosides would be methylated and glucuronidated in vivo in an intact form in humans [231]. Unlike NHDC, aspalathin is less stable during food processing, especially during fermentation of rooibos, and may undergo oxidation. Several oxidation products of aspalathin can be formed such as the flavanones dihydroorientin and dihydroisoorientin. The flavone analogues of aspalathin, orientin, and isoorientin, are present in rooibos [232].

Bioavailability of Dihydrochalcones As we have seen at the beginning of this part, few studies concern the bioavailability of DHCs, except for DHCs found in some well-known edible plants (apple, rooibos). After ingestion, phloridzin and phloretin 2ʹO-(2ʹʹ-O-xylosyl)glucoside can be hydrolyzed into phloretin by lactase

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phloridzin hydrolase in the small intestinal microbiota. However, phloretin 2ʹ-O-(2ʹʹ-O-xylosyl)glucoside was found to be partially stable in the small intestine and consequently much less readily deglycosylated than phloridzin. Glucuronide metabolites of phloretin may be formed after rapid deglycosylation and glucuronidation by UDP (Uridine 50 -diphospho-)-glucuronosyl transferase in the intestinal epithelium or liver. In humans, glucuronides have been detected in ileal fluid, urine, and plasma. Minor amounts of phloretin conjugated with sulfate were also found in ileal samples. In some animal models, phloretin was metabolized into 3-(4ʹ-hydroxyphenyl)propionic acid and phloroglucinol into the colon and detected in urine [208]. Some studies conducted on the bioavailability of aspalathin and nothofagin after the consumption of rooibos teas showed that the intact dihydrochalcone C-glycosides are poorly absorbed in the small intestine and are metabolized to monoglucuronide and monosulfate conjugates in the liver [233]. Moreover, an in vitro study also shows that the NHDC found in Citrus fruits would be converted into propionic acid derivatives by fecal bacteria, after first being cleaved by an intestinal rhamnosidase [208]. It is also interesting to note that some dihydrochalcones can be formed during the metabolism of chalcones or flavanones. For example, davidigenin, a dihydrochalcone with antispasmodic activity, is known to be a hydrogenated metabolite of liquiritigenin, a flavanone, which by contrast has a considerably weaker effect on mouse jejunum [212]. As reported earlier in this part, liquiritigenin and davidigenin have an excellent absorption through the human intestinal epithelial cell line Caco-2 [214]. Moreover, in human liver microsomes, during the metabolism of the corresponding chalcone isoliquiritigenin, davidigenin was identified as a minor phase 1 metabolite [215].

CONCLUSION This chapter has highlighted the distribution of dihydrochalcones in the plant kingdom. This distribution is quite heterogeneous within 46 botanical families. In 10 years, many new dihydrochalcones have been isolated, emphasizing the chemical diversity of this group of polyphenols. Numerous biological activities have also been investigated for these products. Some activities are of interest, but in vivo and clinical studies are still few and are required to prove their actual impact on human health. The pharmacokinetic and pharmacodynamics properties of DHCs must be further studied.

ABBREVIATIONS ABTS2 ADP AGE ALR2 ARE

2, 20 -azino-bis(3-ethylbenzothiazoline-6-sulphonic acid adenosine diphosphate advanced glycation end-products aldose reductase 2 antioxidant Response Element

Dihydrochalcones: Occurrence in the Plant Kingdom Chapter j 7 a7nAChR BACE1 Caco-2 CC50 CCl4 CD EC50 ED50 DHC DPPH DU145 DW HG HHDP HL-60 HPLC HSCCC IC50 KB LPS MIC NADPH NCI-H187 NF-kB NHDC NMDA NO Nrf2 PANC-1 PARP P-388 PC50 RAW 264.7 SC50 SI SMMC-7721 SPC-A-1 STAT3 SW-480 UDP WS-1 WST-8

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alpha7 nicotinic acetylcholine receptor beta-site amyloid precursor protein cleaving enzyme 1 human intestinal epithelial cell line 50% cytotoxic concentration carbon tetrachloride circular dichroism half maximal effective concentration effective dose dihydrochalcones 2,2-diphenyl-1-picrylhydrazyl androgen-independent prostate cancer cells dry weight high glucose hexahydroxydiphenic acid human promyelocytic leukemia cells High Performance Liquid Chromatography High Speed Counter Current Chromatograhy half maximal inhibitory concentration a subline of the ubiquitous keratin-forming tumor cell line HeLa lipopolysaccharide minimum inhibitory concentration reduced form of nicotinamide adenine dinucleotide phosphate NCI-lung cancer cell line nuclear factor-kappa B neohesperidine dihydrochalcone N-methyl-D-aspartate nitric oxide nuclear factor (erythroid-derived 2)-like two human pancreatic cancer cell line poly ADP ribose polymerase murine leukemia cells concentration to achieve 50% cell mortality RAW 264.7 cell line murine macrophages concentration required to inhibit radical formation by 50% selectivity Index human hepatocarcinoma cell line human lung cancer cell line signal transducer and activator of transcription three human colon adenocarcinoma cell line uridine 50 -diphosphote normal fibrobast cells (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)2H-tetrazolium, monosodium salt)

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Chapter 8

Synthetic Advances in the Indane Natural Product Scaffolds as Drug Candidates: A Review Naseem Ahmed Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India E-mail: [email protected]

Chapter Outline Introduction Synthesis Symmetrical Synthesis Asymmetric Synthesis Biological Activities Antimicrobial Activity

383 388 389 406 417 418

Antitumor Activity Concluding Remarks Abbreviations Acknowledgments References

421 428 429 429 429

INTRODUCTION Since the dawn of the 20th century, the average life expectancy of human at birth has nearly doubled due to advances in science and medicine. Plants produce numerous secondary metabolites to enable their survival, which are phytoalexins to fight infections caused by pathogens such as bacteria, fungi, etc. [1]. Therefore, chemists have explored plant and marine natural products for the new drug sources to heal or to relieve the symptoms of diseases both for infectious and metabolic disorders [2]. Many of these secondary metabolites have indane, indanone, indene, and indenol core structures. The core structures have a bicyclic ring where benzene ring fused with 5-membered cyclopentane ring called benzocyclic compound. The cyclopentane ring may be saturated or unsaturated, the functional groups mainly contain ketone and alcohol determines the class of indanes and their biological activity (Fig. 8.1). Based on Studies in Natural Products Chemistry, Vol. 51. http://dx.doi.org/10.1016/B978-0-444-63932-5.00008-5 Copyright © 2016 Elsevier B.V. All rights reserved.

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FIGURE 8.1 Bioactive indane-based products and their analogs.

these structures, various biologically active synthetic and semisynthetic scaffolds were designed and synthesized for the better drug agents. Benzo[b]fluorenes (indane molecules) have been found in many bioactive natural products in recent years as core structure, for example, in secondary metabolites prekinamycin, kinafluorenone, stealthins, kinobscurinone, seongomycin, and cysfluoretin [3] were extracted from Streptomyces murayamaensis. Stealthins A and B were also isolated from Streptomyces

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viridochromogenes that showed the radical-scavenging activities were 20e30 times higher than those of vitamin E. Stealthin C exists as core structure in antibiotic kinamycin biosynthesis and is now synthesized in the laboratory (Fig. 8.2) [4]. Many other benzofluorenes were explored as estrogen receptor antagonists. Because of their biological activities, several synthetic routes have been developed for naturally occurring benzo[b]fluorenes [5]. Fumarofines 1 and ochrobirine 2 were isolated from Fumaria officinalis [6] and Corydalis sibirica (L.), respectively. Alkaloids 3 were isolated from other species of Corydalis sp. and later synthesized using ninhydrin derivatives [7]. Proaporphine alkaloids 4 and 5 [8] and ochotensimine 6 were also isolated from plants. Compounds 1e4 and 6 were characterized as spirobenzyl isoquinoline alkaloids and compound 5 as indane-fused isoquinoline alkaloid and later synthesized using 2-indanones (Fig. 8.3) [9]. Similarly, afzeliindanone (4-[4-hydroxy-3-methoxyphenyl]-indan-1-one) 7 was isolated from the roots of Uvaria afzelii Scot Elliot (Annonaceae) and used as antibacterial drugs in the West African subregion [10]. Pterosins (A, B, C, K, etc.) 8e11 are also indanone-based sesquiterpenoids obtained from bracken fern Pteridium aquilinum. They are used in carcinogenicity and smooth muscle relaxant activities (Fig. 8.4) [11]. Resveratrol 12 was isolated first from the roots of a Japanese plant called white hellebore (Veratrum grandiflorum O. Loes) in 1940 (Fig. 8.5) [12]. Since then, it has been isolated from more than 72 different plants [13]. In vitro enzymatic reactions of resveratrol produce different dimers 13e23 and oligomers 24e35 (indane-based core structures), which possess a wide range of biological activities. For example, (
) pallidol (dimer) has been found as modulator for the estrogen receptor function (estrogenic activity). It might generate the nonstabilized radicals for the selective inhibition of

FIGURE 8.2 Benzofluorene-based natural products.

FIGURE 8.3 Indane-based spirobenzyl isoquinoline and indane-fused alkaloids.

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FIGURE 8.4 Afzeliindanone and pterosins natural products.

FIGURE 8.5 Resveratrol-based dimers and oligomers (not in absolute stereochemistry).

COX-1 activities involved in prostaglandin and various natural products (dimers and oligomers) biosynthesis. Many dimers and oligomers have been isolated from plants such as (
) isopaucifloral F, (
) quadrangularin A and (
) pallidol; laetevirenol A, laetevirenol B, parthenocissin A and pauciflorol F. Recently, a review on resveratrol-based dimers and oligomers has appeared regarding their synthesis and the biological activities [14].

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The marine organisms such as sponges (porifers) and ascidians (tunicates) are the most widely investigated species due to easy gathering and use of chemical defense since they are sessile organisms. Five new indane-based alkaloids: (þ)-trans-trikentrin A, (þ)-cis-trikentrin A 36, cis-trikentrin B 37, iso-trans-trikentrin B 38, and ()-trans-trikentrin B 39 are isolated in pure enantiomers from the marine sponge Trikentrion flabelliforme (Fig. 8.6) [2]. Later, they were synthesized and the absolute configurations were assigned as indane core structures. All have shown antimicrobial activity against the grampositive bacteria Bacillus subtilis [15]. Three other indane-based trikentrins (herbindole A 40, herbindole B 41, and herbindole C 42) are isolated from Axinella sp., an orange sponge species [16]. Their cytotoxic activity against KB cells (nasopharyngeal carcinoma) as well as appetite-inhibiting activity in fishes was observed. The total synthesis with the absolute configuration of herbindole A was established, whereas the absolute configuration of herbindoles B and C was suggested based on herbindoles A. Similarly, secondary metabolites sporolides A 43 and B 44 that differ only in the number of the chlorine are isolated from the fermentation broth of the marine actinomycete Salinispora tropica (Fig. 8.7). Their total synthesis and structure determination were established. Other significant metabolites emanating from S. tropica include salinosporamide A, a 20S proteasome inhibitor structurally related to omuralide and lactacystin was recently advanced to phase I clinical trials as a chemotherapeutic agent [17]. The indenoeindole fused compounds have shown various biological applications such as drug development in oncology (e.g., kinase inhibitors), in CNS disorders (e.g., Alzheimer disease, AD), in endocrinology (e.g., hormone replacement therapy), and oxidative stress (e.g., organ preservation). For example, melodinines 45 isolated and characterized as alkaloids from the plant Melodinus suaveolens has cytotoxic property (Fig. 8.7).

FIGURE 8.6 Marine natural products.

FIGURE 8.7 Sporolides A and B; Indenoeindole adduct 45, and Indenol derivatives 46, 47.

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Another indenoeindole based alkaloid staurosporine isolated from the bacterium Streptomyces staurosporeus has a wide range of biological activities such as antifungal, antihypertensive, and kinase ATP-binding site activity [18]. Some indenol derivatives are reported for analgesic, myorelaxation, and immunomodulatory properties [19]. For example, brazilin 46 augmented cellular immunity in multiple low-dose streptozotocin (MLD-STZ)-induced type-1 diabetic mice (Fig. 8.7). This also increased IL42 production without affecting suppressor cell activity [20]. Brx-019 47 (acetic acid 3,6a,9-triacetoxy-6,6a,7,11b-tetrahydro-indeno[2,1-c]chromen10-yl ester) derived from brazilin exhibited potential immunomodulatory properties with lower toxicity. Some indenol derivatives also exhibited platelet-activating factor antagonist activity and therefore are utilized in certain type of immunological disorders [21]. Considering the importance of indane core structures as vital building blocks in various natural products, organic molecules, heterocycles, chelating agents, and other biologically active scaffolds, I have summarized the recent synthetic advances of indane derivatives, the reactions in which one of the starting material was indane moiety and the biological applications as a potential antipathogenic candidates for infective diseases (viral, microbial, etc.) and as drugs in metabolic disorders such as HIV, cancer, cardiovascular, inflammation, and diabetes. A literature search also revealed that a review dedicated to the indane synthesis and its use in the synthesis of organic and heterocyclic compounds as drug agents is well overdue. In this review, first I introduce recent synthetic routes as symmetric and asymmetric methods to prepare indane core structures and related natural products as precursors in the synthesis of different organic and heterocyclic compounds and their biological or pharmacological applications during the last decade until September 2015.

SYNTHESIS A review is reported for the Pd-catalyzed carbonylative coupling reactions of aromatic halides and related compounds in the organic synthesis with some examples of indane-based derivatives 48 (Scheme 8.1) [22]. Many reviews are also reported focusing the application of ninhydrin (2,2-dihydroxy-1,3-indanone) derivatives in various organic and heterocyclic compounds synthesis [23], essential tools in the analysis of amino acids, peptides, and proteins (latent fingerprints on porous surfaces), chromogenic and fluorogenic properties [24]. The synthesis of C-glycoside derivatives 49 based on indane has shown various biological applications (Scheme 8.2) [25].

SCHEME 8.1 Pd-catalyzed carbonylative synthesis of indanones.

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Symmetrical Synthesis Since century, indane compounds are known for their different uses and therefore many synthetic methods have been developed in the core structure derivatization [26]. Many modern synthetic reagents and metal catalysts are also used for their syntheses. For example, spiro[benzofuran-2,2-naphthalen]-1-ones 50 have been synthesized via a three-component one-pot two-step reaction using 1-indanones, 2-hydroxyphenyl functionalized a,b-unsaturated ketones, and iodine to afford the product in upto 91% yields in 97:3 dr ratio (Scheme 8.3) [27]. 3-Aminoindenones 51 were obtained in 29e72% yield with o-iodoacetophenone and isocyanide under Pd-catalyzed reaction conditions (Scheme 8.4) [28]. Aminoindanes 52e54 are biologically active natural products (Fig. 8.8). A chiral anion phase-transfer of aryldiazonium cations was utilized to achieve highly enantioselective a-amination of indanone derivatives 55 and 56 with high level of enantioselectivity with the BINAM-derived phosphoric acids (Scheme 8.5) [29]. The synthesis of (
)-pterosin A 57 was obtained from 2-bromo1,3-dimethyl-benzene in 10% overall yield. The Suzuki-Miyaura coupling reaction of 6-bromoindanone with potassium vinyl trifluoroborate provided vinyl indanone in 90e93% yields. This further elaborated to pterosin A after reduction with LAH, selective protection of primary alcohol with TESCl, hydroboration and epoxidation of vinyl group followed by protection of primary alcohol with TIPSCl, oxidation of the secondary alcohol, and desilylation with TBAF (Scheme 8.6) [30].

SCHEME 8.2 Synthesis of C-glycoside derivatives based on indane moieties.

SCHEME 8.3 Synthesis of spiro[benzofuran-2,2-naphthalen]-1-ones.

SCHEME 8.4 Synthesis of 3-aminoindenones.

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FIGURE 8.8 Biologically active aminoindanes.

A comprehensive overview regarding isolation, biosynthesis, and biological activity of natural products taiwaniaquinoids 58e61 (indane molecules) obtained from Taiwania cryptomerioides in 1995 is discussed (Fig. 8.9). A total synthesis of (
)-taiwaniaquinol B 61 is reported via a domino intramolecular FriedeleCrafts acylation/carbonyl a-tertealkylation reaction (Scheme 8.7) [31]. The carbocyclization reaction of substituted 3-en-1-yn-1-yl dibenzene with 10 mol% of Pd(OAc)2 in CF3COOH:DCM (4:1) mixture afforded 2-trifluoromethyl-1-methylene-3-phenylindene derivatives 62 in good yield within hours at room temperature (Scheme 8.8) [32]. 1-Indanol derivative 63 was prepared as major diastereomer from cinnamic acid derivatives using Stryker’s reagent (Scheme 8.9) [33]. A tandem oxidative acetoxylation and carbocyclization of arylallenes (R ¼ H, 2-Me, phenanthren-9-yl, etc.; R1 ¼ R2 ¼ Me; R1 ¼ Me, R2 ¼ Et; R1,

SCHEME 8.5 Synthesis of biologically active 2-aminoindanes.

SCHEME 8.6 Synthesis of (
)-pterosin A.

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FIGURE 8.9 abeo-Abietanes (taiwaniaquinols) natural products.

SCHEME 8.7 Total synthesis of (
)-taiwaniaquinol B.

SCHEME 8.8 Synthesis of 2-trifluoromethyl-1-methylene-3-phenylindenes.

SCHEME 8.9 Synthesis of 1-Indanone and 1-Indanol derivatives.

R2 ¼ cyclohexyl) was reported to afford indenes 64 using Pd(OAc)2 and p-benzoquinone (Scheme 8.10) [34]. A Pd-catalyzed intramolecular C(sp3)eH arylation of hetero/aryl chlorides gave diastereoselective indanes 65 and 66 and 1-indanones 67. When several types of C(sp3)eH bond were present in the substrate, the arylation occurred regioselectively at primary CeH bonds compared to secondary or tertiary

SCHEME 8.10 Pd-catalyzed synthesis of indenes.

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positions. In addition, the presence of several primary CeH bonds, selectivity trends correlate with the size of the palladacyclic intermediate with 5-membered rings being favored over 6- and 7-membered rings (Scheme 8.11) [35]. Highly diastereo- and enantioselective indanes 68e70 were synthesized via intramolecular arylation of primary and secondary C(sp3)eH bonds using binepine ligands. It was shown that a ferrocenyl P-substituent on the ligand allows achievement of high stereoselectivities in combination with K2CO3 for the arylation of primary CeH bonds at 90 C temperature with 1e2 mol% Pd/ 2e3 mol% ligand loading. The selection for the major enantiomer was traced due to weak attractive interactions between the phosphine ligand and the substrate by DFT (PBE0-D3) calculations (Scheme 8.12) [36]. A preparative scale synthesis of functionalized 2-arylindanes 71e74 has been developed via Lewis acidemediated ring closure of stilbenyl methanols followed by nucleophilic transfer from trialkylsilyl reagents in moderate to high yields and high diastereoselectivity. The solvent as well as the nucleophile played an important role in determining the types of product arising from either nucleophilic addition (indanes) or loss of a proton beta to the indanyl-

SCHEME 8.11 Pd-catalyzed intramolecular syntheses of indanes and indanones.

SCHEME 8.12

Synthesis of diastereo- and enantioselective indanes with binepine ligands.

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type carbocations (indenes 74). Electron-donating groups on the fused aromatic ring (e.g., Y and Z ¼ OMe) or the presence of electron-withdrawing groups (e.g., NO2) on the nonfused aromatic ring facilitates the cyclization. In contrast, the presence of electron-donating groups (e.g., OMe) on the nonfused aromatic ring impedes the reaction (Scheme 8.13) [37]. In the presence of a triazole carbene catalyst alone, no reaction of 2(aroylvinyl)aryl aldehydes was observed. However, the combination of triazole carbene and 4-methoxyphenolate efficiently catalyzed the dimerization of 2(aroylvinyl)aryl aldehydes to proceed through a benzoineMichaeleMichael reaction cascade producing 6-aroyl-5-(aroylmethyl)-11a-hydroxy benzo[a]fluoren-11-ones 75 as the sole diastereomers in 55e73% yield (Scheme 8.14) [38]. Rh(II)-catalyzed tandem reactions were also developed for the synthesis of functionalized indanones 76 and 77 in highly diastereo- and regioselective fashion from 2-triazole-benzaldehydes and 2-triazole-alkylaryl ketones in good yield in water or methanol solvent (Scheme 8.15) [39].

SCHEME 8.13 Substituted 2-arylindanes and 2-arylindenes synthesis.

SCHEME 8.14

Synthesis of 6-aroyl-5-(aroylmethyl)-11a-hydroxybenzo[a]fluoren-11-ones.

SCHEME 8.15 Synthesis of indanone derivatives.

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SCHEME 8.16 Michael addition and Heck cyclization.

SCHEME 8.17 Synthetic application of Tandem MichaeleHeck reaction.

The phosphine-catalyzed Michael addition followed by Pd-catalyzed Heck cyclization gave the highly functionalized alkylindenes, indanes, and indanones 78 in high yields with good stereoselectivity (some cases exclusively the Z-isomer) (Scheme 8.16). The products have been used in the formal synthesis of sulindac 79, a nonsteroidal antiinflammatory drug (Scheme 8.17) [40]. The Nazarov-type cyclization was used for the synthesis of polysubstituted 1-indanones 80 and 81 from 1,4-enediones where AlCl3 was found the most efficient promoter for the reaction in EtNO2 solvent at 25 C to afford the product in 96% yield with 6:1 dr (Scheme 8.18) [41]. Similarly, 2-trifluoromethylated indanones 82 were synthesized in one-pot via FriedeleCrafts alkylation or tandem FriedeleCrafts alkylation cycloacylation of arenes and phenols with 2-(trifluoromethyl)acrylic acid in the presence of trifluoromethane sulfonic acid (superacid) in good yield (Scheme 8.19) [42]. In the presence of RhCl(PPh3)3 (Wilkinson’s catalyst), phenylcyclobutanes (X ¼ 2-pyridinyl methylene) underwent ring expansion and rearrangement in p-xylene at 150 C to yield indane derivatives 83. Moreover, when the reaction

SCHEME 8.18 Synthesis of polysubstituted 1-indanones.

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SCHEME 8.19 Synthesis of trifluoromethylated indanones.

was performed in mesitylene at 170 C for 4 h, a different result was obtained: indane with E geometry 84 and indene 85 were formed in 96% yield in the ratio of 7:3. However, arylcyclobutanones (X ¼ N) underwent imine formation 84 and 85 with 2-aminopyridines; ring expansion and rearrangement of the intermediate imines took place followed by hydrolysis to yield indanone derivatives in 52e79% in p-xylene at 150 C in 23 h followed by acid hydrolysis (Scheme 8.20) [43]. In the presence of a tertiary amine-thiourea organocatalyst, a series of 2-arylidene-1,3-indanediones with tert-but-4-mercapto-2-butenoates were afforded chiral spiro[indane-1,3-dione-tetrahydrothiophenes] 86 in 75e99% yield with 89e99% ee and 75.4:24.6 to 97.1:2.9% dr (Scheme 8.21) [44]. Further, organocatalytic intramolecular aldolization, ortho-diacylbenzenes gave highly functionalized 3-hydroxyindanones 87 in highly transselective products using metal salt of amino acid. This method allows an easy access to the strained spirocyclic-3-hydroxyindanones, which are related to a number of natural product frameworks (Scheme 8.22) [45]. Densely substituted indenes 88 were achieved from BayliseHillman acetates under two-step protocol via treatment with DABCO followed by reaction with alkyl 3-oxobutanoates in the presence of K2CO3 and the intramolecular FriedeleCrafts cyclization of the resulting keto-diesters with TiCl4 (Scheme 8.23) [46].

SCHEME 8.20

RhCl(PPh3)3 catalyst in the synthesis of indanes.

SCHEME 8.21 Chiral spiro[indane-1,3-dione-tetrahydrothiophene] synthesis.

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SCHEME 8.22 Synthesis of 3-hydroxyindanones.

SCHEME 8.23 Synthesis of densely substituted indenes.

Under superacid-promoted one-pot reaction, indanones 89 and 90 were afforded by dual CeC bond formation between arylisopropyl ketones and benzaldehydes at 50 C. Under the same conditions, acetophenones and benzaldehydes gave the chalcones, an aldol condensation product (Scheme 8.24) [47]. Aromatic tert-butyl sulfinyl ketimines bearing a suitable Michael acceptor at the ortho-position readily undergo an intramolecular conjugate addition to afford aminoindane derivatives 91 in good yield and diastereoselectivity (Scheme 8.25) [48]. A region-divergent synthesis of functionalized indenes 92 and 1-indanones 93 were obtained in good yield via Pt-catalyzed Rautenstrauch/TsujieTrost reactions from propargyl carbonate under one-pot reaction (Scheme 8.26) [49]. The coupling reaction of alkynes and benzaldehydes in the presence of In(OTf)3 and DPP ligand gave 2,3-disubstituted indanones 94 in poor yield and diastereoselectivity via tandem [2 þ 2] cycloaddition and Nazarov reactions.

SCHEME 8.24 Superacid-promoted 1-indanone synthesis.

SCHEME 8.25 Synthesis of aminoindanes.

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SCHEME 8.26 Pt-catalyzed Rautenstrauch/TsujieTrost reaction.

However, a combination of In(OTf)3 and benzoic acid was found to synergistically promote the coupling of alkynes and acetals to form 2,3-disubstituted indanones in excellent yield and diastereoselectivity under the same conditions (Scheme 8.27) [50]. N-sulfonyl aromatic imines and 1,3-dienes proceeded via a direct CeH functionalization under [3 þ 2]-annulation to give 1-aminoindane derivatives 95 in high yield with high regio- and stereoselectivities. In this reaction, Ir-complex coordinated with 1,3-diene to get aryliridium (I) intermediate from the aromatic aldimine and an iridium(I) acetate species via a concerted metalationdeprotonation pathway for high catalytic activity (Scheme 8.28) [51]. Indane-1,3-dione derivatives 96 were synthesized through a Pd(0)catalyzed reaction incorporatingebutylisocyanide. Applying this protocol, indenopyrazole derivatives can also be easily synthesized in high yields in one-pot process (Scheme 8.29) [52]. Under the Hooker oxidation condition (H2O2 and Na2CO3), Hooker intermediates (i) and (ii) were obtained from lapachol via benzilic acid rearrangement. They are further converted into different indane derivatives 97e100 under given reaction conditions (Scheme 8.30) [53].

SCHEME 8.27 [2 þ 2] cycloaddition and Nazarov reactions for 1-indanone.

SCHEME 8.28 Synthesis of 1-aminoindane derivatives.

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SCHEME 8.29

Synthesis of indane-1,3-dione derivatives.

SCHEME 8.30 The Hooker oxidation reaction.

Indenones 101 and indanones 102 were synthesized in modest to good yield through one-pot SuzukieMiyaura cross-coupling followed by acidcatalyzed cyclization (Scheme 8.31) [54]. The use of IBiox N-heterocyclic carbene (NHC) ligands 103 has restricted flexibility and high steric demand in the reaction. It might be the reason for getting high levels of asymmetric induction in the Cu-free allylic alkylation of cinnamyl bromide for the indane derivatives (Scheme 8.32) [55]. In the synthesis of 1- and 3-substituted 2-methoxyindenes by the carboalkoxylations of 2-ethynylbenzyl ethers, the former 104 is obtained effi˚ , whereas the ciently with P(t-Bu)2(o-biphenyl)AuCl/NaBARF in DCM/MS4A latter 105 is produced preferably with P(t-Bu)2(o-biphenyl) AuCl/AgNTf2 in predried DCM as a major product. The products 106 and 107 were obtained as minor in both the cases. They are subjected to ozonolysis to afford two distinct carbonyl products 108 and 109 (Scheme 8.33) [56]. An acid-catalyzed rearrangement of tetrahalo-7,7-dimethoxybicyclo[2.2.1] heptenyls gave the substituted indenones. This domino reaction involves

SCHEME 8.31 Synthesis of indenone and 3-hydroxyindanone.

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SCHEME 8.32 IBiox N-heterocyclic carbene (NHC) ligands for the indane synthesis.

SCHEME 8.33

1- and 3-substituted 2-indenyl ethers synthesis and their ozonolysis.

dehydration, olefin isomerization, ketal hydrolysis [3,3],-sigmatropic rearrangement and dehydrohalogenation reactions. The resultant vicinal dihaloolefin moiety of indenones was utilized to transform into ninhydrin derivatives 110 using Ru(III)-catalyzed oxidation (Scheme 8.34) [57]. Similarly, a superacid-promoted cyclodehydrations led to the functionalized indanes 111 and 112. The indenes are also synthesized having

SCHEME 8.34 Synthesis of indenones and ninhydrin derivatives.

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SCHEME 8.35 Superacid-promoted cyclodehydrations.

N-heterocyclic substituents such as pyridyl, imidazolyl, and pyrimdyl derivatives under the same conditions (Scheme 8.35) [58]. Highly functionalized 3-aryl-2-hydroxy-2,3-dihydro-1H-inden-1-ones 113 were obtained in 81e95% yields by the ring opening of chalcone epoxides with indium(III) chloride catalyst through intramolecular FriedeleCrafts alkylation at room temperature (Scheme 8.36) [59]. Similarly, irradiation of substituted aromatic epoxy ketones with 450-W UV lamp led to the highly substituted indanones 114 formation through a photochemical epoxy rearrangement and 1,5-biradical cyclization tandem reaction (Scheme 8.37) [60]. Highly functionalized indanones 115 were obtained in moderate to high yield under Pd(0)-catalyzed intramolecular acylcyanation of alkenes from

SCHEME 8.36 Indium(III) chloride catalyzed ring opening of chalcone epoxides.

SCHEME 8.37 Photochemical epoxy rearrangement and 1,5-biradicals cyclization.

SCHEME 8.38 Synthesis of highly functionalized indanones.

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a-imino nitriles in the presence of Lewis acid (ZnCl2). The reaction tolerates different substitutions on aromatic ring including electron-donating and electron-withdrawing groups (Scheme 8.38) [61]. Indenamides 116 were synthesized under CuI-catalyzed reductive acylation of ketoximes with NaHSO3 as the terminal reductant in high yield (Scheme 8.39) [62]. Under one-pot condition, b,b-disubstituted indanones 117 and 118 were synthesized using indium(III) triflate catalyst via tandem Nakamura additionehydroarylationedecarboxylation reactions (Scheme 8.40) [63]. A carbatripyrrin intermediate was prepared from indene and 2-pyrrolecarbaldehyde in three steps with 50% overall yield that on reaction with pyrroledialdehydes and 2,5-furandicarbaldehyde in the presence of TFA gave good yields of carbaporphyrins 120 and 121 and oxacarbaporphyrin 119, respectively (Scheme 8.41) [64].

SCHEME 8.39 Synthesis of aminoindenamides.

SCHEME 8.40 Synthesis of b,b-disubstituted indanones.

SCHEME 8.41 Synthesis of carbaporphyrins and oxacarbaporphyrin.

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SCHEME 8.42 Synthesis of spirocyclic lactams.

Spirocyclic lactams 122e125 were obtained from b-ketocarboxylic acids via one-pot cascade reactions involving Curtius rearrangement and intramolecular nucleophilic addition (Scheme 8.42) [65]. An efficient reductive cross-coupling of indanones 126 were observed with SnCl4eZn complex in THF within 5 min to get indane olefins in 55e86% yield at reflux temperature (Scheme 8.43) [66]. Alkylidene cycloalkanones were converted to 2-aryl-3-bromofurans fused benzocycloalkanes 127 in two steps. First, it involves Mg-mediated diastereoselective dibromocyclopropanation of alkylidene cycloalkanone followed by acidic alumina-mediated regioselective ring expansion of the cyclopropyl ketone via Cloke-Wilson rearrangement (Scheme 8.44) [67].

SCHEME 8.43 Reductive cross-coupling of indanones.

SCHEME 8.44 Synthesis of 2-aryl-3-bromofurans fused benzocycloalkanes.

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SCHEME 8.45 Synthesis of trifluoromethyl-aminoindanone derivatives.

SCHEME 8.46

Synthesis of trans-3-(4-bromophenyl)-2-hydroxy-2,3-dihydroindan-1-one.

The reaction between 1-indanones and (S)-N-tert-butanesulfinyl-(3,3,3)trifluoroacetaldimine occurred in the presence of catalytic amounts of LDA with complete stereochemical outcome offering reliable and generalized access to biologically relevant trifluoromethyl-aminoindanone derivatives 128. The products can easily be isolated in diastereomerically pure forms after washing the crude reaction mixture with hexanes (Scheme 8.45) [68]. Highly efficient one-pot intramolecular FriedeleCrafts alkylation of chalcone epoxides provided regioselective products as trans-3-aryl-2-hydroxy1-indanones 129 in 76e98% yield and upto 99.9% ee in the presence of SnCl4 or TiCl4 catalysts under mild conditions (Scheme 8.46) [69]. Generally, boron tribromide (BBr3) is used as the demethylating agent. However, BBr3 is also useful for the CeC bonds formation in cyclic ketones such as indanones 130. Methoxy-containing ketones have shown the selective CeC bonds formation instead of demethylation of the methoxy groups (Fig. 8.10) [70]. Under Biginelli reaction condition, benzoquinazolin-2-ones 131 was obtained in excellent yield using 1-indanone, aldehyde, and urea/thiourea in the

FIGURE 8.10 BBr3-mediated bisindene synthesis.

SCHEME 8.47 Synthesis of benzoquinazolin-2-ones.

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FIGURE 8.11 Indeno-thiazepine.

SCHEME 8.48 Synthesis of substituted ninhydrins.

presence of catalyst [1-methyl-3-(4-sulfobutyl)imidazolium-4-methylbenzene sulfonate] (ionic liquid) within 1.5 h (Scheme 8.47) [71]. Tetracyclic indeno-1,5-thiazepines 132 were synthesized through one-pot cyclocondensation of indaones, aromatic aldehydes, and 2-aminothiophenol using tetrachlorosilane (SiCl4) as a promoter in CH2Cl2 at ambient temperature (Fig. 8.11) [72]. Also, microwave (MW)-assisted SeO2 oxidation afforded the substituted ninhydrins 133 from indan-1-ones to access to indeno[1,2-b]indoles substituted on the A ring in good yields (Scheme 8.48) [73]. 1,2-Indanedione derivatives 134 and 135 were synthesized in good yield from substituted 1-indanones in a four-step sequence for the detection of latent fingerprints on paper substrates (Scheme 8.49) [74]. Indene-indole fused heterocycles 136 were obtained in one-pot threecomponent reaction using heterocyclic ketene aminals, 1H-indene-1,3(2H)dione, and dicarbonyl compounds isatins or acenaphthenequinone in an

SCHEME 8.49 Synthesis of 1,2-indanediones.

SCHEME 8.50 Synthesis of spiro-indenones.

