Pharmacology and Applications of Naturally Occurring Iridoids [1st ed.] 978-3-030-05574-5;978-3-030-05575-2

Table of contents :
Front Matter ....Pages i-xxviii
Classification of Iridoids (Biswanath Dinda)....Pages 1-15
Occurrence and Distribution of Iridoids (Biswanath Dinda)....Pages 17-82
Isolation and Identification of Iridoids (Biswanath Dinda)....Pages 83-118
Chemistry and Biosynthesis of Iridoids (Biswanath Dinda)....Pages 119-143
Pharmacology of Iridoids (Biswanath Dinda)....Pages 145-254
Pharmacokinetics of Iridoids (Biswanath Dinda)....Pages 255-269
Applications of Iridoids in Pharmaceutical, Cosmetic, and Insecticide Industries (Biswanath Dinda)....Pages 271-278
Back Matter ....Pages 279-296

Citation preview

Biswanath Dinda

Pharmacology and Applications of Naturally Occurring Iridoids

Pharmacology and Applications of Naturally Occurring Iridoids

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Biswanath Dinda

Pharmacology and Applications of Naturally Occurring Iridoids

123

Biswanath Dinda Department of Chemistry Tripura University Agartala, Tripura, India

ISBN 978-3-030-05574-5 ISBN 978-3-030-05575-2 https://doi.org/10.1007/978-3-030-05575-2

(eBook)

Library of Congress Control Number: 2018967416 © Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Dedicated to my parents, father-in-law and teacher, Prof. (Mrs) Asima Chatterjee for her life-time achievement on herbal drug discovery

Preface

The field of natural products chemistry is immense, fascinating, and interesting because of limitless structural varieties and substitution patterns of natural products, and their specific metabolic origins and fates, cellular transformations, and versatile physiological and other biological activities. Iridoids and their 7,8-seco-derivatives, called secoiridoids, are one of the major classes of secondary plant metabolites, mainly found in a restricted group of plant families. Most of these plant metabolites are found in commonly used folk medicinal plants and edible fruits and vegetables of many countries. Their physiological activities in plants and some specific insects are indispensible in which they occur. The potent and versatile pharmacological activities of some naturally occurring iridoids prompted for in-depth study on their transcriptomes and metabolomes analyses to reveal the specific gene expression in their biosynthesis for utilization of these genes in biotechnological production of these iridoids as raw materials in pharmaceutical industries. Most of the existing monographs and textbooks have a limited coverage on these plant iridoids. Therefore, I have decided to elaborate all the aspects of the naturally occurring iridoids in this book to furnish a comprehensive idea upon this subject and to bring it in the limelight of the students and researchers. In this book, the occurrence and distribution in plant families and insects, methods of isolation, separation and purifications by different chromatographic techniques, structural diagnosis and elucidation by modern spectroscopic methods, methods of partial and total synthesis, biosynthesis of some bioactive iridoids using both transcriptome and metabolome analyses and tracer technique, pharmacological and other biological activities, metabolic fate in microorganisms and animals, pharmaceutical and nutraceutical applications of iridoids in medicine and dietary supplements, and pesticidal applications in eradication of harmful parasitic insect vectors of some diseases have been elaborated. In addition to these, the application of iridoids as chemotaxonomic markers in the study of chemosystematics and phylogeny of plant families is also highlighted. This book is specifically designed as a textbook for the students of graduate and postgraduate levels of pharmacognosy, pharmacy, and pharmaceutical chemistry. This book will provide a detailed and extensive overview and a unifying concept on vii

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Preface

the naturally occurring iridoids. I feel this book will motivate the interest of the students and researchers in this significant area of natural science for the discovery of gene expression in plants for biosynthesis of these metabolites. This book will be a valuable tool in pharmaceutical industry for application of these plant metabolites in various drug formulations. To the readers of this book, I seek for their valuable suggestions and comments for improvement of this monograph in the next edition. I am grateful to Prof. I. Calis of Near East University, TRNC, for kindly providing the 2D NMR spectra of lamiide and auroside; Prof. S. R. Jensen of the Technical University of Denmark; Prof. R. Tundis of University of Calabria, Italy; and Prof. A. Viljoen of Tshwane University of Technology, Pretoria, South Africa, for kindly providing some of their research papers on iridoids. I am grateful to my publisher for their support and interest in the publication of this monograph. I wish to acknowledge the help of the students, Dr. Goutam Kulsi of Seoul National University, Korea; Dr. Arup Kr. Roy of NEIST, India; Dr. Nayim Sepay and Sri Tapas Halder of Jadavpur University, India, for providing some papers on iridoids; Dr. Ankita Chakraborty of Tripura University; my son, Dr. Subhajit Dinda of DDM College, Tripura; Dr. Brajagopal Samanta of Nabajibon Colony Nabajiban Vidyamandir, West Bengal, India; and Sri Goutam Das, City College, West Bengal, for drawing some structures in preparation of this manuscript. Finally, I wish to express my hearty affections to my wife, Chitralekha, children, Subhajit and Manikarna and son-in-law, Shekhar, and regards to my mother-in-law Mrs. Pravabati Das for their constant encouragement in the completion of this book. Agartala, Tripura, India July 2018

Biswanath Dinda

Contents

1 1

1 Classification of Iridoids . . . . . . . . . . . . . . . . 1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . 1.2 The Numbering of Substituted Iridoid and Glucosides . . . . . . . . . . . . . . . . . . . . . . . 1.3 Classification of Iridoids . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .

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2 Occurrence and Distribution of Iridoids . 2.1 Introduction . . . . . . . . . . . . . . . . . . . 2.2 Occurrence of Iridoids in Plants . . . . 2.3 Distribution of Iridoids in Plants . . . . 2.4 Iridoid Content in Plant’s Organs . . . 2.5 Iridoids in Insects . . . . . . . . . . . . . . . 2.6 Iridoid Content in Insect’s Organs . . . References . . . . . . . . . . . . . . . . . . . . . . . .

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Secoiridoid

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3 Isolation and Identification of Iridoids . . . . . . . . . . . . . . . 3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Extraction of Iridoids from Plants and Insects . . . . . . . 3.3 Isolation Techniques of Iridoids . . . . . . . . . . . . . . . . . . 3.3.1 Thin-Layer Chromatography . . . . . . . . . . . . . . 3.3.2 Open-Column Chromatography . . . . . . . . . . . . 3.3.3 High-, Medium-, and Low-Performance Liquid Chromatography Techniques . . . . . . . . . . . . . . 3.3.4 Droplet- and High-Speed Countercurrent Chromatography Techniques . . . . . . . . . . . . . . 3.3.5 Gas–Liquid Chromatography . . . . . . . . . . . . . 3.3.6 Capillary Electrophoresis . . . . . . . . . . . . . . . . 3.4 Spectroscopic Methods for Identification of Iridoids . . . 3.4.1 UV and IR Spectroscopic Methods . . . . . . . . .

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3.4.2 3.4.3 3.4.4 3.4.5 3.4.6 References .

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H-NMR Spectroscopy . . . . . . C-NMR Spectroscopy . . . . . 2D-NMR Spectroscopy . . . . . Mass Spectrometry . . . . . . . . . X-Ray Crystallographic Study .

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4 Chemistry and Biosynthesis of Iridoids . . . . . . . . . . . . . . . . 4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Syntheses and Transformations of Bioactive Iridoids . . . 4.2.1 Syntheses of Bioactive Iridoids . . . . . . . . . . . . . 4.2.2 Transformations of Bioactive Iridoids . . . . . . . . 4.3 Syntheses and Transformations of Bioactive Secoiridoids 4.3.1 Syntheses of Bioactive Secoiridoids . . . . . . . . . 4.3.2 Transformations of Bioactive Secoiridoids . . . . . 4.4 General Biosynthetic Pathway of Plant Iridoids and Secoiridoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5 Transcriptome and Metabolome Analyses in Iridoid Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6 Biosynthesis of Iridoids in Insects . . . . . . . . . . . . . . . . . 4.7 Biosynthesis of Iridoids in Lamiaceae . . . . . . . . . . . . . . 4.8 Iridoids as Taxonomic and Phylogenic Markers in Plants References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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5 Pharmacology of Iridoids . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Pharmacology of Iridoids . . . . . . . . . . . . . . . . . . . . . . . . 5.2.1 Anti-inflammatory and Antinociceptive Activities 5.2.2 Anti-arthritic Activity . . . . . . . . . . . . . . . . . . . . . 5.2.3 Hepatoprotective Activity . . . . . . . . . . . . . . . . . . 5.2.4 Neuroprotective Activity . . . . . . . . . . . . . . . . . . . 5.2.5 Cardioprotective Activity . . . . . . . . . . . . . . . . . . 5.2.6 Anti-allergic Activity . . . . . . . . . . . . . . . . . . . . . 5.2.7 Hypoglycemic, Hypolipidemic, and Anti-obesity Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.8 Renoprotective Activity . . . . . . . . . . . . . . . . . . . 5.2.9 Antiglycation Activity . . . . . . . . . . . . . . . . . . . . 5.2.10 Pancreas Protective Activity . . . . . . . . . . . . . . . . 5.2.11 Antitumor/Anticancer Activity . . . . . . . . . . . . . . 5.2.12 Anticolitis Activity . . . . . . . . . . . . . . . . . . . . . . . 5.2.13 Gastroprotective Activity . . . . . . . . . . . . . . . . . . 5.2.14 Wound-Healing Activity . . . . . . . . . . . . . . . . . . . 5.2.15 Choleretic Activity . . . . . . . . . . . . . . . . . . . . . . . 5.2.16 Ocular Hypotensive and Antifibrogenic Activities

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Contents

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5.2.17 Antioxidant Activity . . . . . . . . . . . . . . . . . . . 5.2.18 Antibacterial and Antifungal Activities . . . . . 5.2.19 Antiviral Activity . . . . . . . . . . . . . . . . . . . . . 5.2.20 Anti-amoebic Activity . . . . . . . . . . . . . . . . . 5.2.21 Antimalarial Activity . . . . . . . . . . . . . . . . . . 5.2.22 Antileishmanial Activity . . . . . . . . . . . . . . . . 5.2.23 Antitrypanosomal Activity . . . . . . . . . . . . . . 5.2.24 Molluscicidal Activity . . . . . . . . . . . . . . . . . 5.2.25 Anti-osteoporotic Activity . . . . . . . . . . . . . . . 5.2.26 Antidepressant Activity . . . . . . . . . . . . . . . . 5.2.27 Anxiolytic Activity . . . . . . . . . . . . . . . . . . . 5.2.28 Anticonvulsant Activity . . . . . . . . . . . . . . . . 5.2.29 Antispasmodic Activity . . . . . . . . . . . . . . . . 5.2.30 Melanogenesis Inhibitory Activity . . . . . . . . . 5.2.31 Antiaging Activity . . . . . . . . . . . . . . . . . . . . 5.2.32 Immunomodulatory Activity . . . . . . . . . . . . . 5.2.33 Anti-angiogenic Activity . . . . . . . . . . . . . . . . 5.2.34 Antimutagenic Activity . . . . . . . . . . . . . . . . . 5.2.35 Estrogenic Activity . . . . . . . . . . . . . . . . . . . . 5.2.36 Purgative Activity . . . . . . . . . . . . . . . . . . . . 5.2.37 Spermicidal Activity . . . . . . . . . . . . . . . . . . . 5.2.38 Nematocidal and Insecticidal Activities . . . . . 5.2.39 Repellent and Antifeedant Activities . . . . . . . 5.2.40 Miscellaneous Activity . . . . . . . . . . . . . . . . . 5.3 Iridoids in Insect Physiology . . . . . . . . . . . . . . . . . . . 5.3.1 Iridoids in Growth and Adaptation of Insects . 5.3.2 Iridoids as Defensive Chemicals in Insects . . 5.3.3 Iridoids as Sex Pheromones in Insects . . . . . . 5.3.4 Iridoids in Chemical Signals in Insects . . . . . 5.3.5 Iridoids as Allelochemicals in Insects . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Pharmacokinetics of Iridoids . . . . . . . . 6.1 Introduction . . . . . . . . . . . . . . . . . . 6.2 Microbial Metabolism of Iridoids . . 6.3 Mammalian Metabolism of Iridoids . 6.4 Mammalian Disposition of Iridoids . References . . . . . . . . . . . . . . . . . . . . . . .