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ethanol/water medium catalyzed by p-TSA at reflux to afford excellent product yields (Scheme 8.50) [75]. Regio- and diastereoselective synthesis of cyclic fused-isoxazolines 137 and 138 has been accomplished by 1,3-dipolar cycloaddition of 3-methylindan-1-one enamines or 3-phenylindan-1-one enamines and arylnitrile oxides in good yields under mild conditions (Scheme 8.51) [76]. Highly functionalized 2-azafluorenones 139 were synthesized via a threecomponent domino reaction involving C1-aryl acylation, C3-thiolation, and C4-cyanation. This domino reaction enables successful assembly of three new sigma bonds CeC, CeS, and CeN in one-pot reaction within 15e30 min under mild condition (Scheme 8.52) [77]. 2,3-Dihydro-1H-indene-1-methanamines 140 were afforded in 50.9e57.9% yield from the 4-nitro-3-phenylbutanoic acid in four steps under mild conditions (Scheme 8.53) [78]. Under multicatalytic MBHeMichael tandem reaction, asymmetric oxaspirocyclic indanones 141 were afforded from ninhydrin, nitroolefins, and aldehydes, followed by successive iodocyclization that gave the fused chiral natural product mimics (Scheme 8.54) [79]. Rubriflordilactone B (indane moiety) has promising anti-HIV activity. The synthesis of its core structures 142 and 143 follow a radical 1,5-H abstraction/ cyclization and vinylogous Mukaiyama aldol reaction, which successfully

SCHEME 8.51 Synthesis of cyclic fused isoxazolines.

SCHEME 8.52 Synthesis of functionalized 2-azafluorenones.

SCHEME 8.53 Synthesis of 2,3-dihydro-1H-indene-1-methanamines.

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SCHEME 8.54 Synthesis of oxa-spirocyclic indanones.

SCHEME 8.55 Synthesis of tricyclic core structures.

established the array of five continuous stereogenic carbon centers in the target molecule (Scheme 8.55) [80]. The use of Cu-doped ZnO nanocrystalline powder (10 mol%) has found to be efficient catalyst in the one-pot multicomponent synthesis of substituted indeno[1,2-b] pyridines 144 from 1,3-indandione, propiophenone/acetophenone derivatives, aromatic aldehydes, and ammonium acetate in ethanol/H2O at room temperature in high yield (Scheme 8.56) [81]. Under Mannich-type addition reactions, 1-indanone-derived enolates and butanesulfinyl ketimines afforded indanol 145 in up to 98% yields and >99:1 dr. The compounds represent a new type of biologically relevant b-amino ketone derivative bearing quaternary stereogenic carbon that are further converted to the corresponding b-amino ketones and b-amino alcohols possessing three consecutive stereogenic centers (Scheme 8.57) [82].

Asymmetric Synthesis Natural products generally exist as a single enantiomer as a consequence of the inherent chirality of the enzymes that produce them. Further, enzymes, receptors,

SCHEME 8.56 Synthesis of indenopyridine.

SCHEME 8.57

Chiral b-amino ketones and b-amino alcohols.

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SCHEME 8.58 Synthesis of a uricosuric drug (þ)-indacrinone.

and other binding sites in biological systems recognize compounds with a specific chirality. Enantiomers of achiral molecule can display different biological activities and in extreme cases, one enantiomer is an active drug and the other exhibits fatal toxicity. As a consequence of the FDA’s 1992 directive on stereoisomers, studies on therapeutic profiles of single enantiomers of several drugs were launched. Therefore, the pharmaceutical companies have demonstrated the viability of asymmetric phase transfer reactions in the large-scale preparation of drugs. Interestingly, the first landmark example in the domain of chiral phase transfer organocatalysis was developed by Merck as early as in 1984 for the synthesis of a uricosuric drug (þ)-indacrinone (MK-0197) 146 in w75 Kg (Scheme 8.58). Since then, a cost-efficient product for enantiomeric drugs is searched using different chiral phase transfer organocatalysts [83]. A recent review is cited for the homogeneous catalysts and importance of ligands in the asymmetric synthesis for the enantiomerically enriched products in the pharmaceutical, agrochemical, fragrances, and flavor industries with some examples of indane derivatives 147 and 148 (Scheme 8.59) [84]. A report is also available on optically active 2-substituted 1-indanones 149 using amino alcoholemediated asymmetric domino reactions of a-disubstituted ketones, b-ketoesters, enol carbonates, a,b-unsaturated ketones, a silylenol ether, or a b-keto acid under UV-light irradiation or Pd catalysis (Scheme 8.60) [85]. Similarly, a malenantioselective synthesis of (þ)- and ()-pauciflorol F 150 has been achieved using an oxazolidinone-controlled torquoselective Nazarov reaction (Scheme 8.61) [86].

SCHEME 8.59 Homogenous catalysts and ligands in the asymmetric synthesis.

SCHEME 8.60 Synthesis of optically active 2-substituted 1-indanones.

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SCHEME 8.61 Indanone-based natural products.

The dihydroindene ring is a structural subunit found in a large number of naturally occurring compounds with antitumor activity such as “secaloside A” 151 (Fig. 8.12). In addition, several synthetic compounds similar skeleton showed a broad range of biological activities. For example, hydroxylated compound SB-217242 152 is a potent antagonist of endothelin receptors. The core structures of dihyroindenes 153 and 154 were synthesized by [3 þ 2] cycloaddition reaction using catalyst SnCl4 (Scheme 8.62) [87]. The cycloisomerization reactions of allenes bearing cyclic acetal, thioacetal, and dithioacetal subunits when triggered either by the catalytic action of AgSbF6 or by one equiv. of CF3COOH gave four different classes of indeno-fused 1,4-dioxa, oxathia, and dithia heterocycles 155 in most cases as a single diastereomer. Acyclic acetals and dithioacetals were also found suitable starting materials in these transformations yielding 1,2-disubstituted indenes 156 and 157 (Scheme 8.63) [88].

FIGURE 8.12 Natural products with dihyroindenes.

SCHEME 8.62

[3 þ 2] cycloaddition reactions.

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SCHEME 8.63 Synthesis of indeno-fused 1,4-dioxa, oxathia, and dithia heterocycles.

SCHEME 8.64 Synthesis of functionalized indenes.

Both Lewis and Brønsted acids efficiently catalyzed the (3 þ 2)-annulation reaction of donoreacceptor cyclopropanes and alkynes to afford functionalized indenes 158, displaying intense visible emission (lmax ¼ 430 nm, F ¼ 0.28e0.34) (Scheme 8.64) [89]. Similarly, functionalized spirocyclohexane indane-1,3-diones 159 were obtained from genitroketones and 2-arylidene-1,3-indanedione using a chiral squaramide-catalyzed highly diastereo- and enantioselective cascade Michael/ aldol reaction in 57e97% yield with the formation of three stereogenic centers in up to >20:1 dr and 86% ee (Scheme 8.65) [90]. In the presence of bis(trifluoromethane)sulfonamide, the reaction between benzylic alcohols and alkenes gave indane derivatives 160 with high stereoselectivity. In general, the reaction with 1,2-disubstituted and trisubstituted alkenes afforded indane derivatives through a [3 þ 2] annulations reaction (Scheme 8.66) [91]. 5-Endo-trig cyclizations are generally considered to be kinetically unfavorable as described by Baldwin’s rules. Therefore, the observation of such reactions under kinetic control is rare. A highly enantio- and diastereoselective route to complex indanes 161 bearing all-carbon quaternary stereogenic centers via a 5-endo-trig cyclization catalyzed by a chiral ammonium salt is obtained (Scheme 8.67). Through computation, the preference for the formally disfavored 5-endo-trig Michael reaction over the formally favored 5-exo-trig

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SCHEME 8.65 Synthesis of spirocyclohexane indane-1,3-diones.

SCHEME 8.66 Synthesis of indane derivatives with high stereoselectivity.

SCHEME 8.67 Synthesis of highly enantio- and diastereoselective indanes.

Dieckmann reaction is shown to result from thermodynamic contributions to the innate selectivity of the nucleophilic group that outweighs the importance of the approach trajectory as embodied by Baldwin’s rules [92]. The spirocyclic structural motif 162 has been used as suitable precursor to fenestrane compounds. These compounds were obtained using 1,3-indanone, a,b-unsaturated nitrocompound and DABCO in EtOH at 80 C in 45e80% yield and 95:5 dr (Scheme 8.68) [93]. A convergent synthesis of natural products 163 and 167 such as (
)-brazilin 163 and (
)-brazilane 164 has been achieved from 3,4-dimethoxy benzaldehyde via Pd(II)-catalyzed intermolecular/intramolecular FriedeleCrafts cyclization and Lewis acidesupported alkylation reactions. A tetracyclic-substituted indane intermediate is employed to furnish the desired two molecules in good to excellent yield where Pd(OH)2 has played a crucial role in the total synthesis of (
)-brazilane (Fig. 8.13) [94].

SCHEME 8.68 Synthesis of spirocyclic 1,3-indanones.

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FIGURE 8.13 Biologically active natural products.

A catalytic Michael addition reaction promoted by chiral bifunctional organocatalysts afforded g-nitro-a-cyanoketones 168 in excellent diastereoselectivities (up to syn/anti >99/1) and excellent enantioselectivities (upto 99% ee) from a-cyanoketones and nitroalkenes at 20 C to 40 C under mild reaction conditions (Scheme 8.69) [95]. A combination of 9-amino-(9-deoxy)epidihydroquinidine and salicylic acid promoted the reaction of 1-indanones with dibenzoyl peroxide to afford chiral 1-oxo-2,3-dihydro-1H-inden-2-ylbenzoates in high yield and enantioselectivity. Furthermore, treatment with NaBH4 gives easy access to enantio-enriched 1,2-diols 169 and 170 in high yield without any loss of stereoselectivity (Scheme 8.70) [96]. Baeyer-Villiger monooxygenases (M446GPAMO) have been used in the oxidation of racemic 1-indanones to obtain 3-substituted 3,4-dihydroisocoumarins 171 in high yield. The optical purity was determined through regioselective dynamic kinetic resolution processes (Scheme 8.71) [97].

SCHEME 8.69 Synthesis of g-nitro-a-cyanoketones.

SCHEME 8.70

Synthesis of chiral 1-oxo-2,3-dihydro-1H-inden-2-ylbenzoates.

SCHEME 8.71 Enzymatic resolution of (
)-2-alkyl-1-indanone by M446GPAMO.

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SCHEME 8.72 Synthesis of indane-based fluorocompounds.

A review is reported recently showing the importance of indane-based fluorocompounds 172 and 173 in the agrochemical, pharmaceutical, and material industries (Scheme 8.72) [98]. An enantioselective protonation of silylenol ethers of indanones by Au(I) BINAP complex gave a highly diastereoselective McMurry-coupled products 174 and 175 up to 78% yields and 85e98% ee (Scheme 8.73) [99]. A Michael addition of racemic indanone carboxylates to vinyl selenone catalyzed by C6-hydroxylcinchona derivatives is the key step of a synthetic sequence for a practical access to highly enantio-enriched (up to 98% ee) polycyclic pyrrolidines 176 and 178 (Fig. 8.14) bearing contiguous tertiary and quaternary stereocenters (Scheme 8.74) [100]. A domino reaction of (E)-2-(aryl)-2,3-dihydro-1H-inden-1-ones and 1,4-dithiane-2,5-diol in the presence of triethylamine in water afforded stereoselective 2-(aryl)-4-hydroxy-4,5-dihydro-2H-spiro[indene-2,3-thiophen]-1(3H)ones 179. The reaction proceeds via the generation of 2-mercaptoacetaldehyde

SCHEME 8.73 Enantioselective indanone protonation and McMurry reaction.

FIGURE 8.14

Polycyclic pyrrolidine molecules.

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SCHEME 8.74 Asymmetric synthesis of polycyclic pyrrolidines.

SCHEME 8.75 Synthesis of 40 ,5-dihydro-20 H-spiro[indene-2,30 -thiophen]-1(3H)-one.

from 1,4-dithiane-2,5-diol followed by Michael additioneintramolecular aldol sequence with CeC and CeS bond formations and the creation of three contiguous stereocenters in a one-pot reaction (Scheme 8.75) [101]. Highly functionalized indanes 180 and 181 were afforded using novel organocatalysts A and B. The optimal yield (64e87% with 97e99% ee) was ˚ MS (40 mg) in obtained using 20 mol% of organocatalysts (A and B), 4A toluene at 40 C (Scheme 8.76) [102]. Reaction of 4-aryl-1,1,1-trifluorobut-3-en-2-ols (CF3-allyl alcohols) with arenes under activation with anhydrous FeCl3 or FSO3H afforded 1-trifluoromethylated indane derivatives 182 and 183. The formation of the products strongly depends on nucleophilicity of arenes and electrophilicity of cationic intermediates (generated from CF3-allyl alcohols) in the reaction conditions. Benzene, anisole, veratrole, and ortho-xylene led exclusively to CF3-alkenes with trans-configuration. More p-donating polymethylated arenes (pseudocumene, mesitylene) afford only CF3-indanes with predominant cis-orientation of substituents at positions 1- and 3-indane ring. However,

SCHEME 8.76 Synthesis of optically active (1-indanylmethyl)amine compounds.

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SCHEME 8.77

Synthesis of 1-trifluoromethylated indanes.

meta- and para-xylenes have shown a moderate behavior due the formation of both CF3-alkenes and/or CF3-indanes (Scheme 8.77) [103]. Similar reaction of 4-aryl-1,1,1-trifluorobut-3-en-2-ones ArCH]CHCOCF3 (CF3-enones) with arenes in excess of Brønsted superacids (TfOH, FSO3H) is reported to give stereoselectively, trans-1,3-diaryl-1-trifluoromethylindanes 184 in 35e85% yields. These products were investigated as potential ligands for cannabinoid receptors CB1 and CB2 types in good affinity for both receptors with a sixfold selectivity toward the CB2 receptor with no appreciable cytotoxicity toward SHSY5Y cells (Scheme 8.78) [104]. Monofluorinated silylenol ethers (activated by nucleophilic tertiary amine) and isatins produced highly functionalized chiral products with a highly stereoselective CeF bond via Mukaiyama-aldol reaction. Further, reduction of intermediate ketone gave hydroxyoxindoles 185 and 186 bearing two adjacent tetrasubstituted carbon stereocenters (Scheme 8.79) [105]. Substituted indane derivatives were synthesized via Lewis acidecatalyzed Nazarov-type cyclization and used in the total synthesis of mutisianthol and epi-mutisianthol 187 in a four-step linear sequence (Scheme 8.80) [106].

SCHEME 8.78 Synthesis of 1,3-diaryl-1-trifluoromethylindanes.

SCHEME 8.79 Synthesis of fluoro-hydroxyoxindoles.

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SCHEME 8.80 Total synthesis of mutisianthol and epi-mutisianthol.

An atom-economic route to benzo[f]-1-indanones has been developed from gem-dialkylthiotrienynes by intramolecular annulations. The chemoselectivity of the intramolecular cyclizations allows the divergent synthesis of the functionalized benzo[f]-1-indanones 188 in good to excellent yields (Scheme 8.81) [107]. An aminocatalytic asymmetric DielseAlder reaction of 2,4-dienals and 1-indenones (in situ generated from 3-bromo-1-indanones) produced highly fused indane products 189 with multiple chiral centers followed by the cascade N-heterocyclic carbene-mediated benzoin condensation (Scheme 8.82) [108]. A Pd-catalyzed intramolecular asymmetric allylic alkylation reaction has been developed to afford 2,3-disubstituted indanones 190e192 with high diastereo- and enantioselectivities via “hard” carbanion intermediates. These products were used for the synthesis of many core structures of the natural products (Scheme 8.83) [109]. Aminoindanols are present in several natural products and biologically active compounds such as HIV protease inhibitors 193 and rasagiline derivatives with anti-Parkinson activity. The synthesis of rasagiline core structure 194 is reported in excellent yields (Scheme 8.84) [110]. Asymmetric synthesis of the melatonin receptor agonist ramelteon 195 has been achieved via a tandem CeH activationealkylation/Heck reaction and subsequent highly diastereoselective asymmetric Michael addition in 19% overall yield in 15 linear steps (Scheme 8.85) [111]. Lipase Pseudomonas cepacia catalyzed acylation of (
)-2-(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b] furan-6(2H)-one using vinyl

SCHEME 8.81

Synthesis of functionalized benzo[f]-1-indanones.

SCHEME 8.82 Synthesis of highly fused indanes.

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SCHEME 8.83

Asymmetric synthesis of 2,3-Disubstituted indanones.

SCHEME 8.84 Enantioselective synthesis of 3-amino-1-indanol derivatives.

acetate as the acyl-donor in acetone afforded ()-(R)-2-acetoxy-2(methyl)-7,8-dihydro-1H-indeno[5,4-b]furan-6(2H)-one and (þ)-(S)-2(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b]furan-6(2H)-one with high enantiomeric excess. Enantiomerically pure 2-(hydroxymethyl)-7,8-dihydro1H-indeno[5,4-b]furan-6(2H)-ones 196 and 197 are useful intermediates for the preparation of Ramelteon drug for the treatment of insomnia (Scheme 8.86) [112].

SCHEME 8.85 Ramelteon synthesis.

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SCHEME 8.86 Enantioselective synthesis of substituted indeno[5,4-b]furan-6(2H)-ones.

SCHEME 8.87 Asymmetric synthesis of 3-substituted indanones with high ee.

An additive-free Michael addition of N-tert-butanesulfinylimidates and a,b-unsaturated diesters in the presence of LDA afforded highly diastereoselective 3-substituted indanones 198 in excellent yields and high enantiomeric excess (Scheme 8.87) [113]. Enantioselective synthesis of potentially useful chiral 3-aryl-1-indanones was achieved through a Rh-catalyzed asymmetric intramolecular 1,4-addition of pinacolborane chalcone derivatives in the presence of MonoPhos chiral ligand under relatively mild conditions. The protocol offered an easy access to enantio-enriched 3-aryl-1-indanone derivatives 199 in up to 95% yields and up to 95% ee (Scheme 8.88) [114].

BIOLOGICAL ACTIVITIES Indane derivatives are used as precursors in the synthesis of biological important scaffolds. They have shown a broad spectrum of biological activities. Hence, a review is available on the development, properties, and potentials as a novel family of natural organic structures based on indanes [115]. Another review is focused on the synthesis of potential bioactive molecules and the natural products based on Meldrum’s acid motif of indane chemistry

SCHEME 8.88

Chiral 3-aryl-1-indanones synthesis.

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[116]. Here, some recent biological applications of indane-based compounds are taken such as the following.

Antimicrobial Activity 4-Arylthiazolyl hydrazones (TZHs) 206 derived from 1-indanones were synthesized in good yields (66e92%) with MW-irradiation and evaluated for their in vitro Trypanosoma cruzi antiactivity against the epimastigote, trypomastigote, and amastigote forms of the parasite. Most TZHs displayed excellent activity and are more potent and selective than the reference drug benznidazole, a current chemotherapy drug. Analysis of the free sterols from parasite incubated with the compounds showed that inhibition of ergosterol biosynthesis is a possible target for the action of these new TZHs. In particular, TZH emerged as a promising antichagasic compound to be evaluated in animal models (Fig. 8.15) [117]. Different heterodimers 201 comprised of donepezil and huperzine A (HupA) fragments were synthesized and evaluated in search of potent acetylcholinesterase (AChE) inhibitors in AD. Heterodimers comprised of dimethoxyindanone and hupyridone (from HupA) and connected with a multimethylene linker were identified as potent and selective inhibitors of AChE. Diastereomeric heterodimers (RS, S) (with a tetramethylene linker) exhibited the highest potency of inhibition toward AChE with an IC50 9 nM and no detectable inhibitory effect on butyrylcholinesterase at 1 mM (Scheme 8.89) [118]. 4-Aminoquinoline-indanone-based heterodimeric compounds 202 and 203 are identified as trypanocidaleantiplasmodial compounds. In Trypanosoma brucei, the inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the hemodetoxification process. All of these heterodimers also display good brain

FIGURE 8.15 Trypanosoma cruzi antiactivity.

SCHEME 8.89 Potent acetylcholinesterase (AChE) inhibitors.

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FIGURE 8.16 Antiplasmodial compounds.

permeabilities thereby being potentially useful for late-stage human African trypanosomiasis (Fig. 8.16) [119]. 7-Methoxytacrine (7-MEOTA)edonepezil adducts 204 were synthesized and tested for their ability to inhibit electric eel acetylcholinesterase (EeAChE), human recombinant AChE (hAChE), equine serum butyrylcholinesterase (eqBChE), and human plasmatic BChE (hBChE). They exerted mostly nonselective profile in inhibiting cholinesterases of different origin with IC50 in micromolar concentrations. This was also supported by molecular modeling and QSAR studies (Fig. 8.17) [120]. Indenoindoles were synthesized and tested for their in vitro activity against human prostate cancer cells PC-3 and LNCaP. The most effective compound 7,7-dimethyl-5-[(3,4-dichlorophenyl)]-(4bRS,9bRS)-dihydroxy-4b,5,6,7,8,9bhexahydro-indeno[1,2-b]indole-9,10-dione 211 reduced the viability in both cells in a time- and dose-dependent manner. Inhibitory effects were also observed on the adhesion, migration, and invasion of the prostate cancer cells as well as on clonogenic inhibition of MMP-activity. Molecular docking of 205 into MMP-9 human active site was also performed to determine the probable binding mode (Fig. 8.18) [121]. 3-(4-Aryl-5H-indeno[1,2-b]pyridin-2-yl)coumarin derivatives have been synthesized by the reaction of 3-coumarinyl methyl pyridinium salts with appropriate 2-arylidene-1-indanones under Krohnke’s reaction condition and investigated their in vitro antimicrobial activity. Compound 206 displayed close antibacterial activity to the reference drug ampicillin against tested bacterial strains (Fig. 8.19) [122].

FIGURE 8.17 Cholinesterases inhibitor.

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FIGURE 8.18

Human prostate cancer inhibitors.

Dispiropyrrolothiazoles were synthesized and screened for antimycobacterial activity against Mycobacterium tuberculosis H37Rv and INH-resistant M. tuberculosis strains. Two of them were shown good activity with IC50 1 mM concentration. Compound 207 was found to be the most active with IC50 of 0.210 and 8.312 mM, respectively (Scheme 8.90) [123]. Dispiropyrrolidines were synthesized via [3 þ 2]-cycloaddition reactions and screened for their antimycobacterial activity against M. tuberculosis H37Rv in HTS (high-throughput screen). Compound 4-(4-bromophenyl)1emethyldispiro[acenaphthylene-1,2-pyrrolidine-3,2-indane]-2,1(1H)-dione 208 was found to be the most active with IC50 12.50 mM (Fig. 8.20) [124]. One-pot reaction of 2-amino-5-chloro or 5-nitro-benzophenones, cyclanones, and indanones were carried out in an MW oven using TFA catalyst to obtain good yields. The products were evaluated for the growth inhibitory activity toward M. tuberculosis H37Rv (Mtb). The cyclopenta[b]quinoline derivative 209 exhibited bactericidal activity at 50 mg/mL; its intracellular activity is similar to rifampin and not cytotoxic at low concentrations (Fig. 8.21) [125]. 10a-Phenylbenzo[b]indeno[1,2-e] [1,4]thiazin-11(10aH)-ones have been synthesized and tested for their antimicrobial activity. Compounds 210

FIGURE 8.19 Antimicrobial activity.

SCHEME 8.90 Antimycobacterial activity.

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FIGURE 8.20 Antimycobacterial activity.

exhibited promising antibacterial activity and compounds 210a and 210c exhibited activity almost comparable to penicillin for Staphylococcus aureus and B. subtilis, respectively. The derivatives 210e and 210f exhibited high antifungal activity (Fig. 8.22) [126].

Antitumor Activity A phosphine catalyzed [2 þ 3]-cycloaddition between indanone-enone and allenylmethyl ketone followed by Robinson annulations afforded a bicylco [3.2.1] octane 211, which showed the selective estrogen agonist property (Scheme 8.91) [127]. Functionalized aryl enones were synthesized via [3 þ 2] cycloaddition/ oxidative and Nazarov cyclization. These compounds 212 are good for human lipoxygenase inhibitors that convert arachidonic acid into the leukotrienes, responsible for signaling molecules implicated in several inflammatory diseases (Scheme 8.92) [128]. 3-(3,4,5-Trimethoxyphenyl)-4,5,6-trimethoxy,2(3,4-methylenedioxybenzylidene)-indan-1-one 214, a modified structure of gallic acid 213, exhibited potent cytotoxicity (IC50 ¼ 0.010e14.76 mM) against various human carcinoma cells. In cell cycle analysis, compound 213 induced G2/M phase arrest in both MCF-7 and MDA-MB-231 cells. It also induced apoptosis in DU145 cells by cleavage of PARP. In Ehrlich ascites

FIGURE 8.21 Antituberculosis activity.

FIGURE 8.22

Antimicrobial activity.

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SCHEME 8.91 Selective estrogen agonist synthesis.

SCHEME 8.92 Synthesis of human lipoxygenase (HLO) inhibitors.

carcinoma, benzylidene indanone 213 showed 45.48% inhibition of tumor growth at 20 mg/kg dose in Swiss albino mice. Furthermore, in subacute toxicity experiment in Swiss-albino mice, it was found to be nontoxic up to 100 mg/kg dose for 28 days (Fig. 8.23) [129]. Hexahydroindenopyridines (HHIPs) 215e217 are structurally related to melatonin- and serotonin-derived neurohormone. Melatonin receptor ligands have applications in several cellular, neuroendocrine, and neurophysiological disorders including depression and insomnia. Two-step synthesis of HHIP via enamine C-alkylation-cyclization and the influence of substituents on the benzene ring and the nitrogen atom on melatoninergic receptors have been studied. Among the synthesized HHIPs, some of them contain methylenedioxy and 8-chloro-7-methoxy substituents on the benzene ring that revealed affinity for the MT1 and the MT2 receptors (Scheme 8.93) [130]. 2-Phenoxy-indan-1-ones (PIOs) 218 are cholinesterase inhibitors. The experiment showed that PIOs had inhibitory effects on the MDR1-mediated

FIGURE 8.23 Potent cytotoxic agents against various human carcinoma cells.

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SCHEME 8.93 Synthesis of hexahydroindenopyridines (HHIPs) for MT1 and the MT2 receptors.

FIGURE 8.24 2-Phenoxy-indan-1-one derivatives (PIOs) cholinesterase inhibitors.

transport of rhodamine123 with an IC50 ¼ 40e54 mM. Therefore, 5,6-dimethoxy-1-indanones might be the pharmacophoric moiety of PIOs that interacts with the binding site of P-glycoprotein (Fig. 8.24) [131]. Sulindac analogs were synthesized to bind RXRa receptor and modulate its biological activity including inhibition of the interaction of an N-terminally truncated RXRa (tRXRa) with the p85a regulatory subunit of phosphatidyl inositol-3-OH kinase (PI3K). Analog 219 is reported as a potential modulator for inhibiting tRXRa-dependent AKT activation (Fig. 8.25) [132]. Pyrrolothiazolyloxindoles 220 were synthesized and evaluated as acetylcholinesterase (AChE) inhibitors in AD. These compounds are found the most potent inhibitors against acetylcholinesterase enzyme with IC50 0.11 mM better than donepezil (Scheme 8.94) [133]. Benzylidene indanones were synthesized and evaluated as multitargetdirected ligands against AD. The in vitro studies showed that most of these molecules exhibited a significant ability to inhibit self-induced b-amyloid (Ab142) aggregation (10.5e80.1%, 20 mM) and MAO-B activity (IC507.540.5 mM) to act as potential antioxidants (ORAC-FL value of 2.75e9.37) and to function as metal chelators. In particular, compound 221

FIGURE 8.25 Phosphatidyl inositol-3-OH kinase (PI3K) inhibitor.

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SCHEME 8.94 Anticholinesterase activity.

FIGURE 8.26 Multitarget-directed ligands against Alzheimer disease.

had the greatest ability to inhibit Ab142 aggregation (80.1%) and MAO-B (IC50 ¼ 7.5 mM) was also an excellent antioxidant and metal chelator. Moreover, it is capable of inhibiting Cu(II)-induced Ab142 aggregation and disassembling the well-structured Ab-fibrils (Fig. 8.26) [134]. Substituted 1-indanones were synthesized and tested to assess their potential inhibitory activity against AChE. Compounds 222 (IC50 ¼ 14.8 nM) and 223 (IC50 ¼ 18.6 nM) exhibited markedly higher inhibitory activities than tacrine and similar activities to donepezil. These compounds also crossed the bloodebrain barrier in vitro study (Fig. 8.27) [135]. A new series of hybrid molecules were synthesized for BACE1 receptor as an attractive target in AD. In vitro testing results showed compound 224 (IC50 ¼ 2.49
0.08 mM) bearing the bulky bis(4-fluorophenyl) methyl) piperazine substituent as the most potent BACE1 inhibitor (Fig. 8.28) [136]. Topoisomerase inhibitors camptothecin, etoposide, and teniposide have been clinically used in the treatment of cancers. 2-phenyl- and hydroxylated 2-phenyl-4-aryl-5H-indeno[1,2-b]pyridines 225e228 were synthesized and evaluated for their topoisomerase inhibitory activity as well as their cytotoxicity against the human cancer cells. Mostly, hydroxylated compounds containing furyl or thienyl moiety at position 4 of central pyridine exhibited strong topoisomerase I and II inhibitory activity compared to camptothecin and etoposide, respectively. The structureeactivity relationship (SAR) study revealed that indenopyridine compounds with hydroxyl group at phenyl ring 2 in combination with furyl or thienyl moiety at position 4 are important for

FIGURE 8.27 Anti-Alzheimer disease (AD) agents.

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FIGURE 8.28 Potent BACE1 inhibitor.

topoisomerase inhibition. The hydroxyl group containing compounds at metaposition of the phenyl ring 2 at position 2 and furanyl or thienyl substitution at position 4 of indenopyridine showed concrete correlations between topo I and II inhibitory activity and cytotoxicity against cancer cells (Scheme 8.95) [137]. Chiral 2,3-dihydro-1H-indenes were synthesized and evaluated as melatonergic ligands (MT2-selective ligands). Compounds 229e232 exhibited powerful MT2 agonistic activity (EC50 < 50 nM) as well as excellent MT2 selectivity (>2200-fold) (Fig. 8.29) [138]. 1-Indanone and related indane derivatives were synthesized and evaluated as potential inhibitors of recombinant human MAO-A and MAO-B. The results showed that C6-substituted indanones are particularly potent and selective MAO-B inhibitors with IC50 values 0.001e0.030 mM. C5-substituted indanone and indane derivatives are comparatively weaker MAO-B inhibitors. Similarly, 2,4-diaryl-5H-indeno[1,2-b]pyridines 233 were designed

SCHEME 8.95

Prepared compounds as topo I and II inhibitory activity.

FIGURE 8.29 MT2-selective ligands as antagonists.

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and synthesized by introducing hydroxyl and chlorine groups and evaluated for topoisomerase inhibitory activity and cytotoxicity against HCT15, T47D, and HeLa cancer cells. Compounds with meta- or para-hydroxyl on phenyl 2 or 4 ring have enhanced topo I and II inhibitory activity and cytotoxicity. However, additional substitution of chlorine group on furyl or thienyl ring generally reduced topo I and II inhibitory activity but improved cytotoxicity (Fig. 8.30) [139]. Indenopyrazoles were synthesized using indanones and phenylisothiocyanates. Among them, methyl 3-((6-methoxy-1,4-dihydroindeno [1,2-c]pyrazol-3-yl)amino)-benzoate (GN39482) 234 was found to possess a promising antiproliferative activity by tubulin inhibitor toward human cancer cells without affecting any antimicrobial and antimalarial activities at 100 nM. When, R1 ¼ OMe and R2 ¼ CO2Me of the anilinoquinazoline framework gave the high cell growth inhibition. Indeed, compound 234 inhibited the acetylated tubulin accumulation and the microtubule formation and induced G2/M cell cycle arrest in HeLa cells, revealing that a promising antiproliferative activity toward human cancer cells is probably caused by the tubulin polymerization inhibition (Scheme 8.96) [140]. Ring-fused 3-oxindoles 235 were designed and synthesized as hybrid structure of anticancer drug 236 þ S2 (Hoffmann-La Roche) or MI-219 anticancer drugs as inhibitors of the MDM2-p53 interaction with two contiguous quaternary carbon centers via an aldol reaction starting from 3-substituted oxindoles and ninhydrin in the presence of 5 mol% catalyst DABCO$6H2O in water at room temperature for 15 h to afford up to 98% yield. In vitro biological activity was the evaluation against human prostate cancer cells PC-3, human lung cancer cells A549, and human leukemia cells

FIGURE 8.30

Topoisomerase inhibitory activities.

SCHEME 8.96 Tubulin inhibitor agents.

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FIGURE 8.31 Indanone-based Anticancer agents.

SCHEME 8.97

Synthesis of fuctionalized indenes.

K562 by MTT-based assays using the standard drug cisplatin as a positive control. They exhibited two to three times better in vitro inhibitory activity against human leukemia cells K562 compared to cisplatin (Fig. 8.31) [141]. Functionalized 1,3-dicyano indenes 237 were synthesized from electronrich a-aryl ketonitriles in the presence of K3Fe(CN)6 and NaOAc via tandem process involving dimerization, heterolytic CeC bond cleavage, intermolecular coupling, and the subsequent intramolecular cyclization in 58e75% yield for their good fluorescent properties (Scheme 8.97) [142]. Meropenem (indane containing broad-spectrum b-lactam antibiotic) in combination with clavulanate has shown efficacy in patients with extensively drugresistant tuberculosis. The stability of prodrugs in aqueous solution at pH 6.0 and 7.4 was significantly dependent on the ester promoiety with the major degradation product identified as the parent compound meropenem 238. However, in simulated gastrointestinal fluid (pH 1.2) the major degradation product identified was ring-opened meropenem with the promoiety still intact, suggesting the gastrointestinal environment may reduce the absorption of meropenem prodrugs in vivo unless administered as an enteric-coated formulation (Fig. 8.32) [143]. A series of indenoindole derivatives 239 were synthesized and in vitro screened for their activity against human prostate cancer

FIGURE 8.32

Antituberculosis agent.

428 Studies in Natural Products Chemistry

SCHEME 8.98 Antiprostate cancer activity in PC-3 and LNCaP cells.

cells PC-3 and LNCaP. The most effective compound 7,7-dimethyl-5[(3,4-dichlorophenyl)]-(4bRS,9bRS)-dihydroxy-4b,5,6,7,8,9b hexahydro-indeno [1,2-b]indole-9,10-dione reduced the viability in both cell lines in a time- and dose-dependent manner. Inhibitory effects were observed on the adhesion, migration, and invasion of the prostate cancer cells as well as on clonogenic possibly by inhibition of MMP activity. Molecular docking of these compounds was also performed in MMP-9 human active site to determine the probable binding mode (Scheme 8.98) [144].

CONCLUDING REMARKS This review has clearly reflected that the indane class of compounds is a core structure in various natural products. Various synthetic methods are explored for their core structure synthesis and are used as versatile precursors for the derivatization of symmetric and asymmetric molecules of large variety of natural products, organic molecules, drug-related scaffolds, and heterocyclic compounds. 1-, 2- and 1,3-indanones are highly reactive at carbon(s) adjacent to carbonyl group(s). This trigger toward a number of organic reactions such as cycloaddition; cyclocondensation; Wittig, PicteteSpengler, and BayliseHillman, cascade reactions/domino reactions; and several multicomponent reactions in the synthesis of acyclic and cyclic molecules, mainly five- and six-membered heterocycles, and also open new avenues for other class of complex structures in the areas of chiral ligands, inorganic coordination, and fluorescent compounds syntheses. A broad spectrum of biological activities against microbes and metabolic disorder diseases speak to the pharmacological potential of this class of compounds. However, the diverse biological activity implies that these molecules might be nonspecific with respect to their pharmacodynamics. To better understand the behavior of these molecules in biological systems and enable the development of more potent analogs, novel molecule synthesis and systematic SAR studies are required. Although wonderful advances have been achieved in this field, the synthesis of novel scaffolds need to be explored for the benefit of synthetic, pharmacologists and medicinal chemists. There is no doubt that indane molecules will show more synthetic possibilities in the future.

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ABBREVIATIONS CNS HIV BINAM LAH TESCl TIPSCl TBAF DABCO NaBARF DCM/MS LDA MBH BINAP MTT MMP TFA PARP QSAR MAO BACE1 GR24

central nervous system human immunodeficiency virus (S)-2,20 -bis(diphenylphosphinoamino)-1,10 -binaphthyl lithium aluminum hydride chlorotriethylsilane chlorotriisopropylsilane tetra-n-butylammonium fluoride 1,4-Diazabicyclo[2.2.2]octane sodium tetrakis[(3,5-trifluoromethyl)phenyl]borate dichloromethane/molecular sieve lithium diisopropylamide MoritaeBayliseHillman (2,2ʹ-bis(diphenylphosphino)-1,1ʹ-binaphthyl) 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide matrix metalloproteinase trifluoroacetic acid poly(ADP-ribose) polymerase qualitative structure and activity relationship monoamine oxidase beta-site amyloid precursor protein cleaving enzyme 1 (3aR,8bS,E)-3-(((R)-4-methyl-5-oxo-2,5-dihydrofuran-2-yloxy)methylene)3,3a,4,8b-tetrahydro-2H-indeno[1,2-b]furan-2-one

ACKNOWLEDGMENTS Thanks to my PhD students Mr. Sumit Kumar and Mr. Nishant Verma for immense support.

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434 Studies in Natural Products Chemistry [130] J. Parraga, L. Moreno, A. Diaz, N. ElAouad, A. Galan, M.J. Sanz, D.-H. Caignard, B. Figadere, N. Cabedo, D. Cortes, Eur. J. Med. Chem. 86 (2014) 700e709. [131] H.-H. Hua, Y.-C. Biana, Y. Liua, R. Shengb, H.-D. Jianga, L.-S. Yua, Y.-Z. Hub, S. Zeng, Int. J. Pharm. 460 (2014) 101e107. [132] Z.-G. Wang, L. Chen, J. Chen, J.-F. Zheng, W. Gao, Z. Zeng, H. Zhou, X.-k. Zhang, P.Q. Huang, Y. Su, Eur. J. Med. Chem. 62 (2013) 632e648. [133] M.A. Ali, R. Ismail, T.S. Choon, R.S. Kumar, H.O.N. Arumugam, A. Almansour, K. Elumalai, A. Singh, Bioorg. Med. Chem. Lett. 22 (2012) 508e511. [134] L. Huang, C. Lu, Y. Sun, F. Mao, Z. Luo, T. Su, H. Jiang, W. Shan, X. Li, J. Med. Chem. 55 (2012) 8483e8492. [135] L. Huang, H. Miao, Y. Sun, F. Meng, X. Li, Eur. J. Med. Chem. 87 (2014) 429e439. [136] A. Rampa, F. Mancini, A. De Simone, F. Falchi, F. Belluti, R.M.C. Di Martino, S. Gobbi, M. Bartolini, A. Cavalli, A. Bisi, Bioorg. Med. Chem. Lett. 25 (2015) 2804e2808. [137] T.M. Kadayat, C. Song, S. Shin, T.B.T. Magar, G. Bist, A. Shrestha, P. Thapa, Y. Na, Y. Kwon, E.-S. Lee, Bioorg. Med. Chem. 23 (2015) 160e173. [138] X. Zhang, Z. Wang, Q. Huang, Y. Luo, X. Xie, W. Lu, RSC Adv. 4 (2014) 25871e25874. [139] T.M. Kadayat, C. Song, Y. Kwon, E.-S. Lee, Bioorg. Chem. 62 (2015) 30e40. [140] H. Minegishi, Y. Futamura, S. Fukashiro, M. Muroi, M. Kawatani, H. Osada, H. Nakamura, J. Med. Chem. 58 (2015) 4230e4241. [141] X.-L. Liu, B.-W. Pan, W.-H. Zhang, C. Yang, J. Yang, Y. Shi, T.-T. Feng, Y. Zhou, W.C. Yuan, Org. Biomol. Chem. 13 (2015) 601e611. [142] L. Liu, Y.f. Fan, Q. He, Y. Zhang, D. Zhang- Negrerie, J.h. Huang, Y. Du, K. Zhao, J. Org. Chem. 77 (2012) 3997e4004. [143] L. Moreno, I. Berenguer, A. Diaz, P. Marı´n, J. Pa´rraga, D.-H. Caignard, B. Figade`re, N. Cabedo, D. Cortes, Bioorg. Med. Chem. Lett. 24 (2014) 3534e3536. [144] G. Lobo, M. Monasterios, J. Rodrigues, N. Gamboa, M.V. Capparelli, J. Martı´nez-Cuevas, M. Lein, K. Jung, C. Abramjuk, J. Charris, Eur. J. Med. Chem. 96 (2015) 281e295.

Chapter 9

Garcinoic Acid: A Promising Bioactive Natural Product for Better Understanding the Physiological Functions of Tocopherol Metabolites Stefan Kluge,*, x, a Martin Schubert,*, x, a Lisa Schmo¨lz,*, x Marc Birringer,{ Maria Wallert*, x, Stefan Lorkowski*, x, 1

*Friedrich Schiller University Jena, Jena, Germany; xCompetence Cluster for Nutrition and Cardiovascular Health (nutriCARD), Halle-Jena-Leipzig, Germany; {University of Applied Sciences Fulda, Fulda, Germany 1 Corresponding author: E-mail: [email protected]

Chapter Outline Introduction Garcinia kola Bioactive Ingredients of the Garcinia kola Nut Biflavones and Benzophenone Derivatives Garcinal Garcinoic Acid Vitamin E Biological Significance of Vitamin E Absorption, Transport, and Distribution of Vitamin E Metabolism of Vitamin E Synthesis of Vitamin E Long-Chain Metabolites

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Isolation of Garcinoic Acid Synthesis of Garcinoic Acid Semisynthesis of Long-Chain Metabolites From Garcinoic Acid Bioactivity of Garcinoic Acid, Vitamin E, and Long-Chain Metabolites Cytotoxicity Cytotoxic Effects of Vitamin E Metabolites of Vitamin E Garcinoic Acid Antioxidative Properties Antiinflammatory Actions

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a. These authors contributed equally. Studies in Natural Products Chemistry, Vol. 51. http://dx.doi.org/10.1016/B978-0-444-63932-5.00009-7 Copyright © 2016 Elsevier B.V. All rights reserved.

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436 Studies in Natural Products Chemistry Cyclooxygenases and Their Lipid Mediator Products Vitamin E Modulates Prostaglandin E2 Release and Cyclooxygenase Activity Effect of Long-Chain Metabolites of Vitamin E on Cyclooxygenase 2 Expression Vitamin E and Lipoxygenases

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Modulation of Lipid Homeostasis Tocopherols and Macrophage Foam Cell Formation Effects of Long-Chain Metabolites and Garcinoic Acid on Macrophage Foam Cell Formation Conclusions and Perspectives Abbreviations Acknowledgments References

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INTRODUCTION Organisms produce bioactive natural products (secondary metabolites) as an adaption to their environment or as defense mediators. In contrast to primary metabolites such as protein, fat, and carbohydrates, they are not essential for growth, development, or reproduction [1,2]. Nevertheless, secondary metabolites are, like no other compounds, representatives for medical progress and have enormous importance for human health care. The use of natural products as medicines developed over generations and has been described throughout history in the form of folk medicine. The traditional African, Korean, Chinese, Islamic, and herbal medicines are the most important forms of historical folk medicine. Especially in Africa and Asia, 80% of the population still relies on traditional medicine for their primary health needs [3]. In these regions, fungi, plants, marine algae, or marine sponges are the most popular sources for bioactive natural products, but many of these compounds remain unexplored [2]. Nevertheless, plants are the dominant source of natural products in folk medicine. Plants have been well documented for their medicinal use for several thousands of years [4]. A well-known example is the plant Alhagi maurorum, which was used by the Romans for treating nasal polyps [5]. Plantbased traditional medicine was very important for primary health care over hundreds of years, but during the 18th century, the understanding of medicine changed. After Leeuwenhoek identified the first microorganism, enormous progress in the prevention of diseases was made. The knowledge associated with traditional medicine has promoted further investigations of compounds and extracts obtained from medicinal plants as potential medicines. This led to the isolation of many natural products from different sources. One of the most famous examples is the antiinflammatory agent acetylsalicylic acid (aspirin) derived from the natural product salicin, which was isolated from the bark of the willow tree Salix alba [6,7]. During this

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period, ethnopharmacological knowledge has been used for early drug discovery. Today, advances in analytical technologies improve the discovery of new bioactive natural products. These compounds have unique structural properties in comparison to products from standard combinatorial chemistry, making them the most promising source of lead structures for drug development [8,9]. A good example for the development from a medical plant used in traditional African medicine to a source of bioactive products for putative drugs is the African plant Garcinia kola. The parts of this plant contain many bioactive compounds, including the d-tocotrienol (d-T3) derivate garcinoic acid, which comprises an interesting molecule for functional studies. The aim of this review is to summarize the knowledge on this promising molecule and its use in research on vitamin E and its metabolites.

GARCINIA KOLA G. kola or bitter kola is a dicotyledonous plant of the family Clusiacea (Fig. 9.1). It can be found in the rain forests of west and central Africa where it grows as a medium-sized tree with a height up to 12 m [10,11], but G. kola is also used for commercial farming, especially in Nigeria. The plant has reddish fruits containing two to four seeds. Both fruit components can be eaten [12]. G. kola plants bloom between December and January and their fruits mature from June to August [13]. From the botanical point of view, the fruits belong to the class of berries, but the seeds are often called G. kola nuts [14]. The nuts are dried and afterward available over the whole year, which gives them a small economical relevance [12]. Because of the bitter flavor of its seeds, the plant is colloquially called “bitter kola” or “bitter nut.” The locals also name it “Orogbo” (Yoruba), “Aku ilu” (Igbo), and “Namijin goro” (Hausa) [3]. Apart from its small economical relevance, G. kola is very important for African ethnomedicine. Approximately 60e80% of the African population depend on herbal cures for their primary health care [3]. In the traditional African medicine, each part of the G. kola plant is used for different medical applications. For example, the root is used for oral hygiene and the tree bark as an abstergent agent. The latex of the tree is put on fresh wounds to prevent septic inflammation and to support healing [15]. The nuts are used for treating bronchitis and infections of the pharynx and colic [10]. Furthermore, the nuts are also used as antivenom for people with suspected intoxication [16]. It is also speculated that G. kola nuts protect against the toxic effects of alcohol [17]. Because of their bitter flavor, the bitter nuts are also used as stimulants for inducing anorexia [15]. Furthermore, antimicrobial effects [18e20], antiviral effects [10], antiparasite effects [21], antidiabetic effects [22], and hepatoprotective effects [23] have been described.

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FIGURE 9.1 (A) Botanical illustration of the fruits of Garcinia kola E. Heckel (Drawing by W.G. Smith published in 1875.). The fruits are shown completely and in cross section. Further, the seeds, colloquially called “bitter nut,” can be seen. The illustration is entitled “bitter nut.” (B) Photography of G. kola seeds. (C) Photograph of G. kola plant with fruits (By courtesy of Paul Latham.). (D) Cross section of G. kola fruit, showing seeds (By courtesy of Paul Latham.).

Bioactive Ingredients of the Garcinia kola Nut The main components of G. kola nuts are carbohydrates, protein, fiber, fat, and water [3,12]. In contrast to the real kola nuts (Cola nitida), the bitter nuts do not contain caffeine [17], but they are a good source for calcium, potassium, sodium, and magnesium [3,24]. Furthermore, many other bioactive compounds, including tannins, saponins, alkaloids, and glycosides, have been isolated from G. kola nuts [3,13]. The nut also contains flavonoids and benzophenone derivatives such as kolaflavones and Garcinia-biflavones 1 (3,4,4,5,5,7,7-heptahydroxy-3,8-biflavanone) and 2 (3,4,4,5,5,5,7,7-hexahydroxy-3,8-biflavanone), which might be responsible for the observed antimicrobial effects of G. kola nuts [3]. Furthermore, two chromanols, garcinal and garcinoic acid, which have been described as strong antioxidants, have been isolated from G. kola seeds [25].

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Biflavones and Benzophenone Derivatives Most of the biochemical and physiological effects of the G. kola nut are attributed to its content of biflavones and benzophenone derivatives. One of the most investigated nut biflavones is kolaviron, a dimeric flavonoid (Fig. 9.2). In addition to its hepatoprotective effects [22] and its ability to lower blood cholesterol [26], antiinflammatory capacity has been shown for this compound in different animal models. For example, diabetic rats were supplemented with 100 mg/kg kolaviron for 6 weeks. The treatment with kolaviron resulted in a reduction of inflammatory processes, indicated by reduced serum concentrations of interleukin (IL)-1b and monocyte chemotactic protein 1 (MCP1) [27]. Similar results have been found in hepatic tissues of diabetic rats, where treatment with kolaviron reduced the amount of proinflammatory cytokines such as IL-1b, IL-6, and tumor necrosis factor a (TNFa) [28]. Further studies investigated the effects of kolaviron on inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX) 2 expression in hepatic tissues of dimethylnitrosamine-treated rats. Dimethylnitrosamine is known as a hepatotoxin that enhances expression of iNOS and COX2 proteins as part of the proinflammatory response. After treatment with kolaviron, a significant reduction of dimethylnitrosamine-upregulated iNOS and COX2 expression was measured, indicating that kolaviron acts as an antiinflammatory factor. In addition, electrophoretic mobility shift assays showed that this effect may result from reduced formation of the transcription factors nuclear factor “kappa-light-chain-enhancer” of activated B cells (NFkB) and activator protein 1 (AP-1) [29]. Furthermore, interactions of kolaviron with several intracellular immune mediators, such as IL-1a, IL-1b, IL-18, and IL-33, have been observed in murine RAW264.7 macrophages. In this context, kolaviron has been shown to modulate expression and phosphorylation of proteins involved in NFkB, mitogen-activated protein kinase, AP-1, and protein kinase B (PKB/ Akt) signaling, leading to an inhibition of the lipopolysaccharides (LPS1)induced immune response [30]. Garcinal The isolation procedure from G. kola not only provides garcinoic acid and d-T32, but also garcinal [13-(6-hydroxy-2,8-dimethyl-3,4-dihydro-2H,2-chromenyl)-2,6,10-trimethyl-2,6,10-tridecatrien-1-al] [25]. This structure is closely related to garcinoic acid; solely an aldehyde moiety terminates the side chain instead of a carboxylate moiety (Fig. 9.3).

1. Lipopolysaccharides are endotoxins composed of lipid and polysaccharide components found in gram-negative bacteria that provoke strong immune responses in eukaryotes. 2. Tocotrienols are composed of a chroman ring system and an unsaturated side chain; they constitute a subgroup of vitamin E (the reader is referred to the section “Vitamin E”).

440 Studies in Natural Products Chemistry FIGURE 9.2 Chemical structures of biflavones of Garcinia kola. Adapted from O.A. Adaramoye, V.O. Nwaneri, K.C. Anyanwu, E.O. Farombi, G.O. Emerole, Clin. Exp. Pharmacol. Physiol. 32 (2005) 40e46.

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FIGURE 9.3 Chemical structure of garcinal [13-(6-hydroxy-2,8-dimethyl-3,4-dihydro-2H, 2-chromenyl)-2,6,10-trimethyl-2,6,10-tridecatrien-1-al]. Adapted from K. Terashima, Y. Takaya, M. Niwa, Bioorg. Med. Chem. 10 (2002) 1619e1625.

However, the metabolic pathways leading to the formation of garcinal in plants have not been elucidated. Based on the structural similarity to garcinoic acid, garcinal likely has a comparable bioactive potential. Nevertheless, the bioactive properties of garcinal are largely unknown. To the best of our knowledge, merely two works addressed the effects of the isolated compound. According to these, garcinal is 1.5 times more potent than a-tocopherol (a-TOH3) and has a similar antioxidative activity as garcinoic acid as well as d-T3 [25]. Furthermore, replacing the terminal functional group of the side chain of garcinoic acid (or garcinal respectively) does not alter the antioxidative capacity [25]. These findings support the hypothesis that garcinoic acid and garcinal may have similar properties in biological systems. Although the health-promoting effects of extracts from G. kola (vide supra) are generally ascribed to the biflavones, garcinoic acid and garcinal should be taken into account. This became evident when different fractions of the crude extract were examined regarding their antioxidant and radical-scavenging activities. It turned out that the most potent fraction contained the Garcinia biflavone 1 and 2 but also garcinoic acid and garcinal [31]. Given the antioxidative potential of the isolated chromanols, garcinoic acid and garcinal likely contribute substantially to the effects of extracts from G. kola. Garcinal is therefore an interesting compound for functional studies due to its structural properties and for explaining the health-promoting effects of G. kola.

Garcinoic Acid Garcinoic acid (trans-130 -carboxy-d-tocotrienol) is an interesting d-T3 derivative and its occurrence in G. kola nuts was first described by Terashima and coworkers in 1997 [32]. A few years later, the same group published a method for the isolation of garcinoic acid from G. kola nuts [25]. However, G. kola nuts are not the only source of d-tocotrienolic acid. The extraction of garcinoic acid from members of the Clusiaceaen plant family [33] and the development of a stereo-controlled synthesis [34] have been described. For an explicit description of the isolation and synthesis of garcinoic acid, the reader is

3. Tocopherols are characterized by a chroman ring system and a saturated side chain; they constitute a subclass of vitamin E (the reader is referred to the section “Vitamin E”).

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FIGURE 9.4 Chemical structure of garcinoic acid (trans-130 -carboxy-d-tocotrienol). Adapted from K. Terashima, Y. Takaya, M. Niwa, Bioorg. Med. Chem. 10 (2002) 1619e1625.

referred to the section “Synthesis of Vitamin E Long-Chain Metabolites.” Garcinoic acid is in principle a metabolite of d-T3 with the carboxylic group placed at the end of the aliphatic side chain (Fig. 9.4), which would be formed in humans in the liver after dietary intake of d-T3. Thus, garcinoic acid shares structural similarities with d-T3 [33]. Garcinoic acid shows many bioactive properties. The high antioxidant potential is probably one of the best investigated ones [25,31]. Furthermore, antiproliferative effects were shown in carcinoma cells by Mazzini et al. [33]. The acid also acts as a DNA polymerase b inhibitor, indicating that garcinoic acid is able to disturb base excision repair in tumor cells [34]. This finding supports the results of Mazzini and coworkers. For an explicit description of the bioactive properties of garcinoic acid, the reader is referred to the section “Bioactivity of Garcinoic Acid, Vitamin E and Long-Chain Metabolites.” Because of its high content of bioactive components, the G. kola nut has great potential for pharmaceutical applications, which is reflected by a number of patents. In 1987, the first patent for a biflavone isolated from G. kola as an ingredient for the treatment of liver diseases was registered [35]. The natural product reduced hepatocyte damage in a galactosamine-treated rat model of acute hepatotoxicity and improved liver values in patients with hepatitis [35]. Furthermore, an extract containing a mixture of different biflavones (Garcinia biflavones 1, 1a, and 2 as well as kolaflavones) of G. kola is used as an antiglycation agent and is also registered in a patent [36]. This compound lowers the accumulation rate of advanced-glycation adducts in the human body; high concentrations of these adducts can damage cells and tissues [36]. The existing patents on bioactive compounds of G. kola for the use as pharmaceuticals provide evidence for the growing interest in this plant [35,36]. The role of G. kola as an important part of the African ethnomedicine evolved to an interesting source of natural compounds for modern drug development. Although only patents on biflavones have been registered to date, garcinoic acid is also a promising lead compound for future pharmaceuticals.

VITAMIN E Vitamin E is naturally found in a variety of plant products, such as oils, nuts, germs, seeds, and in smaller quantities in vegetables and some fruits. Due to their lipophilic character, the several molecules summarized as “vitamin E”

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are associated to fats in dietary sources. In fact, vitamin E is a hypernym for different molecules, which can be classified as TOH, T3, and a less consistent group of vitamin Eerelated structures (Fig. 9.5). The common feature of all molecules is the chroman ring and a covalently connected phytyl-like side chain, whose respective constitutions define the individual vitamin E forms. Characteristic for the TOH is their saturated side chain, whereas T3 carry three double bonds in this substructure. The methylation pattern of the chroman ring determines the classification as a-, b-, g-, or d-form of the TOH or T3, respectively. More precise, besides position 8, positions 5 and 7 are crucial: a means methylation at position 5, 7, and 8, b at position 5 and 8, g at position 7 and 8, and d solely at position 8 of the chroman ring. Natural forms of vitamin E exist in the RRR configuration (TOH) or the R configuration (T3), whereas synthetic vitamin E is a mixture of the different stereoisomers. Members of the group of the vitamin Eerelated structures can either be more similar to TOH, such as tocomonoenol or marine-derived TOH, or to T3, such as desmethyl(P21)T3, desmethyl-(P25)T3, and plastochromanol-8 (Fig. 9.5).

Biological Significance of Vitamin E Although it is controversially discussed how vitamin E benefits human health, it is an essential factor, as the classification as a vitamin shows. Vitamin E was discovered in 1922 as vital for the fertility of rats [36a], but is also essential for the maintenance of human health. Several disease states have been linked to vitamin E deficiency. A severe effect of inadequate vitamin E supply is anemia. Vitamin E is known for its strong antioxidative properties; if these are lost, erythrocytes are prone to rupture due to higher fragility of their cell membrane [37]. Based on this observation, erythrocyte hemolysis was used as a biomarker to set the recommended daily allowance of 15 mg per day for adults [37]. Not only erythrocytes, but also components of the nervous system are negatively affected by vitamin E deficiency. An isolated vitamin E deficiency, i.e., a deficiency not caused by fat malabsorption, characterizes “ataxia with vitamin E deficiency.”4 This disease is caused by defects in the gene encoding for the a-TOH transfer protein, namely TTPA, leading to an impaired ability to retain a-TOH and to depleted a-TOH plasma levels [38,39]. Likely due to the loss of antioxidant protection, nerve cells degenerate and neurological symptoms such as ataxia, dysarthria, hyporeflexia, and decreased vibration sense occur [40]. Vitamin E deficiency might also occur due to fat malabsorption, for example, caused by cystic fibrosis or some liver diseases as well as genetic 4. Ataxia with vitamin E deficiency is an autosomal recessive disorder characterized by markedly reduced plasma levels of vitamin E, ataxia (neurological symptom with a lack of voluntary coordination of muscle movements), spinocerebellar degeneration, and peripheral neuropathy that resembles Friedreich ataxia.

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FIGURE 9.5 Chemical structures of vitamin E forms and vitamin Eerelated natural compounds.

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defects, such as abetalipoproteinemia [41e43]. Further, the MarinescoSjo¨gren syndrome and chylomicron retention disease likely cause vitamin E deficiency, as they are characterized by impaired chylomicron assembly or delivery [44,45]. Consequently, peripheral nerves die due to the lack of vitamin E, leading to spinocerebellar ataxia. Long-term vitamin E deficiency is further characterized by muscle degeneration. This process can ultimately lead to death if the heart muscle is affected [46]. Given its protective role on neurons, vitamin E was expected to prevent age-related neurodegenerative diseases such as Alzheimer disease. Indeed, vitamin E supplementation slowed down the progression of Alzheimer disease in some human intervention trials [47,48]. Supportive findings were also made in mice, where vitamin E deficiency caused axonal degeneration in brain areas important for memory and cognition [49]. Furthermore, impaired motor coordination and cognitive function was normalized by supplementation with vitamin E in vitamin Eedepleted mice [50]. Vitamin E status seems to be important not only for the maintenance of neurons, but also for their development. Several animal studies suggest that the sufficient supply with vitamin E (of the mother) is critical for the development of the central nervous system and cognitive function of the offspring [51e53]. Furthermore, vitamin E along with folic acid may play a supportive role in the prevention of neural tube defects in human [54,55]. For a long time, the effects of vitamin E were attributed to its antioxidant properties (vide supra), but more recent work was dedicated to its nonantioxidant properties. Hence, it became evident that vitamin E modulates gene expression and enzyme activities and interferes with signaling cascades independent of its antioxidative capacity [56]. Examples for such functions are the suppression of inflammatory mediators, reactive oxygen species (ROS5), and adhesion molecules; the induction of scavenger receptor; and the activation of NFkB [57]. Given these (and further known) actions, vitamin E is most likely playing a role in several, but not only, inflammatory diseases (for more details, the reader is referred to the section “Bioactivity of Garcinoic Acid, Vitamin E and Long-Chain Metabolites”). In addition, T3danother relevant form of vitamin E in our dietdare gaining more attention. Neuroprotective, anticancerogenic, antidiabetic, and cardioprotective effects have been suggested for this group of vitamin E [58]. However, further research is required, as the results obtained from clinical trials for TOH are inconsistent with respect to beneficial effects on chronic diseases such as cancer and cardiovascular diseases (CVD6) [59]. 5. Reactive oxygen species are oxygen-containing molecules that are highly reactive, such as superoxides, peroxides, hydroxyl radicals, and singlet oxygen. 6. Cardiovascular diseases comprise disorders of the heart and blood vessels including coronary heart disease, cerebrovascular disease, peripheral arterial disease, rheumatic heart disease, congenital heart disease, deep vein thrombosis, pulmonary embolism, and others.

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Absorption, Transport, and Distribution of Vitamin E Vitamin E comprises a class of lipophilic molecules and hence its intestinal uptake follows the pathway known for lipids. A key step is the lipid emulsification, i.e., the incorporation into micelles formed with the help of phospholipids and bile acids. The transfer into enterocytes of the intestine is carried out by passive diffusion, scavenger receptor class B type 1 (SRB1) [60], or Niemann-Pick C1-like protein 1 [61]. As there are no specific transport plasma proteins known for a-TOH [62], it is assumed that vitamin E transport in blood follows that of lipoproteins (reviewed in Ref. [61]). Here, key players in the uptake of vitamin E are SRB1 in peripheral tissue and low-density lipoprotein (LDL) receptor as well as LDL receptorerelated protein in the liver [63,64]. Once in the liver, discrimination between the different forms of vitamin E occurs. Responsible for this process is the a-tocopherol transport protein (a-TTP), which promotes the incorporation of 2R- or RRR-a-TOH into verylow-density lipoproteins (VLDL) [65,66], whereas other forms and stereoisomers are secreted into bile [67]. Besides a-TTP, the TOH-associated protein and the TOH-binding protein are known mediators of the intracellular transport of vitamin E. Interestingly, a-TOH secretion from the liver is apparently not dependent on VLDL assembly and secretion, thus oxysterol-binding proteins [68] and ATP-binding cassette transporter A1 (ABCA1) [69] have been suggested to contribute to the release from the liver. Furthermore, ABCA1 mediates the efflux of vitamin E in the intestine, macrophages, and fibroblasts [69], and multidrug resistance P glycoprotein has been identified as a transporter for the excretion of a-TOH via bile [70].

Metabolism of Vitamin E The metabolism of vitamin E mainly takes place in the liver, whereas extrahepatic pathways have also been suggested [71,72]. Interestingly, rates of vitamin E metabolism increase with higher levels of the vitamin to prevent its accumulation to toxic levels. As indicated before, the preferred form of vitamin E in humans is a-TOH, which is due to the preferential binding of a specific hepatic protein, namely a-TTP. It has been hypothesized that a-TTP protects the a-form from metabolism, in turn leading to its enrichment. Given the lower affinities of the other vitamin E forms to a-TTP, their rate of catabolism is likely more pronounced [73]. In principle, metabolism of all forms of vitamin E follows the same route, which was confirmed by the detection of the respective end products of hepatic metabolism, a-, g-, and d-carboxyethyl-hydroxychromanol (CEHC) (Fig. 9.6) [74,75]. However, the catabolic rates depend on the vitamin E form, possibly due to different affinities to key enzymes [73,76]. The classification of the metabolic end product as a-, g-, and d-CEHC indicates that the chroman ring is not modified in this process; the aliphatic side chain is rather the substructure

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FIGURE 9.6 Principle hepatic metabolism of vitamin E. Adapted from M. Birringer, P. Pfluger, D. Kluth, N. Landes, R. Brigelius-Flohe´, J. Nutr. 132 (2002) 3113e3118.

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where modification takes place. The same applies to T3, whereas further enzymes such as 2,4-dienoyl-coenzyme A (CoA) reductase and 3,2-enoylCoA isomerase (known from the metabolism of linoleic acid) are likely needed for metabolizing the unsaturated side chain [77]. Metabolism of vitamin E is therefore characterized by the shortening of the side chain au fond. Catabolism of the vitamin E molecule takes place in three cell compartments: the endoplasmic reticulum (microsomes), peroxisomes, and mitochondria. However, the transfer of the metabolites between the compartments is not yet understood. The initial step takes place at the endoplasmic reticulum and results in the formation of 130 -hydroxychromanol (130 OH) metabolites via u-hydroxylation by cytochrome P450 (CYP) 4F2 or CYP3A4, respectively [76,78]. Subsequent u-oxidation by alcohol and aldehyde dehydrogenase (an aldehyde intermediate is formed) leads to 130 -COOH metabolites. Hence, the metabolites are handled like fatty acids and the side chain is shortened by b-oxidation, resulting in the elimination of propionylCoA or acetyl-CoA, respectively. The first two rounds take place in the peroxisome, leading to the intermediate-chain metabolites 110 -COOH and 90 COOH, respectively. Three further rounds of b-oxidation are carried out in the mitochondria, forming the short-chain metabolites (SCM) 70 -COOH and 50 COOH as well as the final product CEHC or 30 -COOH. During catabolism, the metabolites are modified simultaneously by conjugation, i.e., the metabolites are either sulfated or glucuronidated, but glycine-, glycine-glucuronide-, and taurine-modified metabolites have also been identified [79]. The more hydrophilic conjugated SCM are released via urine. In human urine, however, vitamin E is mainly found in conjugated form after glucuronidation [75,80e82]. The long-chain metabolites (LCM7) and their metabolic precursors are secreted via bile into the intestine. This fecal route is considered as the major way of excretion for vitamin E. In contrast to urine, the metabolites in fecal samples are not conjugated [80,83].

SYNTHESIS OF VITAMIN E LONG-CHAIN METABOLITES The LCM can be obtained in vitro by incubation of cultured cells with the respective TOH precursors (the reader is referred to the section “Bioactivity of Garcinoic Acid, Vitamin E and Long-Chain Metabolites”). The culture supernatants of these cells can be used to investigate the cellular effects of the LCM or their action on isolated enzymes, as it has been already practiced by Jiang et al. [84]. However, this method is not feasible for all investigations, as the cells produce a mixture of carboxychromanols with different chain lengths, including SCM, as well as sulfated and nonconjugated metabolites. Furthermore, not all cell types exhibit the capability to metabolize all forms of TOH 7. The long-chain metabolites of vitamin E are the metabolites of tocopherols and tocotrienols with a side chain that is comprised of 13 carbon atoms.

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[85,86]. A purification of defined metabolites is therefore needed if one is interested in investigating the specific effects of a single metabolite. An alternative way to obtain pure metabolites is their chemical (semi) synthesis. The semisynthesis of a- and d-130 -OH and the respective 130 -COOH metabolites has been established using the natural product garcinoic acid [33,87]. The first step in the entire process is the extraction (or synthesis) of garcinoic acid from appropriate sources, which is described in the following section. The subsequent synthesis of the a- and d-LCM from garcinoic acid is outlined in another section.

Isolation of Garcinoic Acid The isolation of garcinoic acid was first mentioned in 1984 by Franco Delle Monache and colleagues, who used Clusia grandiflora from Venezuela as source material [88]. In general, the family of Clusiaceae is the source of choice for isolating garcinoic acid. The Clusiaceae family is comprised of about 40 genera including about 1600 species, which are found in tropical regions worldwide [89e91]. Members of the family are sources of, inter alia, edible fruits, drugs, pigments, and dyes [90] and have therefore been used in traditional medicine in the regions of their occurrence [89]. So far, three genera of the Clusiaceae are known to contain garcinoic acid, namely Tovomitopsis, Clusia, and Garcinia. An overview of reported isolation procedures is provided in Table 9.1. Tovomitopsis psychotriifolia, a plant from Costa Rica, has been shown to contain garcinoic acid in its leaves. In 1995, Setzer et al. extracted the compound from fresh chopped leaves using 80% aqueous ethanol with a subsequent isolation by liquid chromatography and thin-layer chromatography (TLC) using a 1:1 ethyl acetate/hexane mixture. Determination of the structure was carried out by nuclear magnetic resonance (NMR). Here, the detected structure was trans-d-tocotrienolic acid, whereas Monache et al. mainly found the cis-isomer [92]. Among the Clusia genus, several members produce garcinoic acid. The trunk of Brazilian Clusia obdeltifolia contains a mixture of garcinoic acid in its cis- and trans-configuration. Extraction of the compounds from dried and powdered material was carried out by hexane with subsequent evaporation of the solvent [93]. Following fractionation with ethyl acetate/hexane and hexane/acetone on a silica column led to the isolation of garcinoic acid. Here, the cis-form was more prominent than the trans-form with an approximate ratio of 9 to 1, as determined by NMR [93]. The related plant Clusia burlemarxii, found in Brazil, also contains garcinoic acid in its leaves. The natural product was extracted from the dried and powdered material by maceration with 95% ethanol, concentration, mixing with 80% ethanol and subsequent treatment with ethyl acetate. Garcinoic acid was then purified by column chromatography over silica gel with mixtures of

Methoda Plant

Source

Extraction

Separation Process

Input

Yield

Refs.