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7 Applications of Iridoids in Pharmaceutical, Cosmetic, and Insecticide Industries . . . . . . . . . . . . . . . . . . . . . . . . 7.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2 Applications of Iridoids in Pharmaceutical, Cosmetic, and Insecticide Industries . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Contents

. . . . . . . . . 271 . . . . . . . . . 271 . . . . . . . . . 271 . . . . . . . . . 277

Plant Species Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

Abbreviations

AA ABTS ACC ACD ACh AChE ACE ACTH ADD AGE AIBN Akt ALP ALT AMPK AP AP-1 APAP Ara(f) ASK-1 AST ATP BACE-1 BALF BAT Bax BBB Bcl-2 BDNF BDZ

Adjuvant-induced arthritis 2,2'-Azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) Acetyl CoA carboxylase Anti-convulsant drug Acetylcholine Acetylcholine esterase Angiotensin-converting enzyme Adrenocorticotropin After discharge duration Advanced glycation endproduct 2,2'-Azobisisobutyronitrite Protein kinase B Alkaline phosphatase Alanine transaminase 5'-Adenosine monophosphate-activated protein kinase Acute pancreatitis Activator protein-1 N-Acetyl-p-aminophenol D-Arabinofuranosyl Apoptosis signal-regulating kinase 1 Aspartate transaminase Adenosine triphosphate Beta-site amyloid precursor protein cleaving enzyme-1 Bronchoalveolar lavage fluid Brown adipose tissue Bcl-2 associated x Blood–brain barrier B-cell lymphoma 2 Brain-derived neurotrophic factor Benzodiazepine

xiii

xiv

BHT Big ET-1 BINAL-H BiP BMP-2 Bn BSA Bu BUP CAD Cag A CaMKII CaMKKb CD C/EBPa CEL CerS3 CFU ChAT CK CK-MB CLP CMA COPD COSY COX-2 CPK CPR CPT CREB CRH CRP CSA CSF CTx CYP2E1 DA DAT DCE DCM DEET DESI DHP DIBA-H DMAP

Abbreviations

Butyrated hydroxytoluene/3,5-diisobutyl-4-hydroxytoluene Big endothelin-1 2,2'-Dihydroxy-1,1'-binaphthyl-lithium aluminum hydride Immunoglobulin-binding protein Bone morphogenetic protein-2 Benzyl Bovine serum albumin Butyl Bupropion Coronary artery disease Cytotoxin-associated gene A Calcium/calmodulin-dependent protein kinase II Calcuim-/calmodulin-dependent protein kinase kinase beta Contact dermatitis/ Crohn’s disease CCAAT/enhancer-binding protein alpha Ne-Carboxy ethyl lysine Ceramide synthase 3 Colony-forming unit Choline acetyl transferase Creatine kinase Creatine kinase of types found in muscle and brain Cecal ligation and puncture Chaperone-mediated autophagy Chronic obstructive pulmonary disease Correlated spectroscopy Cyclooxygenase-2 Creatine phosphokinase Coronary perfusion rate 8-Cyclopentyltheophylline cAMP response element-binding protein Corticotropin-releasing hormone C-reactive protein 10-Camphorsulfonic acid Cerebrospinal fluid C-terminal telopeptide Cytochrome P4502E1 Dopamine Dopamine transporter 1,2-Dichloroethane Dichloromethane N,N-Diethyl-meta-toluamide Desipramine 3,4-Dihydroxyphenethyl/dihydropyran Diisobutylaluminum hydride 4-Dimethylaminopyridine

Abbreviations

DMAPP DMBA DMSO DNFB DPPH Drp-1 DSCS DSS DTH EC50 ED50 EGF EIMS EPM EPO EPOR ER ER ERK ESIMS Et ET-1 FABMS FAS Fas FasL FFA FLS fMLP FoxO1 FRAP Fru FST FVP GABAA Gal GAP-43 GDNF GFR GFR-a1 GGT GI Glc GLP-1

xv

Dimethylallyl pyrophosphate 7,12-Dimethylbenz[a]-anthracene Dimethylsulfoxide 2,4-Dinitrofluorobenzene 2,2-Diphenyl-1-picrylhydrazyl Dynamin-related protein-1 Disodium cromoglycate Dextran sulfate sodium Delayed-type hypersensitivity Equivalent concentration of test sample to scavenge 50% of free radical from the medium Effective dose of a drug to produce 50% of the activity Epidermal growth factor Electron-impact mass spectrometry Elevated plus maze Erythropoietin Erythropoietin receptor Endoplasmic reticulum Estrogen receptor Extracellular signal-regulated kinase Electrospray ionization mass spectrometry Ethyl Endothelin-1 Fast atom bombardment mass spectrometry Fatty acid synthase First apoptosis signal Fas ligand Free fatty acid Fibroblast-like synoviocyte N-Formylmethionyl-leucyl-phenylalanine Forkhead box O1 Ferric reducing ability of plasma D-Fructofuranosyl Force swimming test Flash vacuum pyrolysis Gamma aminobutyric acid receptor A b-D-Galactopyranosyl Growth-associated protein-43 Glial cell line-derived neurotrophic factor Glomerular filtration rate GDNF-receptor alpha-1 Gamma-glutamyl transferase Gastrointestinal b-D-Glucopyranosyl Glucagon-like peptide-1

xvi

GLP-1R GLUT-4 GP G6Pase G6PD GPP GSR GRP78 GS GSH GSH-Px/GPx GSK-3 HA HBV HBe Ag HBs Ag HCC HCV HCVpp HEK-293 12-HETE HFD 5-HIAA HMBC HMG-CoA HMGCR HO-1 HORAC Hp HPA hPK HSP-70 HSV-1 5-HT HUVEC hv HYD IAP-1 IBD ICAM-1 IDE IFN-c IG IjBa IKK

Abbreviations

Glucagon-like peptide-1 receptor Glucose transporter-4 Glycogen phosphorylase Glucose 6-phosphatase Glucose-6-phosphate dehydrogenase Geranylpyrophosphate Glutathione reductase Glucose-regulated protein of 78 kDa Glutamine synthetase Glutathione Glutathione peroxidase Glycogen synthase kinase-3 Hemagglutinating antibody Hepatitis B virus Hepatitis B envelope antigen Hepatitis B surface antigen Hepatocellular carcinoma Hepatitis C virus Hepatitis C virus pseudoparticles Human embryonic kidney-293 protein 12-Hydroxyeicosatetraenoic acid High-fat diet 5-Hydroxyindole acetic acid Heteronuclear multiple bond correlation 3-Hydroxy-3-methylglutaryl-coenzyme A 3-Hydroxy-3-methylglutaryl-coenzyme A reductase Heme oxygenase-1 Hydroxyl radical averting capacity Harpagophytum procumbens Hypothalamic-pituitary-adrenocortical axis Human primary keratinocytes Heat shock protein-70 Herpes simplex virus-1 5-Hydroxytryptamine Human umbilical vein endothelial cell Ultraviolet or visible irradiation Hydrocortisone Inhibitor of apoptosis protein-1 Inflammatory bowel disease Intracellular adhesion molecule-1 Insulin-degrading enzyme Interferon gamma Iridoid glycoside mixture Inhibitor of kappa B activity, alpha form Inhibitor of kappa B kinase

Abbreviations

IKKb IMI IMP iNOS i.p. IP-10 IPP i-PrOH IR ISP i.v. JAK-2 LAMP2A LC-3II LC50 LDA LDH LLF L-NMMA L-02/LO2 LPL-1 LPS LRP-5 LTB4 LTC4 MALDI-TOF-MS MAPK MAO-B MATF MBC MCP-1 m-CPBA MDA Me MEC MeJA MEP MES MFC MIC MLNL MMI MMP

xvii

Inhibitor of nuclear factor kappa B kinase subunit beta Imipramine Idiopathic mesenteric phlebosclerosis Inducible nitric oxide synthase Intraperitoneal Interferon gamma-induced protein-10 Isopentenyl pyrophosphate iso-Propyl alcohol Insulin resistance Isoproterenol Intravenous Janus kinase-2 Lysosome-associated membrane protein type 2A Microtubule-associated protein-light chain-3-type-II Lethal concentration of a drug that causes death of 50% of the tested animal group Lithium diisopropylamide Lactate dehydrogenase Ligustrum lucidum fruits L-NG-Monomethyl-arginine Human fetal hepatocytes Lipoprotein lipase-1 Lipopolysaccharide Lipoprotein receptor-related protein-5 Leukotriene B4 Leukotriene C-4 Matrix-assisted laser desorption ionization-time of flight-mass spectrometry Mitogen-activated protein kinase Monoamine oxidase B Microphthalmia-associated transcription factor Minimum bactericidal concentration Monocyte chemoattractant protein-1 meta-Chloroperbenzoic acid Malondialdehyde Methyl Minimum effective concentration Methyl jasmonate 2-Methyl-D-erythritol-4-phosphate Maximal electroshock Minimum fungicidal concentration Minimum inhibitory concentration Mesenteric lymph node lymphocyte Macrophage migration index Mitochondrial membrane potential

xviii

MMP-9 MPO mPT MPTP Mrp-3 a-MSH MST MTT MVA m/z NASH NBS NE NEFA NF-jB NFT NGF NIDDM NMP 41/7 NMRI NOESY Nox-4 1-NPy NQO1 Nrf-2 NT-3 OB-R OCN OFT ONOOOPG OPLC ORAC ORCA2 ORTEP OVA OVX Ox-LDL PAI-1 PBL PC-12 PCA PCC