Tovomitopsis psychotriifolia

Leaves

EtOH

LC, TLC

HEX/AcOH

0.16% of starting weight

[92]

Clusia obdeltifolia

Trunk

HEX

CC

1. EtAc/HEX 2. HEX/ACE

6 kg

1.512 g

[93]

Clusia burlemarxii

Leaves

1. EtOH 2. EtAc

CC

1. TCM/MeOH 2. AcOH/MeOH

1.6 kg

5 mg

[89]

Clusia pernambucensis

Bark

EtAc

CC, TLC

1. cHEX/EtAc 2. EtAc/MeOH

197 g

85.3 mg

[94]

HPLC

H2O/MeOH/ACN

Garcinia kola

Seed

1. MeOH 2. MeOH/TCM

CC

1. MeOH/TCM 2. HEX/ACE

1 kg

3.8 g

[87]

Garcinia amplexicaulis

Bark

1. DCM 2. MeOH

CPT

HEP/EtAc/ MeOH/H2O

270 g

10 mg

[95]

ACE, acetone; ACN, acetonitrile; AcOH, acetate; CC, column chromatography; cHEX, cyclohexane; CPT, centrifugal partition chromatography; DCM, dichloromethane; EtAc, ethyl acetate; EtOH, ethanol; HEP, heptane; HEX, hexane; HPLC, high-performance liquid chromatography; LC, liquid chromatography; MeOH, methanol; TCM, chloroform; TLC, thin-layer chromatography. a For detailed information, the reader is referred to the text.

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TABLE 9.1 Overview of Procedures for Garcinoic Acid Isolation

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chloroform and methanol in increasing polarity and in a second washing step with mixtures of ethyl acetate and methanol in increasing polarity. Again, the cis-isomer was more prominent [89]. A third member of the family, Clusia pernambucensis from Brazil, contains garcinoic acid in the bark [94]. The extract was obtained by maceration with ethyl acetate and subsequently fractionated by column chromatography with a cyclohexane/ethyl acetate gradient and sequentially an ethyl acetate/methanol gradient. After profiling with TLC, the appropriate fraction was purified by reverse-phase high-performance liquid chromatography (HPLC) using an isocratic 8:32:60 mixture of water, methanol, and acetonitrile. In addition to the cis-isomer of garcinoic acid, the related compounds d-T3, d-T3 alcohol, and d-T3 methyl ester were obtained. However, in terms of quantity, garcinoic acid was substantially more abundant than the other compounds [94]. Members of the genus Garcinia are another valuable source of garcinoic acid. The isolation of garcinoic acid from seeds of G. kola, which originate from Nigeria, was first described by Terashima et al. in 1997 [25,96]. Based on this procedure, Birringer et al. developed a modified method [87]. Here, the mashed seeds were extracted with methanol, and after evaporation of the solvent, the extract was dissolved in a 95:5 mixture of methanol and chloroform. The crude extract was obtained by drying. For the isolation of garcinoic acid, the extract was again dissolved in 95:5 methanol/chloroform and applied to a silica gel column for purification. Further chromatographic separation on silica gel with a 65:35 mixture of hexane and acetone led to purified garcinoic acid, as characterized by NMR and mass spectroscopy (MS) [87]. A further member, Garcinia amplexicaulis from New Caledonia, contains garcinoic acid in the bark. Extraction of garcinoic acid from dried and grounded material was carried out with dichloromethane and subsequently methanol in a Soxhlet apparatus. The extract was further fractionated with a 2:1:2:1 mixture of heptane, ethyl acetate, methanol, and water using centrifugal partition chromatography. Garcinoic acid was subsequently isolated from the appropriate fraction by preparative HPLC using methanol and determined by NMR and MS [95].

Synthesis of Garcinoic Acid With the first isolation and description of garcinoic acid (d-trans-tocotrienolic acid) from Clusia grandiflora, the groundwork for approaches to synthesize this bioactive compound was laid. In 2005, David Maloney and Sidney Hecht reported a procedure to synthesize garcinoic acid (Fig. 9.7). The basis for their stereo-controlled synthesis was to elaborately produce two molecules: alkyl iodide, (S)-1-iodo-5-(2,5-dimethoxy-3-methylphenyl)3-methylpentan-3-ol (4), and vinyl iodide, (2E,6E,10E)-ethyl 11-iodo2,6,10-trimethylundeca-2,6,10-trienoate (5). The alkyl iodide (4) was synthesized in two reaction steps from 4-(2,5-dimethoxy-3-methylphenyl)

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FIGURE 9.7 Stereo-controlled synthesis of garcinoic acid. Adapted from D.J. Maloney, S.M. Hecht, Org. Lett. 7 (2005) 4297e4300.

butan-2-one (1). The Negishi coupling of tert-butylsilyloxy-5-iodo4-methylpent-4-ene (2) and 4-iodo-1-(trimethylsilyl)but-1-yne (3) yielded the vinyl iodide (5). Suzuki coupling of (4) and (5) gave the protected prenylated 1,4-benzoquinone, (2E,6E,10E,14R)-ethyl 14-hydroxy-16-(2,5-dimethoxy3-methylphenyl)-2,6,10,14-tetramethylhexadeca-2,6,10-trienoate (6). The acid-catalyzed cyclodehydration followed by saponification leads to synthetic garcinoic acid (7) [34]. In principle, this synthesis route provides an alternative way to obtain the a- and d-LCM, starting with synthetic garcinoic acid.

Semisynthesis of Long-Chain Metabolites From Garcinoic Acid Garcinoic acid, either isolated from the various natural sources or chemically synthesized, can be used for the semisynthesis of a- and d-LCM. Mazzini et al. reported the respective approach in 2009 [33]. A synthesis route leading to a-TOH was outlined, using the isolated compound from G. kola (obtained according to the procedure provided by Terashima et al. [25]) (Fig. 9.8).

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FIGURE 9.8 Semisynthesis of a-130 - and d-130 -LCM of vitamin E from garcinoic acid. Adapted from M. Birringer, D. Lington, S. Vertuani, S. Manfredini, D. Scharlau, M. Glei, M. Ristow, Free Radic. Biol. Med. 49 (2010) 1315e1322.

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Here, the unsaturated side chain of garcinoic acid is first hydrogenated in a platinum-catalyzed reaction to receive d-130 -COOH. The corresponding a-LCM, a-130 -COOH, is obtained by permethylation of d-130 -COOH, catalyzed by SnCl2. A reduction with LiAlH4 leads to a-130 -OH. To obtain a-TOH, the alcohol can be converted into a ditosylate derivative, and subsequently, the tosyl groups are removed by treatment with LiAlH4 and heating in an aqueous basic solution (not shown). Finally, a hydroxy group resides at the chroman ring and the chain loses its functional moiety [33]. This synthesis route was reproduced by Birringer et al. later. Again, G. kolaederived garcinoic acid was used, but d-130 -OH was derived by reduction of d-130 -COOH with LiAlH4, additionally. Hereby, the d-LCM as well as the a-LCM can be obtained from garcinoic acid at sufficient purity for further usage in functional assays [87].

BIOACTIVITY OF GARCINOIC ACID, VITAMIN E, AND LONG-CHAIN METABOLITES Several functions of vitamin E have been proposed until today. In the early days of vitamin E research, the focus was on the radical chain breaking and radical scavenging capacity of a-TOH, which is regarded as the most potent member of the vitamin E family in this respect [97]. However, Angelo Azzi was the first who provided evidence for further properties of a-TOH that are independent of its function as an antioxidant. He found that a-TOH regulates several cell functions via modulation of signal transduction, nuclear receptors, as well as gene and protein expression besides its function as a natural antioxidant [98,99]. T3 possess similar and sometimes even stronger biological activities than TOH; in particular, T3 show antioxidative, antiatherogenic, anticancer, antidiabetic, antiinflammatory, and neuroprotective properties [58,100]. Apart from the well-known functions of the different vitamin E forms, the bioactivity of their metabolites is not well understood. Vitamin E metabolism has been studied intensively since the 1990s, but it took about a decade until the first groups were able to detect a-, g-, and d-130 OH as well as the corresponding 130 -COOH metabolites in cell culture supernatants [76], in human liver cells [87], and also in human serum [101]. Current research on LCM is focused on their antiinflammatory properties. Investigations of different groups showed regulatory actions of the LCM on enzymes of the inflammatory cascade [102,103]. Further studies revealed antioxidative and cytotoxic effects [33,87], as well as regulatory properties in lipid metabolism [101]. Based on these studies, the LCM seem to have higher activity and modes of action different from those of the respective vitamin E forms. Garcinoic acid is a natural compound with high structural similarity to the LCM of d-T3 (and identical to the 13-carbon side chain acid metabolite) [25], indicating that the bioactivity of this substance may be comparable to the LCM of TOH and T3. However, only a few studies on the biological actions of

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garcinoic acid have been described so far. The acid exhibits high antioxidative potential [25,31] and antiproliferative effects [33]. However, almost nothing is known about its antiinflammatory or regulatory potential. The following paragraphs provide an overview on the properties of garcinoic acid and the different LCM in comparison to their precursors.

Cytotoxicity Recent animal studies on toxic effects of natural or nonnatural vitamin E forms and derivatives on reproduction and development revealed no toxic effects [104]. Physiological vitamin E intake can be increased up to 300 mg/day (mixture of TOH and T3, w190 IU/day) without causing any complications [105,106]. No clear adverse effects have been described, even for short-term high-dose administration of vitamin E. However, persistent high-dose supplementation has been shown to interfere with blood clotting and is therewith associated to an increased risk of hemorrhagic stroke in animal studies [104]. In the past, TOH was considered to be a safe food additive [107], but an increase in total mortality after high-dose vitamin E intake was discussed during the last years [108]. However, excessive intake of vitamin E results in increased metabolite formation and excretion [109]. This could be a hint that the metabolites of vitamin E may cause noxious effects after a high-dose intake of vitamin E.

Cytotoxic Effects of Vitamin E Reports on cytotoxic effects of vitamin E are inconsistent. There are considerable differences in the cytotoxicity of the different vitamin E forms. McCormick and coworkers investigated the cytotoxic potential of a-, g-, and d-TOH in RAW264.7 macrophages. Concentrations up to 60 mM g-TOH and especially d-TOH decreased cell viability by 50% and 90%, respectively, whereas a-TOH had no effect [110]. This has been confirmed in CEM/VLB100 and murine C6 glioma cells [111,112]. Experiments with d-TOH in different cell types, such as MCF-7 cells, HepG2 cells, and fibroblasts, indicate that d-TOH-triggered cytotoxicity may depend on the cell type. While d-TOH incubation results in a massive reduction of viability in MCF-7 breast cancer cells and fibroblasts, no effect was observed for HepG2 liver cells [110]. The first hypothesisdthe cell typeedependent cytotoxicity due to different intracellular accumulation of TOHdwas disproved [110]. Another concept implies that the degree of methylation of the chroman ring is important for cytotoxicity [110]. In comparison to TOH, T3 show diverse cytotoxic effects. In A549 and U87MG cells, d-T3 exhibited the highest cytotoxicity followed by g- and a-T3. Further, the cytotoxicity of T3 derivatives also depends on the cell type [113]. Moreover, cell viability was also reduced in HepG2 liver cells by 40 mM of d-T3 or g-T3 [114]. Thus, T3 are able to reduce cell viability in cell types where TOH have no effect. Taken together, the d-forms of TOH and T3 seem to be the most

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cytotoxic vitamin E forms. Moreover, lower concentrations of T3 are needed compared to TOH. TOH and T3 are also known to affect cell proliferation. Antiproliferative effects of all TOH forms have been observed in C6 glioma cells with concentrations higher than 50 mM. Here, a-TOH and g-TOH were the most potent proliferation inhibitors [112]. The underlying mechanism is probably a block of the cell cycle via p27-mediated inhibition of the cyclin E/cyclindependent kinase 2 complex [115] and by increased p53 expression [116]. In particular g-TOH and d-TOH, but not a-TOH, affect these pathways [112]. Similar effects can be induced by T3. Because of their higher reactivity, antiproliferative effects of T3 have been studied in cancer cells to use T3 as therapeutic reagents. T3dd-T3 more effectively than g-T3dreduced cell proliferation in HL-60, A549, and U87MG cells by induction of apoptosis [113,117]. Thus, TOH (cell cycle arrest) and T3 (apoptosis) exert their antiproliferative effects via different mechanisms.

Metabolites of Vitamin E As mentioned before, high doses of vitamin E increase formation of metabolites and their excretion. Therefore, TOH and T3 metabolites might contribute to cytotoxic effects of vitamin E. Studies of Conte et al. in 2004 provided first impressions of CEHC-mediated cytotoxic effects in cancer cell lines. In this work, g-TOH, g-T3, and g-CEHC inhibition of cell proliferation were compared to their respective a-homologues. It should be emphasized that the g-forms of TOH and T3 have higher transformation rates to CEHC than the respective a-forms. This has been evaluated in PC3, LNCaP, and HepG2 cells [118]. g-T3 and g-CEHC are the most potent inhibitors of cancer cell proliferation. At 10 mM, both compounds reduced proliferation of PC3 cells by 70e82%, while their a-analogues were less effective [119]. Francesco Galli and coworkers presume that this effect is triggered by a block of cyclin D1, but further investigations are needed to prove this concept [119]. In conclusion, the SCM are as effective as their precursors in inhibiting cell growth, with g-forms being most potent. In contrast to SCM, LCM are widely uncharted. Based on earlier results of Galli et al. and Conte et al. indicating that carboxy-SCM exhibit pro-apoptotic properties, Birringer et al. discovered similar effects for the 130 -LCM [87,118,119]. In this study, HepG2 cells were incubated with a-130 -COOH and d-130 -COOH and a-130 -OH and d-130 -OH. The carboxy metabolites appeared to be potent inducers of cell death, while the hydroxy metabolites did not affect cell survival. Furthermore, the d-forms have been more active than the a-forms. This is reflected by the EC50 values of the two substances: 6.5 mM for d-130 -COOH and 13.5 mM for a-130 -COOH [87], in comparison to a-TOH (EC50 > 100 mM) and a-CEHC, which showed very low antiproliferative effects at concentrations >10 mM [119]. This finding is in line with the observation that a-130 -COOH and d-130 -COOH significantly increased the

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ratio of apoptosis of HepG2 cells, compared to their metabolic precursors a-TOH and d-TOH [87]. The treatment of HepG2 cells with a-130 -COOH and d-130 -COOH also caused increased expression of caspase-3, which is a key enzyme of apoptosis. While d-130 -OH slightly increased caspase-3 expression, a-130 -OH, a-TOH, and d-TOH did not [87]. To sum up, the LCM show effects on cell proliferation and cell viability similar to those of their metabolic precursors, but there are significant differences in their activity and the LCM act at much lower concentrations.

Garcinoic Acid Based on its structural similarities to d-130 -COOH, it is hypothesized that garcinoic acid has comparable antiproliferative and cytotoxic properties as other vitamin E analogues. To confirm this hypothesis and to get more information about the structural requirements for antiproliferative properties, Mazzini et al. [33] investigated cell proliferation in glioma C6 cells after incubation with garcinoic acid. The acid reduced growth of C6 cells by 50% at concentrations of 10 mM. This effect has also been observed for a-CEHC and d-CEHC in this study, indicating that the length of the side chain has barely influence on the antiproliferative properties [33,119]. Nevertheless, d-130 COOH and a-130 -OH showed higher inhibitory effects on proliferation of C6 cells than a- and d-CEHC. This indicates that the presence of the carboxyl or hydroxyl group of the vitamin E metabolites enhances antiproliferative effects [33,87]. Based on the limited data on the cytotoxicity of garcinoic acid, its properties seem to be comparable to the other vitamin E metabolites. We found that garcinoic acid showed cytotoxic effects in the RAW264.7 mouse macrophage model system in which we revealed EC50 concentrations of about 5.5 mM (unpublished data). The cytotoxicity of natural compounds is of particular interest for cancer treatment. Several plant-derived anticancer agents are already in clinical use. In particular, taxanes, camptothecines, vinca alkaloids, and podophyllotoxins are worth mentioning [120]. The compounds exert different modes of action, but all have been shown to have antiproliferative effects on cancer cells [121e124]. This is also a characteristic of garcinoic acid, making it interesting for cancer research. Although the effects of garcinoic acid on cancer cells and the underlying mechanisms have still to be characterized, one promising property is already known: garcinoic acid inhibits DNA polymerase b with an IC50 of about 4 mM [34]. Compared to other natural DNA polymerase b inhibitors, garcinoic acid is one of the most potent ones (reviewed in Ref. [125]). Cells deficient in DNA polymerase b activity are hypersensitive to certain chemotherapeutic agents due to their impaired ability to repair induced DNA damage [126]. For this reason, the further characterization of the cytotoxic effects of garcinoic acid is of great interest. If garcinoic acid is able to induce DNA damage and simultaneously to suppress DNA damage repair mechanisms, it might be a

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powerful agent for cancer treatment. However, the effects of garcinoic acid should first be well characterized in cellular systems before experiments in animal models or even clinical trials in humans can be conducted.

Antioxidative Properties The antioxidative properties of the different vitamin E forms and metabolites have been extensively studied during the last decades, considering a-TOH as the most important antioxidant, mainly due to the protection against peroxidation of polyunsaturated fatty acids (PUFA8) in phospholipids of cellular membranes and plasma lipoproteins, a finding made at least in vitro [56,127]. Higher PUFA intake requires higher vitamin E supply to provide adequate antioxidative protection against lipid peroxidation. Unsaturated fatty acids tend to form radicals, which can be scavenged by the free hydroxyl group at the chroman ring of a-TOH; the reaction product is afterward excreted to bile as a-TOH hydroquinone [128]. All TOH and T3 forms exhibit antioxidative properties. Besides the free hydroxyl group, the mobility of the molecule in cellular membranes is a crucial factor [97,129]. The T3 have higher membrane mobility due to their unsaturated side chain. This should lead to an increase in their antioxidative capacity compared to the respective TOH forms. Yoshida and coworkers compared the effects of either TOH or T3 treatment on peroxyl radical scavenging, but no differences were detectable in membrane uptake or reactivity. However, another investigation on leptosome complexes revealed different results. In this experiment, a-T3 and a-TOH were integrated separately into synthetic membranes. Afterward, lipid peroxidation was induced in another part of the liposomal complex. It appeared that a-T3 was more potent in inhibiting peroxyl radical formation than its TOH equivalent. The more pronounced antioxidative potential of a-T3 seemed to be a result of its better intermembrane mobility, making a-T3 able to reach the radicals faster than a-TOH [130]. This observation has been confirmed by Serbinova and coworkers in rat liver microsomes [97]. However, there are also studies showing similar antioxidant activities of TOH and T3 [130,131]. In addition to membrane mobility, the number of methyl groups of the chroman ring increases the antioxidative capacity of TOH and T3. Despite this, the position of the methyl group in relation to the hydroxyl group at the chroman ring is important. For this reason, the a-forms have higher antioxidative potential than b-, g-, and d-derivatives. This has been shown for TOH and T3 in liposomal membranes. After induction of peroxyl radicaletriggered lipid peroxidation, the a-derivatives were the most potent inhibitors of oxidative stress. The antioxidant activity decreased from a 8. Polyunsaturated fatty acids are a class of fatty acids characterized by more than one double bond; they are often essential for human nutrition.

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through b to g down to d [130]. A further investigation in rat serum confirmed this observation [132]. Apart from these results, there are several in vitro studies indicating a reverse order of antioxidant efficiency with a-TOH being the least potent compound compared to d- and g-TOH [133,134]. In conclusion, TOH and T3 are highly potent antioxidants with a theoretically decreasing antioxidant activity from a- through b- to g- and down to d-forms. Furthermore, T3 seem to be more active than the respective TOH equivalents. Due to the similarity of the chemical structure of garcinoic acid with T3, comparable antioxidant activities of these compounds can be expected. The antioxidative properties of this natural compound have been investigated in two independent studies. Okoko and coworkers used a methanolic extract from G. kola seeds for in vitro experiments. First, the extract was divided into five fractions by TLC. Afterward, the radical scavenging abilities of each fraction were compared to those of vitamin C. The fraction with the highest activity in hydroxyl radical scavenging was further investigated via HPLC analysis. Chromatographic fractioning and spectroscopic analysis revealed four compounds, including Garcinia biflavones GB1 and GB2, garcinal, and garcinoic acid [31]. The combination of these four compounds had a 40% higher antioxidative activity than vitamin C at a concentration of 0.5 mg/mL. Further investigations in U937 macrophage cells revealed inhibitory effects on nitric oxide formation [31]. However, Okoko and coworkers were not able to draw a conclusion whether a single compound or the combination of the four substances is responsible for the observed effects. The lack of compound-specific investigations is a crucial limitation of this study. In another investigation, the antioxidative potential of garcinoic acid has been compared to a-TOH using antioxidant activity assays. Terashima et al. found that the antioxidant activity of the natural product was 1.53 times that of a-TOH. This value was comparable to d-T3 (1.47) and d-TOH (1.53), molecules sharing high structural similarity to garcinoic acid [25]. Terashima and coworkers chemically modified garcinoic acid by shortening of the side chain. It appeared that the antioxidative activity was significantly affected by structural features, i.e., the shorter the side chain the higher the antioxidative potential. The garcinoic acid analogue with the shortest side chain had 18.7 times higher antioxidant activity than a-TOH [25]. To conclude, garcinoic acid seems to be one of the most potent antioxidative compounds in G. kola seeds with an antioxidant activity comparable to compounds such as d-TOH and d-T3. The lack of in vivo studies with garcinoic acid makes predictions difficult whether the antioxidative capacity of garcinoic acid can contribute to drug development and disease treatment. Natural antioxidants in general are believed to have beneficial effects on different diseases. One of the best investigated groups of natural antioxidants are the polyphenols. Compounds such as quercetin, resveratrol, and curcumin are well-investigated members of this class of compounds that have almost similar antioxidative properties as garcinoic acid. All three substances are potent radical scavengers, especially

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for hydroxyl radicals [135e137]. Furthermore, quercetin and curcumin have inhibitory effects on nitric oxide formation in different cell types [138,139]. In contrast to garcinoic acid, the use of these polyphenolic compounds for the treatment of diseases in which oxidative stress is involved has already been investigated in mouse models and humans. For example, natural antioxidants showed beneficial effects in nonalcoholic fatty liver disease (NAFLD9) and Alzheimer disease (reviewed in Refs. [140,141]). NAFLD is a metabolic disorder associated with high levels of free fatty acids and an increased cardiovascular and liver-related morbidity [142]. High oxidative and inflammatory damage in hepatocytes can also lead to nonalcoholic steatohepatitis (NASH10) [143]. Experiments in mice fed a Western diet showed that quercetin lowers oxidative stress in hepatocytes, which in turn leads to reduced liver steatosis [144]. In addition, resveratrol showed promising effects for NAFLD patients in a controlled clinical trial, mainly through lowering inflammatory markers and the reduction of oxidative stress [145]. Resveratrol was further used in studies on Alzheimer disease. Studies demonstrated the importance of neuroinflammation and oxidative stress in the pathogenesis of this disease. One of the most important factors contributing to the development of Alzheimer disease is b-amyloid, because of its ability to generate superoxide anions and a-carbon-centered radicals. The high ROS production caused by b-amyloid may lead to neuronal death [146,147]. Due to its antioxidant activity, resveratrol was used for the treatment of Alzheimer disease in rats, where the compound protected glioma cells from b-amyloid-triggered oxidative damage [148]. Furthermore, curcumin also protected neuronlike PC12 cells from b-amyloid toxicity and displayed neuroprotective effects larger than those of well-known antioxidants such as a-TOH [149]. Besides studies in cellular models, Lim and coworkers have also shown that dietary curcumin suppresses inflammation and oxidative damage in the brain of Tg2576 mice [150]. Furthermore, the epidemiological study by Ganguli and coworkers provides evidence that the Indian population, known for its curcumin-rich diet, shows reduced prevalence of Alzheimer disease compared to the US population [151]. Based on the fact that oxidative stress is a crucial factor for the development of both diseases and natural antioxidants have already shown promising effects on disease prevention, it can be hypothesized that the antioxidative properties of garcinoic acid bear potential for its use in drug development as well as disease prevention and treatment. The well-known effects of other

9. Nonalcoholic fatty liver disease is characterized by the accumulation of fat in the liver of people with no or low alcohol consumption that can lead to inflammation and scarring of the liver. 10. Nonalcoholic steatohepatitis is hallmarked by the accumulation of fat in the liver of people with no or low alcohol consumption accompanied by chronic inflammation, progressive scarring, and cirrhosis of the liver.

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natural antioxidants in the prevention of NASH and Alzheimer disease are a promising starting point for in vivo experiments with garcinoic acid. Apart from the vitamin E isoforms and garcinoic acid, almost nothing is known about the antioxidant activity of the 130 -LCM. Because of their high reactivity, the two LCM 130 -OH and 130 -COOH may act as prooxidants. To prove this hypothesis, Birringer et al. [87] investigated 130 -LCM-triggered ROS production. HepG2 cells were treated with a-130 -OH, d-130 -OH, a-130 -COOH, and d-130 -COOH. The corresponding TOH forms were used as controls. Generation of intracellular and mitochondrial ROS was measured via dichlorofluorescein assay [152]. Incubation with 10 mM a-130 -COOH or d-130 -COOH increased intracellular ROS formation while a-130 -OH, d-130 -OH, and both TOH forms showed no effect. Similar effects have been observed for mitochondrial ROS production. Here, a- and d-130 -COOH increased mitochondrial ROS production by 30e50% while the other compounds had no effect. A decrease in mitochondrial ROS production was observed only for d-TOH [87]. In conclusion, a-130 COOH and d-130 -COOH seem to have strong prooxidant potential while a-130 OH and d-130 -OH do not act as prooxidants. Due to the structural similarity to the a-130 -COOH and d-130 -COOH, it can be expected that garcinoic acid exhibits a similar prooxidant potential, but this has to be confirmed experimentally. These observations differ from the results for the antioxidant effects of the different TOH and T3 forms. Particular attention should be paid to studies showing that a-TOH can possibly act as prooxidant [153,154].

Antiinflammatory Actions Multiple cell types of the innate immune system and paracrine-acting as well as autocrine-acting mediators contribute to the complex process of inflammation. Here, the interplay of proinflammatory and antiinflammatory mediators is vital for the outcome of the inflammatory process, i.e., resolution or chronic inflammation. CVD and cancer, two of the leading causes of death worldwide, are inflammatory diseases, thus highlighting the importance of research for new antiinflammatory treatment approaches. Moreover, diseases of civilization, such as diabetes and obesity as well as asthma, rheumatoid arthritis, osteoporosis etc., have been linked to inflammation. For this reason, the natural modulators of inflammation are of particular interest. Although several mediators of inflammation and underlying pathways have been identified, we here draw attention to the factors only, which have been investigated in the context of LCM and garcinoic acid.

Cyclooxygenases and Their Lipid Mediator Products Eicosanoids comprise a group of lipid mediators involved in inflammation, which include prostaglandins, thromboxanes, leukotrienes (LT) and lipoxins. All eicosanoids are metabolically derived from arachidonic acid. Key enzymes

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of the conversion of arachidonic acid to eicosanoids are COX1 and COX2 as well as lipoxygenases (LOX; the reader is referred to the section “Vitamin E and Lipoxygenases”). Arachidonic acid is released by action of phospholipases A2 from phospholipids of the cell membrane. The bifunctional COX (cyclooxygenation and peroxidation function) forms prostaglandin G2 from arachidonic acid by cyclization and addition of two molecules of oxygen and reduces it further to prostaglandin H2. This endoperoxide serves as substrate for specific synthases and isomerases, which form prostaglandins of the E2, F2, D2, and I2 series as well as thromboxane A2 [155]. While COX1 is constitutively expressed, COX2 can be induced by a variety of proinflammatory stimuli. Hence, COX2 is regarded as the more important source of eicosanoids during inflammation. All of the abovementioned prostaglandins are implicated in proinflammatory actions (reviewed in Ref. [156]).

Vitamin E Modulates Prostaglandin E2 Release and Cyclooxygenase Activity Tocopherol Inhibit Cyclooxygenase Activity The release of prostaglandin E2 (PGE2) is widely used as a marker for the activity of COX. The effect of TOH on the release of PGE2 has been studied in several cell types and settings. In BV-2 microglia cells the induction of PGE2 by LPS could be attenuated by a-TOH dose-dependently. While 25 mM showed no effect, 50 mM diminished the effect significantly and 100 mM almost completely blocked the induction [157]. An interesting finding was made in human aortal endothelial cells: a-TOH induced the release of PGE2 dose-dependently in concentrations above 10 mM. In contrast, COX activity, measured as conversion of exogenous arachidonic acid to PGE2, was attenuated by a-TOH at 10 mM or higher. The authors postulated that a-TOH induces (1) the release of arachidonic acid from membrane phospholipids and (2) the expression of cPLA2. The discrepancy in the abovementioned results is explained by a more relevant effect of a-TOH on substrate release (i.e., the release of arachidonic acid from membrane phospholipids) than on COX activity [158]. These findings implicate that the effects of TOH on PGE2 release depend on the cell type. However, similar findings were made in macrophages. In peritoneal macrophages obtained from rats treated with 5 mg/day a-TOH (i.p.) for 6 days, the production of PGE2 in response to different stimuli was diminished. Interestingly, macrophages from control animals showed a response similar to untreated control cells, when preincubated with a-TOH [159]. In a different approach with peritoneal macrophages the most effective reduction of PGE2 production was observed with d-TOH (1.25e12.5 mM) and a-TOH (12.5e150 mM). g-TOH was less effective and b-TOH had no effect (up to 12.5 mM). Interestingly, all TOH forms reduced COX activity, measured

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as the conversion of PGE2 from exogenous arachidonic acid. Again, d-TOH was most potent followed by b-, a-, and g-TOH in descending order [160]. Thus, the substitution of the chroman ring seems to be important for the modulation of PGE2 synthesis. However, it is possible that the different TOH forms act in different ways, either on substrate availability or on COX activity. Are Tocotrienols the More Potent Vitamin E Form? T3 have also been shown to be potent inhibitors of PGE2 release. In malign mammary epithelial cells, PGE2 release was reduced about 50% of controls by 3 mM g-T3 [161]. Different effects were observed in mouse RAW264.7 macrophages stimulated with LPS to induce PGE2 release and subsequently incubated with three different T3 forms at 10 mg/mL. While g-T3 showed no effect, d-T3 was the most potent inhibitor with about 55% reduction followed by a T3-rich fraction and a-T3. Surprisingly, a-TOH increased the effect of LPS induction [162]. In IL-1b-stimulated A549 lung epithelial cells, g-T3 was as effective as d-TOH in inhibiting release of PGE2. The IC50 for both compounds were about 1e3 mM. g-T3 was more potent than its g-TOH counterpart (IC50 of 6e7 mM), while a-T3 exerted only weak inhibitory action (20% at 20 mM), and a- and b-TOH were completely ineffective below 50 mM [84]. The aforementioned results suggest that the T3 are more potent inhibitors of COX activity than their respective TOH forms. However, the substitution pattern of the chroman ring appears to be also a major determinant for the effectivity of the compound. Tocopherol Metabolites Outclass Their Metabolic Precursors While little is known about the bioactivity of TOH LCM in general, some studies focused on their effects on COX activity. We recently reported that a-130 -COOH is a potent COX-regulating metabolite. In mouse RAW264.7 macrophages, the upregulation of COX2 mRNA and protein by LPS and the subsequent increase in PGE2 release was diminished by a-130 -COOH and a-TOH. Whereas a-TOH reduced PGE2 production about 55%, a-130 -COOH abolished PGE2 production almost completely. These findings are of particular significance as 100 mM a-TOH was less effective than 5 mM of a-130 -COOH. This underlines the higher effectivity of the LCM. In addition to PGE2, the LPS-induced formation of further arachidonic acidederived eicosanoids, namely prostaglandin D2 and prostaglandin F2a, was blocked by a-130 -COOH. In contrast, a-TOH did not diminish the induction by LPS significantly [102]. In agreement with this, Jiang et al. reported no effect of 50 mM a-TOH on PGE2 production in lung epithelial cells [84]. Compared to a-TOH, d-TOH is more potent in inhibiting PGE2 production (vide supra). In contrast to Wallert et al., Jiang et al. used no synthetic LCM, but cell culture medium collected from cells treated with TOH, containing the self-synthesized metabolites 90 COOH, 110 -COOH, and 130 -COOH. An intact-cell assay with preinduced

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COX and arachidonic acid as substrate revealed that the medium containing the d-metabolites is superior to that with g-metabolites in inhibiting COX activity. Unfortunately, the authors used a cell line that is unable to metabolize a-TOH to its respective carboxychromanols [85,86], resulting in no effect of a-TOH in this assay. d-90 -COOH and d-130 -COOH isolated from cell culture supernatants inhibited COX2 with IC50 of 6 or 4 mM, respectively. However d90 -COOH was unable to inhibit activity of purified COX1 and COX2 enzymes in concentrations 140 mM) and g-CEHC (g-30 -COOH; IC50 > 300 mM) [84]. This finding indicates that LCM rather than SCM may be responsible for the antiinflammatory effects of TOH. This assumption is supported by the fact that A549 lung epithelial cells are not able to produce SCM [85,86]. Anyway, d-SCM would be preferable for comparison, as the structure of the chroman ring likely influences the effectivity. Garcinoic Acid: A New Player on the Court? To date, no systematic investigation of the modulation of COX activity by garcinoic acid, the principal d-130 -LCM of d-T3, has been published. With respect to its structural similarities, garcinoic acid shares the chroman ring with d-TOH, which has been shown to be the most potent TOH in this context [160]. In addition, d-T3 is more effective in modulating COX activity than the other T3, which in turn can be considered more effective than TOH [84,162]. The unsaturated chain is a structural feature of garcinoic acid shared with T3. For this reason, we expect that garcinoic acid is more potent in modulating COX than TOH. As garcinoic acid carries a carboxylic acid moiety, one can compare it to the 130 -carboxychromanols generated from TOH. In particular, 130 -COOH have been shown to be substantially more effective in inhibiting COX activity than their metabolic precursors [84,102]. Based on these observations, garcinoic acid is likely more potent than TOH and comparable to (d-)T3 or its LCM, respectively. However, experiments are required to confirm whether this hypothesis holds true. Vitamin E and Cyclooxygenase Expression While the effects of the different vitamin E forms on COX activity are evident, the underlying mechanisms are not yet fully resolved. A common way to decrease the activity of an enzymedin addition to its inhibitiondis its downregulation. As COX1 is constitutively expressed, no regulation is expected nor has been shown experimentally [158,161,162]. Divergent results have been obtained with respect to the influence of vitamin E on COX2 expression. In murine microglia cells, 50 mM a-TOH abolished LPS-induced gene expression and 100 mM moreover reduced protein synthesis of COX2,

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likely via NFkB [157]. However, contradictory results were obtained in other studies. COX2 levels were reduced neither by 100 mM a-TOH in LPS-treated murine macrophages [102] nor by 60 mM a-TOH in IL-1b-stimulated human lung epithelial cells [158]. For the suggested molecular mode of action on COX activity, the reader is referred to the section “Tocopherol Inhibit Cyclooxygenase Activity.” In contrast to TOH that may exert posttranscriptional effects on COX activity, T3 have been shown to downregulate COX expression. In LPS-treated RAW264.7 macrophages, 10 mM of a-, g-, and d-T3 blocked COX2 expression while a-TOH did not [162]. In line with this, 10 mM of g-T3 downregulated constitutive COX2 expression in human pancreatic cancer cells and 50 mM completely blocked the expression [163]. These findings are supported by further studies, characterizing g-T3 [161,164] and d-T3 [165] as highly efficient suppressors of COX2 expression. Interestingly, in both studies comparing the effects of T3 forms on COX2 expression, d-T3 was the most potent one [162,165]. The higher ability of d-T3 to diminish COX2 activity is in accordance with results for the different TOH forms. However, the ability to regulate COX2 expression seems to be a characteristic of T3.

Effect of Long-Chain Metabolites of Vitamin E on Cyclooxygenase 2 Expression Based on the findings for TOH and T3, it can be assumed that a-TOH LCM are rather ineffective in regulating expression of COX2. Surprisingly, Wallert et al. reported significant blocking of LPS-induced expression of COX2 by a-130 -COOH in murine RAW264.7 macrophages: preincubation with 5 mM a-130 -COOH and subsequent coincubation with LPS significantly diminished the effect of LPS on COX2 expression at mRNA and protein levels. In contrast, 100 mM of a-TOH showed no significant effect [102]. These results show that the a-LCM act in a different fashion and at lower concentrations than their respective metabolic precursors. The underlying pathways have not been elucidated so far and remain to be investigated. Effect of Garcinoic Acid on Cyclooxygenase 2 Expression So far, no studies have been published that investigate the effects of garcinoic acid on COX2 expression. Due to the unsaturated chain, garcinoic acid is structurally comparable to d-T3 but also shares similarities with a-130 -COOH. Considering this, it can be assumed that garcinoic acid may also interfere with the LPS-mediated upregulation of COX2. Preliminary results of our group indicate that garcinoic acid indeed has the potential to block the LPS-induced upregulation of COX2 mRNA as well as protein (unpublished data). However, this is merely a first hint and further experiments are needed. Nevertheless, garcinoic acid would not be the first compound isolated from plants for the treatment of inflammatory diseases in folk medicine. Well-known examples

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are curcumin from Curcuma longa, capsaicin from Capsicum species, and epigallocatechin-3-gallate from Camellia sinensis [166]. All of these compounds have been shown to inhibit COX2 expression [167,168]. Especially C. longa has been used for centuries in Ayurvedic medicine to treat inter alia the inflammation-related diseases asthma, rheumatism, and diabetes [169]. Today, more than 50 completed clinical trials with curcumin display the interest in this valuable ingredient of C. longa in modern medicine. As with C. longa, G. kola is used in folk medicine to treat inflammation-related diseases (the reader is referred to the section “Garcinia kola”). Despite kolaviron, garcinoic acid has now been identified as an antiinflammatory active ingredient of G. kola. In principle, garcinoic acid is an interesting natural compound with antiinflammatory actions that should be further characterized. Possibly, the properties of kolaviron and garcinoic acid can be used jointly in the form of a G. kola nut extract to treat CVD, cancer, and other diseases of civilization.

Vitamin E and Lipoxygenases Lipoxygenases and Their Lipid Mediators LT are formed by LOX, a family of enzymes with four subclasses, namely 5-, 8-, 12-, and 15-LOX, which are classified according to the position at which these enzymes catalyze the dioxygenation of PUFA. The release of arachidonic from membrane phospholipids by cPLA2 is crucial for LT synthesis. 5-LOX catalyzes the oxidation of arachidonic acid and thus the formation of 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which in turn is converted to LTA4 by the same enzyme. LT A4 is the precursor of LTB4 or LTC4, which are in turn the precursors of LTD4 and LTE4, respectively, formed by LTA4 hydrolase and LTC4 synthase, respectively [170]. Tocopherols Inhibit Lipoxygenase Activity The first demonstration of 5-LOX inhibition by TOH was published in 1985 [171]. It was shown that a- and g-TOH inhibit the conversion of arachidonic acid to 5-HPETE by 5-LOX from potato tubers. Interestingly, the inhibition was as efficient as with known 5-LOX inhibitors, such as nordihydroguaiaretic acid and butylated hydroxytoluene, and furthermore irreversible and noncompetitive with arachidonic acid [171]. LT B4 is a major product of the 5-LOX pathway (vide supra) and is thus widely analyzed in activity and signaling studies. In 1999, Devaraj and Jialal noticed that preincubation of human peripheral blood mononuclear cells (PBMC) with a-TOH (but not b-TOH) impaired the release of IL-1b in response to LPS. Treatment of the cells with LTB4 restored IL-1b release. By the use of 5-LOX inhibitors it was confirmed that 5-LOX mediates the effects of a-TOH. Furthermore, a-TOH diminished LTB4 release [172]. A later study of the same group confirmed these results. PBMC isolated from a-TOH-supplemented healthy subjects showed impaired ability to produce TNFa in response to LPS compared to

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cells obtained at baseline or after washout. Preincubation of LPS-stimulated PBMC with 50 or 100 mM a-TOH as well as 5-LOX inhibitors showed the same effect. The impaired TNFa release could be restored by LTB4 [173]. In vitro experiments show that concentrations of 25 mM of a-TOH are not sufficient to inhibit release of TNFa. This raises the question whether a supplementation with 1200 IU/day (corresponds to about 800 mg/day) is sufficient to achieve the required plasma levels of a-TOH. It might be possible that the a-LCM mediate or contribute to the effects observed in vivo, but this remains to be shown experimentally. Two human trials in hemodialysis patients support the abovementioned findings [174,175]. Patients under hemodialysis exhibit increased 5-LOX levels in their PBMC. In these studies, patients were subjected to a-TOH administration to improve oxidative stress markers [174]. Supplementation with a-TOH, 300 mg/day i.m., 600 mg/day orally [150], or via vitamin E-coated cuprammonium rayon membranes [151] for 4 weeks diminished LTB4 release and 5-LOX activity. The expression of 5-LOX was not affected by the treatments [175,176]. Although there is evidence that TOH are capable of inhibiting 5-LOX activity and LTB4 production, further research is required. The majority of studies were done on a-TOH, but the different vitamin E forms seem to act differently and there might be more potent forms [171e173]. Furthermore, a-TOH was administered in the mentioned human trials and the effects were attributed to the TOH itself, regardless of metabolic conversions. Effects of Metabolites and Tocotrienol on Lipoxygenase Activity Despite the observation that T3 inhibit 12-LOX activity (reviewed in Ref. [177]), little is known about T3 and their effects on LOX. In fact, just a single study addressed effects of T3 on 5-LOX. In this study, g-T3 was compared to different TOH forms and d-130 -COOH [103]. For this, HL60 cells were differentiated into neutrophils and eosinophils to induce 5-LOX expression. Activity of 5-LOX was subsequently stimulated by different concentrations of the calcium ionophore A23187 and measured as formation of LTB4 and LTC4. In cells incubated with 1 mM, a-TOH was less effective (IC50 ¼ 60 and 40 mM, respectively) than its g- and d-counterparts (IC50 ¼ 5 mM). Interestingly, g-T3 was as effective as g-TOH, and d-130 -COOH was the most potent compound tested (IC50 ¼ 4 mM). Strikingly, d130 -COOH inhibited formation of LTB4 with an apparent IC50 of 7 mM, when cells were stimulated with 5 mM A23187, while none of the other vitamin E forms was able to inhibit 5-LOX activity in this setting with concentrations up to 50 mM. The superiority of d-130 -COOH was confirmed in a cell-free assay with recombinant 5-LOX. Here, the LCM efficiently inhibited the activity of 5-LOX with an IC50 of 0.5e1 mM, while all the other vitamin E forms failed to inhibit 5-LOX with concentrations of up to 50 mM. The efficiency of the carboxychromanol is thus similar to that of zileuton, a specific inhibitor of the 5-LOX-activating protein. For this

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reason, d-130 -COOH is thought to inhibit 5-LOX directly. However, final evidence is pending. An alternative way by which d-130 -COOH may modulate 5-LOX activity is by inhibiting the increase in intracellular Ca2þ levels in response to N-formylmethionine leucyl-phenylalanine or thapsigargin. In this respect, the metabolite was superior to its metabolic precursor d-TOH, which failed to inhibit the induction in calcium influx [103]. Garcinoic Acid and Lipoxygenase Activity No experimental data regarding garcinoic acid and LOX activity are currently available, but based on the observation that the structurally related LCM d-130 COOH is a potent inhibitor of 5-LOX activity, garcinoic acid may likely exert similar effects on this enzyme. The finding that g-T3 is also able to inhibit 5-LOX activity with an efficiency comparable to g-TOH further supports this hypothesis, because the unsaturated chain has obviously no effect on the inhibitory capacity. The same may likely be true for garcinoic acid, but this has to be confirmed experimentally. 5-LOX and its products are involved in many inflammation-related diseases, including CVD, cancer, osteoporosis, inflammatory bowel disease, rheumatoid arthritis, skin diseases, and bronchial asthma. The latter is the major 5-LOX-associated disease and zileuton, the only approved 5-LOX inhibitor so far, is available for treatment [178]. Nevertheless, zileuton has two major drawbacks, liver toxicity and a short halflife [179]. There is thus an urgent need to find new potent 5-LOX inhibitors. Many natural products have been identified as 5-LOX inhibitors (reviewed in Ref. [178]). However, most of them are not well characterized and far from use as drugs [178]. Flavocoxid, a mixture of the bioflavonoids baicalin from Scutellaria baicalensis and catechins from Acacia catechu, made it to a phase III trial but the problem with this natural 5-LOX inhibitor is the reported risk of acute liver injury [180]. Garcinoic acid could line up with the known natural 5-LOX inhibitors, with the potential advantage of modification of multiple inflammatory pathways simultaneously (the reader is referred to the respective chapters on COX). Furthermore, extracts of G. kola have hepatoprotective effects [23], so a nut extract might exert effects on 5-LOX without liver injury. Moreover, garcinoic acid could be hepatoprotective itself, as the related structures TOH and T3 have been reported to be beneficial for liver health repeatedly [181,182]. If garcinoic acid is indeed a 5-LOX inhibitor, its exact mechanism of action should be investigated to assess its clinical potential. The lack of 5-LOX inhibitors with satisfying properties shows the need of new sources for their development and garcinoic acid is a promising candidate.

Modulation of Lipid Homeostasis In addition to inflammation, dysbalanced lipid homeostasis is a key factor for diseases such as atherosclerosis. A plethora of signaling pathways and cellular

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processes are required to regulate lipid homeostasis, involving uptake, intracellular trafficking and storage, metabolism, as well as efflux of lipids. The following sections will only focus on that parts of lipid metabolism that have been linked to the LCM so far, namely, expression of the scavenger receptor cluster of differentiation 36 (CD36), uptake of oxidized LDL (oxLDL), and phagocytosis as well as intracellular lipid storage. These are essential elements of macrophage foam cell formation, which in turn is a key event in the pathogenesis of atherosclerosis.

Tocopherols and Macrophage Foam Cell Formation Macrophage-derived foam cells contribute significantly to the pathogenesis of atherosclerosis. This cell type is therefore studied extensively with respect to its role in inflammation and lipid metabolism. CD36 is a scavenger receptor that significantly contributes to the uptake of oxLDL and is thus involved in the accumulation of cholesterol in intracellular lipid droplets, a hallmark of macrophage foam cells. Therefore, factors that modulate CD36 expression and the uptake of oxLDL are of particular interest. The ability of TOH to modulate the regulation of CD36 and the uptake of oxLDL as well as subsequent processes has been described in several studies: a-TOH is able to suppress the upregulation of CD36 during macrophage differentiation [183,184]. Furthermore, it blocks the upregulation of CD36 in response to oxLDL in THP-111 macrophages [185] and to modified LDL in PBMC-derived macrophages [183]. Moreover, the uptake of oxLDL can be decreased by a-TOH in several macrophage models [183e185]. The incubation with oxLDL causes a lipid accumulation in macrophages, which can be also prevented by a-TOH [185]. In line with this, the accumulation of cholesteryl esters in response to modified LDL is diminished in a-TOH-treated macrophages [183]. The regulatory effects of a-TOH on CD36 have been observed also in mice. Apolipoprotein E-knockout mice fed a diet supplemented with 100 mg/kg a-TOH per day for 8 weeks showed a reduced extent of atherosclerotic lesions as well as the expression of CD36 therein and serum concentrations of oxLDL than the respective control group [186]. Similar findings were obtained in LDL-receptor-knockout mice. Here, supplementation with a-TOH acetate and a-TOH (equivalent to 50 IU vitamin E per kilogram of diet, ad libitum) for 18 months resulted in a decrease in lesional and nonlesional expression of CD36 [187]. These findings are also supported by results from liver disease research. The HepG2 liver cell line shows decreased CD36 expression when treated with a-TOH [188]. Rats fed a diet enriched with 80 IU/kg diet (ad libitum) a-TOH 11. THP-1 cells are a human monocytic cell line derived from an acute monocytic leukemia patient. THP-1 monocytes can be differentiated into macrophages using phorbol 12-myristate 13-acetate.

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acetate showed reduced hepatic CD36 mRNA levels compared to controls [189], and a comparable result was obtained with merely 6 mg/kg of the diet a-TOH combined with 11 mg/kg of the diet g-TOH ad libitum [190]. A study with guinea pigs points to a posttranslational regulatory mechanism of a-TOH decreasing CD36 protein levels in the liver [191].

Effects of Long-Chain Metabolites and Garcinoic Acid on Macrophage Foam Cell Formation A surprising result was obtained when we examined the effects of LCM on CD36 expression. In contrast to the downregulatory potential of 100 mM a-TOH, its LCM a-130 -OH and a-130 -COOH upregulated CD36 mRNA and protein in human THP-1 macrophages and human PBMC-derived macrophages obtained from healthy volunteers with as little as 10 and 5 mM, respectively. Generally, primary cells showed a slightly lower response. In addition, the increase in CD36 expression by oxLDL was attenuated by a-TOH and markedly augmented with the LCM [101]. Given the LCM-induced CD36 expression, an increase in oxLDL uptake is expected, but this was not the case. Treatment with LCM before addition of oxLDL led to decreased oxLDL uptake in THP-1 and PBMC-derived macrophages. In line with this, the accumulation of neutral lipids by oxLDL was attenuated in LCM-pretreated cells [101]. We found that garcinoic acid also induces the expression of CD36 in the nonproliferating THP-1 macrophage model. Here, the effectivity of garcinoic acid was comparable to that of the aand d-LCM (unpublished data). Since the current state of knowledge on the regulation of lipid metabolism by garcinoic acid is based only on cellular models, it is difficult to draw conclusions whether these observed effects may have an influence on in vivo models. As mentioned before, garcinoic acid shows functions similar to other natural compounds such as resveratrol, especially with regard to its antioxidative properties. For this reason, resveratrol is preferred for deducing possible in vivo effects of garcinoic acid on lipid homeostasis. Independent experiments in THP-1 and 3T3-L1 cells showed that CD36 expression is upregulated by resveratrol [192,193]. Unfortunately the uptake of oxLDL has not been measured in these cell models. In addition to the mentioned in vitro studies, Chen and coworkers investigated the effect of resveratrol treatment on lipid homeostasis in skeletal muscles of rats fed a high-fat diet. After 8 weeks of high-fat feeding, the basal CD36 mRNA expression was increased in the intervention group in comparison to controls. The treatment with resveratrol led to a further induction of CD36 expression [194]. Based on this observation it was quite surprising that the enhanced expression of an important lipid importer did not lead to increased intracellular lipid accumulation, indicating that the induction of CD36 expression by resveratrol has no negative effect on in vivo lipid balance [194]. Because of the similarities between the properties of resveratrol and garcinoic acid, it could be hypothesized that a possible upregulation of CD36 expression by garcinoic acid will also have no negative

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effects on lipid metabolism in vivo. However, further experiments are needed to prove this concept.

CONCLUSIONS AND PERSPECTIVES With the evidence of circulating a-LCM in human blood, a new perspective in vitamin E research was presented. In addition to the well-studied TOH and the latterly more focused T3, their LCM must be taken into account to correctly interpret the effects of vitamin E in humans. We speculate that the LCM comprise a new class of regulatory molecules that complicate the interpretation of studies on the effects of vitamin E in vivo as these molecules exert effects that are different from their metabolic precursors. So far, only a few studies have focused on this class of compounds. However, the LCM seem to share properties with their precursors but to exert also unique or even adverse effects. It is evident that the LCM and precursors act in the same manner with respect to cytotoxicity and modulation of COX2 and 5-LOX activity but it is of note that the LCM are significantly more potent than their precursors in these cases. Hence, the LCM may indeed play a role in mediating these effects of vitamin E in the human body although the blood concentrations are significantly lower than those of TOH. In addition, the LCM exhibit different effects, like their prooxidative capacity reported by Birringer et al. [87]. This in turn is surprising, as vitamin E in general is well known for its antioxidative properties. Moreover, the LCM apparently upregulate CD36, while the downregulation of this receptor by TOH has been shown repeatedly. Furthermore, the LCM can act in areas where the TOH are virtually not effective. A prime example is the regulation of COX2 expression (for more information, the reader is referred to the section “Bioactivity of Garcinoic Acid, Vitamin E and Long-Chain Metabolites”). The natural product garcinoic acid is structurally related to the a-LCM. However, little is known about its bioactivity (Fig. 9.9). Merely, its antioxidative and antiproliferative potential as well as its inhibition of DNA polymerase b have been examined. Due to the structural similarities to TOH, T3, and the LCM, many, yet unknown, effects of garcinoic acid can be expected, making garcinoic acid an interesting natural product for pharmacologic research itself. Although little is known on the effects of garcinoic acid, G. kola nuts have been reported as inter alia antidotal, antiinflammatory, antidiabetic, and hepatoprotective. It is likely that garcinoic acid contributes to these properties as it has strong antiinflammatory and antioxidative properties. First results support this hypothesis, as garcinoic acid has shown antiinflammatory actions via downregulation of COX2 expression. For this reason it will be interesting to see what effects garcinoic acid shows in different cell and animal models. If the proposed beneficial properties shown in Fig. 9.10 come true, garcinoic acid has to be tested in clinically relevant studies in animals and later on humans. This may lead to the transfer of knowledge from folk medicine to modern medicine to cure disease.

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FIGURE 9.9 Known and proposed effects of garcinoic acid.

FIGURE 9.10 Proposed beneficial effects of garcinoic acid on human diseases. For detailed information, the reader is referred to the relating chapters. CVD, cardiovascular disease; NASH, nonalcoholic steatohepatitis.

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In addition, garcinoic acid is a helpful substrate that can be reliably isolated from G. kola nuts in pure form for synthesizing the d-LCM, namely d-130 -OH and d-130 -COOH, as well as the a-LCM, namely a-130 -OH and a-130 -COOH. The isolation of garcinoic acid from G. kola nuts is a simple yet effective method with a yield superior to other reported isolation procedures (the reader is referred to Table 9.1). Thus the procedure provides a reliable base for the synthesis of large amounts of LCM. Pure a- and d-LCM can be simply and efficiently obtained with the semisynthesis route presented by Mazzini and Birringer. Taken together, this procedure is the most effective way to obtain sufficient amounts of the respective LCM of interest for cellular, animal, as well as human experiments. For this reason, the isolation of garcinoic acid allows the synthesis of the LCM in an elegant and efficient way and the investigation of physiological functions of the a- and d-LCM in vitro as well as their pharmacological modes of action in vivo in appropriate animal disease models. To unravel unknown effects and better understand known effects of the different vitamin E forms, as well as to elucidate the underlying regulatory mechanisms that likely involve the LCM, some central questions should be addressed. These include inter alia (1) Which proteins are involved in the uptake and intracellular trafficking of garcinoic acid and of the LCM? (2) Which cellular receptors, signaling proteins, or enzymes mediate the effects of garcinoic acid and of the LCM? (3) What are the regulatory mechanisms that mediate expression of genes in response to garcinoic acid and to the LCM? (4) Which molecular structures are responsible for the effects of garcinoic acid or of the LCM? (5) Do the different LCM differ in their effects and effectiveness? To answer these questions, systematic and comprehensive studies are required. The studies likely involve the identification of potential transporters, binding protein receptors for garcinoic acid, and the LCM. These studies should be complemented by profiling of the effects of garcinoic acid and LCM on gene expression and signaling pathways in different cell types as well as studies in animal models that will shed new light on the regulatory modes of action of the different vitamin E forms and their metabolites. To understand the structureeactivity relationship, further structurally related compounds, such as synthetic derivatives of garcinoic acid or of the LCM or enantiomer-pure molecules as well as compounds that represent substructures of the molecule, i.e., the chroman ring or the side chain, should be studied. To sum up, the availability of the LCM as pure compounds provides new perspectives for vitamin E research that will likely contribute to a better understanding of the physiological function of vitamin E. In this respect, the natural product garcinoic acid is a very helpful tool that provides simple and efficient access to the pure a- and d-LCM for functional studies.

ABBREVIATIONS 130 -COOH 130 -OH

130 -carboxychromanol 130 -hydroxychromanol

474 Studies in Natural Products Chemistry 5-HPETE ABCA1 ACE ACN AcOH AP-1 AVED CC CD36 CEHC cHEX CoA COX CPT CVD CYP DCM EMSA EtAc HEP HEX HPLC ICM IL iNOS LC LCM LDL LOX LPS LT MAPK MCP1 MS NAFLD NASH NFkB NMR NPC1L1 oxLDL PBMC PGE2 PKB PKC PUFA ROS SCM SRB1

5-hydroperoxyeicosatetraenoic acid ATP binding cassette transporter A1 acetone acetonitrile acetate activator protein 1 ataxia with vitamin E deficiency column chromatography cluster of differentiation 36 carboxyethyl-hydroxychromanol cyclohexane coenzyme A cyclooxygenase centrifugal partition chromatography cardiovascular diseases cytochrome P450 dichloromethane electrophoretic mobility shift assays ethyl acetate heptane hexane high-performance liquid chromatography intermediate-chain metabolite(s) interleukin inducible nitric oxide synthase liquid chromatography long-chain metabolite(s) low-density lipoproteins lipoxygenase lipopolysaccharides leukotriene mitogen-activated protein kinase monocyte chemotactic protein 1 mass spectroscopy nonalcoholic fatty liver disease nonalcoholic steatohepatitis nuclear factor “kappa-light-chain-enhancer” of activated B cells nuclear magnetic resonance Niemann-Pick C1-like protein 1 oxidized LDL peripheral blood mononuclear cells prostaglandin E2 protein kinase B (Akt) protein kinase C polyunsaturated fatty acid(s) reactive oxygen species short-chain metabolite(s) scavenger receptor class B type 1

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tocotrienol(s) chloroform thin-layer chromatography tumor necrosis factor a tocopherol(s) tocopherol transfer protein very-low-density lipoproteins

ACKNOWLEDGMENTS Work of M.B. is funded by grants from “Forschung fu¨r die Praxis” of the Hessisches Ministerium fu¨r Wissenschaft und Kunst. Work of S.L. is supported by grants from the Deutsche Forschungsgemeinschaft and the German Federal Ministry of Research and Education as part of the Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig.

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Chapter 10

Antibiotics Derived From Marine Organisms: Their Chemistry and Biological Mode of Action Bibi Nazia Auckloo, Bin Wu1 Ocean College, Zhejiang University, Hangzhou, China 1 Corresponding author: E-mail: [email protected]

Chapter Outline Introduction Sources of Marine Antibiotics Marine Invertebrates Marine Sponges Marine Microorganisms (Bacteria and Fungi) Chemistry and Activities of Marine Antibiotics Protein/Polypeptide Polyketide/Macrolactones Anthroquinone Class Polybrominated Biphenyl Class

483 485 485 485 486 487 487 497 500 501

Terpenoid Class Alkaloid Class Mode of Action Disruption of Membrane Leading to Restriction of DNA Synthesis Inhibition of Bacterial RNA Polymerase Quorum Sensing Manipulation/Inhibition Opinion and Conclusion References

502 504 506

506 507 509 510 511

INTRODUCTION The ocean covers 70% of the Earth’s surface accommodating approximately 87% of life on the planet. The marine biosphere offers a wide range of invaluable and unique compounds which possess diverse biological properties [1,2]. A great number of natural products originate directly from marine animals such as sponges, cnidarians, and mollusks while some arise from microbes like bacteria or fungi which are linked to other organisms or dwell in Studies in Natural Products Chemistry, Vol. 51. http://dx.doi.org/10.1016/B978-0-444-63932-5.00010-3 Copyright © 2016 Elsevier B.V. All rights reserved.

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marine sediment. According to the database created by Hu et al. [3], a pool of 12,322 new compounds has been isolated from marine organisms from 1985 to 2008. Further inquiries by Blunt et al. [4e7] revealed an increase in isolation of new compounds from marine organisms accounting a total of 6948 from 2009 to 2014. The structural miscellany and biochemical distinctiveness of natural products derived from marine origin surpasses to a high extent the ones from terrestrial origin, thus are considered as potential candidates in the development of novel and beneficial agents for medical applications [8e12]. Microorganisms striving under specific circumstances such as extreme variations in temperature, pressure, salinity, dissolved oxygen, and nutrients availability generate antimicrobial or antibiotics having vast inhibitory potential against harmful gram-positive as well as gram-negative bacteria [13]. Anaerobic bacteria have long been neglected until the isolation of the prime antibiotic closthiamide from Clostridium cellulolyticum [14] which lead to the application of genetics in revealing the anaerobic world [15]. Besides acting as antibacterial agents, marine bacteria were noted to generate compounds such as Salinosporamide A which was shown to be a proteasome inhibitor in clinical trial [16], marinomycins which have the ability of acting as antitumor antibiotics [17], apratoxin A exhibiting anticancer capacities [18]. More information can be accessed in Ref. [19]. Compared to natural products isolated from terrestrial sources, a huge number of marine microorganisms producing significant natural products have long been underexplored due to the difficulty in their cultivation and isolation in the laboratory [20]. In the past years, it has been shown that there was a continuous decline in isolation of effective antibacterial compounds due to increased research expenses, unavailability of sophisticated methodologies which could be able to identify new promising compounds, lack of expertise, and manpower, as well as lack of freedom to carry out researches due to regulatory barriers. As a matter of evolution, pathogens mutate at a rapid pace, thus modifying its genetic materials which boost up its capacity of becoming more resistant by acquiring metabolic power [21]. Consequently, a major threat to humanity which is on the top priority list worldwide is the resistance of bacteria to antibiotics which is drastically escalating the rate of patients with infectious diseases. For instance, two million deaths are recorded as a result of bacterial infections around the world. For the very first time, the World Health Organization (WHO) has organized the “World Antibiotic Awareness Week” which was held from 16 to 22 November, 2015 in order to reveal information about antibiotic resistance for its good use in the future [22]. Therefore, it is a matter of life and death to engage in the development of new promising drugs and going through the “antibiotic era” once again. This chapter will focus mainly on the antibiotics produced by marine organisms, their related chemistry and antibacterial activities either in vitro or in vivo as well as their mechanisms of action where available.

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SOURCES OF MARINE ANTIBIOTICS As mentioned above, the ocean is an untapped source of scaffolds with unique products which further encouraged researches in the isolation of promising antibacterial compounds which could be developed and clinically tested for therapeutic remedies and medical purposes. Marine organisms are usually divided into three main groups namely plankton, nekton, and benthos where all possess a wider molecular diversity compared to terrestrial organisms due to their prolonged evolutionary history [23].

Marine Invertebrates From previous studies, marine invertebrates comprising about 60% of marine fauna [24] were seen to generate bioactive natural products which can be considered as beneficial therapeutic agents for human, with more information available in Ref. [25]. Based on the investigation carried out by Leal et al. [26], almost 10,000 new marine natural products were isolated from invertebrates since 1990 to 2009 with the most ubiquitous origins being from Porifera and Cnidaria. However, this section will focus mainly on the isolation of antimicrobial peptides from marine invertebrates followed by antibacterial compounds from marine sponges. Marine invertebrates have a specific mechanism in defending themselves against invasive microbes by the innate immune system comprising of both the cellular (encapsulation or phagocytosis) and humoral (antimicrobial agents in blood cells and plasma) reactions [27]. This innate immune system permits the formation of antimicrobial peptides (about 10 ;kDa) which can be classified as a-helices, b-sheet, or small proteins [28]. Due to resistance of bacteria to previous known antibiotics, antimicrobial peptides exerting a vast array of toxicity to pathogens are paving the way into pharmaceutical industries and research institutions in order to be developed as prospective antibiotics for future use [29e31]. Some antimicrobial peptides which have been demonstrated to act against pathogenic microorganisms are myticusin-1 which was isolated from Mytilus coruscus mussels in China [32], and myxinidin isolated from the hagfish Myxine glutinosa L. found in Canada [33] which are both discussed below.

Marine Sponges Marine sponges from the phylum Porifera are considered as the most primeval organisms dwelling in a wide range of marine ecosystems in temperate, polar, and tropical regions [34]. These multicellular, sessile invertebrates account for approximately 15,000 species discovered till now with a diversity in their morphological appearance mainly shapes and colors [35]. Sponges are generally exposed to many predators among them being pathogenic microorganisms and despite the fact that they are immobile, these unique marine

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organisms have developed chemical defenses by producing and releasing specific compounds for protection and for space competition purposes [36,37]. From 2010 to 2014, numerous tremendous secondary metabolites isolated from marine sponges have been discovered accounting for a total of 1460 [4e7]. Sponges generate a diversity of substances which can be classified in different chemical classes such as peptides, terpenes, or alkaloids [38e45] with promising antibacterial activities [46e49]. Sponges from different part of the world such as Brazil [50,51], New Zealand [52], or France [53] have revealed strong antimicrobial effect against both gram-positive and gramnegative bacteria. According to previous work, about 800 antibiotic substances have been identified from marine sponges [54]. Some examples include manoalide isolated from Luffariella variabilis [55], axinellamine B, axinellamine C, axinellamine D [56], and petrosamine B [57] from the Australian Axinella sp., and Oceanapia sp., respectively. Moreover, haliclonacyclamine E and arenosclerin A, B, and C from Arenosclera brasiliensis found in Brazil showed antibiotic impact on 11 antibiotic-resistant bacteria [54]. The manzamine-type alkaloids (12, 34-oxamanzamine E, 8-hydroxymanzamine J, and 6-hydroxymanzamine E) derived from the Indonesian Acanthostrongylophora species [58] also displayed promising results which make them potential candidates for the future.

Marine Microorganisms (Bacteria and Fungi) Since the discovery of the first antibiotic namely penicillin by Alexander Fleming in 1929, terrestrial microorganisms has been the chief focus of research. Due to a high duplication rate of metabolites isolation from the soil, pathogens increased resistance and upsurge in infectious diseases; marine microorganisms have now become the spotlight of researchers worldwide. Soil actinomycetes are exceptional prokaryotes which were seen to produce a great number of unique natural products among which is antibiotics [59]. Nowadays, marine actinobacteria are considered as a fruitful generator of potent natural products which can be beneficial in the pharmaceutical industry [60]. Due to the completely different marine conditions, marine actinomycetes were shown to display wider genetic and metabolic diversity leading to the production of novel metabolites [60e63]. However, a strong point to be noted is that there is uncertainty about the source indigenous marine actinomycetes populations which might have been transported from land to the sea [64,65]. Cultivation methodologies used in the laboratory have shown that actinomycetes dwell in every part of the ocean from the deep sea to living in symbiotic relationship with some other marine organisms [66]. Marine bacteria have proved themselves in producing novel interesting secondary metabolites which are efficacious against some pathogenic microbes. For instance, abyssomicin C isolated from the Verrucosispora strain from marine sediment at a depth of 289 m [67], diazepinomicin (ECO-4601) generated from Micromonospora

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strain obtained from the marine ascidian Didemnum proliferum [68], hormaomycin B and C isolated from actinomycete strain (SNM55) from marine sediment in Korea [69] as well as lobophorin E and F obtained from the actinobacterial strain SCSIO 01,127 in the South China Sea sediment [70] revealed persuasive antibacterial capabilities. Together with marine bacteria, marine fungi also have the skills to yield antimicrobial agents such as the antibiotic pestalone produced from a mixed culture of marine fungus (strain CNL-365, Pestalotia sp.) obtained from the phaeophyta Rosenvingea sp. in the Bahamas Islands and an unidentified, antibiotic-resistant marine bacterium [71] as well as terretonin G isolated from the fungus Aspergillus sp. OPMF00272 from poriferan in Japan [72]. Furthermore, three new chlorine containing antibiotics (8-chloro-9-hydroxy8,9-deoxyasperlactone, 9-chloro-8-hydroxy-8,9 deoxyasperlactone, and 9-chloro-8-hydroxy-8,9-deoxyaspyrone) had been isolated from the fungus Aspergillus ostianus strain TUF 01F313 obtained from an unidentified marine sponge at Pohnpei showed fascinating inhibitory effects on the marine bacterium Ruegeria atlantica [73]. Two new oxaphenalenone dimers, talaromycesone A and B isolated from Talaromyces sp. strain LF458 obtained from the tissues of the sponge Axinella verrucosa at 20 m deep in the Mediterranean Sea also revealed effective antibacterial activities [74]. Table 10.1 gives a summary of antibiotics and/or antibacterial agents derived from marine organisms.

CHEMISTRY AND ACTIVITIES OF MARINE ANTIBIOTICS So far, terrestrial antibiotics have been found to possess diverse mode of action acting on different types of pathogens and researchers are now going in more details about the specific mechanisms in order to maneuver imminent treacherous bacteria using marine antibiotics. Previous studies focused mainly on the elucidation of the chemical structures of novel antibacterial compounds from the ocean and limited works have been carried out on the detailed mode of action of the marine antibiotics. This part will give you an insight of the recent works done, the various chemical classes of antibiotics, the bioactivities, and mode of action of some marine antibiotics displaying the countless benefits of marine natural products, which can be used to path the way for a better future without infectious diseases.

Protein/Polypeptide The Lactococcus lactis strain PSY2 isolated from the surface of marine yellow perch fish Perca flavescens exhibited antibacterial activities against grampositive and gram-negative bacteria namely Arthrobacter sp., Acinetobacter sp., Bacillus subtilis, Escherichia coli, Listeria monocytogenes, Pseudomonas aeruginosa, and Staphylococcus aureus. It was seen that the shelf-life of the

Chemical Class

Source

Protein/ polypeptide

Mussel Mytilus coruscus

Isolated Compound

Potential Target

Mode of Action

Reference

Myticusin-1

Bacillus subtilis, Staphylococcus aureus, Sarcina luteus, and Bacillus megaterium

Act on cell wall

[32]

Hagfish Myxine glutinosa L.