Abbreviations

Matrix metalloproteinase-9 Myeloperoxidase Mitochondrial permeability transition 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Multidrug resistance-associated protein-3 Alpha-melanocyte stimulating hormone Median survival time 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide Mevalonic acid Mass-to-charge ratio Non-alcoholic steatohepatitis N-Bromosuccinimide Norepinephrine Non-esterified fatty acid Nuclear factor kappa B Neurofibrillary tangles Nerve growth factor Non-insulin-dependent diabetes mellitus Nuclear matrix proteins 41 and 7 Naval Medical Research Institute Nuclear Overhauser effect spectroscopy NADPH oxidase-4 1-Nitropyrene NAD(P)H-quinone acceptor oxidoreductase-1 Nuclear factor-(erythroid derived-2)-related factor-2 Neurotrophin-3 Obesity (leptin) receptor Osteocalcin Open field test Peroxynitrite anion radical Osteoprotegerin Over-pressured layer chromatography Oxygen radical absorbance capacity Octadecanoid-derivative responsive Catharanthus AP2-domain protein-2 Oak Ridge thermal ellipsoid plot Ovalbumin Ovariectomized Oxidized-low-density lipoprotein Plasminogen activator inhibitor-1 Peripheral blood lymphocyte Pheochromocytoma-12 Passive cutaneous anaphylaxis Pyridinium chlorochromate

Abbreviations

PIICP PDGF PDK1 PDZK1

PET PFC PFR-2 PGE2 Ph PI3K Piv p-JNK PKC PKDL PLA2 PMA p-MAPK AP-2 pMCAO p-MKK PMN PPAR-a PPAR-c p-Smad-2 PTZ Py RA RAGE RANKL RD RD50 Rha RHF ROESY ROS RSV rt RT-PCR Runx-2 Rut SIRT

xix

Human procollagen II C-terminal propeptide Platelet-derived growth factor 3-Phosphoinositide-dependent protein kinase-1 Protein of four PDZ domains of protein–protein interactions, post-synaptic density protein/protein of Drosophila disks-large/tight-junction protein (ZO1) Planar electrochromatography Plaque-forming cell Paraflagellar rod-2 protein Prostaglandin E2 Phenyl Phosphoinositide-3-kinase Pivaloyl Phosphorylated-c-Jun-N-terminal kinase Protein kinase C Post-kala-azar dermal leishmaniasis Phospholipase A2 Phorbol-12-myristate-13-acetate Phosphorylated mitogen-activated protein kinase-activator protein-2 Permanent middle cerebral artery occlusion Phosphorylated mitogen-activated protein kinase kinase Polymorphonuclear leukocytes Peroxisome proliferator-activated receptor alpha Peroxisome proliferator-activated receptor-gamma Phosphorylated protein similar to that of Drosophila gene, mothers against decapentaplegic-homolog-2 Pentylenetetrazole Pyridine Rheumatoid arthritis Receptor of advanced glycation endproducts Receptor activator of nuclear factor kappa B ligand Rhabdomyosarcoma Effective dose of drug to repel 50% of insect population in an environment a-L-Rhamnopyranosyl Radiation-induced fibrosarcoma Rotating-frame nuclear Overhauser effect spectroscopy Reactive oxygen species Respiratory syncytial virus Room temperature Real-time polymerase chain reaction Runt-related transcription factor 2 Rutinose Sirtuin

xx

a-SMA SNARE SOCS SOD SRB SREBP1/2 STAT-3 STZ T50 Tn-T TAK1 TAM TBARS TC T2DM TG TGF-b TH TLJN TLR-4 TMS-CHN2 TNBS TRADD TRAF-2 TRAP TNF-RSC Ts TSOD TST TUNEL TXB2 UCP-1 VCAM-1 VEGF VHSV VL VSV WAT wnt Xyl

Abbreviations

Alpha-smooth muscle actin Soluble (N-ethylmaleimide sensitive factor)-activating protein receptor Suppressor of cytokine signaling Superoxide dismutase Sulforhodamine B Sterol regulatory element-binding proteins one and two Signal transducer and activator of transcription-3 Streptozotocin Time required for 50% tumor induction Troponin T TGF-beta-activated kinase-1 Tumor-related macrophages Thiobarbituric acid reactive substance Total cholesterol Type 2 diabetes mellitus Triglycerides Transforming growth factor-beta Tyrosine hydroxylase Tong Luo Jiu Nao Toll-like receptor-4 Trimethylsilyl diazomethane 2,4,6-Trinitrobenzene sulfonic acid TNF-receptor-1-associated death domain protein TNF-receptor-associated factor-2 Tartrate-resistant acid phosphatase Tumor necrosis factor-alpha receptor-associated signaling complex Tosyl Tsuma Suzuki obese diabetes Tail suspension test Terminal deoxynucleotidyl transferase deoxyuridine-5-triphosphate nick-end labeling Thromboxane B2 Uncoupling protein-1 Vascular cell adhesion molecule-1 Vascular endothelial growth factor Viral hemorrhagic septicemia virus Visceral leishmaniasis Vesicular stomatitis virus White adipose tissue Wingless-type integration site protein b-D-Xylopyranosyl

List of Figures

Fig. 1.1 Fig. 1.2 Fig. 1.3 Fig. 2.1 Fig. 2.2 Fig. 2.3 Fig. 3.1 Fig. 3.2

Fig. 3.3

Fig. 3.4

Fig. 3.5 Fig. 3.6 Fig. 3.7 Fig. 3.8

Chemical structures of some representative iridoids . . . . . . . . . . Numbering of substituted iridoid glucosides . . . . . . . . . . . . . . . Chemical structures of some representative iridoids from different groups of skeletal patterns . . . . . . . . . . . . . . . . . . . . . . Chemical structures of the plant iridoids that are listed in Table 2.2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemical structures of some selected iridoid alkaloids . . . . . . . Chemical structures of some insect iridoids that are listed in Table 2.3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemical structures of some selected plant iridoids . . . . . . . . . . Shielding and deshielding effects of C-6 OH group on C-4 and C-8 in a deacetylasperulosidic acid and b antirrhinoside in 13 C-NMR spectra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . a and b Significant 1H–1H-COSY correlations observed in lamiide 207 in CD3OD. Source of the COSY spectrum: Prof. I. Calis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . a and b Significant 1H–1H-COSY correlations observed in auroside 387 in CD3OD. Source of the COSY spectrum: Prof. I. Calis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . a and b Significant HSQC correlations observed in lamiide 207 in CD3OD. Source of HSQC spectrum: Prof. I. Calis . . . . . Significant HSQC correlations observed in auroside 387 in CD3OD. Source of HSQC spectrum: Prof. I. Calis . . . . . Significant HMBC correlations in lamiide 207 in CD3OD. Source of HMBC spectrum: Prof. I. Calis . . . . . . . . . . . . . . . . . Significant HMBC correlations observed in auroside 387 in CD3OD. Source of HMBC spectrum: Prof. I. Calis. . . . . . . .

2 3 12 36 69 71 91

99

106

107 108 109 109 110

xxi

xxii

Fig. 3.9

Fig. 3.10

Fig. 3.11

Fig. 4.1 Fig. 4.2

Fig. 5.1 Fig. 5.2

List of Figures

ORTEP drawing of aucubin crystal structure with atomic numbering and thermal ellipsoids at 50% probability. Adapted from Li et al. [100] with permission of Elsevier. Copyright (2009) Elsevier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ORTEP drawing of triohima A crystal structure with atomic numbering and thermal ellipsoids at 50% probability. Adapted from Li et al. [101] with permission of Elsevier. Copyright (2009) Elsevier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ORTEP drawing of molucidin crystal structure with atomic numbering and thermal ellipsoids at 50% probability. C and O atoms are gray and red colors, respectively. Adapted from Karasawa et al. [102] with permission from Elsevier. Copyright (2015) Elsevier . . . . . . . . . . . . . . . . . . . . . . Chemical structures of some plant iridoids that have been synthesized . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Complete functional genes involved in secologanin pathway of iridoid biosynthesis in Catharanthus roseus. Colors indicate transcriptional activation (blue) or repression (yellow) relative to untreated samples. Tissue of C. roseus: leaf.Sdlg, seedling. Suspension cells (Cell Sus): O2, ORCA2; O3, ORCA3. Treatments of plant tissue: Not, no treatment; MeJA, methyl jasmonate (6, 12, or 24 h). Genes: GES, geraniol synthase; G8O, geraniol 8-oxidase; IS, iridoid synthase; IO, iridoid oxidase; 7-DLGT, 7-deoxyloganetic acid glucosyl transferase; 7-DLH, 7-deoxyloganic acid hydroxylase; LAMT, loganic acid O-methyl transferase; SGD, strictosidine b-D-glucosidase; SLS, secologanin synthase; STR, strictosidine synthase (13 genes); TDC, tryptophan decarboxylase. Adapted from [38] with permission of Springer Nature. Copyright (2014) Springer Nature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemical structures of some bioactive plant iridoids . . . . . . . . . Chemical structures of some bioactive plant and insect iridoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

113

114

115 124

133 230 240

List of Tables

Table 2.1 Table 2.2 Table Table Table Table Table Table

2.3 3.1 3.2 3.3 3.4 3.5

Table 3.6

Iridoid-bearing angiosperm plant families with orders as per APG-IV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Occurrence of iridoids in some selected plant species of different genera in a family . . . . . . . . . . . . . . . . . . . . . . . . . . Occurrence of iridoids in different families of insects . . . . . . . . Separation and isolation of iridoids by HPLC . . . . . . . . . . . . . . Separation and isolation of iridoids by MPLC and LPLC . . . . . Isolation of iridoids by DCCC . . . . . . . . . . . . . . . . . . . . . . . . . Isolation of iridoids by HSCCC . . . . . . . . . . . . . . . . . . . . . . . . 1 H-NMR spectral data (d ppm, J in Hz) of some selected iridoids and secoiridoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 C-NMR spectral data (in d, ppm) of some selected iridoids and secoiridoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18 19 71 86 87 89 89 94 101

xxiii

List of Schemes

Scheme Scheme Scheme Scheme

3.1 3.2 3.3 3.4

Scheme Scheme Scheme Scheme Scheme Scheme

4.1 4.2 4.3 4.4 4.5 4.6

Scheme 4.7 Scheme 4.8 Scheme 4.9 Scheme 4.10 Scheme 4.11 Scheme 4.12 Scheme 4.13 Scheme 4.14 Scheme 4.15 Scheme 4.16 Scheme 4.17

EI-mass fragmentation pattern of aucubin . . . . . . . . . . . . EI-mass fragmentation pattern of harpagide . . . . . . . . . . . EI-mass fragmentation pattern of loganin. . . . . . . . . . . . . ESI-Negative mode mass fragmentation pattern of geniposide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Total synthesis of loganin . . . . . . . . . . . . . . . . . . . . . . . . Total synthesis of (+)-geniposide . . . . . . . . . . . . . . . . . . . Total synthesis of plumericin and allamandin . . . . . . . . . Total synthesis of (+)-iridodial . . . . . . . . . . . . . . . . . . . . . Total synthesis of 12-epi-PGF2a analogue . . . . . . . . . . . . Synthesis of enone derivative of Corey lactone aldehyde analogue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Total synthesis of (15R/15S)-9-epi-15F2c-isoprostane . . . . Total synthesis of sarracenin . . . . . . . . . . . . . . . . . . . . . . Total synthesis of sweroside aglucone-O-methyl ether and secologanin aglucone-O-methyl ether . . . . . . . . . . . . Enzymatic hydrolysis of isoligustroside and isooleuropein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Enzymatic hydrolysis of 10-hydroxyoleoside-type secoiridoid glucosides . . . . . . . . . . . . . . . . . . . . . . . . . . . Secologanin pathway of iridoid biosynthesis in Catharanthus roseus . . . . . . . . . . . . . . . . . . . . . . . . . . . . Postulated biosynthetic pathway of decarboxylated iridoids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Proposed biosynthetic pathway of iridoids in insects . . . . Postulated biosynthetic pathway of nepetalactone and other iridoids in Nepeta cataria . . . . . . . . . . . . . . . . Postulated biosynthetic pathway of dolichodial in Teucrium marum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Postulated biosynthetic pathways of lamioside and ipolamiide in Lamium amplexicaule . . . . . . . . . . . . .