Myxinidin

Salmonella enterica serovar Typhimurium C610, Escherichia coli D31, Aeromonas salmonicida A449, Yersinia ruckeri 96-4, and Listonella anguillarum 02-11

d

[33]

Actinomycete strain (SNM55)

Hormaomycin B and C

Kocuria rhizophila NBRC 12708

d

[69]

Lactococcus lactis strain PSY2

Bacteriocin PSY2

Arthrobacter sp., Acinetobacter sp., B. subtilis, E. coli, Listeria monocytogenes, Pseudomonas aeruginosa, and S. aureus

d

[75]

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TABLE 10.1 Summary of Antibiotics/Antibacterial Agents Derived From Marine Organisms

Hc-cathelicidin

Dislocate the pathogen’s cell membrane

[76]

Oyster Crassostrea madrasensis

C. madrasensis protein

Vibrio cholerae, Vibrio parahaemolyticus, Salmonella sp., Shigella sp., Streptococcus sp. and Staphylococcus sp.

d

[77]

Actinomycete strain (CNS-575)

Etamycin

Hospital- and community-associated methicillin-resistant S. aureus, Streptococcus pyogenes, Streptococcus agalactiae, coccobacilli, Moraxella catarrhalis

Obstruction of protein synthesis in bacterial cells

[78]

Marine sponge Neamphius sp.

Neamphamide B

Mycobacterium smegmatis

d

[79]

Streptomyces sp. CNB-091

Salinamide A

Enterobacter cloacae ATCC 13047 and Haemophilus influenza ATCC 49247

Inhibition of bacterial RNA polymerase

[99]

Streptomyces sp. CNB-091

Salinamide F

S. aureus, E. coli, Enterococcus faecalis, H. influenza, Neisseria gonorrhoeae, E. cloacae

Inhibition of bacterial RNA polymerase

[100]

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Sea snake Hydrophis cyanocinctus

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Continued

Chemical Class

Source

Polyketide/ macrolactones

Marine Verrucosispora strain

Isolated Compound

Potential Target

Mode of Action

Reference

Abyssomicin C

Methicillin-resistant S. aureus

Restrict the biosynthetic precursor of folic acid

[67]

Actinobacterial strain SCSIO 01127

Lobophorin E and lobophorin F

S. aureus ATCC 29213, E. faecalis ATCC 29212 and Bacillus thuringensis SCSIO BT01

d

[70]

Talaromyces sp. strain LF458

Talaromycesone A and B

Staphylococcus epidermidis and the methicillin-resistant S. aureus

d

[74]

B. subtilis MTCC 10403

7-O-methyl-50 -hydroxy30 heptenoateemacrolactin

Aeromonas hydrophila, V. parahemolyticus ATCC 17802

Affect the lipophilic membrane

[82]

Streptomyces sp. JRG-04

Aromatic polyketide compound 4

S. aureus MTCC 3160

Disrupt the cell membrane

[83]

Bacillus sp. 09ID194

Macrolactins X, Y, Z

B. subtilis (KCTC 1021), E. coli (KCTC 1923), and Saccharomyces cerevisiae (KCTC 7913)

d

[84]

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TABLE 10.1 Summary of Antibiotics/Antibacterial Agents Derived From Marine Organismsdcont’d

Polybrominated biphenyl class

Macrolactin S

E. coli, S. aureus and B. subtilis

d

[85]

Fungal strains KF970 and LF327 from the family Lindgomycetaceae obtained from a marine sponge

Lindgomycin and ascosetin

B. subtilis, S. epidermidis and methicillin-resistant S. aureus

d

[86]

Streptomyces cyaneofuscatus M-27

Cosmomycin B

d

d

[87]

Streptomyces sp. (CMB-M0150)

Aranciamycin I and Aranciamycin J

Mycobacterium bovis BCG, B. subtilis

d

[88]

Pseudomonas stutzeri

Zafrin

S. aureus, and Salmonella typhi

Destructive effect on the cytoplasmic membrane

[89]

Pseudoalteromonas phenolica sp. O BC30T

MC21-A 1

Render the cell membranes of bacteria permeable

[90]

P. phenolica O-BC30T

MC21-B 2

Disruption of the cell wall or cell membrane of the pathogens

[91]

Methicillin-resistant S. aureus, B. subtilis and Enterococcus serolicida

Continued

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Anthroquinone class

Bacillus sp.

491

Chemical Class

Terpenoid class

Isolated Compound

Potential Target

Mode of Action

Reference

Sponge Luffariella variabilis

Manoalide

d

d

[55]

Fungus Aspergillus sp. OPMF00272

Terretonin G

S. aureus FDA209P, B. subtilis PCI219 and Micrococus luteus ATCC9341

d

[72]

Red sea sponge named Prianos sp.

Prianicin A and prianicin B

Beta hemolytic Streptococcus

d

[92]

Strain CNQ-525 (genus: Tentatively called MAR4)

Chlorine-containing terpenoid dihydroquinones

Methicillin-resistant S. aureus, Vancomycin-resistant Enterococcus faecium

d

[73]

Soft coral Sarcophyton trocheliophorum

Sarcotrocheliol acetate and sarcotrocheliol

S. aureus, Acinetobacter spp., and MRSA

d

[93]

Acanthella cavernosa

10- And 15-formamido-kalihinol F

d

Inhibit bacterial folate (cofactor for metabolic processes) biosynthesis

[94]

Source

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TABLE 10.1 Summary of Antibiotics/Antibacterial Agents Derived From Marine Organismsdcont’d

Alkaloid class

Axinellamine B, axinellamine C, axinellamine D

Helicobacter pylori

d

[56]

Sponge Oceanapia sp.

Petrosamine B

H. pylori

Ability to inhibit the enzyme aspartate semialdehyde dehydrogenase needed for protein synthesis

[57]

Sponge Arenosclera brasiliensis

Haliclonacyclamine E, arenosclerin A, arenosclerin B, and arenosclerin C

P. aeruginosa and 10 methicillin-resistant S. aureus strains

d

[54]

Sponge Acanthostrongylophora species

12,34-Oxamanzamine E, 8-hydroxymanzamine J, and 6-hydroxymanzamine E

Mycobacterium tuberculosis

d

[58]

Micromonospora strain

Diazepinomicin (ECO-4601)

Certain gram-positive bacteria

d

[68]

Fugus Stachybotrys sp. MF347

Stachyin B

B. subtilis, S. epidermidis and methicillin-resistant S. aureus

d

[95]

Fungus Trichoderma sp. strain MF106

Trichodin A

B. subtilis and S. epidermidis

d

[96]

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Sponge Australian Axinella sp.

493

Continued

Chemical Class

Source

Chlorinated benzophenone

Marine fungus strain CNL-365, Pestalotia sp.

Chlorinecontaining antibiotics

Phenazine antibiotic

Not provided (d).

Isolated Compound

Potential Target

Mode of Action

Reference

Pestalone

Methicillin-resistant S. aureus and vancomycin-resistant E. faecium

d

[71]

Fungus Aspergillus ostianus strain TUF 01F313

8-Chloro-9-hydroxy8,9-deoxyasperlactone, 9-chloro-8-hydroxy-8,9 deoxyasperlactone, and 9-chloro-8-hydroxy8,9-deoxyaspyrone

Ruegeria atlantica

d

[73]

Halophilic marine bacterium

LL-14I352a

E. coli

Disruption of cytoplasmic membrane and ability to restrict DNA synthesis

[97]

Novel Pseudomonas sp.

a-pyrone I

B. subtilis, S. aureus, M. catarrhalis, and E. faecium

Interruption of the cellular uptake of amino acids and acetates leading to the disruption of membrane

[98]

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TABLE 10.1 Summary of Antibiotics/Antibacterial Agents Derived From Marine Organismsdcont’d

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reef cod fillet, Epinephelus diacanthus was extended to greater than 21 d at 4 C upon spraying 2.0 mL of 1600 AU/mL bacteriocin on the latter compared to the short lifetime of the control (less than 14 d). Therefore, the bacteriocin PSY2 which was confirmed as a protein due to its inactivity against trypsin treatment acted as an antibiotic which could be utilized for the preservation of high-cost seafood [75]. A new compound designated as Hc-cathelicidin (Hc-CATH) comprising of 30 amino acids was the first cathelicidin to be isolated from the sea snake Hydrophis cyanocinctus. It was seen to exhibit powerful antimicrobial activities by dislocating the pathogen’s cell membrane thus killing the bacterial cells. Low cytotoxicity against mammalian cells was also observed making it a good candidate for further development as an antibiotic [76]. Crassostrea madrasensis, an edible oyster found in India, generated a protein with bacterial inhibitory capacities against various human pathogens namely Vibrio parahaemolyticus, Streptococcus sp., and Staphylococcus sp. in the agar well diffusion assay with minimum inhibitory concentration (MIC) being greater than 0.1 mL [77]. A new compound namely Myticusin-1 was isolated from hemolymph of adult mussels M. coruscus in Zhoushan, China. Myticusin-1 is an 11 kDa peptide (104 amino acids) including 10 cysteines forming five disulfide bonds, and 30 residues N terminal sequence, where its tertiary configuration was principally categorized by alpha-helixes. Myticusin-1 was proven to exhibit resilient antibacterial activities against gram-positive strains namely B. subtilis, S. aureus, Sarcina luteus, and Bacillus megaterium (MIC < 5 mM). A weaker effect was seen against gram-negative strains such as E. coli, V. parahaemolyticus, P. aeruginosa, and Vibrio harveyi (MIC > 10 mM). This compound was perceived to act on the cell wall of both S. luteus and E. coli where laminar mesosomes were seen to appear followed by cell wall effects including unevenness of its thickness as well as the separation of the cytoplasmic membrane from the cell wall [32]. Hormaomycin B and C (Fig. 10.1) from a marine mudflat-derived actinomycete strain (SNM55) were isolated from Mohang, Korea. Hormaomycin B and C were peptide-derived compounds with highly modified amino acid residues. The two cyclic depsipeptides possessed distinctive structural units, namely 4-(Z)-propenylproline, 3-(2-nitrocyclopropyl) alanine, 5-chloro1-hydroxypyrrol-2-carboxylic acid, and b-methylphenylalanine. Both were shown to possess substantial inhibitory properties against pathogenic bacterial strains Kocuria rhizophila NBRC 12,708 [69]. Another depsipeptide called etamycin (Fig. 10.1) was for the first time isolated from an actinomycete strain (CNS-575) from Nasese shoreline, Viti Levu, Fiji. The structure of etamycin was certified as a three distinct rotamer appearing in the 2D nuclear magnetic resonance spectrum. Etamycin, belonging to the streptogramin antibiotic class, was shown to have potential antibacterial activities against a range of clinically relevant hospital-associated

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R = H hormaomycin B R = CH3 hormaomycin C

etamycin

neamphamide B FIGURE 10.1 Structures of antibiotics in protein/polypeptide class.

and community-associated methicillin-resistant S. aureus (HA- and CA-MRSA) where the MIC was only 1e2 mg/L. In addition, gram-positive bacteria namely Streptococcus pyogenes and Streptococcus agalactiae as well as Gram-negative bacteria such as coccobacilli and Moraxella catarrhalis were also affected by etamycin which furthermore showed no cytotoxity even at 128 mg/L. Etamycin exhibited promising time-kill kinetics in comparison to

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vancomycin (another MRSA antibiotic) as well as exposed its ability to prevent death in a murine model of systemic lethal MRSA infection. Etamycin, alone, was seen to be prominent in the obstruction of protein synthesis in bacterial cells as compared to other streptogramin antibiotic [quinupristindalfopristin (Synercid): presently used in complex cutaneous infections] which are only able to act in pairs where quinupristin bind to 50S ribosomal subunit averting polypeptide elongation and dalfopristin enhance the latter’s activity by binding to another site on the 50S ribosomal subunit in order to inhibit protein synthesis [78]. Neamphamide B (Fig. 10.1), a cycle depsipeptide, was isolated from the marine sponge Neamphius sp. in Japan. Neamphamide B possessed antimycobacterial abilities against Mycobacterium smegmatis at MIC 1.56 mg/mL under both aerobic and hypoxic conditions. Furthermore, it was also proven active against Mycobacterium bovis Bacillus Calmette-Gue´rin (BCG) with MIC values 6.25e12.5 mg/Ml making it a good antimycobacterial agent [79]. A new cationic compound comprising of three positively charged amino acids (one histidine and two lysine) and one negatively charged amino acid (aspartic acid) having approximately 50% of hydrophobic amino acid content was designated as myxinidin. It was isolated from the acidic epidermal mucus of the hagfish M. glutinosa L. found in Canada. A wide range of pathogenic bacteria such as Salmonella enterica serovar Typhimurium C610, E. coli D31, Aeromonas salmonicida A449, Yersinia ruckeri 96-4, and Listonella anguillarum 02e11 was tested against myxinidin where the latter was highly dominant at the minimum bactericidal concentration 1.0e2.5 mg/mL. It was further noted that myxinidin was able to preserve its antibacterial capacities in elevated sodium chloride concentration (up to 0.3 M) as well as showed no hemolytic activities against mammalian blood cells. Myxinidin was also exposed to be 16 times stronger than pleurocidin NRC-17 (another antimicrobial peptide) against the tested pathogenic microorganisms [33]. Additional studies suggested that this type of compound had the ability to disrupt the cytoplasmic membrane [80] or the restriction of nucleic acid synthesis [81].

Polyketide/Macrolactones An actinobacterial strain SCSIO 01,127 from the Streptomyces genus isolated from sediment in the South China Sea was revealed to produce two new lobophorins analogs called lobophorin E and F (Fig. 10.2). Both compounds exhibited antibacterial activities against S. aureus ATCC 29,213, Enterococcus faecalis ATCC 29,212, and Bacillus thuringensis SCSIO BT01. It was noted that the MIC of these two compounds were 8 and 2 mg/mL, respectively, against B. thuringensis SCSIO BT01. Moreover, lobophorin F displayed better antibacterial activities against S. aureus ATCC 29,213 and E. faecalis ATCC 29,212 with the MIC being 8 mg/mL. It was also proven that the lack of hydroxyl group on C-32 could be beneficial in the enhancement of the antimicrobial features [70].

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FIGURE 10.2 Structures of antibiotics in polyketide/macrolactones class.

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The spirotetronate polyketide namely abyssomicin C (Fig. 10.2) which was isolated from marine Verrucosispora, had the ability to restrict the biosynthetic precursor of folic acid (vitamin B9) named para-aminobenzoic acid (pABA, 41). As a result, DNA synthesis was affected causing some kind of mutation and eventually lead to the cell’s detriment. This compound was proven to hinder development of methicillin-resistant S. aureus with its MIC being 5.2 mg/mL [67]. The bacteria B. subtilis MTCC 10,403 associated with the seaweed Anthophycus longifolius produced a novel antimicrobial metabolite labeled as 7-O-methyl-50 -hydroxy-30 -heptenoateemacrolactin which has a polyketide backbone. According to the agar diffusion method, 7-O-methyl-50 -hydroxy-30 heptenoateemacrolactin disclosed a diameter of 18 mm as the inhibitory zone against Aeromonas hydrophila and 16 mm against V. parahemolyticus ATCC 17,802 at a concentration of 100 mg on disk. Finally, due to its lipophilic characteristics, 7-O-methyl-50 -hydroxy-30 -heptenoateemacrolactin was seen to penetrate easily through the lipophilic membrane of the bacteria, henceforth exhibiting higher bactericidal capacities [82]. A novel Streptomyces sp. JRG-04 isolated from the mangrove sediment gave rise to an aromatic polyketide which was structurally related to aromatic benzoisochromanequinone polyketide antibiotic compound having good bioactivities against diverse bacteria. This new compound was found potent against both gram-positive and gram-negative bacteria where it had an MIC of 1.25e2.5 mg/mL against S. aureus MTCC 3160 compared to other antibiotic compounds like streptomycin with MIC values 1.5e2.5. An MIC of 5 mg/mL could disrupt the cell membrane of methicillin resistant S. aureus resulting in cell death as shown by staining their nucleic acid with both ethidium bromide (impermeable to membrane) and acridine orange (permeable to cell membrane). It was also noted that this novel compound had no cytotoxic effect on Cardiomyoblasts (H9C2) cell lines [83]. A low salinity mass culture broth of a marine Bacillus sp. 09ID194 yielded three original 24-membered macrolactones which are named macrolactin X, Y, and Z (Fig. 10.2). These three compounds exhibited antimicrobial activities against B. subtilis (KCTC 1021), E. coli (KCTC 1923), and Saccharomyces cerevisiae (KCTC 7913). It was also pointed out that in order to be more effective against pathogenic organisms, the hydroxyl group on C-15 in the macrolactone ring of the macrolactins boosted up the antibiotic activities [84]. Macrolactin S (Fig. 10.2), a 24-membered ring lactone, was isolated from a culture broth of marine Bacillus sp. which was obtained from the sea sediment of East China Sea. This one was perceived to possess 5 oxygenated methines, 12 olefinicmethines, 5 methylenes, a methyl and a lactone carbonyl carbon and it was the first macrolactin to be hydroxylated at C-12. This new compound was demonstrated to be a powerful antibacterial agent, which could act against E. coli, S. aureus, and B. subtilis at an MIC of 0.2, 0.7, and 100 mg/mL, respectively [85]. Lindgomycin and ascosetin (Fig. 10.2) were unusual

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polyketides isolated from mycelia and culture broth of two Lindgomycetaceae fungal strains KF970 and LF327 derived from association with a sponge in the Baltic Sea. Both compounds were seen to possess two distinct domains, a bicyclic hydrocarbon and a tetramic acid, linked by a bridging carbonyl. High inhibitory activities were displayed against B. subtilis and Staphylococcus epidermidis with IC50 (concentration causing 50% inhibition of the desired activity) values ranging from 2 to 6 mM. Moreover, strong antibiotic capacities were noted against methicillin-resistant S. aureus with IC50 values 5.1 (0.2) mM for Lindgomycin and 3.2 (0.4) mM for ascosetin [86]. Two new oxaphenalenone dimers talaromycesone A and B (Fig. 10.2) were isolated from the culture broth and mycelia of the marine fungus Talaromyces sp. strain LF458 obtained from tissues of the sponge A. verrucosa at a depth of 20 m. Talaromycesone A was seen to exhibit antibacterial activities against clinically relevant strains S. epidermidis and the methicillin-resistant S. aureus at IC50 value 3.70 (0.13) mM and 5.48 (0.03) mM, respectively, whereas talaromycesone B exhibited antibacterial capacities against the same pathogens at IC50 values 17.36 (0.05) mM and 19.50 (1.25) mM, respectively [74].

Anthroquinone Class Streptomyces cyaneofuscatus M-27 associated to seaweed (Phylum heterokontophyta) from the Central Cantabrian Sea were seen to produce cosmomycin B (Fig. 10.3). According to a study carried out previously by Li et al. [87], cosmomycin B isolated from a soil sample in Yunnan Province showed the ability to inhibit gram-positive bacteria as well as hinder DNA synthesis of P388 of leukemia cell in vitro with IC50 value 5.47 mg/mL. Aranciamycin I and J (Fig. 10.3) are two novel anthracycline antibiotics and aranciamycin A and aranciamycin, two known compounds were isolated from the Australian marine-derived Streptomyces sp. (CMB-M0150) in marine sediment. Aranciamycins were noted as different from other anthracycline compounds isolated from microorganisms due to the lack of an amino group on their sugar moiety. The four compounds were able to inhibit the growth of M. bovis BCG in vitro at MIC ranging from 10 to 30 mM and IC50 values varying from 0.7 to 1.7 mM as well as against B. subtilis strains at MIC ranging from 3.7 to 15 mM and IC50 values varying from 1.1 to 6.0 mM. Taking into consideration the low cytotoxicity of these isolated marine compounds, more work should be carried out on its mode of action for future development in the medical field [88]. Zafrin (Fig. 10.3), a new compound isolated from the marine bacterium Pseudomonas stutzeri derived from the intestinal tract of a Ribbon fish (Desmodema spp.), was revealed to be 4b-methyl-5, 6, 7, 8 tetrahydro-1 (4b-H)phenanthrenone. Zafrin was a stable uncharged metabolite being both hydrophobic and lipophilic and exhibited potent antibacterial activities against some

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FIGURE 10.3 Structures of antibiotics in anthroquinone class.

pathogens like S. aureus, and Salmonella typhi with MIC values for the gram-positive bacteria varying from 50 to 75 mg/mL to 75e125 mg/mL for gram-negative bacteria. Zafrin revealed a destructive effect on the cytoplasmic membrane of B. subtilis with a faster time kill kinetics compared to other antibiotics such as ampicillin, vancomycin, and tetracycline [89].

Polybrominated Biphenyl Class The marine bacteria Pseudoalteromonas phenolica sp. O BC30T were reported to produce a 3,30 ,5,50 -tetrabromo-2,20 -biphenyldiol (halogenated biphenyl compound) called MC21-A as illustrated in Fig. 10.4 which was considered as a symmetrical aromatic benzene. This new marine derived antibiotic with MIC of 1e2 mg/mL had the capacity to render the cell membranes of bacteria permeable, thus leading to cells death. Moreover, a concentration of up to

502 Studies in Natural Products Chemistry

FIGURE 10.4 Structures of antibiotics in polybrominated biphenyl class.

50 mg/mL demonstrated no cytotoxicity against human normal fibroblast, rat pheochromocytoma, and vero cells [90]. Another antibiotic called MC21-B (Fig. 10.4) has been isolated from the same marine bacterium P. phenolica O-BC30T. MC21-B was revealed to contain three bromines, a hydroxyl residue, aromatic benzene as well as halogens and was proven to be 2,20 ,3-tribromo-biphenyl-4-40 -dicarboxylic acid. MC21-B had potent antibacterial activity against 10 clinical isolates of MRSA which also showed MIC between 1 and 4 mg/mL. Moreover, MC21-B acted significantly against B. subtilis and Enterococcus serolicida. Gram-positive and gram-negative bacteria possessing contrasting cell wall structures suggested that the mode of action of this metabolite was related to the disruption of the cell membrane of the pathogens. When comparing MC21-B and MC21-A, it was also proposed that the number of bromines present in the structures might have an important role in the strength of antibacterial activity [91].

Terpenoid Class Terretonin G (Fig. 10.5), a sesterterpenoid, was isolated from the fungus Aspergillus sp. OPMF00272 from a porifera collected in Okinawa, Japan. An antimicrobial assay using paper disk revealed that Terretonin G exhibited antibiotic capacities against gram-positive bacteria S. aureus FDA209P, B. subtilis PCI219, and Micrococus luteus ATCC9341 with an inhibition zone of 10, 8, and 8 mm, respectively [72]. The Red Sea sponge named Prianos sp., residing at a depth of 30 m generated two compounds called prianicin A and B as seen in Fig. 10.5. Both had similar structures which were composed of a 6-membered ring cyclic peroxide, but the stereochemistry of the propionic acid side chain as well as the carbon skeleton were different. These two metabolites exhibited strong inhibition zone being 13 mm and >13 mm at MIC values 2.5 and 1.0 mg/mL, respectively, against beta hemolytic Streptococcus. Their actions were 4e10 times more efficient than tetracycline [92]. The strain CNQ-525 (Genus: tentatively called MAR4) resulting from the ocean sediments at 152 m deep in La Jolla, California produced three novel chlorine-containing terpenoid dihydroquinones (1e3; Fig. 10.5).

503

FIGURE 10.5 Structures of antibiotics in terpenoid class.

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In all the three compounds isolated, the cyclohexane section’s structure and the presence of chlorotetrahydropyran ring were suggested to be the result of a halogen (“Clþ”) induced cyclization. The three isolated compounds associated to the napyradiomycins antibiotics class, expressed important antibacterial activities against MRSA, and vancomycin-resistant Enterococcus faecium (VREF). Compound 1 (3-chloro-10a-(3-chloro6-hydroxy-2,2,6-trimethylcyclohexylmethyl)-6,8-dihydroxy-2,2,7-trimethyl3,4,4a,10a-tetrahydro-2H-benzo[g]chromene-5,10-dione) was effective against MRSA and VREF with MIC values 1.95 and 3.90 mg/mL, respectively. Compound 3 (3-chloro-10a-(3-chloro-6-hydroxy-2,2,6trimethylcyclohexylmethyl)-6,8-dihydroxy-2,2,7-trimethyl-3,4,4a,10a-tetrahydro-2H-benzo[g]-chromene-5,10-dione) was active against MRSA and VREF with MIC values 1.95 mg/mL compared to compound 2 (3-chloro10a-(3-chloro-6-hydroxy-2,2,6-trimethylcyclohexylmethyl)-6,8-dihydroxy2,2,7-trimethyl-3,10adihydro-2H-benzo[g]chromene-5,10-dione) with MIC values 15.6 mg/mL against both MRSA and VREF [93]. Two novel compounds named sarcotrocheliol acetate and sarcotrocheliol as shown in Fig. 10.5 were isolated from the soft coral Sarcophyton trocheliophorum from the Red Sea, Saudi Arabia. These two metabolites were classified as pyrane-based cembranoids, which are considered as diterpenoids with 14-membered ring structures. Both compounds showed strong antibacterial activities against S. aureus, Acinetobacter spp., and MRSA with MIC varying from 1.53 to 4.34 mM with the inhibition zones’ diameter ranging from 12 to 18 mm [94]. Two novel diterpenes compounds named 10- and 15-formamido-kalihinol F were isolated from two Philippine Acanthella cavernosa marine sponge specimens. These antibiotics had the ability to inhibit bacterial folate (cofactor for metabolic processes) biosynthesis [95].

Alkaloid Class Stachyin B (Fig. 10.6), a new spirocyclic drimane coupled by two drimane fragment building blocks, was isolated from the fugus Stachybotrys sp. MF347. This novel compound was the first discovered spirocyclic drimane coupled by a spirodihydrobenzofuranlactam unit and a spirodihydroisobenzofuran unit where the linking point was an NeC bond. Stachyin B was seen to inhibit various gram-positive bacteria namely B. subtilis [IC50: 1.42 (0.07)] mM, S. epidermidis [IC50: 1.02 (0.09)] mM, and the MRSA [IC50: 1.75 (0.09)] mM. The low cytotoxic activities of this novel compound for the mouse fibroblasts cell line NIH-3T3 and the carcinoma cell line HepG2 were at IC50 values 13.01 (0.46) mM and 14.27 (1.54) mM, respectively [96]. Trichodin A (Fig. 10.6), being an unusual pyridine, was acquired from the marine fungus Trichoderma sp. strain MF106 obtained from the Greenland Seas. Trichodin A was categorized as intramolecular cyclization of a pyridine

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FIGURE 10.6 Structures of antibiotics in alkaloid class.

basic backbone with a phenyl group. Gram-positive B. subtilis and S. epidermidis were successfully inhibited by this new compound at IC50 values 27.05  0.53 mM and 24.28  3.90 mM, respectively [97]. The marine sponge A. brasiliensis produced four novel tetracyclic alkylpiperidine alkaloids called arenosclerin A, arenosclerin B, arenosclerin C, and haliclonacyclamine E as demonstrated in Fig. 10.6. Arenosclerin A, arenosclerin C, and haliclonacyclamine E displayed antimicrobial activities against 11 hospital acquired antibiotic-resistant bacteria (a P. aeruginosa and 10 MRSA strains) as well as S. aureus ATCC 6538 with the inhibition zone

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ranging from 7 to 13 mm. However, arenosclerin B was seen to act only against 5 microbes namely S. aureus, P. aeruginosa, and three antibioticresistant S. aureus strains. The four alkaloids compounds proved to be cytotoxic against HL-60 (Leukemia), L929 (fibrosarcoma), B16 (melanoma), and U138 (colon) cancer cell lines at a range of 1.5e7.1 mg/mL [54]. A new substance called petrosamine B (a pyridoacridine alkaloid), isolated from the sponge Oceanapia sp. had the ability to inhibit the enzyme aspartate semialdehyde dehydrogenase needed for protein synthesis in the bacteria Helicobacter pylori at IC50 35 mg/mL [57]. A marine actinomycete of the genus Micromonospora (strain DPJ12) isolated from the marine ascidian D. proliferum in Japan produced a new dibenzodiazepine alkaloid named diazepinomicin (Fig. 10.6) which consisted of a dibenzodiazepine core connected to a farnesyl side chain. Antimicrobial activities were eminent against certain gram-positive bacteria with MIC around 32 mg/mL [68].

MODE OF ACTION The researches carried out about the detailed mode of action of marine antibiotics are scarce. However, this section will provide some of the specific targets of marine antibiotics and their related ways of actions.

Disruption of Membrane Leading to Restriction of DNA Synthesis A culture LL-141,352, isolated from a tunicate collected from the Pacific Ocean was identified as a halophilic marine bacterium. According to the biochemical induction assay, a new phenazine antibiotic LL-14I352a shown in Fig. 10.7 was revealed to possess antibacterial activities. LL-14I352a which contain an amino acid residue had the tendency to ease its transport through cytoplasmic membrane of the pathogens. LL-14I352a showed strong antibacterial activities against E. coli with an imp outer membrane mutation (MIC/MBC, 0.5/2 mg/mL) compared to the unchanged E. coli type. Moreover, this compound showed its ability to restrict DNA synthesis by 82% (IC50: 0.10 mL/mL) obtained from the

FIGURE 10.7 Structures of LL-14I352a and a-pyrone I.

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measurement of radiolabeled precursors 3H-Tdr, 3H-Udr, and 3H-AA into trichloroacetic acid (TCA)-precipitable material from E. coli imp cultures [98]. A novel species of Pseudomonas was isolated from the culture F92S91 obtained from a marine sponge in Fiji generated a new a-pyrone I (Fig. 10.7). The strain B. subtilis was manipulated to acquire a lacZ reporter gene fused with cerulenin and triclosan-responsive promoter which had the capacity to detect fatty acid biosynthesis enzymes inhibitors. a-Pyrone I revealed the highest antibacterial activities against B. subtilis (MIC: 1 mg/mL) and S. aureus, M. catarrhalis, and E. faecium with MIC values ranging from 2 to 4 mg/mL. a-Pyrone I was seen to interrupt the cellular uptake of amino acids and acetates leading to the disruption of membrane of B. subtilis. Cellular uptake of radiolabeled precursors for DNA, RNA, and protein were noted to be inhibited upon exposure of a-pyrone I [99].

Inhibition of Bacterial RNA Polymerase Salinamide A (SalA), as seen in Fig. 10.8, generated by the marine Streptomyces sp. CNB-091 isolated from the jellyfish Cassiopeia xamachana is considered as a bicyclic depsipeptide antibiotic which is comprised of seven amino acids residues and two nonamino acid residues. SalA had the expertise of inhibiting the RNA polymerase active-center function allosterically through conformational changes. SalA target overlapped with a “bridge helix cap” which in turn is divided into three subregions namely the “bridge-helix N-terminal hinge” (BH-HN), the “F-loop,” and the “link region.” More precisely, the RNA polymerase active-center function could be hindered by SalA where the proposed BH-HN hinge-opening and hinge-closing was repressed affecting RNA chain construction. By carrying out macromolecular synthesis assay by observing the integration of [14C]-uracil into RNA demonstrated RNA synthesis inhibition upon addition of SalA in a bacterial culture. Consequently, SalA restricted addition of nucleotide in transcription initiation and elongation. Potent antibacterial activities were noted against gram-negative bacteria such as Enterobacter cloacae ATCC 13,047 and Haemophilus influenza ATCC 49,247 with MIC 1.56 and 6.25 mg/mL, respectively [100]. A new depsipeptide analog named salinamide F (Fig. 10.8) was also isolated from the same marine-derived Streptomyces sp., strain CNB-091 which showed potential ability to constrain bacterial RNA polymerase. The inhibitory activity of Salinamide F was detected by the fluorescencedetected RNAP-inhibition assay. This compound had the same mode of action on bacterial RNA polymerase as SalA where it showed IC50 of 4 mM against S. aureus RNAP and 2 mM for E. coli RNAP. Significant antibacterial effects were also seen against E. faecalis, H. influenza, Neisseria gonorrhoeae, E. cloacae with MIC50 values 12.5, 100, 12.5, 25, and 50 mg/mL, respectively [101].

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FIGURE 10.8 Structures of salinamide A and F.

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Quorum Sensing Manipulation/Inhibition The microbial world is a vast environment where each bacterium plays a unique role by producing, sensing, or reacting to a diversity of chemical signals [102]. Bacteria had developed advanced strategies due to the so-called intracellular and intercellular communication which is usually controlled by quorum sensing (QS). In other words, QS can engender chemical signal which in turn can regulate gene expression depending on the cell-population density [103]. QS is utilized by gram-positive as well as gram-negative bacteria in order to control a great number of physiological events like virulence, antibiotic production, biofilm formation, competence, as well as sporulation [103e106]. Thus, in order to interfere with signals promoting virulence and biofilm formation in pathogenic microorganisms, QS should be mastered and thus enable scientist to identify signals which could boost up antibiotic production against pathogens. For example, according to a previous study, the detrimental effect of P. aeruginosa (involved in cystic fibrosis) was altered by another microorganism being Candida albicans (reside in body cavities). In general, P. aeruginosa has the capability to kill C. albicans by sticking to its surface and execute the cells. However, in order to protect itself, C. albicans changed its shape into filamentous cells which is activated by a bacterial signal 3-0-C12 homoserine lactone (30C12HSL), one of two P. aeruginosa quorum signaling compounds [101]. Therefore, this showed that interspecies communication has the aptitude to control signals in favor or in detriment of different pathogenic microorganisms. Another study carried out by Hentzer et al. showed the possibility of in situ exposure of N-acyl homoserine lactone (AHL)-mediated QS in P. aeruginosa biofilms. According to the secondary metabolite obtained from the Australian macroalgae Delisea pulchra, a halogenated furanone compound was synthesized. This new compound was seen to obstruct with P. aeruginosa cell-to-cell communication thus decreasing QS-controlled gene expression. In other words, the halogenated furanone could infiltrate microcolonies and halter cell signaling and QS in biofilm cells. Affecting the virulence of P. aeruginosa by interfering with biofilm formation showed another prospect for antibacterial activity [107]. An antibiotic malyngolide (MAL) isolated from the cyanobacterium Lyngbya majuscule in the Indian River Lagoon, USA, showed QS inhibition properties. It was seen that MAL-restricted responses of N-AHL reporters (more precisely LasR reporters) of P. aeruginosa at concentrations varying from 3.57 to 57 mM. Moreover, this QS inhibitor repressed elastase (enzyme able to breakdown protein) production (EC50: 10.6  1.8 mM) thus showed capacity to govern heterotrophic bacterial interactions [108].