.. .. ..

111 112 112

. . . . . .

. . . . . .

112 121 122 123 123 125

.. .. ..

125 126 127

..

128

..

129

..

130

..

131

.. ..

132 135

..

135

..

136

..

137 xxv

xxvi

List of Schemes

Scheme 4.18 Scheme 4.19 Scheme 4.20 Scheme 6.1 Scheme 6.2 Scheme Scheme Scheme Scheme Scheme

6.3 6.4 6.5 6.6 6.7

Scheme Scheme Scheme Scheme Scheme Scheme

6.8 6.9 6.10 6.11 6.12 6.13

Postulated biosynthetic pathway of lamalbid in Lamium barbatum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Postulated biosynthetic pathway of catalpol in Scutellaria albida . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Proposed biosynthetic pathways of iridoids in Galium species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metabolism of gentiopicroside by human intestinal bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metabolism of gentiopicroside by fungi, Penicillium and Cordyceps spp. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metabolism of geniposide by human intestinal bacteria . . . . Metabolism of gardenoside by human intestinal bacteria . . . Metabolism of aucubin by human intestinal bacteria . . . . . . Metabolism of swertiamarin by Aspergillus spp. . . . . . . . . . Metabolism of swertiamarin by human intestinal bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metabolism of catalpol by human intestinal bacteria . . . . . . Metabolism of loganin by human intestinal bacteria . . . . . . Metabolism of oleuropein by human fecal microbiota . . . . . Metabolism of verproside in rats . . . . . . . . . . . . . . . . . . . . . Metabolism of swertiamarin in rats . . . . . . . . . . . . . . . . . . . Metabolism of geniposide and secologanin in rats . . . . . . . .

137 138 140 256 257 258 258 259 259 259 260 260 261 262 265 268

Summary of Contents

The entitled monograph describes the various aspects of naturally occurring iridoids namely their generic name, classification, occurrence and distribution in plants and insects, isolation techniques, characterization by spectroscopic and chemical methods, synthesis of bioactive iridoids and secoiridoids, biosynthesis, methods of identification of transcriptomes and metabolomes involved in their biosynthesis, role as phylogenic markers in plants, pharmacological activities, pharmacokinetics in mammals, insects and microorganisms, and applications in food supplements, herbal medicines, modern medicines and natural pesticides. The entire subject is presented in seven chapters. The emphasis is given in pharmacology of iridoids and their prospective applications in pharmaceutical and insecticidal industries. The naturally occurring iridoid monoterpenoids 1, and their secoderivatives, known as secoiridoids 2, are widespread in about 56 plant families of dicotyledons (angiosperms)and in one family of monocotyledons (Cyperaceae).Some of these iridoids have been isolated from 8 families of insects. So far about 3000 iridoids of diverse skeletal and substituent pattern have been reported. Many of them possess significant pharmacological activities and have been isolated from several edible plants of folk-lore use.

H

7

H

6

O H

OR 1: R= H, Glc

8 10

O H

OR

2

The most of significant aspects of iridoid research are discussed in different chapters. In Chap. 1, iridoid glycosides, secoiridoid glycosides and their aglycones of different basic skeletons and conjugated patterns are presented. xxvii

xxviii

Summary of Contents

In Chap. 2, the occurrence and distribution of iridoids in the plant species of different genus in 60 plant families and 8 insect families are discussed. In Chap. 3, the purification and isolation of iridoids from crude plant and insect extracts using different chromatography techniques have been discussed. In addition, their identification using different spectroscopic techniques including 2D NMR and NMR spectral data of some common iridoids and secoiridoids are presented. These methods could be useful in the identification of iridoids of unknown structures and their quantification in plant extracts and herbal drugs. In Chap. 4, the synthesis of some bioactive iridoids, secoiridoids and their pharmacologically useful analogues, biosynthesis, and analysis of transcriptomes and metabolomics involved in their biosynthetic pathways are elaborately discussed. Furthermore, their role in the study of phylogeny and evolutionary systematics of plants are discussed. The identified genes involved in their biosynthesis could be useful for commercial production by tissue culture process. In Chap. 5, about 40 types of pharmacological activities of iridoids including anti-inflammatory, anticancer/antitumor, antiviral, antiprotozoal, neuroprotective and neurogenic, hepatoprotective, cardioprotective, hypoglycemic and hypolipidemic, repellent/antifeedant activities as well as physiological role of iridoids in insects are discussed. Some of these bioactive iridoids could be prospective drugs in pharmaceutical and pesticidal industries. In Chap. 6, the metabolism of iridoids in microorganisms and mammals and pharmacokinetics in mammals are briefly discussed, Moreover, disposition of some iridoids in animals is highlighted. In Chap. 7, applications of iridoids as their extracts/ mixture and pure isolates in diet supplements, herbal drugs, modern medicines including cosmetics and dyes, and in pesticides are presented.

Chapter 1

Classification of Iridoids

1.1

Introduction

Iridoids are the highly oxygenated monoterpenes, represented by the cyclopenta[c] pyranoid skeletal structure 1, based on the structure of monoterpene iridane, 4,8-dimethyl-cis-2-oxabicyclo-[4.3.0]-nonane 2 (Fig. 1.1) [1]. These compounds are widespread as secondary plant metabolites in the angiosperm plant families and some ant species [2]. In many plants, these iridoids exist as 7,8-secoderivatives, known as secoiridoids 1a (Fig. 1.1), which are formed by the cleavage of cyclopentane ring at the C-7–C-8 bond. These compounds are found in about 57 plant families of dicotyledons mainly belonging to the Asterids clade in wide structural diversities [3]. Although these compounds were first isolated from plants in 1800 s, the pioneering work on the structures of this class of compounds started after isolation of iridodial 3, iridomyrmecin 4, and isoiridomyrmecin(=iridolactone) 5 (Fig. 1.1) from some species of Iridomyrmex (namely I. detectus, I. humilis, I. conifer, I. nitidus, and I. purpureus), a genus of ants mostly found in Australia [4]. Later on, iridodial 3 was isolated from an Australian plant of genus, Myoporum [5]. Based on these information, the generic name of this class of compounds was adapted as ‘iridoids’ because of their structural similarity with iridodial 3, which on intramolecular acylation gives the pyran skeletal structure of iridoid [6]. Application of iridoids, iridodial 3, and dolichodial 3a (Fig. 1.1) in defense mechanism of ants of genera, Iridomyrmex, Dolichoderus (D. scabridus), and Tapinoma (T. sessile), stimulated the interest on the search of more iridoids from plants [7]. Several insects in the orders Coleoptera, Lepidoptera, Hymenoptera, and Hemiptera ingest these iridoid-containing plants and sequester these compounds and use them as defenses against their predators or to increase their reproductive behavior [8]. Iridoids are found in a number of folk medicinal plants that have been used in folk medicine for treatment of various diseases including skin disorders, sedatives, hypotensive, diabetes, and other inflammatory diseases [9]. The active research work on the pharmacology of naturally occurring iridoids revealed that © Springer Nature Switzerland AG 2019 B. Dinda, Pharmacology and Applications of Naturally Occurring Iridoids, https://doi.org/10.1007/978-3-030-05575-2_1

1

2

1 Classification of Iridoids

Fig. 1.1 Chemical structures of some representative iridoids

these compounds exhibit a wide range of pharmacological activities such as antidiabetic, hypolipidemic, cardioprotective, hepatoprotective, neuroprotective, wound healing, and antitumor activities [9–13]. In some plant families such as in Bignoniaceae, Oleaceae, and Plantaginaceae, these compounds are used as chemotaxonomic markers for the study of systematics of plants [14–16]. Several plant iridoids and secoiridoid-originated indole alkaloids, such as vincristine and vinblastine, are used in modern medicine for the treatment of inflammatory disorders including tumor [17]. A number of review articles on the isolation and structure elucidation, chemistry, distribution, biosynthesis, biological activity, and listings with spectroscopic data of plant iridoids are available [18–25]. From these review articles, it is evident that about 3000 plant-derived iridoids have been reported. Thus, there is a need to develop the chemistry and pharmacology of these naturally occurring iridoids for their commercial utilization in drug formulations in pharmaceutical industry.

1.2

The Numbering of Substituted Iridoid and Secoiridoid Glucosides

The trivial names of iridoids and secoiridoids are frequently used in the naming of these compounds. In most cases, the naming of the iridoids is done from the genus of the plant source. The numbering of the skeletal structures of iridoid and

1.2 The Numbering of Substituted Iridoid and Secoiridoid Glucosides

3

Fig. 1.2 Numbering of substituted iridoid glucosides

secoiridoid glucosides with substituent is shown in 6 and 6a (Fig. 1.2). The substituent on C-1 is given a single prime (′) designation, while the additional substituents are designated as double prime (″), triple prime (″′), etc., according to their substitution position on the basic carbon skeleton of the iridoid glucoside, except in cases of substituents on other substituents. The substituents on a substituent are designated by successive primes.

1.3

Classification of Iridoids

Iridoids are broadly classified into five groups: iridoid glycosides, iridoid aglycones or non-glycosidic iridoids, secoiridoid glycosides, secoiridoid aglycones, and diand trimeric iridoid, and secoiridoid glycosides. Iridoid glycosides are divided into five subgroups: iridoid glycosides of eight-carbon basic skeleton, iridoid glycosides of nine-carbon basic skeleton, iridoid glycosides of ten-carbon basic skeleton, iridoid glycosides of fourteen-carbon basic skeleton or iridoid glycosides of plumeria type, and alkaloid-conjugated iridoid glycosides. Iridoid glycosides of ten-carbon basic skeleton are divided into two subgroups: simple iridoid glycosides of ten-carbon basic skeleton and iridoid glycosides of valeriana type. Iridoid aglycones are divided into four subgroups: simple iridoid aglycones and derivatives, rearranged iridoid aglycones, iridoid aglycones of valeriana type, and iridoid aglycones of plumeria type. Secoiridoid glycosides are divided into four subgroups: simple secoiridoid glycosides, terpene-conjugated secoiridoid glycosides, phenolic-conjugated secoiridoid glycosides, and alkaloid-conjugated secoiridoid glycosides. The following iridoids are illustrative of these groups and subgroups (Fig. 1.3).

4

1 Classification of Iridoids

Group I: Iridoid glycosides IA: Iridoid glycosides with eight-carbon basic skeleton

IB: Iridoid glycosides of nine-carbon basic skeleton IBa. Iridoid glycosides with ninth carbon on C-4

IBb. Iridoid glycosides with ninth carbon on C-8

1.3 Classification of Iridoids

IC: Iridoid glycosides with ten-carbon basic skeleton ICa. Simple iridoid glycosides with ten-carbon basic skeleton

5

6

1 Classification of Iridoids

ICb. Valeriana-type iridoid glycosides with ten-carbon basic skeleton In these iridoid glycosides, isovaleroyl group is present in C-1 carbon and glucose or other sugar moiety is present in C-11 or C-7 or C-10 carbon of basic skeleton.