510 Studies in Natural Products Chemistry

OPINION AND CONCLUSION For a long time, antibiotics have been on the primary bench in combatting bacterial infections. However, due to resistance and evolution of pathogens, antibacterial agents lost their effectiveness and power. For example, S. aureus, a pathogenic microorganism causing pneumonia or deep abscesses [109e111], has become methicillin-resistant and is tagged as “superbug.” As a matter of fact, many more harmful bacteria are following this path leading to increased threat for the entire universe. Study on the isolation of antibacterial compounds, their mechanisms of action as well as their biosynthetic pathway have been neglected for so long and now its on the urge to find new solutions to the aggravating problems of infectious diseases. The ocean is a treasure of cure for infectious diseases and only awaits to be discovered. Microorganisms thriving in extreme conditions such as the hydrothermal vents, arctic regions, or highly saline conditions have the capacity to generate unique and promising compounds which needs to be unveiled by advanced and innovative techniques of isolation and culturing. Moreover, selective, planned methodologies should be developed to be able to culture the unculturable microorganisms by carefully designing special, suitable, original media, and optimized laboratory conditions. Culturing the unculturable should also integrate the aspect of coculture which might play a vital role in activating dormant gene clusters, thus giving access to the encrypted, hidden organisms. Different techniques should be developed about triggering and challenging the organisms to produce highly active, intriguing, and valuable metabolites. Such techniques could be “metal-stress” methods or variation in the type of media used. The “metal-stress” strategy refers to the addition of different concentrations of heavy metals such as Cobalt, Zinc, or Nickel to name a few, to the microorganisms’ culture which showed the ability of activating dormant gene clusters as shown in a previous study carried out by Ding et al. [112]. Strains can also be engineered using the latest techniques of genomics, advanced biotechnology, metagenomics, and proteomics. New branches of science especially the chemical techniques should be integrated into the research of new potent antibiotics from the ocean such as mass spectroscopy, nuclear magnetic resonance, and diverse Chromatography techniques. Additional barrier restraining proper understanding of the real origin of the target metabolite is the wrong interpretation in symbiotic systems. As a step forward to be able to master the links between symbionts, host, and the environment, cutting-edge molecular techniques including the application of fluorescent probes along with classical methods should be applied to disclose the real heroes producing the lead compounds in the complex marine environment. Another important point to take into consideration is the understanding of the true role of antibiotics in nature. Antibiotics were only seen as weapons generated by microorganisms until recently new hypothesis have been put

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forward about their genuine role in nature as signaling agents for proper communication and stable environments. Decrypting the mystery of the exact function of antibiotics in its natural environment will be a first victory against the threatening rise of infectious disease. By decoding this secret, we might be able to discover other molecules which have the ability to boost up the power of antibiotics, thus making them more tenacious and efficacious against the most resistant pathogens. Studying the reason behind the resistance of microbes against antibiotics is another essential aspect, and it should be emphasized that the discovery of new antibacterial agents is not the only important point, but its further and continuous development in order to reach clinical trials is equally vital to achieve progress in combatting diseases caused by pathogens. It should also be pointed out that the relationship between antibiotics and the host, either humans or animals, must be meticulously scrutinized in order to improve its effectiveness and accuracy. The key to success of concretizing all of the above into reality needs the collaboration of scientists, government, as well as industries worldwide. From this chapter, it can be concluded that the ocean may be the sole defender of humanity against infectious diseases.

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Index ‘Note: Page numbers followed by “f” indicate figures and “t” indicate tables.’

A A-seco-triterpenoids, 52e53, 137 A-seco-cycloartane triterpenoids, 126e128 A-seco-dammarane triterpenoids, 129 A-seco-friedelane triterpenoids, 135 A-seco-lanostane triterpenoids, 124e125 A-seco-lupane triterpenoids, 136 A-seco-oleanane triterpenoids, 134 A-seco-tirucallane triterpenoids, 129e130 A-seco-ursane triterpenoids, 134 antibacterial activity, 69e70 antitumor activity, 60e64, 61f antiviral activity, 67e69 biological activity, 59e60 biosynthesis, 57e59 formation of 2,3-seco- and 2, 4-seco-triterpenoids, 58 fragmentation of ring A of triterpenoids, 58 effects on immune system, 64e66 isolation and structure elucidation, 53e55 naturally occurring A-seco-triterpenoids and biological activities, 77te123t other types of biological activity, 70e73 pentacyclic A-seco-triterpenoids, 136 Schisandra Nortriterpenoids, 130e133 seco-triterpenoids as biomarkers, 55e57 synthesis of, 73e75 tetracyclic A-seco-triterpenoids, 133 ABCA1. See ATP-binding cassette transporter A1 (ABCA1) 18(13/14)-Abeo-schiartane, 52, 53f, 67e68 (e)-rel-Abiesonic acid 3-methyl ester, 70 Absorption of vitamin E, 446 Abyssomicin C, 486e487, 498f, 499 Acer nikoense (A. nikoense), 37 Acetylcholinesterase inhibitors (AChE inhibitors), 418, 423e424 Acetylsalicylic acid, 436e437 AChE inhibitors. See Acetylcholinesterase inhibitors (AChE inhibitors) Acid-catalyzed cyclization, 398

Actinomycete Salinispora tropica, 387, 387f Activation protein-1 (AP-1), 42e43, 439 Acumitin, 319, 324f, 368e369 Acyclic squalene, 57 N-Acyl homoserine lactone (AHL), 509 AD. See Anti-Alzheimer disease (AD) Adenine nucleotide translocator (ANT), 204 50 Adenosine monophosphate (AMP), 155e156 Adenosine triphosphate (ATP), 156e157 Adianane dorstenic acid A, 63 Adunchalcone, 302e319, 317f, 367e368 Aesculus hippocastanum. See Horse chestnut (Aesculus hippocastanum) Afzeliindanone, 385, 386f Aging, 208e209 Aglaia argentea (A. argentea), 62 Aglycone, 66 chiisanogenin, 66, 71 AHL. See N-Acyl homoserine lactone (AHL) Aldose reductase (ALR2), 365e367 Alhagi maurorum (A. maurorum), 436 Alkaloids, 385, 385f, 504e506 Alkyl iodide, 451e452, 452f Alkylresorcinols, 36 ALR2. See Aldose reductase (ALR2) Alzheimer’s disease, 202, 443e445, 459e460 b-Amino ketones, 406 1-Aminoindane derivatives, 397 Aminoindanes, 389, 390f, 396 3-Aminoindenones, 389 1,2-bis-(2-Aminophenoxy)-ethaneN,N,N0 ,N0 -tetraacetic acid tetrakis(acetoxymethylester) (BAPTA-AM), 207 AMP. See 50 ; Adenosine monophosphate (AMP) Amphipathic properties of KA, 152 Anaerobic bacteria, 484 Analgesic drugs, 158, 159t Angelica keiskei (A. keiskei), 34e35

517

518 Index Angustific acid A, 68e69 Animal models, cancer development reduction in, 242e244 ANT. See Adenine nucleotide translocator (ANT) Anthelmintic activity, 168e169 Anthroquinone class, 500e501 Anti-Alzheimer disease (AD), 424, 424f Anti-inflammatory properties, 158, 159t Antiapoptotic genes, 158e160 Antibacterial activity A-seco-triterpenoids, 69e70 KA, 162e164, 164te165t Antibacterial agents, 484, 487, 488te494t Antibiotic(s), 484, 488te494t agents from marine microorganisms, 488te494t kinamycin biosynthesis, 384e385 Anticonvulsant drug, 160e162 Antidiabetic activity, 155e156, 156t Antifungal activity, KA, 166, 166te167t Antiinflammatory actions, 461e468 cyclooxygenases and lipid mediator products, 461e462 effect of LCM of vitamin E, 465e466 lipoxygenases, 466e468 vitamin E, 466e468 vitamin E modulates prostaglandin E2 release and cyclooxygenase activity, 462e465 Antimicrobial activity, 418e421, 420fe421f antimycobacterial activity, 420, 421f antituberculosis activity, 421f cholinesterases inhibitor, 419f human prostate cancer inhibitors, 420f Antioxidant activities, 158, 159t function, 211 Antioxidant responsive elements (AREs), 233 activation, 237e239 Antioxidative properties, 458e461 Antiplasmodial compounds, 418e419, 419f Antiprotozoal activity, 167e168, 168t Antitumor activity, 421e428 A-seco-triterpenoids, 60e64, 61f antiprostate cancer activity, 428 antituberculosis agent, 427f estrogen agonist synthesis, 422 fuctionalized indenes, 427 HLO, 422 indanone-based anticancer agents, 427f multitarget-directed ligands, 424f

potent cytotoxic agents, 422f prepared compounds, 425 topoisomerase inhibitory activities, 426f Antitumor agents, 209e210 Antitumoral activities, 158e160, 161te162t Antiviral activity A-seco-triterpenoids, 67e69 KA, 168 Anwuweizonic acid, 73e74 AP-1. See Activation protein-1 (AP-1) Aphanamgrandiol A, 58 Apo-15-lycopenal, 230 Apocarotenoids, 224e225, 238 chemical formation, 230e232, 232f enzymatic formation, 230, 231f Apoptosis, 202, 235 activation, 233e236 phytochemicals suppress and promote MPT, 208e210 signaling in cancer cells, dietary components enhancing, 209e210 Apostichopus japonicus (A. japonicus), 176, 187f Aranciamycin I and J, 500, 501f Arenosclerin A, B, C, 505e506, 505f AREs. See Antioxidant responsive elements (AREs) Aromatic tert-butyl sulfinyl ketimines, 396 6-Aroyl-5-(aroylmethyl)-11a-hydroxy benzo [a]fluoren-11-ones, 393 Artemisia plants, 37 Artocarpus elasticus (A. elasticus), 302e319 2-Aryl-3-bromofurans fused benzocycloalkanes, 402 2-Arylindanes, 392e393 4-Arylthiazolyl hydrazones (TZHs), 418 Ascosetin, 498f, 499e500 Aspalathin, 253e254 Aspergillus sp., 487 A. saitoi, 34e35 Aspirin. See Acetylsalicylic acid Astaxanthin (Ast), 213, 213f Asymmetric oxaspirocyclic indanones, 405e406 Asymmetric synthesis, 406e417 biologically active natural product, 411f chiral 3-aryl-1-indanones synthesis, 417 diastereoselective indanes, 410 enantioselective synthesis, 416e417 fluoro-hydroxyoxindoles, 414 functionalized indenes, 409 high enantiomeric excess, 417

Index highly fused indanes, 415 indanone-based natural products, 408 optically active, 413 spirocyclic 1,3-indanones, 410 total synthesis of mutisianthol, 415 Ataxia with vitamin E deficiency, 443 AtKO. See KO from Arabidopsis thaliana (AtKO) ATP. See Adenosine triphosphate (ATP) ATP-binding cassette transporter A1 (ABCA1), 240e241, 446 Azadirachta indica. See Neem tree (Azadirachta indica) 2-Azafluorenones, 405 Azaphilonoids, 36e37

B Bacillus subtilis (B. subtilis), 387 Bacteria, 486e487 bacterial RNA polymerase, inhibition of, 507 BaeyereVilliger monooxygenases, 411 oxidation, 57 Balsacone M, 319, 327f Balsacones A, 283e302, 301f, 365e367 Balsacones B, 283e302, 301f, 365e367 Balsacones C, 283e302, 301f, 365e367 Balsacones J-L, 319, 327f, 369 BAPTA-AM. See 1,2-bis-(2-Aminophenoxy)ethane-N, N, N0 , N0 -tetraacetic acid tetrakis(acetoxymethylester) (BAPTA-AM) BBr3. See Boron tribromide (BBr3) Bcl-2 proteins, 235 BCO1. See b,b-Carotene-15,150 -oxygenase (BCO1) BCO2. See b,b-Carotene-9,100 -oxygenase (BCO2) BDNF. See Brain-derived neurotrophic factor (BDNF) Benzo[f]-1-indanones, 415 Benzofluorenes, 384e385, 385f, 439 Benzoquinazolin-2-ones, 403e404 p-Benzoquinone, 390e391 Betulinic acid, 73 BH-HN. See Bridge-helix N-terminal hinge (BH-HN) Biflavones, 439 Bioactive ingredients of G. kola nuts, 438e442 Bioactive natural compounds, 214, 436

519

Bioavailability of DHCs, 371e372 Biological activities, 341e372, 342te364t, 383e384, 417e428 A-seco-triterpenoids, 59e60 naturally occurring A-seco-triterpenoids and, 77te123t types, 70e73 antimicrobial activity, 418e421, 420fe421f antitumor activity, 421e428 bioavailability of DHCs, 371e372 C-benzylated DHCs, 368e369, 369f DHC dimers, 369 DHC glycosides, 369e371 DHC lignans, 369 DHCs with simple patterns of O-substitution, 365e367 prenylated DHCs, 367e368 Biosynthesis of KA, 152e155, 153f Bipinnatones A, 302e319, 317f, 367e368 Bipinnatones B, 302e319, 317f, 367e368 1,5-Biradical cyclization, 400 Bitter gourd (Momordica charantia), 23e25 Bitter kola. See Garcinia kola (G. kola) Bivittoside D, 181, 181f, 183 Bogkretic acid (BKA), 205 Bohadschia vitiensis (B. vitiensis), 181 Boron tribromide (BBr3), 403, 403f Brain-derived neurotrophic factor (BDNF), 202 Breast cancer, 223e224 Bridge-helix N-terminal hinge (BH-HN), 507 Bryonia dioica. See White bryony (Bryonia dioica) Bryonia dioica (B. dioica), 25 Buddha fruit (Siraitia grosvenorii), 23e25 Butanol layer, 179e180

C c-AMP response element binding protein (CREB), 42e43 C-benzylated DHCs, 319, 320te323t, 324f, 368e369, 369f C-glycoside derivatives, 388e389 CA-MRSA. See Community-associated methicillin-resistant S. aureus (CA-MRSA) Ca2+ efflux as indicators of transient, 206e207 Caffeoylquinic acids, 37 Calcium (Ca2+), 203 Calorie-dense foods, 224

520 Index Cancer, 38, 191e195, 223e224 development reduction in animal models, 242e244 survivors, 245 Cancer cells dietary components enhancing apoptosis signaling in, 209e210 in vitro, 233e242 activation of antioxidant responsive elements, 237e239 IGF system, 236e237 Nf-kB, 239e240 reduction of cell viability, arrest of cycle progression, 233e236 regulation of PPARs, 240e241 regulation of RAR/RXR, 241e242 Carbamazepine, 160e162 Carbaporphyrins, 401 carbatRipyrrin intermediate, 401 Carboxyatractyloside (CAT), 205 a-,g-, and d-Carboxyethylhydroxychromanol (a-,g-, and d-CEHC), 446e448, 447f Carboxylic group, 156e157 Carcinogenesis, 2 Cardiovascular diseases (CVD), 445 Carinatin C, 67 a-Carotene, 225 b-Carotene, 8e9, 8f, 225 b,b-Carotene-15,150 -oxygenase (BCO1), 230 b,b-Carotene-9,100 -oxygenase (BCO2), 230 Carotenoids, 225, 234 dietary interventional studies, 244e246 CAT. See Carboxyatractyloside (CAT) CD36. See Cluster of differentiation 36 (CD36) CDDO. See 2-Cyano-3,12-dioxooleana1,9(11)-dien-28-oic acid (CDDO) CDDO-Me. See Methyl 2-cyano-3,12dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) CDKs. See Cyclin-dependent kinases (CDKs) a-,g-, and d-CEHC. See a-,g-, and d-Carboxyethyl-hydroxychromanol (a-,g-, and d-CEHC) Cell lines, 233 Cell viability reduction, 233e236 Central nervous system (CNS), 73 Chalcones (CH), 5, 282e283 chemopreventive effects, 34e35, 34f epoxides, 400

Chemical formation of apocarotenoids, 230e232, 232f. See also Enzymatic formation of apocarotenoids Chemistry, 282e341 DHCs C-benzylated, 319, 320te323t, 324f dimers, 324, 328te330t, 331f geranylated, 302e319, 303te313t, 317f glycosides, 327e341, 332te339t, 341f lignans, 319, 325te326t, 327f monoterpene, 302e319, 303te313t, 317f prenylated, 302e319, 303te313t, 317f ring labeling and atom numbering for, 283f with simple patterns of O-substitution, 283e302, 284te299t, 301f Chemoprevention, 2 potential mechanisms, 42e43 Chemopreventive effects of chalcones, 34e35 of diterpenoids, 33 EBV-EA induction test, 3 of fatty acids, 38e39 of flavonoids, 34e35 improvement of bioavailability of triterpenoids, 39e41 inhibitory effects on mouse skin carcinogenesis, 9e23 on TPA-induced EBV-EA activation, 5e9 of phloroglucinols, 35e36 plant and fungal materials investigation, 5 potential mechanisms of chemoprevention, 42e43 preventive malignancy type by triterpenoids, 41 reciprocal effect to another agent, 40e41 of secondary metabolic compounds, 36e38 side effects, 39e40 of steroids, 33e34 toxicity, 39e40 of triterpenoids, 23e33 two-stage carcinogenesis test on mouse skin, 3e5 Chemotaxonomic markers, 56 Chiisanogenin, 71 Chiisanoside, 71 Chinaberry tree (Melia azedarach), 29e30 Chiral 1-oxo-2,3-dihydro-1H-inden-2ylbenzoates, 411

Index Chiral spiro[indane-1,3-dionetetrahydrothiophenes], 395 Chlorine-containing terpenoid dihydroquinones, 502e504, 503f Chrysanthemum (Chrysanthemum morifolium), 31 Chrysanthemum morifolium. See Chrysanthemum (Chrysanthemum morifolium) Chylomicron retention disease, 443e445 Clusia genus, 449e451 Clusiacea, 437 Clusiaceae family, 449 Cluster of differentiation 36 (CD36), 468e471 CNB-091, 507 cNOS-. See Constitutive NO synthase(cNOS-) CNS. See Central nervous system (CNS) CoA. See 2,4-Dienoyl-coenzyme A (CoA) Colossolactone G, 68e69 Colossolactone V, 68e69 Colossolactone VII, 68e69 Community-associated methicillin-resistant S. aureus (CA-MRSA), 495e497 Constitutive NO synthase- (cNOS-), 167e168 Coptis species (Ranunculaceae family), 365e367 Corylopsis pauciflora (Hamamelidaceae), 341 Cosmetics, 185 Cosmomycin B, 500, 501f Coumarins, 37 COX-2. See Cyclooxygenase-2 (COX-2) CPR. See Cytochrome P450 reductase (CPR) Crassostrea madrasensis (C. madrasensis), 495 CREB. See c-AMP response element binding protein (CREB) Croton (Euphorbiaceae), 283e302 b-Cryptoxanthin, 226e227 Cucumaria frondosa (C. frondosa), 177e178, 189f, 192f Cucumaria japonica (C. japonica), 177 Cucumaria okhotensis (C. okhotensis), 190, 190f Cucurbitane-(Cu), 5 Cu-type triterpenoids, 23e25, 26f Curcumin, 8e9, 8f, 210, 214e215, 239e240, 459e460 CVD. See Cardiovascular diseases (CVD)

521

2-Cyano-3,12-dioxooleana-1, 9(11)-dien-28-oic acid (CDDO), 41 a-Cyanoketones, 411 Cycle progression arrest, 233e236 Cyclic triterpenoid pristimerin, 54 Cyclin-dependent kinases (CDKs), 234 Cycloartane-(Cy), 5, 52, 53f, 63 cycloartane-type triterpenoids, 25e27, 26f sootependial, 64e65 2,6-Cyclolycopene-1,5-epoxide, lycopene-5,6-epoxide, 232 Cyclooxygenase activity, 462e465 cyclooxygenase 2 expression, LCM effect of vitamin E, 465e466 expression, 464e465 Cyclooxygenase-2 (COX-2), 42e43, 439 Cyclooxygenases and lipid mediator products, 461e462 Cyclopentane ring, 383e384 Cyclophilin D (Cyp-D), 204 Cyclosporin A (CysA), 204 Cylas formicarius. See Sweetpotato weevil (Cylas formicarius) Cyp-D. See Cyclophilin D (Cyp-D) CYPs. See Cytochromes P450s (CYPs) CysA. See Cyclosporin A (CysA) CysA-sensitive MPT, 215 Cytochrome P450 reductase (CPR), 169 Cytochromes P450s (CYPs), 154, 448 Cytotoxic activities, 158e160, 161te162t Cytotoxic manwuweizic acid, 73e74 Cytotoxicity, 60, 62, 179, 455e458 garcinoic acid, 457e458 vitamin E, 455e456 metabolites of, 456e457

D Daemonorol F. See 2,4-dihydroxy-6methoxy-3-methyl-dihydrochalcone Daemonorops (Arecaceae), 283e302 Dammarane-(Da), 5, 52, 53f dammarane-type shoreic acid, 67 dammarane-type triterpenoids, 27, 27f Dammarenolic acid, 67 Davidigenin (DG), 365e367 Davidigenin-20 -O-(6000 -O-syringoyl)-bglucoside, 341f, 369e371 Dennisic acid A, 302e319, 317f Dennisic acid B, 302e319, 317f

522 Index Desmodema spp. See Ribbon fish (Desmodema spp.) DG. See Davidigenin (DG) DHA. See Docosahexaenoic acid (DHA) DHCs. See Dihydrochalcones (DHCs) Diarylheptanoids, 37 Diazepinomicin, 486e487 Dibenzodiazepine, 505f, 506 2,4-Dienoyl-coenzyme A (CoA), 446e448 Dietary carotenoids, 224 classification, sources, and metabolism, 225e227 dietary interventional studies with carotenoids, 244e246 effect on cancer cells in vitro, 233e242 epidemiologic studies, 227e229 oxidative cleavage reactions, 229e232 reduction of cancer development in animal models, 242e244 Dietary components enhance apoptosis signaling in cancer cells, 209e210 protect cells, 208e209 Dietary interventional studies with carotenoids, 244e246 2,3-Dihydro-1H-indene-1-methanamines, 405 1,4-Dihydrobenzothiopyrano[4,3-c]pyrazole, 209e210 20 ,4,40 ,60 -Dihydrochalcone, 282e283 Dihydrochalcone M-1, 302e319, 317f Dihydrochalcone M-2, 302e319, 317f Dihydrochalcones (DHCs), 253e254 biological activities, 341e372 C-benzylated, 319, 320te323t, 324f chemistry, 282e341 class of compounds, 253e254 dimers, 324, 328te330t, 331f, 369 distribution in botanical orders, 282f in embryophyta division, 256te281t geranylated, 302e319, 303te313t, 317f glycosides, 327e341, 332te339t, 341f, 369e371 lignans, 319, 325te326t, 327f, 369 monoterpene, 302e319, 303te313t, 317f occurrence in plant kingdom, 254e282, 254f prenylated, 302e319, 303te313t, 317f ring labeling and atom numbering for, 283f with simple patterns of O-substitution, 283e302, 284te299t, 301f

Dihydroindene ring, 408, 408f 4,6-Dihydroxy-2-methoxy-3-methyldihydrochalcone, 283e302, 301f (rel-1b-(4, 6-Dihydroxy-2-methoxy)benzoyl-rel-2a-(2, 6-dimethoxy-4hydroxy)-benzoyl-rel-3b, 4a)diphenyl-cyclobutane, 324, 331f 3,40 -Dihydroxy-2,4,6trimethoxydihydrochalcone, 283e302, 301f 40 ,60 -Dihydroxy-20 , 4-dimethoxy-50 -(200 -hydroxybenzyl)dihydrochalcone, 319, 324f, 368e369 4,40 -Dihydroxy-20 ,60 dimethoxydihydrochalcone, 283e302, 301f (R)-20 , b-Dihydroxy-30 ,40 -dimethoxydihydrochalcone, 283e302, 301f 2,3-Dihydroxy-4,30 ,40 ,50 tetramethoxydihydrochalcone, 283e302, 301f 2,4-Dihydroxy-6-methoxy-3-methyldihydrochalcone, 283e302, 301f (rel)-1b,2a-di-(2,4-Dihydroxy-6methoxybenzoyl)-3b, 4a-di-(4methoxyphenyl)-cyclobutane, 324, 331f rel-(1b,2a)-di-(2,4-Dihydroxybenzoyl)-rel(3b,4a)-di-(4-hydroxyphenyl)cyclobutane, 324, 331f 1-(2,4-Dihydroxyphenyl)-3-{3,4-dihydro3,8-dihydroxy-2-methyl-2-(4-methyl3-pentenyl)-2H-1-benzopyran-5-yl}1-propanone, 302e319, 317f, 367e368 1-(2,4-Dihydroxyphenyl)-3-{4-hydroxy6,6,9-trimethyl-6a,7,8,10a-tetrahydro6H-dibenzo(b,d)pyran-5-yl}-1propanone, 302e319, 317f 1-(2,4-Dihydroxyphenyl)-3-{4-hydroxy6,6,9-trimethyl-6a,7,8,10a-tetrahydro6H-dibenzo[Pb,d]pyran-5-yl}-1propanone, 317f, 367e368 1-(2,4-Dihydroxyphenyl)-3-{8-hydroxy-2methyl-2-(3,4-epoxy-4-methyl-1pentenyl)-2H-1-benzopyran-5-yl}-1propanone, 302e319, 317f 1-(2,4-Dihydroxyphenyl)-3-{8-hydroxy-2methyl-2-(4-hydroxy-4-methyl-2pentenyl)-2H-1-benzopyran-5-yl}-1propanone, 302e319, 317f Dihyroindenes, 408

Index Dikamaliartane-A, 62 Dikamaliartane-D, 67 Dimers, 324, 328te330t, 331f, 369 4-(2,5-Dimethoxy-3-methylphenyl) butan-2-one, 451e452, 452f 7,12-Dimethylbenz[a]anthracene (DMBA), 2e3 Dimethylnitrosamine, 439 Dinor-seco-friedelane dzununcanone, 70e71 1,1-Diphenyl-2-picrylhydrazyl (DPPH), 37e38 Distribution in botanical orders, 282f DHCs, 254e255 DHCs in botanical families, 254f in embryophyta division, 256te281t of vitamin E, 446 2,3-Disubstituted indanones, 396e397 b,b-Disubstituted indanones, 401 1,2-Disubstituted indenes, 408e409 Diterpene, 151e152, 154e155, 158, 166, 168 Diterpenoids, chemopreventive effects of, 23e33, 34f Diuretic, 158, 159t DMBA. See 7,12-Dimethylbenz[a]anthracene (DMBA) DMBA/TPA-induced carcinogenesis test, 3e4 DNA methylation, 215e216 synthesis, 499 disruption of membrane to, 506e507 DNA methyltansferase (DNMT), 215e216 DNMT. See DNA methyltansferase (DNMT) Docosahexaenoic acid (DHA), 38 Docosapentaenoic acid (DPA), 38e39 Dorstenia brasiliensis (D. brasiliensis), 63 DPA. See Docosapentaenoic acid (DPA) DPPH. See 1,1-Diphenyl-2-picrylhydrazyl (DPPH) Dracaena (asparagaceae), 283e302 Dracaena cochinchinensis (Chinese dragon’s blood), 283e302 Dracaena species (Asparagaceae), 255e282 Dragon’s blood, 283e302 Dysoxyhainanin B, 69e70

523

Dysoxyhainic acid G, 69e70 Dysoxyhainic acid I, 69e70

E EBV-EA. See EpsteineBarr virus early antigen (EBV-EA) ECC-1 lines. See Endometrial cancer cells-1 lines (ECC-1 lines) Echinoside A, 193 EeAChE. See Electric eel acetylcholinesterase (EeAChE) EGCG. See Epigallocatechin-3-gallate (EGCG) Eichlerianic acid, 67 Eicosanoids, 461e462 Eicosapentaenoic acid (EPA), 38 Elastichalcone A, 302e319, 317f Elastichalcone B, 302e319, 317f Electric eel acetylcholinesterase (EeAChE), 419 Electron transport system (ETC), 203e204 Elfvingic acid H methyl ester, 61e62 5-Endo-trig cyclizations, 409e410 Endometrial cancer cells-1 lines (ECC-1 lines), 234 Ent-kaur-16-en-19-oic acid. See Kaurenoic acid (KA) Ent-kaurenal, 153f Ent-kaurene, 153f Ent-kaurene oxidases (KO), 154 Ent-kaurenoic acid, 153f Ent-kaurenol, 153f Enzymatic formation of apocarotenoids, 230, 231f. See also Chemical formation of apocarotenoids EPA. See Eicosapentaenoic acid (EPA) 20-Epi-koetjapic acid, 66, 69e70 EPIC. See European Prospective Investigation into Cancer and Nutrition (EPIC) Epigallocatechin-3-gallate (EGCG), 215e216 EpsteineBarr virus, 64 EpsteineBarr virus early antigen (EBV-EA), 2e3 induction test, 3 eqBChE. See Equine serum butyrylcholinesterase (eqBChE) Equine serum butyrylcholinesterase (eqBChE), 419 Ergosterol biosynthesis, 418 Erioschalcones A, 302e319, 317f, 367e368

524 Index Erioschalcones B, 302e319, 317f, 367e368 ERK1/2. See Extracellular signal-regulated protein kinase (ERK1/2) Erogol, 185e186 b-Escin, 40e41 Etamycin, 495e497, 496f ETC. See Electron transport system (ETC) Ethnopharmacological knowledge, 436e437 (2E,6E,10E)-Ethyl 11-iodo-2,6,10trimethylundeca-2,6,10-trienoate, 451e452, 452f (2E,6E,10E,14R)-Ethyl 14-hydroxy-16-(2,5dimethoxy-3-methylphenyl)2,6,10,14-tetramethylhexadeca2,6,10-trienoate, 451e452, 452f Etlinglittarolin, 302e319, 317f Euphane-(Eu), 5 euphane-type triterpenoids, 27, 27f Euphorbia antiquorum (E. antiquorum), 27 European Prospective Investigation into Cancer and Nutrition (EPIC), 228e229 Evelynins A, 283e302, 301f, 365e367 Evelynins B, 283e302, 301f, 365e367 Extracellular mechanisms, 235 Extracellular signal-regulated protein kinase (ERK1/2), 209, 212

F Fatty acids, chemopreventive effects of, 38e39, 39f Fernane-(Fe), 5 Ferulic acid, 211, 211f Flavonoids (FL), 5, 214 chemopreventive effects, 34f, 35 Fleminchalcones A, 302e319, 317f, 367e368 Fleminchalcones B, 302e319, 317f Fleminchalcones C, 302e319, 317f, 367e368 Folic acid, 499 Fornicatins A, 71e72 Fornicatins B, 71e72 Fornicatins D, 71e72 Fornicatins F, 71e72 Friedelane, 52, 53f FriedeleCrafts cyclization, 395 Fumaria officinalis (F. officinalis), 385 Fumarofines, 385, 385f Functional food and products, triterpene glycosides inclusion cosmetics, 185

means for disease prophylaxis, 185e188 means of functional food, 183e184 medical drinks, 185 Functional foods, 177 Fungal materials investigation, 5 Fungi, 486e487

G Galphimine- A, 66, 73 Galphimine- B, 73 Galphimine- E, 66 Galphimine- F, 73 Galphin A, 70e71 Galphin B, 70e71 Galphin C, 70e71 Ganoderma lucidum. See Reishi mushroom (Ganoderma lucidum) Garcinal, 439e441, 441f Garcinia genus, 451 Garcinia kola (G. kola), 437 chemical structures of biflavones of, 440f nuts, 437 bioactive ingredients of, 438e442 Garcinia-biflavones 1, 438, 440f Garcinia-biflavones 2, 438, 440f Garcinoic acid, 437, 441e442, 442f, 464 bioactivity, 454e471 antiinflammatory actions, 461e468 antioxidative properties, 458e461 cytotoxicity, 455e458 modulation of lipid homeostasis, 468e471 on cyclooxygenase 2 expression, 465e466 effects, 470e471 known and proposed, 472f proposed beneficial, 472f isolation, 449e451, 450t and lipoxygenase activity, 468 semisynthesis of long-chain metabolites from, 452e454 synthesis, 451e452 GDNFs. See Glial cell lineederived neurotrophic factors (GDNFs) Geranylated DHCs, 302e319, 303te313t, 317f Geranylgeranyl pyrophosphate (GGPP), 153f, 154 Ginkgo biloba (G. biloba), 202e203 Glial cell lineederived neurotrophic factors (GDNFs), 202 Glutathione (GSH), 205

Index Glycosides, 327e341, 332te339t, 341f, 369e371 Glycyrrhetic acid, 8e9, 8f, 73 Gracilipene, 58e59 Gram-negative bacteria, 495e497 Gram-positive bacteria, 69e70, 495e497 GSH. See Glutathione (GSH)

H HA-MRSA. See Hospital-associated methicillin-resistant S. aureus (HAMRSA) hAChE. See Human recombinant AChE (hAChE) Haliclonacyclamine E, 505e506, 505f hBChE. See Human plasmatic BChE (hBChE) HBD. See Hydrogen-bond-donor (HBD) Hc-CATH. See Hc-cathelicidin (Hc-CATH) Hc-cathelicidin (Hc-CATH), 495 Helianthus annuus. See Sunflower (Helianthus annuus) Hepatocellular carcinoma cells (HepG2), 235e236, 238 Hepatoprotective product, 178e179 HepG2. See Hepatocellular carcinoma cells (HepG2) 3,4,4,5,5,7,7-Heptahydroxy-3,8-biflavanone, 438 Herpes simplex virus-1 (HSV-1), 67 N-Heterocyclic carbene (NHC), 398e399 Hexahydroindenopyridines (HHIPs), 422e423 3,4,4,5,5,5,7,7-Hexahydroxy-3,8biflavanone, 438 (S)-Hexahydroxydiphenoyl (HHDP), 255e282 HHDP. See (S)-Hexahydroxydiphenoyl (HHDP) HHIPs. See Hexahydroindenopyridines (HHIPs) High-performance liquid chromatography (HPLC), 449e451 HIV-1 RT. See Human immunodeficiency virus 1 reverse transcriptase (HIV-1 RT) HMG-CoA. See 3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) Hoelen (Poria cocos), 28 Holostane derivatives, 175e176, 176f Holothuria grisea (H. grisea), 194e195, 194f Holothuria pervicax (H. pervicax), 180