ID: Plumeria-type iridoid glycosides with fourteen-carbon basic skeleton

1.3 Classification of Iridoids

7

IE: Alkaloid-conjugated iridoid glycosides In these iridoid glycosides, an alkaloid moiety is connected to the iridoid moiety via esterification in the sugar unit. In compound 38, the iridoid geniposidic acid is conjugated to the alkaloid, daphcalycine, and in 39, to the alkaloid, daphnezomine R.

H

H

HO H

O

H

O

O

N

COOH

O HO HO

H

daphcalycinosidine A 38 [56]

O OH H

O

O

H

O HO HO

O N H daphcalycinosidine B 39 [56]

Group II: Iridoid aglycones or non-glycosidic iridoids IIA. Simple iridoid aglycones and derivatives

H

HO

O OMe

COOH

O OH H

O

8

1 Classification of Iridoids

IIB. Rearranged iridoid aglycones

IIC. Valeriana-type iridoid aglycones

1.3 Classification of Iridoids

9

IID. Plumeria-type iridoid aglycones

Group III: Secoiridoid glycosides IIIA. Simple secoiridoid glycosides

H

COOMe H

OHC

HO

O H

O

O

H OGlc

H

secologanin 64 [78]

H

OGlc

secoxyloganin 65 [79]

O

H

OGlc

swertiamarin 68 [82]

OGlc

OGlc H O O

O isosweroside 72 [85]

O

OGlc

morroniside 70 [84]

H

OH

COOMe O

O H

OGlc

secogalioside 73 [83]

H

O O

H

gentiopicroside 69 [83]

H

COOMe

O

O H

O H

OGlc

O

O

O H

O

OGlc secologanic acid 66 [80] sweroside 67 [81] HO

HO

O H

O

HOOC

O

O

COOMe

O

COOMe O

H

OGlc

kingiside 71 [84]

10

1 Classification of Iridoids

IIIB. Terpene-conjugated secoiridoid glycosides In these secoiridoid glycosides, either a monoterpenoid such as nerol-8-oic acid, foliamenthoic acid, menthiafolic acid or a triterpenoid such as ursolic acid and oleanolic acid derivatives is linked through esterification. The following examples are illustrative.

IIIC. Phenolic-conjugated secoiridoid glycosides In these secoiridoid glycosides, phenolic acids such as dihydro-p-coumaric acid, dihydrocaffeic acid, cinnamic acid or hydroxybenzoic acid derivatives are conjugated through esterification. The following examples are illustrative.

1.3 Classification of Iridoids

11

IIID. Alkaloid-conjugated secoiridoid glycosides The following examples are illustrative. COO HOOC

COO H

COOMe H

N O H

OGlc

lonijaposide A 83 [94]

HO

COOMe

N O H

OGlc

lonijaposide B 84 [94]

Group IV: Secoiridoid aglycones

Group V: Di- and trimeric iridoid and secoiridoid glycosides These iridoid glycosides are formed through esterification on direct linkage or via a phenol and a monoterpenol conjugate. The following examples are illustrative.

12

1 Classification of Iridoids

Fig. 1.3 Chemical structures of some representative iridoids from different groups of skeletal patterns

References 1. Tietze LF (1983) Angew Chem Int Ed 22:828 2. Breitmaier E (2008) Terpenes: flavors, fragrances, pharmaca, pheromones, 1st ed, Wiley-VCH Verlag GmbH, Germany; Angiosperm Phylogeny Group III, An update of the angiosperm phylogeny group classification for the orders and families of flowering plants: APG III (2009) Bot J Linn Soc 161:105 3. Ilc T, Parage C, Boachon B, Navrot N, Werek-Reichhart D (2016) Front Plant Sci 7:509 4. Cavill GWK, Ford DL, Locksley HD (1956) Aust J Chem 9:288; Cavill GWK, Ford DL (1960) ibid 13:296; Wilson EO, Pavan M (1959) J Antomol 66:70 5. Achmad SA, Cavill GWK (1965) Aust J Chem 18:1980

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6. Halpern O, Schmid H, Einleitung A (1958) Helv Chim Acta 11:1109; Briggs LH, Cain BF, Le Quesne PW, Shoolery JW (1963) Tetrahedron Lett 4:69 7. Cavill GWK, Clark DV (1971) In: Jacobson M (ed), Naturally occurring insecticides, Dekker, New York, pp 271–305; Cavill GWK, Hinterberger H (1960) Aust J Chem 13:514 8. Bowers MD (2003) J Chem Ecol 29:2359; Opitz SEW, Muller C (2009) Chemoecology 19:117 9. Ghisalberti EL (1998) Phytomedicine 5:147 10. Dinda B, Debnath S, Harigaya Y (2007) Chem Pharm Bull 55:689; Dinda B, Debnath S, Banik R (2011) ibid 59:803 11. Tundis R, Loizzo MR, Menichini F, Statti GA, Menichini F (2008) Mini-Rev Med Chem 8:399 12. Viljoen A, Mncwangi N, Vermaak I (2012) Curr Med Chem 19:2104 13. Dinda B, Debnath S (2013) In: Ramawat KG, Merillon JM (eds) Natural products: phytochemistry, botany and metabolism of alkaloids, phenolics and terpenes. Springer, Berlin, pp 3009–3067 14. Van Poser GL, Schripsema J, Henriques AT, Jensen SR (2000) Biochem Syst Ecol 28:351 15. Taskova RM, Gotfredsen CH, Jensen SR (2006) Phytochemistry 67:286 16. Jensen SR, Franzyk H, Wallander E (2002) Phytochemistry 60:213 17. Cragg GM, Newman DJ (2005) J Ethnopharmacol 100:72 18. Junior P (1990) Planta Med 56:1 19. Bianco A (1990) Nat Prod Chem 7:439 20. Jensen SR (1991) In: Harborne JB, Tomas-Barberan FA (eds) Ecological chemistry and biochemistry of plant terpenoids, Proc Phytochem Soc Europe. Clarendon Press, Oxford, pp 133–158; Rimpler H (1991) ibid, pp 314–330; Grayson DH (1996) Nat Prod Rep 13:195 21. Inouye H, Uesato s (1986) In: Herz w, Grisebach H, Kirby GW, Tam CH (eds) Progress in the chemistry of organic natural products, vol 50. Springer, Vienna, pp 169–236; Uesato S (1988) Yakugaku Zasshi 108:381 22. El-Naggar LJ, Beal JL (1980) J Nat Prod 43:649 23. Boros CA, Stermitz Fr (1990) J Nat Prod 53:1055; (1991) J Nat Prod 54:1173 24. Al-Hazimi HMG, Alkhathlan HZ (1996) J Chem Soc Pakisthan 18:336 25. Dinda B, Debnath S, Harigaya Y (2007) Chem Pharm Bull 55:159; (2007) ibid 55:689; Dinda B, Chowdhury DR, Mohanta BC (2009) ibid 57:765; Dinda B, Debnath S, Banik R (2011) ibid 59:803 26. Rimpler H (1972) Phytochemistry 11:3096; Ismail LD, El-Azizi MM, Khalifa TI, Stermitz FR (1996) Phytochemistry 42:1223 27. Rimpler H, Pistor H (1974) Z Naturforsch 29c:368; Damtoft S, Frederikson LB, Jensen SR (1994) Phytochemistry 35:1259 28. Danielson TJ, Hawes EM, Bliss CA 91973) Can J Chem 51:760; Catalano S, Flamini G, Bilia AR, Morelli I, Nicoletti M (1995) Phytochemistry 38:895 29. Esposito P, Guiso M (1973) Gazz Chim Ital 103:517; Takashima J, Ikeda Y, Komiyama K, Hayashi M, Kishida A, Ohsaki A (2007) Chem Pharm Bull 55:343 30. Guiso M, Marini-Bettolo R, Agostini A (1974) Gazz Chim Ital 104:25 31. Lichli H, von Wartburg A (1966) Helv Chim Acta 49:1552 32. Searpati ML, Esposito P (1967) Gazz Chim Ital 97:1209; Baillent F, Delaveau P, Rabaron A, Plat M, Koch M (1977) Phytochemistry 16:723; Ortiz de Urbina AV, Martin ML, Fernandez B, Sun Roman L, Cubillo L (1994) Planta Med 60:512 33. Duff RB, Bacon JSD, Mundie CM, Farmer VC, Russell JD, Forrester AR (1965) Biochem J 96:1; Weinges K, Kunstler K, Schilling G, Jaggy H (1975) Liebigs Ann Chem 2190 34. Singh B, Rastogi RP (1972) Indian J Chem 10:29 35. Jensen SR, Gotfredsen CH, Sebnem Harput U, Saracoglu I (2010) J Nat Prod 73:1593 36. Winde E, Hansel R (1960) Arch Pharm 293:556 37. Battersby AR, Hall ES, Southgate R (1969) J Chem Soc C 722; Jensen SR, Lyse-Petersen SE, Nielsen BJ (1979) Phytochemistry 18:273; Battersby AR, Burnett AR, Parsons PG (1970) Chem Commun 826

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38. Takeda Y, Nishimura H, Inouye H (1975) Phytochemistry 14:2647; Sati OP, Chaukiyal DC, Nishi M, Miyahara K, Kawasaki T (1986) Phytochemistry 25:2658 39. Takeda Y, Nishimura H, Inouye H (1977) Phytochemistry 16:1401 40. Inouye H, Saito S, Shingu T (1970) Tetrahedron Lett 11:3581; Ersoz T, Ivancheva S, Akbay P, Sticher O, Calis I (2001) Z Naturforsch 56c:695 41. Searpati ML, Guiso M (1967) Tetrahedron 23:4709; Agostini A, Guiso M, Marini-Bettolo R, Martinazzo G (1982) Gazz Chim Ital 112:9 42. Endo T, Taguchi H (1973) Chem Pharm Bull 21:2684 43. Briggs LH, Cain BF, Le Quesne PW, Shoolery JN (1963) Tetrahedron Lett 4:69; Kanchanapoom T, Kasai R, Yamasaki K (2002) Phytochemistry 59:551 44. Inouye H, Arai T, Miyoshi Y (1964) Chem Pharm Bull 12:888; Kanchanapoom T, Kasai R, Yamasaki K (2002) Phytochemistry 59:551 45. Chang WL, Wang HY, Shi LS, Lai JH, Lin HC (2005) J Nat Prod 68:1683 46. Inouye H, Ueda S, Uesato S, Shingu T, Thies PW (1974) Tetrahedron 30:2317; Junior P (1983) Planta Med 47:161 47. Taguchi H, Endo T (1974) Chem Pharm Bull 22:1935 48. Gering B, Wichrl M (1987) J Nat Prod 50:1048 49. Jensen SR, Nielsen BJ, Norn V (1985) Phytochemistry 24:487 50. Hase T, Iwagawa T (1982) Chem Lett 13; Iwagawa T, Hase T (1989) Phytochemistry 28:2393 51. Fukuyama Y, Minoshima Y, Kishimoto Y, Chen IS, Takahashi H, Esumi T (2004) J Nat Prod 67:1833 52. Halpern O, Schmid H, Einleitung A (1958) Helv Chim Acta 11:1109 53. Abe F, Mori T, Yamauchi T (1984) Chem Pharm Bull 32:2947 54. Cimanga K, Hermans N, Apers S, Miert SV, de Heuvel HV, Claeys M, Pieters L, Vlietinck A (2003) J Nat Prod 66:97 55. Kanchanapoom T, Kasai R, Yamasaki K (2002) Phytochemistry 59:551 56. El Bitar H, Nguyen VH, Gramain A, Sevenet T, Bodo B (2004) Tetrahedron Lett 45 (515):2027 57. Zhang H, Rothwangl K, Mesecar AD, Sabahi A, Rong L, Fong HHS (2009) J Nat Prod 72:2158 58. Djerassi C, Nakano T, James AN, Zalkow LH, Eisenbraun EJ, Shoolery JN (1961) J Org Chem 26:1192 59. Hyeon SB, Isoe S, Sakan T (1968) Tetrahedron Lett 9:5325 60. Dinda B, Debnath S, Majumder S, Arima S, Sato N, Harigaya Y (2005) Indian J Chem 44B:2362 61. Jensen SR, Mikkelsen CB, Nielsen BJ (1981) Phytochemistry 20:71 62. Jensen SR, Kirk O, Nielsen BJ, Norrestam R (1987) Phytochemistry 26:1725 63. Yoshikawa M, Fukuda Y, Taniyama T, Kitagawa I (1986) Chem Pharm Bull 34:1403 64. Abe F, Yamauchi T, Wan ASC (1989) Chem Pharm Bull 37:2639 65. Morota T, Nishimura H, Sakai H, Chin H, Sugama K, Karsuhara T, Mitsuhashi H (1989) Phytochemistry 28:2385 66. Tallent WH (1964) Tetrahedron 20:1781 67. Godeau RP, Pelissier Y, Fouraste I (1978) Trav Soc Pharm Montpellier 38:343 68. Jonville MC, Capel M, Frederich M, Angenot L, Dive G, Faure R, Azas N, Ollivier E (2008) J Nat Prod 71:2038 69. Adesogan EK, Alo BI (1979) Phytochemistry 18:1886 70. Ono M, Ito Y, Kubo S, Nohara T (1997) Chem Pharm Bull 45:1094 71. Thies PW (1968) Tetrahedron 24:313; Denee R, Bos R, Hazelhoff B (1979) Planta Med 37:45 72. Handjieva N, Popov S, Marekov N (1978) Phytochemistry 17:561 73. Lin S, Shen YH, Li HI, Yang XW, Chen T, Lu LH, Huang ZS, Lin Rh, Xu XK, Shang WD, Wang H (2009) J Nat Prod 72:650

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74. Choi EJ, Liu QH, Jin Q, Shin JE, Hong JK, Lee DG, Woo ER (2009) Bull Korean Chem Soc 30:1407 75. Albers-Schonberg G, Schmid H (1961) Helv Chim Acta 44:1447 76. Stephens PJ, Pan JJ, Delvin FJ, Krohn K, Kurtan T, Blaylock BT, Bryan RF (2007) J Org Chem 72:3521 77. Adesogan EK (1979) Phytochemistry 18:175; Karasawa S, Yoza K, Tung NH, Uto T, Morigana O, Suzuki M, Kwofie KD, Amoa-Bosompem M, Boakye DA, Ayi I, Adegle R, Sakyimah M, Ayertey F, Aboagye F, Appiah AA, Owusu KBA, Tuffour I, Atchoglo P, Frempong KK, Anyan WK, Appiah-Opong R, Nyarko AK, Yamashita T, Yamaguchi Y, Edoh D, Koram K, Yamaoka S, Ohta N, Shoyama Y (2015) Tetrahedron Lett 56:7158 78. Souzu I, Mitsuhashi H (1970) Tetrahedron Lett 11:191 79. Calis I, Sticher O (1984) Phytochemistry 23:2539 80. Chapelle JP (1976) Planta Med 29:268 81. Inouye H, Ueda S, Nakamura Y (1966) Tetrahedron Lett 7:5229 82. Kubota T, Tomita Y (1961) Tetrahedron Lett 2:176 83. Bock K, Jensen SR, Nielsen BJ (1976) Acta Chem Scan B 30:743 84. Souzu I, Mitsuhashi H (1969) Tetrahedron Lett 10:2725 85. Gross GA, Sticher O (1986) Helv Chim Acta 69:1113 86. Loew P, Szezepanski CV, Coseia CJ, Arigoni D (1968) Chem Commun 1276 87. Battersby AR, Burnett AR, Knowles GD, Parsons PG (1968) Chem Commun 1277 88. Kamikawa T, Inoue K, Kubota T, Woods MC (1970) Tetrahedron 26:4561 89. Ross S, El-Sayyad SM, Ali AA, El-Keltawy NE (1982) Fitoterapia 53:91 90. Houghton PJ, Lian LM (1986) Phytochemistry 25:1907 91. La Londe RT, Wong C, Tsai AI (1976) J Am Chem Soc 98:3007; Shasha B, Leibowitz J (1961) J Org Chem 26:1948 92. Inouye H, Nakamura Y (1968) Tetrahedron Lett 9:4919 93. Damtoft S, Franzyk H, Jensen SR (1992) Phytochemistry 31:4197; Bai N, He K, Ibarra A, Bily A, Roller M, Chen X, Ruhl R (2010) J Nat Prod 73:2 94. Song W, Li S, Wang S, Wu Y, Zi J, Gan M, Zhang Y, Liu M, Lin S, Yang Y, Shi J (2008) J Nat Prod 71:922 95. Borges CMP, Drakanawma C, de Mendonca DIMD (2010) J Braz Chem Soc 21:1121 96. Li ZM, Chen JJ, Li Y, Gao K, Chang J, Yao XJ (2009) Tetrahedron Lett 50:4132 97. Chai X, Su YF, Zheng YH, Yan SL, Zhang X, Gao XM (2010) Biochem Syst Ecol 38:210 98. Tanahashi T, Takenaka Y, Okazaki N, Koge M, Nagakura N, Nishi T (2009) Phytochemistry 70:2072 99. Kitagawa I, Shibuya H, Baek NI, Yokokawa Y, Nitta A, Wiriadinara H, Yoshikawa M (1988) Chem Pharm Bull 36:4232 100. Takagi S, Yamaki M, Yumioka E, Nishimura T, Sakina K (1982) Yakugaku Zasshi 102:313; Machida K, Sasaki H, Iijima T, Kikuchi M (2002) Chem Pharm Bull 50:1041 101. Tanahashi T, Nagakura N, Inoue K, Inouye H (1998) Tetrahedron Lett 29:1793 102. Takenaka Y, Tanahashi T, Nagakura N (1998) Phytochemistry 48:317 103. Tian XY, Wang YH, Yu SS, Fang WS (2006) Org Lett 8:2179

Chapter 2

Occurrence and Distribution of Iridoids

2.1

Introduction

Iridoid monoterpenoids are widespread in the angiosperm plant families and are preferentially synthesized by the eudicots of Asterid clade. These are also synthesized by monocots. About sixty plant families have been reported to produce iridoids of diverse skeletal structures. The plant families from the orders, Dipsacales, Gentianales, and Lamiales, produce iridoids in high concentrations [1]. Previously, the plant taxonomists, namely Bentham and Hooker, Engler, Takhtajan, Gronquist, Dahlgren, Thorne, Hufford, Downie, Palmer, and Albach, classified the iridoid-bearing flowering plants mainly based on morphological and chemical data [2–10]. Earlier published monographs and review articles followed the then classification systems [11, 12]. Recent extensive mitochondrial gene sequencing analysis of floral parts, fruits, and other organs showed several amendments of the placement of plant families as reported in Angiosperm Phylogeny Group-IV (APG-IV) [13].

2.2

Occurrence of Iridoids in Plants

The iridoid compounds have been reported in twenty-two orders of flowering plants in both dicotyledons and monocotyledons. In the eudicots, most of these families belong within the superorders of asteroids, rosids, and superrosids. In the monocots, iridoids are reported in the family, Cyperaceae of order, Poales. Iridoid-bearing angiosperm plant families along with orders are listed in Table 2.1.

© Springer Nature Switzerland AG 2019 B. Dinda, Pharmacology and Applications of Naturally Occurring Iridoids, https://doi.org/10.1007/978-3-030-05575-2_2

17

18

2 Occurrence and Distribution of Iridoids

Table 2.1 Iridoid-bearing angiosperm plant families with orders as per APG-IV Order

Iridoid producing plant family(s)

Apiales Aquifoliales Asterales Bruniales Celastrales Cornales Cucurbitales Dipsacales Ericales

Apiaceae (=Umbelliferae), Griseliniaceae, Toricelliaceae Cardiopteridaceae, Stemonuraceae Asteraceae, Calyceraceae, Goodeniaceae, Menyanthaceae, Stylidiaceae Columelliaceae Celastraceae Cornaceae (including Alangiaceae), Hydrangeaceae, Loasaceae, Nyssaceae Cucurbitaceae Adoxaceae, Caprifoliaceae (including Dipsacaceae, Valerianaceae) Actinidiaceae, Ericaceae, Fouquieriaceae, Roridulaceae, Sarraceniaceae, Symplocaceae Escalloniaceae Fabaceae Eucommiaceae, Garryaceae Apocynaceae, Gelsemiaceae, Gentianaceae, Loganiaceae, Rubiaceae Icacinaceae Acanthaceae, Bignoniaceae, Buddlejaceae, Lamiaceae, Lentibulariaceae, Martyniaceae, Oleaceae, Orobanchaceae, Paulowniaceae, Pedaliaceae, Plantaginaceae (including Callitrichaceae, Hippuridaceae), Scrophulariaceae, Stilbaceae, Verbenaceae Centroplacaceae, Euphorbiaceae, Malpighiaceae, Passifloraceae, Salicaceae Malvaceae Metteniusaceae Cyperaceae Meliaceae Daphniphyllaceae, Hamamelidaceae Montiniaceae

Escalloniales Fabales Garryales Gentianales Icacinales Lamiales

Malpighiales Malvales Metteniusales Poales Sapindales Saxifragales Solanales

2.3

Distribution of Iridoids in Plants

So far, iridoids including secoiridoids have been isolated from the plants of fifty-seven families. In the families, Hamamelidaceae, Martyniaceae, Roridulaceae, and Stylidiaceae, the iridoids were detected but not isolated in pure states. In APG-IV, several plant species are placed in new plant families based on their gene analysis. For instance, the genera of Dipsacaceae and Valerianaceae are included in the family, Caprifoliaceae. Similarly, the genera of Callitrichaceae and Hippuridaceae are placed in the family, Plantaginaceae. The plant species of Buddlejaceae were earlier included in families, Scrophulariaceae and Loganiaceae, and are now placed in its own family. Moreover, the previous orders, Oleales, Scrophulariales, and Hippuridales, are merged within the order, Lamiales. The distribution of iridoids in some selected species of different plant families is listed in Table 2.2 and their structures in Fig. 2.1 to highlight the oxidation states and

2.3 Distribution of Iridoids in Plants

19

skeletal pattern of iridoids and secoiridoids in these plant families. In few cases, the structure numbers of iridoids of catalpol derivatives are mentioned using subset numbers, a, b, c, d, etc., to indicate the types of substitutions found in plant families. In Table 2.2, the iridoids of a single species of each genus are mentioned in alphabetical order and families are also listed in alphabetical order of eudicots and monocots.