525

Holothuria scabra (H. scabra), 176 Holothurians. See Sea cucumbers Holotoxin A1, 181, 182f Homogeneous catalysts, 407 Honeybush, 341 Hooker oxidation condition, 397e398 Hop plant (Humulus lupulus), 35 Hopane-(Ho), 5 Hormaomycin B and C, 495, 496f Horse chestnut (Aesculus hippocastanum), 40e41 Hospital-associated methicillin-resistant S. aureus (HA-MRSA), 495e497 Hostmanins A-D, 302e319, 317f 5-HPETE. See 5-Hydroperoxyeicosatetraenoic acid (5-HPETE) HPLC. See High-performance liquid chromatography (HPLC) HSV-1. See Herpes simplex virus-1 (HSV-1) Human bronchial epithelial cells (NHBE cells), 242 Human cancers, 3 Human immunodeficiency virus 1 reverse transcriptase (HIV-1 RT), 67 Human plasmatic BChE (hBChE), 419 Human recombinant AChE (hAChE), 419 Humulus lupulus. See Hop plant (Humulus lupulus) HupA. See Huperzine A (HupA) Huperzine A (HupA), 418 Hydrogen-bond-donor (HBD), 162e164 5-Hydroperoxyeicosatetraenoic acid (5-HPETE), 466 Hydrophis cyanocinctus (H. cyanocinctus), 495 6b-Hydroxy nigranoic acid, 72e73 16b-Hydroxy-2,3-seco-lup-20(29)-ene-2, 3-dioic acid, 68e69 4-Hydroxy-2,40 -dimethoxydihydrochalcone, 283e302, 301f 13-(6-Hydroxy-2,8-dimethyl-3,4-dihydro2H,2-chromenyl)-2,6,10-trimethyl2,6,10-tridecatrien-1-al. See Garcinal [1,7-bis(4-Hydroxy-3-methoxphenyl)-1, 6-heptadiene-3, 5-dione]. See Curcumin [(E)-3-(4-Hydroxy-3-methoxy-phenyl)prop2-enoic acid]. See Ferulic acid (4-[4-Hydroxy-3-methoxyphenyl]-indan-1one). See Afzeliindanone

526 Index 3-Hydroxy-3-methyl-glutaryl-CoA (HMG-CoA), 152 2-[6-Hydroxy-3,7-dimethylocta-2(E),7dienyl]-20 ,3,4,40 -tetrahydroxydihydrochalcone, 302e319, 317f, 367e368 3-Hydroxy-asebotin, 341f 3a-Hydroxy-masticadienonic acid, 209e210 130 -Hydroxychromanol (130 -OH), 448 3-Hydroxyindanones, 395e396 3-Hydroxyphloretin 40 -(300 -O-caffeoyl-400 , 600 -di-O-(S)-HHDP)-b-D-glucoside, 341f, 369e371 3-Hydroxyphloretin 40 -O-(300 -O-galloyl-400 , 600 -di-O-(S)-HHDP)-b-D-glucoside, 341f, 369e371 3-Hydroxyphloretin 40 -O-(40 ,600 -di-O-(S)HHDP)-b-D-glucoside, 341f, 369e371 3-Hydroxyphloretin 40 -O-(400 ,600 -di-Ogalloyl)-b-D-glucoside, 341f, 369e371 Hypoglycemic, 155e156

I IGF receptor type I (IGF-IR), 236 IGF system. See Insulin-like growth factor system (IGF system) IGF-IR. See IGF receptor type I (IGF-IR) IL-1b. See Interleukin-1b (IL-1b) Illiciumolide B, 65, 68e69 IMM. See Inner mitochondrial membrane (IMM) Immunostimulatory means, 188e191 Indane derivatives, 409e410 indane-1,3-dione derivatives, 397e398 indane-based fluorocompounds, 412 indane-fused isoquinoline alkaloid, 385, 385f natural product bioactive indane-based products, 384f biological activities, 417e428 resveratrol-based dimers and oligomers, 386f synthesis, 388e417 1,2-Indanedione derivatives, 404 1-Indanol derivative, 390e391 1-Indanone, 391e392 Indanones, 393, 400e401 Indenamides, 401 Indene-indole fused heterocycles, 404e405

Indeno[1,2-b] pyridines, 406 Inducible nitric oxide synthase (iNOS), 158, 439 Inflammatory enzymes, 42e43 Inner mitochondrial membrane (IMM), 204. See also Outer mitochondrial membrane (OMM) phytochemicals regulate MTP, 211e213 iNOS. See Inducible nitric oxide synthase (iNOS) Insecticidal activity, 168 Insulin-like growth factor system (IGF system), 236e237 Intercellular communication, 509 Interleukin-1b (IL-1b), 439 Intracellular communication, 509 Intracellular mechanisms, 235 4-Iodo-1-(trimethylsilyl)but-1-yne, 451e452, 452f (S)-1-Iodo-5-(2,5-dimethoxy-3methylphenyl)-3-methylpentan-3-ol, 451e452, 452f IPP. See Isopentenyl pyrophosphate (IPP) IPTG. See Isopropyl b-D-1thiogalactopyranoside (IPTG) Iryantherin-D, 319, 327f, 369 Isochamuvaritin, 319, 324f, 368e369 Isolation methods of individual triterpene glycosides, 180e181 Isomacatrichocarpin C, 302e319, 317f Isopentenyl pyrophosphate (IPP), 152 Isopropyl b-D-1-thiogalactopyranoside (IPTG), 169

J Jasmonic acid derivatives, 38

K KA. See Kaurenoic acid (KA) Kadsuphilactone B, 67 Kadsuracoccinic acid A, 63 Kadsuranic acid A, 68e69 Kaurenoic acid (KA), 151e152 biosynthesis, 152e155, 153f kauralexins, 154f microbiological and insecticide effect anthelmintic and molluscicidal activity, 168e169 antibacterial activity, 162e164, 164te165t antifungal activity, 166, 166te167t

Index antiprotozoal activity, 167e168, 168t antiviral activity, 168 insecticidal activity, 168 pharmacological effects analgesic and anti-inflammatory properties, 158, 159t antidiabetic activity, 155e156, 156t cytotoxic and antitumoral activities, 158e160, 161te162t diuretic and antioxidant activities, 158, 159t in neurological diseases, 160e162, 163t smooth muscle relaxant effect, 156e157, 157t platforms to producing kaurenoid compounds, 169 Keap1. See Kelch-like ECH-associated protein 1 (Keap1) Kefir fungi, 184 Kelch-like ECH-associated protein 1 (Keap1), 215 KO. See Ent-kaurene oxidases (KO) KO from Arabidopsis thaliana (AtKO), 154 Koetjapic acid, 68e70 Kolaflavones, 438, 440f Kolaviron, 439, 440f

L Lactococcus lactis strain PSY2, 487e495 Lanostane-(La), 5, 52, 53f, 63 abiesanolide A, 70 acids, 64 lanostane-type australic acid, 63 lanostane-type triterpenoids, 28e29, 28f Lansic acid 3-ethyl ester, 70 LCM. See Long-chain metabolites (LCM) LD50. See Lethal dose (LD50) LDL receptor. See Low-density lipoprotein receptor (LDL receptor) Lemaphyllane (Le), 5 Lethal dose (LD50), 64 Leukotrienes (LT), 461e462 Lignans, 319, 325te326t, 327f, 369 Lamesticumin A, 70 Limonene, 152e153 Limonoids (Li), 5, 29e30, 30f, 72 Lindgomycin, 498f, 499e500 Lipid homeostasis, modulation of, 468e471 macrophage foam cell formation, 469e470 garcinoic acid effects, 470e471 long-chain metabolites effects, 470e471 tocopherols foam cell formation, 469e470

527

Lipid mediators, 466 Lipopolysaccharides (LPS), 439 Liposomal ursolic acid, 41 Lipoxygenases (LOX), 42e43, 461e462 effects of metabolites and tocotrienol, 467e468 garcinoic acid and, 468 lipid mediators, 466 tocopherols inhibits activity, 466e467 Liquid chromatography analyses, 228 Liver X receptor alpha (LXRa), 240e241 LL-14I352a, 506e507, 506f LNCaP. See Lycopene in androgenresponsive human prostate carcinoma cells (LNCaP) Lobophorin E and F, 497, 498f Long-chain metabolites (LCM), 448 bioactivity, 454e471 antiinflammatory actions, 461e468 antioxidative properties, 458e461 cytotoxicity, 455e458 modulation of lipid homeostasis, 468e471 effects, 470e471 vitamin E, 448e454, 465e466 garcinoic acid isolation, 449e451, 450t garcinoic acid synthesis, 451e452 semisynthesis of long-chain metabolites, 452e454 Long-ipedlactone J, 68e69 Long-term vitamin E deficiency, 443e445 Low-density lipoprotein receptor (LDL receptor), 446 LOX. See Lipoxygenases (LOX) LPS. See Lipopolysaccharides (LPS) LT. See Leukotrienes (LT) Lupane (Lp), 5, 52, 53f lupane-type dysoxyhainic acid H, 70 lupane-type triterpenoids, 30f, 31 Lupeol, 74 Lutein, 227 LXRa. See Liver X receptor alpha (LXRa) Lycopene, 225e226 Lycopene in androgenresponsive human prostate carcinoma cells (LNCaP), 234 Lycopene-1, 2-epoxide, 232

M M446GPAMO. See BaeyereVilligerdmonooxygenases Macatrichocarpins C-D, 302e319, 317f

528 Index Macrolactin S, 498f, 499e500 Macrolactin X, Y, Z, 498f, 499 Macrophage foam cell formation, 469e470 garcinoic acid effects, 470e471 long-chain metabolites effects, 470e471 MAL. See Malyngolide (MAL) Male albino mice (Mus musculus L.), 155e156 Malus genus, 255e282 Malyngolide (MAL), 509 Manwuweizic acid, 73e74 MAO-B. See Type B monoamine oxidase (MAO-B) MAR4, 502e504 Marine biosphere, 483e484 invertebrates, 485e486 microorganisms, 485e487 antibiotics/antibacterial agents, 488te494t organisms, 387, 387f sponges, 485e486 Marine animals, 483e484 Marine antibiotics antibiotics/antibacterial agents, 488te494t chemistry and activities of, 487e506 alkaloid class, 504e506 anthroquinone class, 500e501 polybrominated biphenyl class, 501e502 polyketide/macrolactones, 497e500 protein/polypeptide, 487e497, 496f terpenoid class, 502e504 mode of action, 506e509 sources, 485e487 marine invertebrates, 485e486 marine microorganisms, 486e487 Marinesco-Sjo¨gren syndrome, 443e445 Marinomycins, 484 Mass spectroscopy (MS), 451 Matrix metalloproteinases (MMPs), 42e43 Maximum tolerated dose (MTD), 40 MC21-A, 501e502, 502f MC21-B, 502, 502f MCLA. See [2-Methyl-6-(4-methoxyphenyl)3,7-dihydro-imidazo-(1,2-a)-pyrazin3-one-HCl] (MCLA) McMurry-coupled products, 412 MCP1. See Monocyte chemotactic protein 1 (MCP1) MDR. See Multiple drug resistance (MDR) Means

for disease prophylaxis, 185e188 of functional food, 183e184 of production, 177 Medical drinks, 185 Medicinal plants, 52 Melatonergic ligands, 425, 425f Melia azedarach. See Chinaberry tree (Melia azedarach) Melodinus suaveolens (M. suaveolens), 387e388, 387f Membrane disruption to DNA synthesis restriction, 506e507 lipid fluidity, 214e216 7-MEOTA. See 7-Methoxytacrine (7-MEOTA) 7-Methoxytacrine (7-MEOTA), 419 Methyl 2-cyano-3,12-dioxooleana-1, 9(11)-dien-28-oate (CDDO-Me), 40 Methyl esters, 62 1-Methyl-4-phenyl-1,2,3,6-tetra-hydropyridine, 213 7-O-Methyl-50 -hydroxy-30 heptenoateemacrolactin, 499 [2-Methyl-6-(4-methoxyphenyl)-3, 7dihydro-imidazo-(1, 2-a)-pyrazin-3one-HCl] (MCLA), 206 3-Methylindan-1-one enamines, 405 MGDG. See Monogalactosyl diacylglyceride (MGDG) MIC. See Minimal inhibitory concentration (MIC) Microbial world, 509 Microorganisms, 484 Microwave (MW), 404 Minimal inhibitory concentration (MIC), 69e70, 495 Mitochondria(l), 202 apoptosis signaling regulation, 208e209 permeability transition, 204e205 regulation, 205e206 regulating cell survival and death, 203e207 regulation of MPT by phytochemicals, 214e216 superoxide flash, 206e207 superoxide flash and Ca2+ efflux, 206e207 Mitochondrial membrane permeability transition (MPT), 202 phytochemicals regulate MTP at IMM, 211e213

Index promote in apoptosis, 208e210 Mitochondrial Na+/Ca2+ exchangers (mNCX), 205e206 MLD-STZ. See Multiple low-dose streptozotocin (MLD-STZ) MMPs. See Matrix metalloproteinases (MMPs) mNCX. See Mitochondrial Na+/Ca2+ exchangers (mNCX) Mode of action, marine antibiotics, 506e509 Mola mola. See Ocean sunfish (Mola mola) Molecular mechanism, 203 Molecular mechanism behind ambivalent functions, 210e216 MPT regulation by phytochemicals, 214e216 phytochemicals regulate MTP at IMM, 211e213 Molluscicidal activity, 168e169 Momordica charantia. See Bitter gourd (Momordica charantia) Momordica charantia (M. charantia), 25 Monocyte chemotactic protein 1 (MCP1), 439 Monogalactosyl diacylglyceride (MGDG), 189e190 Monoterpene DHCs, 302e319, 303te313t, 317f Moraceae, 255e282 Mouse skin carcinogenesis, inhibitory effects on, 9e23 compounds on, 19te21t fatty acids, 24te25t selected compounds, 22te23t selected triterpenoids, 10te18t Moxa, 37 MPT. See Mitochondrial membrane permeability transition (MPT) mPTP. See Permeabilityn transition pore (mPTP) MS. See Mass spectroscopy (MS) MTD. See Maximum tolerated dose (MTD) Multiflorane (Mu), 5 multiflorane-type triterpenoids, 30f, 31 Multiple drug resistance (MDR), 195 Multiple low-dose streptozotocin (MLDSTZ), 387e388, 387f Mus musculus L. See Male albino mice (Mus musculus L.) MW. See Microwave (MW) Myrobalan tree (Terminalia chebula), 32

529

Myticusin-1, 495 Myxinidin, 497

N NAFLD. See Nonalcoholic fatty liver disease (NAFLD) NASH. See Nonalcoholic steatohepatitis (NASH) Nazarov-type cyclization, 394 Neamphamide B, 496f, 497 Neem tree (Azadirachta indica), 29e30 Neohesperidin dihydrochalcone (NHDC), 369e371 Nerve growth factor (NGF), 202 Neurological diseases, KA in, 160e162 Neuroprotection, 202 Neuroprotective agents, 203 mitochondria regulate cell survival and death, 203e207 molecular mechanism behind ambivalent functions, 210e216 phytochemicals suppress and promote MPT in apoptosis, 208e210 NF-kB. See Nuclear factor-kB (NF-kB) NGF. See Nerve growth factor (NGF) NHBE cells. See Human bronchial epithelial cells (NHBE cells) NHC. See N-Heterocyclic carbene (NHC) NHDC. See Neohesperidin dihydrochalcone (NHDC) Nigranoic acid, 54, 67e69 nigranoic acid 3-ethyl ester, 54 Ninhydrins, 398e399, 404 Nitric oxide, 158 Nitric oxideecyclic guanosine monophosphate pathway (NOcGMP), 156e157 NMR. See Nuclear magnetic resonance (NMR) NO-cGMP. See Nitric oxideecyclic guanosine monophosphate pathway (NO-cGMP) No-observed-adverse-effect level (NOAEL), 39e40 NOAEL. See No-observed-adverse-effect level (NOAEL) Nonalcoholic fatty liver disease (NAFLD), 459e460 Nonalcoholic steatohepatitis (NASH), 459e460 Noncytotoxic koetjapic acid, 64e65

530 Index 29-Nor-3,4-seco-cycloartanes, 66 Nor-secofriedelane galphimine-B, 73 18-Norschiartanes, 52, 53f, 67e68 Nrf2. See Nuclear factor erythroid 2-related factor (Nrf2) Nuclear factor “kappa-light-chain-enhancer” of activated B cells, 64e65, 439 Nuclear factor erythroid 2-related factor (Nrf2), 42e43, 237e239 Nuclear factor-kB (NF-kB), 42e43, 152, 239e240 Nuclear magnetic resonance (NMR), 449

O Ocean sunfish (Mola mola), 38e39 Oceanapia sp., 506 Ochrobirine, 385, 385f Oleanane (On), 5, 52, 53f koetjapic acid, 64 oleanane-type triterpenoids, 30f, 31e32 triterpenoid, 65 Oleanolic acid, 73 OMM. See Outer mitochondrial membrane (OMM) Onocerane A,C-bis-seco-triterpenoids, 70 Optically active 2-substituted 1-indanones, 407 Outer mitochondrial membrane (OMM), 204. See also Inner mitochondrial membrane (IMM) Oxacarbaporphyrin, 401 Oxidative cleavage reactions, 229e232 chemical formation of apocarotenoids, 230e232, 232f enzymatic formation of apocarotenoids, 230, 231f Oxidative stress, 214e216, 460e461 Oxidized LDL (oxLDL), 468e471 3-Oxoolean-12-en-27-oic acid, 63 Oxymacatrichocarpin C, 302e319, 317f Ozonolysis, 398e399

P pABA. See Para-aminobenzoic acid (pABA) Papaya, 226e227 Para-aminobenzoic acid (pABA), 499 PARP. See Poly ADP ribose polymerase (PARP) Passiflora edulis (P. edulis), 25e27 Patents, 177, 188

PBMC. See Peripheral blood mononuclear cells (PBMC) PC-3. See Prostate cancer cells (PC-3) Pd-catalyzed carbonylative coupling reactions, 388 Pd-catalyzed Heck cyclization, 394 Peltophorum pterocarpum. See Yellow flame tree (Peltophorum pterocarpum) Pentacyclic A-seco-triterpenoids, 136 Pentacyclic triterpenoids, 57 Perilla (Perilla frutescens), 32e33 Perilla frutescens. See Perilla (Perilla frutescens) Peripheral benzodiazepine receptor. See Translocator protein 18 kDa (TSPO) Peripheral blood mononuclear cells (PBMC), 466e467 Permeabilityn transition pore (mPTP), 204 Peroxisome proliferator-activated receptors (PPARs), 240e241 Peroxynitrite (PN), 4 Persistent pore formation, 206e207 Pervicosides, 180, 180f Pestalotia sp., 487 Petrosamine B, 506 PGE2. See Prostaglandin E2 (PGE2) Phenolic compounds (PH), 5, 36 2-Phenoxy-indan-1-ones (PIOs), 422e423, 423f 1-Phenyl-3-methy-5-pyrazolone, 182 Phenytoin, 160e162 Phloretin 40 -O-(30 -O-galloyl-40 ,60 -O-(S)HHDP)-b-D-glucoside, 341f, 369e371 Phloridzin, 369e371 Phloroglucinols (PL), 5 chemopreventive effects, 34f, 35e36 Phosphatidyl inositol-3-OH kinase (PI3K), 423, 423f Phosphine-catalyzed Michael addition, 394 Phylum Echinodermata, 175e176 Phylum heterokontophyta. See Seaweed (Phylum heterokontophyta) Phytochemicals, 2 Phytochemicals suppress in apoptosis, 208e210 dietary components enhancing apoptosis signaling in cancer cells, 209e210 protect cells, 208e209 molecular mechanism behind ambivalent functions, 210e216

Index regulate MTP at IMM, 211e213 regulation of MPT, 214e216 PI3K. See Phosphatidyl inositol-3-OH kinase (PI3K); Protective phosphatidylinositol-3-kinase (PI3K) Pierotin A, 324, 331f, 369 Pierotin B, 302e319, 317f PIOs. See 2-Phenoxy-indan-1-ones (PIOs) Pistacia terebinthus. See Terebinth tree (Pistacia terebinthus) PK11195, 206, 207fe208f PKB. See Protein kinase B (PKB) Plant materials investigation, 5, 6te8t PN. See Peroxynitrite (PN) PN/TPA-induced carcinogenesis test, 4 Poly ADP ribose polymerase (PARP), 367e368 Polybrominated biphenyl class, 501e502 Polycyclic pyrrolidines, 412e413, 412f Polycyclic triterpenoids, 52 Polygonatone D, 283e302, 301f Polyketide/macrolactones, 497e500, 498f Polyphenol functions, 210, 210f Polyphenolic phytochemicals, 214 Polyphenols function, 214, 214f Polysaccharide fraction, 186 Polysubstituted 1-indanones, 394 Polyunsaturated fatty acids (PUFA), 38, 458 Pore structure, 204e205 Poria cocos. See Hoelen (Poria cocos) Poricoic acids A, 60 Poricoic acids C, 60 Poricoic acids G, 60 Poricoic acids H, 60 Porifera, 485e486 Potent BACE1 inhibitor, 424, 425f PPARs. See Peroxisome proliferator-activated receptors (PPARs) Preneoplastic lesions, 224 Prenylated DHCs, 302e319, 303te313t, 317f, 367e368 Preschisanartanes, 52, 53f, 67e68 Preschisanartanin E, 71 Prianicin A and B, 502, 503f Prianos sp., 502 Proinflammatory enzymes, 64e65 Prophylaxis means for prophylaxis disease, 185e188 and treatment, 187e188 Propindilactone Q, 71 Prostaglandin E2 (PGE2), 462

531

vitamin E modulating, 462e465 Prostate cancer cells (PC-3), 237 Protective phosphatidylinositol-3-kinase (PI3K), 209 Protein kinase B (PKB), 243e244, 439 Protein/polypeptide, 487e497, 496f Pseudoalteromonas phenolica sp. O BC30T, 501e502 Pseudomonas, 506e507 Pt-catalyzed Rautenstrauch/TsujieTrost reactions, 396e397 Pteridium aquilinum (P. aquilinum), 385 Pterocarpus (Fabaceae), 283e302 PUFA. See Polyunsaturated fatty acids (PUFA) Pyridothiopyranopyrimidine, 209e210 a-Pyrone I, 506e507, 506f

Q Quorum sensing (QS), 509 manipulation/inhibition, 509

R Racemic balsacone M, 327f, 369 Radioactive isotopes cucumariosides A2e2 and A4e2, 183f triterpene glycosides modification by, 181e183 Ramelteon drug, 415e416 RAR. See Retinoic acid receptors (RAR) RAREs. See Retinoic acid response elements (RAREs) Reactive nitrogen species (RNS), 203e204 Reactive oxygen species (ROS), 4e5, 445 Red Sea sponge, 502 Reductive cross-coupling of indanones, 402 Reishi mushroom (Ganoderma lucidum), 28 Retinoic acid, 8e9, 8f Retinoic acid receptors (RAR), 241e242 Retinoic acid response elements (RAREs), 241 Retinoid X receptor (RXR), 240e242 60 -O-Rhamnosyl-(1000 /600 )-gluco-pyranosyl asebogenin, 341f, 369e371 RhCl(PPh3)3, 394e395 Rhodomyrtosone E, 324, 331f Ribbon fish (Desmodema spp.), 500e501 RNS. See Reactive nitrogen species (RNS) Root vegetable, 225 ROS. See Reactive oxygen species (ROS)

532 Index Rosaceae, 255e282 Rosenvingea sp., 487 RXR. See Retinoid X receptor (RXR)

S Saccharomyces cerevisiae (S. cerevisiae), 154e155 Sakenins A-H, 302e319, 317f Sakenins F, 317f, 367e368 Sakenins H, 317f, 367e368 Salicin, 436e437 Salinamide A (SalA), 507, 508f Salinamide F, 507, 508f SAR. See Structureeactivity relationship (SAR) Scavenger receptor class B type 1 (SRB1), 446 Schiartanes, 52, 53f, 67e68 Schindilactone A, 71 Schindilactone I, 71 Schisanartanes, 52, 53f, 67e68 Schisandra Nortriterpenoids, 130e133 Schisanlactone A, 68e69 Schizandronic acid, 59 SCM. See Short-chain metabolites (SCM) Sea cucumber glycosides, 191e195 Sea cucumbers, 175e176, 184 triterpene sapogenins, 187 Seaweed (Phylum heterokontophyta), 500 Seco-coccinic acid A, 60 Seco-coccinic acid B, 60 Seco-coccinic acid C, 60 Seco-coccinic acid E, 60 9,10-Seco-cycloartane illiciumolide A, 65 Seco-dammarane cyclocarin A, 71 glycosides cyclocariosides DeG, 71 Seco-derivatives, 66 Seco-dinortriterpenoid dzununcanone, 54 3,4-Seco-fernane EC-2, 63 2,3-Seco-fernane triterpenoid alstonic acid B, 58 3,4-Seco-lanostane triterpenoids, 60 3,4-Seco-lupa-4(23),20(29)-dien-3-ol, 74 3,4-Seco-lupane acids, 72 Seco-lupane lippiolic acid, 65 3,4-Seco-mariesane acid, 70 2,3-Seco-oleanane dillenic acid D, 69e70 3,4-Seco-oleanane EC-4, 63 Seco-oleanane triterpenoids, 70e71 3,4-Seco-oleanane triterpenoids, 69e70

2,3-Seco-taraxane 2,3-dimethyl ester, 63 2,3-Seco-taraxer-14-ene-2,3,28-trioic acid 2,3-dimethyl ester, 70 3,4-Seco-tirucallane isohelianol acetate, 55 3,4-Seco-triterpene terminalin A, 58e59 Seco-triterpenoids as biomarkers, 55e57 Secondary metabolic compounds, 2e3, 36e38, 52, 436 alkylresorcinols, 36 azaphilonoids, 36e37 caffeoylquinic acids, 37 coumarins, 37 diarylheptanoids, 37 jasmonic acid derivatives, 38 phenolic compounds, 36 tannins, 38 Secondary metabolites. See also Secondary metabolic compounds Selectivity indexes (SI), 367e368 Semi-synthetic 2-cyano-3,4-secolanosta-26oic acid, 73e74 Sentulic acid, 63 Sesamin, 212, 212f Shea tree (Vitellaria paradoxa), 31 Shorea javanica (S. javanica), 27 Short-chain metabolites (SCM), 448 SI. See Selectivity indexes (SI) Sieboldin, 369e371 Signal transducer and activator of transcription 3 (STAT3), 42e43 Silica gel column chromatography, 189 Siraitia grosvenorii. See Buddha fruit (Siraitia grosvenorii) Sirtuin 1 (SIRT1), 244 Smooth muscle relaxant effect, 156e157, 157t Snake gourd (Trichosanthes kirilowii), 31 Sootepin A, 62 Sootepin E, 62, 68e69 Sphagneticola trilobata (S. trilobata), 158 Spiro[benzofuran-2,2-naphthalen]-1-ones, 389 Spirocyclic lactams, 402 Spirocyclohexane indane-1,3-diones, 409e410 Sponges, 485e486 SRB1. See Scavenger receptor class B type 1 (SRB1) Stachyin B, 504, 505f STAT3. See Signal transducer and activator of transcription 3 (STAT3)

Index Stereo-controlled synthesis, 451e452 Steroids (ST), 5 chemopreventive effects, 33e34, 34f Stichoposide C and D, 193 Strain CNQ-525, 502 Streptococcus agalactiae (S. agalactiae), 495e497 Streptococcus pyogenes (S. pyogenes), 495e497 Streptomyces sp., 497, 499 S viridochromogenes, 384e385 S. cyaneofuscatus M-27, 500 S. murayamaensis, 384e385 S. staurosporeus, 387e388 Structureeactivity relationship (SAR), 25e27, 424e425 O-Substitution, DHCs with simple patterns of, 283e302, 284te299t, 301f, 365e367 N-Sulfonyl aromatic imines, 397 Sulindac, 394 Sunflower (Helianthus annuus), 32 Superacid-promoted one-pot reaction, 396 “Superoxide flash”, 203, 206 Sweetpotato weevil (Cylas formicarius), 168 Symmetrical synthesis, 389e406 binepine ligands, 392 biologically active 2-aminoindanes, 390 densely substituted indenes, 396 Pd-catalyzed intramolecular syntheses of indanes and indanones, 392 pterosin A, 390 taiwaniaquinol B, 391 tricyclic core structures, 406 Synercid, 495e497 Synthesis, 388e417 asymmetric synthesis, 406e417 symmetrical synthesis, 389e406

T Tacca species (Dioscoreaceae), 255e282 Taccabulin A, 283e302, 301f, 365e367 Taccabulin E, 301f, 365e367 Taiwania cryptomerioides (T. cryptomerioides), 390 Taiwaniaquinoids, 390, 391f Talaromycesone A and B, 498f, 500 Tannins, 38 Taraxane pycanocarpine, 63 Taraxastane (Ta), 5 dihydrolacunosic acid, 55

533

taraxastane-type triterpenoids, 30f, 32 Terebinth tree (Pistacia terebinthus), 152 Terminalia chebula. See Myrobalan tree (Terminalia chebula) Terminalin A, 72e73 N-Terminally truncated RXRa (tRXRa), 423 Terpenes, 152 Terpenoid class, 502e504 Terretonin G, 502, 503f Tert-butylsilyloxy-5-iodo-4-methylpent-4ene, 451e452, 452f Tetracyclic A-seco-triterpenoids, 133 Tetracyclic indeno-1, 5-thiazepines, 404, 404f 12-O-Tetradecanoylphorbol-13-acetate (TPA), 2e3 Thalassodendrone. See 60 -O-rhamnosyl(1000 /600 )-gluco-pyranosyl asebogenin Thelenota ananas (T. ananas), 176 Thelenota anax (T. anax), 193 Thin-layer chromatography (TLC), 54, 449 Tirucallane (Ti), 5, 52, 53f tirucallane-type triterpenoids, 30f, 32 Tissue plasminogen activator (TPA), 65 TLC. See Thin-layer chromatography (TLC) TNF-a. See Tumor necrosis factor alpha (TNF-a) a-Tocopherol transport protein (a-TTP), 446 Tocopherols, 441e442 foam cell formation, 469e470 inhibit cyclooxygenase activity, 462e463 inhibits lipoxygenase activity, 466e467 metabolites, 463e464 Tocotrienols, 463 on lipoxygenase activity, 467e468 d-tocotrienol (d-T3), 437 Tovomitopsis psychotriifolia (T. psychotriifolia), 449 TPA. See 12-O-Tetradecanoylphorbol-13acetate (TPA); Tissue plasminogen activator (TPA) TPA-induced EBV-EA activation, inhibitory effects on, 5e9 inhibitory effects of reference compounds, 9t plant and fungal materials investigation, 6te8t structures of reference compounds, 8f TRAIL. See Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)

534 Index Trans-1, 3-diaryl-1-trifluoromethylindanes, 414 Trans-3-aryl-2-hydroxy-1-indanones, 403 Trans-130 -carboxy-d-tocotrienol. See Garcinoic acid Translocator protein 18 kDa (TSPO), 203 Transport of vitamin E, 446 2-Triazole-benzaldehydes, 393 2,20 ,3-Tribromo-biphenyl-4-40 -dicarboxylic acid, 502 Trichodin A, 504e505, 505f Trichosanthes kirilowii. See Snake gourd (Trichosanthes kirilowii) Trifluoroacetic acid, 182 2-Trifluoromethyl-1-methylene-3phenylindene, 390e391 Trifluoromethyl-aminoindanone derivatives, 403 1-Trifluoromethylated indane derivatives, 413e414 2-Trifluoromethylated indanones, 394e395 Triglycosides sessiloside, 71 4,20 ,40 -Trihydroxy-30 methoxydihydrochalcone, 283e302, 301f 4,20 ,40 -Trihydroxy-60 -methoxy-30 -methyldihydrochalcone. See Polygonatone D (E)-1-(2,4,6-Trihydroxyphenyl)-3-(4hydroxyphenyl)-2-propan-1-one, 282e283 Cis-Trikentrin B, 387, 387f Trikentrion flabelliforme (T. flabelliforme), 387, 387f Trilobatin, 369e371 Triterpene glycosides, 175e176 cancer, 191e195 functional food and products, 183e188 immunostimulatory means, 188e191 isolation methods, 180e181 methods for producing extracts and products containing, 177e180 quantification methodologies and modification, 181e183 sea cucumber glycosides, 191e195 Triterpenoids, 5, 52, 55 chemopreventive effects, 23e33 improvement of bioavailability, 39e41 preventive malignancy type by, 41 reciprocal effect to another agent, 40e41 side effects, 39e40

toxicity, 39e40 tRXRa. See N-Terminally truncated RXRa (tRXRa) Trypanosoma brucei (T. brucei), 418e419 Trypanosoma cruzi (T. cruzi), 418, 418f TSPO. See Translocator protein 18 kDa (TSPO) a-TTP. See a-Tocopherol transport protein (a-TTP) Tubulin polymerization inhibition, 426 Tumor cells, 209 Tumor necrosis factor alpha (TNF-a), 65, 439 Tumor necrosis factor-related apoptosisinducing ligand (TRAIL), 40e41 Turpentine, 152 Two-stage carcinogenesis test on mouse skin DMBA/TPA-induced carcinogenesis test, 3e4 PN/TPA-induced carcinogenesis test, 4 UVB/TPA-induced carcinogenesis test, 4e5 Type B monoamine oxidase (MAO-B), 202 Tyrosine kinase activity, 236 Tyrosine phosphatase 1B, 155e156 TZHs. See 4-Arylthiazolyl hydrazones (TZHs)

U Ultraviolet B (UVB), 4e5 Unsaturated fatty acids, 458 Uricosuric drug, 406e407 Ursane (Ur), 5, 52, 53f ursane-type triterpenoids, 30f, 32e33 Ursolic acid (Ur1), 32e33, 73 Uvaria afzelii (U. afzelii), 385 UVB/TPA-induced carcinogenesis test, 4e5

V Vancomycin-resistant Enterococcus faecium (VREF), 502e504 VDAC. See Voltage-dependent anion channel (VDAC) Verrucosispora strain, 486e487 Very-low-density lipoproteins (VLDL), 446 Vinyl iodide, 451e452, 452f Vitamin B9. See Folic acid Vitamin E, 442e448, 464e468 absorption, transport, and distribution, 446 bioactivity, 454e471 antiinflammatory actions, 461e468 antioxidative properties, 458e461

Index cytotoxicity, 455e458 modulation of lipid homeostasis, 468e471 biological significance, 443e445 chemical structures of forms, 444f LCM synthesis, 448e454 garcinoic acid isolation, 449e451, 450t garcinoic acid synthesis, 451e452 semisynthesis of long-chain metabolites, 452e454 metabolism, 446e448 natural compounds, 444f principle hepatic metabolism, 447f semisynthesis of a-130 -and d-130 -LCM, 453f synthesis of LCM, 448e454 Vitellaria paradoxa. See Shea tree (Vitellaria paradoxa) VLDL. See Very-low-density lipoproteins (VLDL) Voltage-dependent anion channel (VDAC), 204

VREF. See Vancomycin-resistant Enterococcus faecium (VREF)

W White bryony (Bryonia dioica), 23e25 World Antibiotic Awareness Week, 484 World Health Organization (WHO), 484 Wuweiziartane, 52, 53f Wuweizilactone acid, 67e68

X Xanthophylls, 225, 226f

Y Yellow flame tree (Peltophorum pterocarpum), 36

Z Zafrin, 500e501, 501f Zeaxanthin, 227, 236

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