Table 2.2 Occurrence of iridoids in some selected plant species of different genera in a family Family, plant species A. Eudicots 1. Acanthaceae Andrographis laxiflora Asystasia bella

Avicennia marina

Barleria spp.

Brillantaisia owariensis Chamaeranthemum gaudichaudii Eranthemum pulchellum Hygrophila polysperma Nelsonia canescens Phaulopsis imbricata Thunbergia alata and T. mysorensis 2. Actinidiaceae Actinidia polygama

3. Adoxaceae Adoxa moschatellina Sambucus williamsii Viburnum betulifolium 4. Apocynaceae Allamanda neriifolia

Alstonia scholaris

Iridoids reported

Reference (s)

Teuhircoside 95 Catalpol 14, mussaenoside 20, 8-epi-loganin 96, gardoside methyl ester 97

[14] [14]

Marinoid A 98, marinoid B 99, marinoid C 100, marinoid D 101, marinoid E 102 Shanzhiside methyl ester 103, 6-O-acetyl shanzhiside methyl ester 104, barlerin 105, acetylbarlerin 106, ipolamiidoside 107 Owariensisone 108 Anthirrinoside 109

[15]

Eranthemoside 110 Isoaucubin 111, mussaenosidic acid 112 Shanzhiside methyl ester 103, galiridoside 113 8 (S)-7,8-Dihydroaucubin 114 Stilbericoside 8, 6-epi-stilbericoside 115, thunbergioside 116

[18] [14] [14] [14] [14, 19]

a-Iridodiol 117, b-iridodiol 118, cis-iridodiol 119, (+)-neomatatabiol 120, iridomyrmecin 4, dehydroiridomyrmecin 122, iso-dehydromyrmecin 123, iso-neonepetalactone 124

[20]

Secologanin 64, morroniside 70, adoxoside 125 Williamsoside A 126, williamsoside B 127, williamsoside C 128, williamsoside D 129 Viburnalloside 31, decapetaloside 131

[21] [22]

Allamcin 132, 3-O-Methylallamcin 133, allamancin 134, 3-O-methylallamancin 135, allamandicin 136, isoallamandicin 137 Scholarein A 138, scholarein B 139, scholarein C 140, scholarein D 141, isoboonein 142, alyxialactone 143, loganin 18

[24]

[16]

[17] [14]

[23]

[25]

(continued)

20

2 Occurrence and Distribution of Iridoids

Table 2.2 (continued) Family, plant species

Iridoids reported

Reference (s)

Alyxia reinwardtii

Alyxialactone 143, 4-epi-alyxialactone 144, pulosarioside 145 Loganin 18, secologanin 64, loganic acid 146 Cerberidol 47, 3-O-allopyranosylcerberidol 148, 3,10-bis-O-allopyranosylcerberidol 149, epoxycerberidol 150, 3-O-allosylcerberidol 151, cyclocerberidol 152, 3-O-allosylcyclocerberidol 153 Plumericin 60, plumieride 34, 15-demethylplumieride 154, plumieridin 155, isoplumieride 156, 15-demethylisoplumieride 157, allamandicin 136 Sangunoside 158 Plumericin 60 Plumericin 60, isoplumericin 62, dihydroplumericin 159, dihydroplumericinic acid 160, fulvoplumierin 161, allamandin 130 7-epi-Loganin 162, loganic acid 146, 7-deoxyloganic acid 163, secoxyloganin 65 Theveside 164, theviridoside 165, 10-O-b-Dfructofuranosyltheviridoside 166, 6′-O-b-Dglucopyranosyltheviridoside 167 Loganin 18

[26]

Gentiopicroside 69

[36]

Ipolamiide 121, strictoloside 154a, theviridoside 165 7-Deoxy-8-epi-loganic acid 163a, 7-deoxygardoside 168, argylioside 169, radiatoside 170 Campenoside 171, 5-hydroxycampanoside 172 Cachinol 173, 1-O-methylcachinol 174, cachineside I 175 Plantarenaloside 176, plantarenalosigenin 1-O-bgentiobioside 177, stansioside 178, stansiosigenin 1-O-b-gentiobioside 179 Specioside 180, specionin 181, catalposide 182 Catalpol 14 Ajugol 11, aucubin 13, agnuside 17, crescentoside A 183, crescentoside B 184, crescentoside C 185, crescentin I 186, crescentin II 187, crescentin III 188

[37]

Specioside 180, macfadienoside 189 Plantarenaloside 176 Eccremocarpol A 190, eccremocarpol B 191

[45] [46] [47] (continued)

Catharanthus roseus Cerbera manghas

Himatanthus sucuuba

Hunteria umbellata Nerium indicum Plumeria rubra

Rauwolfia serpentina Thevetia peruviana

Winchia calophylla 5. Asteraceae Aster auriculatus 6. Bignoniaceae Adenocalymma marginatum Argylia radiata

Astianthus viminalis Campsis grandiflora Campsidium valdivianum Catalpa speciosa Chilopsis linearis Crescentia cujete

Cybistax antisyphilitica Deplanchea speciosa Eccremocarpus scaber

[27] [28]

[29]

[30] [31] [32]

[33] [34]

[35]

[38]

[39] [40] [41]

[42] [43] [44]

2.3 Distribution of Iridoids in Plants

21

Table 2.2 (continued) Family, plant species

Iridoids reported

Reference (s)

Incarvillea emodi (syn. Amphicome emodi) Kigelia pinnata

Amphicoside (= picroside II) 192, plantarenaloside 176, boschnaloside 176a Norviburtinal 193, minecoside 194, specioside 180, verminoside 195, ajugol 11 Macfadyenoside 189, cynanchoside 196, 5,7-bisdeoxycynanchoside 197 6b-Hydroxyipolamiide 198 Verminoside 195, 6-O-p-coumaroylajugol 199, 6-O-caffeoylajugol 200, 6-O-feruloylajugol 201 Verminoside 195, 6-O-caffeoylajugol 200, 6-O-caffeoylcatalpol 202 Verminoside 195, minecoside 194, 6O-caffeoylajugol 200, 6-O-isoferuloylajugol 203, 7-O-acetylloganic acid 204 Theviridoside 165, ipolamiide 121, strictoloside 154a, 10-O-vanilloyltheviridoside 165a Pondraneoside 206 Lamiide 207, pseudocalymmoside 208, durantoside II 209 Amphicoside 192, minecoside 194, specioside 180, nemoroside 210, 6-O-octadienoylcatalpol 211 Stereospermoside 212, ajugol 11, verminoside 195, specioside 180 Specioside 180 Stansioside 178, 5-deoxystansioside 214, plantarenaloside 176 Tecoside 215, undulatin 216, 6-O-veratroylcatalpol 195d

[48]

6-O-p-Methoxycinnamoylaucubin 218, 6-p-methoxycinnamoylcatalpol 219

[63]

Secologanin 64, secoxyloganin 65, swerosidic acid 220, sylvestroside I 221, sylvestroside III 222

[64]

Abelioside A 223, abelioside B 224 Kanokoside A 225, 4′-deoxykanokoside A 226, kanokoside C 227, 4′-deoxykanokoside C 228, valerosidate 28 Sweroside 67, loganin 18, cantleyoside 89, loganic acid-6′-O-b-D-glucoside 217 Morroniside 70, kingiside 71, loniceroside (= secologanin) 64, sweroside 67, sarracenin 147 7-Deoxyloganic acid 163 Loganin 18, loganic acid 146, valerosidate 28, patrinovalerosidate 229

[65] [66]

Macfadyena cynanchoides Memora peregrina Ophiocolea floribunda Perichlaena richardii Phyllarthron madagascariense Pithecoctenium crucigerum Podranea ricasoliana Pseudocalymma elegans Radermachera sinica Stereospermum cylindricum Tabebuia rosea Tecoma stans Tecomella undulata 7. Buddlejaceae Buddleja globosa 8. Calyceraceae Acicarpha tribuloides 9. Caprifoliaceae Abelia grandiflora Centranthus longiflorus subsp longiflorus Dipsacus asperoides Lonicera morrowii Morina nepalensis Patrinia villosa

[49] [50] [51] [52] [53] [54]

[55] [56] [57] [58] [59] [60] [61] [62]

[67] [68] [69] [70] (continued)

22

2 Occurrence and Distribution of Iridoids

Table 2.2 (continued) Family, plant species

Iridoids reported

Reference (s)

Scabiosa variifolia

Loganin 18, loganic acid 146, sweroside 67, swertiamarin 68, cantleyoside 89 Loganin 18, secologanin 64, loganetin 230, glucologanin 231 Loganin 18, secologanin 64, secologanin dimethylacetal 232, grandifloroside 233, sweroside 67, vogeloside 234, triohimas A 86, triohimas B 235, triohimas C 236, naucledal 87 Volvaltrate A 237, volvaltrate B 238, volvaltrate C 239, volvaltrate D 240, IV HD valtrate 241, valeriotriate B 242, jatamanvaltrate B 243, jatamanvaltrate C 58 Alboside I 244

[71]

Kingiside 71, 8-epi-kingiside 245, 8-epi-kingisidic acid 246, kingisidic acid 247, sweroside 67, secoxyloganin 65 Gonocaryoside A 248, gonocaryoside B 249, gonocaryoside C 250, gonocaryoside D 251, gonocaryoside E 252

[76]

6-O-(3″, 4″, 5″-Trimethoxybenzoyl)-ajugol 253, ajugol 11, 6-O-p-hydroxybenzoylajugol 254, 6-O-vanilloylajugol 255

[78]

(7R)-7-Caffeoyloxysweroside 256, (7S)-7caffeoyloxysweroside 257

[79]

Loganin 18, loganic acid 146, loganetin 230, 7-O(p-coumaroyl)-loganin 258, secoxyloganin 65, sweroside 67, dimethylsecologanoside 259

[80]

7-O-Acetylloganic acid 204, 7-O-benzoylloganic acid 260, 7-O-(E/Z)-feruloylloganic acid 261

[81]

Loganin 18, loganic acid 146, secoxyloganin 65, cornuside 262, 7a/b-O-Methylmorroniside 263, 7a/7b-O-ethylmorroniside 264, 7-Obutylmorroniside 265, b-dihydrocornin 266, 10-hydroxyhastatoside 267, cornifin B 268, logmalicid A 269, Logmalicid B 270

[82]

Plumericin 60

[83]

Daphylloside 271, 10-O-deacetylasperulosidic acid methyl ester 272, 10-O-p-coumaroyl-10-Odeacetyldaphylloside 273, 10-O-benzoyl 10-Odeacetyldaphylloside 274, 11demethoxy-11-ethoxydaphylloside 275, 10-O-pcoumaroyl-10-O-deacetylasperuloside 276, 10-Obenzoyl-10-O-deacetylasperuloside 277

[84]

Symphoricarpos albus Triosteum pinnatifidum

Valeriana officinalis

Weigela subsessilis 10. Cardiopteridaceae Citronella gongonha

Gonocaryum calleryanum 11. Celastraceae Maytenus laevis

12. Centroplacaceae Bhesa paniculata 13. Columelliaceae Desfontaina spinosa

14. Cornaceae Alangium platanifolium var. trilobum Cornus officinalis

15. Cucurbitaceae Momordica charantia 16. Daphniphyllaceae Daphniphyllum angustifolium

[72] [73]

[74]

[75]

[77]

(continued)

2.3 Distribution of Iridoids in Plants

23

Table 2.2 (continued) Family, plant species 17. Ericaceae Andromeda polifolia Arbutus unedo Astroloma humifusum Craibiodendron henryi Monotropa uniflora Pyrola japonica Trochocarpa laurina Vaccinium bracteatum 18. Escalloniaceae Escallonia myrtoidea

19. Eucommiaceae Eucommia ulmoides

20. Euphorbiaceae Acalypha indica 21. Fabaceae Parkia javanica 22. Fouquieriaceae Fouquieria diguetii

23. Garryaceae Aucuba japonica Garrya elliptica 24. Gelsemiaceae Gelsemium sempervirens

Iridoids reported

Reference (s)

Andromedoside 278, vaccinoside 279 Unedide 213, monotropein 25 Galioside 280, 10-O-benzoylgalioside 281, scandoside methyl ester 282 10-O-(E/Z)-p-Coumaroylscandoside 283, 10-O(E/Z)-p-coumaroyldeacetylasperulosidic acid 284 Monotropein 25 Monotropein 25 Schismoside 285 Vaccinoside 279, 10-O-(E/Z)-p-coumaroyl-6ahydroxy-dihydromonotropein 286

[85] [86] [87]

Asperuloside 24, 6′-O-bD-glucopyranosylasperuloside 287, daphylloside 271, geniposide 23

[93]

Asperuloside 24, asperulosidic acid 288, aucubin 13, geniposidic acid 289, deacetylasperulosidic acid 290, scandoside 10-O-acetate 291, eucommiol 292, 1-deoxyeucommiol 293, epieucommiol 294, eucomoside I 295, eucomoside A 296, eucomoside B 297, eucomoside C 298, 3,4-dihydro-3bethoxyasperuloside 299, 3.4-dihydro-3bethoxy-deacetylasperuloside 300, ajugoside 11a, genipin 41, geniposide 23

[94]

Isodihydronepetalactone 301, isoiridomyrmecin 5

[95]

Javanicoside A 302, javanicoside B 303

[96]

Galioside 280, galioside 10-acetate 280a, splendoside 304, splendoside 10-acetate 304a, 6bhydroxysplendoside 305, 6b-hydroxysplendoside 10-acetate 305a, 7b-hydroxysplendoside 306, 6b,7b-epoxysplendoside 307

[97]

Aucubin 13, eucommiol 292, eucommioside II 295a Geniposide 23, genipin 41, geniposidic acid 289

[98]

Gelsemide 308, gelsemide 7-O-glucoside 309, semperoside 310, 9-hydroxysemperoside 311, gelsemiol 45, gelsemiol-1-O- glucoside 312, gelsemiol 3-O-glucoside 313, GSIR-1 314

[100]

[88] [89] [90] [91] [92]

[99]

(continued)

24

2 Occurrence and Distribution of Iridoids

Table 2.2 (continued) Family, plant species

Iridoids reported

Reference (s) [101] [102] [103]

Chelonanthus chelonoides

Sweroside 67 Gentiopicroside 69, sweroside 67, swertiamarin 68 Decentapicrin A 315, decentapicrin B 316, decentapicrin C 317 Sweroside 67, chelonanthoside 318, dihydrochelonanthoside 319

Coutoubea spicata

Swertiamarin 68, gentiopicrin 69

[105]

Curtia tenuifolia

Sweroside 67, secologanin 64, secologanol 320, swertiamarin 68, gentiopicroside 69, vogeloside 234, 7-O-p-coumaroylloganin 258 Centauroside 92, 6′-O-m-hydroxybenzoylloganin 258a, gentianine 321, gentianidine 322 Eustomoside 323, eustoside 324, eustomorusside 325, sweroside 67, swertiamarin 68, gentiopicroside 69 Gentiopicroside 69, grandifloroside methyl ester 326 Fagraldehyde 51, sweroside 67, swertiamarin 68, gentiopicroside 69 Loganic acid 146, loganic acid 6′-O-b-D-glucoside 217, swertiamarin 68 Vogeloside 234, epivogeloside 234a Sweroside 67, lisianthioside 327 Swertiamarin 68

[106]

Sweroside 67 Amerogentin 81, gentianine 321 Sweroside 67, swertiamarin 68, gentiopicrin 69, amerogentin 81, ameroswerin 328 Sweroside 67, gentiopicrin 69, langaside 329 Loganic acid 146, secologanoside 330, morroniside 70, sweroside 67, 7a/7b-methoxyswerosides 331, 6′-Ob-D-glucopyranosylmorroniside 332

[115] [116] [117]

Loganin 18, loganic acid 146, sylvestroside III 222, cantleyoside 89, scaevoloside 333

[120]

Griselinoside 334

[121]

Deutzioside 9, deutziol 335, a/b-deutziogenin 336, scabroside 337, a/b-scabrogenin 338, scabrosidol 10 Loganin 18, 7-O-glucopyranosyl loganin 258a, 7-O-isoferuloylloganic acid 261a, hydrangeside B 339

[122]

25. Gentianaceae Anthocleista djalonensis Blackstonia perfoliata Centaurium littorale

Erythraea centaurium Eustoma russellianum

Exacum tetragonum Fagraea fragrans Gentiana decumbens Halenia campanulata Lisianthius seemanii Lomatogonium carinthiacum Potalia amara Sabatia elliottii Swertia chirata Tachiadenus longiflorus Tripterospermum japonicum

26. Goodeniaceae Scaevola racemigera 27. Griseliniaceae Griselinia littoralis 28. Hydrangeaceae Deutzia scabra

Hydrangea paniculata

[104]

[107] [108]

[109] [110] [111] [112] [113] [114]

[118] [119]

[123]

(continued)

2.3 Distribution of Iridoids in Plants

25

Table 2.2 (continued) Family, plant species

Iridoids reported

Reference (s)

Kirengeshoma palmata

Sweroside 67, 6b-hydroxysweroside 340, loganin 18

[124]

Secologanoside 330, secoxyloganin 65

[125]

Harpagide 12, 8-O-acetylharpagide 12a, 6-epi-8O-acetylharpagide 341, ajugol 11, ajugoside 11a, reptoside 342, ajureptoside 343, ajureptoside A 344, ajureptoside B 345, ajureptoside C 346, ajureptoside D 347 Allobetonicoside 348, 6-O-acetylmioporoside 349, 8-O-acetylharpagide 12a, reptoside 342 6-O-Benzoylphlorigidoside B 350, 6-O-transcinnamoylphlorigidoside B 351, 6-O-trans-pcoumaroylshanzhiside methyl ester 104a, 4′-Otrans-p-coumaroylmussaenoside 352 Harpagide 12, 8-O-acetylharpagide 12a, 6-epi-8-Oacetylharpagide 341, clandonoside 353, 8-Oacetylclandonoside 353a, clandonensine 354, clandonoside II 355 Aucubin 13, 8-O-acetylharpagide 12a, melittoside 356, reptoside 342, ajugoside 11a, 8-Oacetylmioporoside 349a Wallichiiside A 357, wallichiiside B 358, wallichiiside C 359, wallichiiside D 360, wallichiiside E 361, wallichiiside F 362, wallichiiside G 363 6,9-epi-8-O-Acetylshanzhiside methyl ester 364, 5,9-epi-penstemoside 365, 5,9-epi7,8-didehydropenstemoside 366 Galiridoside 113 6-O-a-L (2″, 3″,4″-Tri-O-benzoyl)rhamnopyranosylcatalpol 368, 6-O-a-L-(2″, 3′′-diO-benzoyl, 4″-O-E/Z-p-coumaroyl)rhamnopyranosylcatalpol 369, 6-O-a-L (2′′,3′′-Di-O-benzoyl)rhamnopyranosylcatalpol 370, catalpol 14, geniposidic acid 289, gardoside 398, 8-epi-loganic acid 146a, gmelinoiridoside 371 6-O-a-L-(2′′-O-trans-cinnamoyl)Rhamnopyranosylcatalpol 372, 6-O-a-L-(3″-O-trans-cinnamoyl)rhamnopyranosylcatalpol 373, 6-O-a-L-(4″-O-E/Zferuloyl)-rhamnopyranosylcatalpol 374, 6-O-a-L(4′′-O-E/Z-p-coumaroyl)-rhamnopyranosylcatalpol 375 Lamioside 22, 5-deoxylamioside 22a, 6-deoxylamioside 22b, lamiide 207, lamiol 376, lamalbide 377, ipolamiidoside 107, ipolamiide 121, shanzhiside methyl ester 103, barlerin 105

[126]

29. Icacinaceae Poraqueiba sericea 30. Lamiaceae Ajuga reptans

Betonica officinalis Callicarpa formosana var. formosana

Caryopteris clandonensis

Clerodendrum thomsoniae Eriophyton wallichii

Eremostachys glabra

Galeopsis tetrahit Gmelina philippensis

Holmskioldia sanguinea

Lamium amplexicaule

[127] [128]

[129]

[130]

[131]

[132]

[133] [133]

[134]

[135]

(continued)

26

2 Occurrence and Distribution of Iridoids

Table 2.2 (continued) Family, plant species

Iridoids reported

Reference (s)

Lamiophlomis rotata

Shanzhiside methyl ester 103, 8-Oacetylshanzhiside methyl ester 105, 6-Oacetylshanzhiside methyl ester 104, 8deoxyshanzhiside 378, loganin 18, penstemoside 379, phlomiol 377b, gentiopicroside 69, lamiolactone 380, lamiophlomiol A 381, lamiophlomiol B 382, lamiophlomiside 205 Ajugoside 11a, 8-O-acetylharpagide 12a, 6-Oacetylajugol 199a, 7-deoxy-8-epi-loganic acid 159, 7,8-epoxy-8-epi-loganic acid 383, galiridoside 113, 10-deoxygeniposidic acid 289a Harpagide 12, 8-O-acetylharpagide 12a, melittoside 356, ajugol 11, ajugoside 11a Velpetin 384, nepetacilicioside 385 8-O-Acetylharpagide 12a Lamiide 204, 8-epi-loganin 96, phlomiside 386, auroside 387 Stegioside I 388, stegioside II 389, stegioside III 390 6-O-a-L-Rhamnopyranosylcatalpol 211d, 6-O-a-L(2″-O-isoferuloyl) -rhamnopyranosylcatalpol 375a, 6-O-a-L-(3″-O-isoferuloyl)rhamnopyranosylcatalpol 375b Salvialoside A 391, salvialoside B 392, salvialoside C 393, salvialoside D 394, salvialoside E 395, shanzhiside methyl ester 103, barlerin 105, 6-O-syringyl barlerin 105a Lamiol 376, 5-deoxylamiol 376a, 5deoxylamioside 22a, 4-methyl antirrinoside 396 Scutelloside 397, gardoside 398, 6′-O-E-pcoumaroyl gardoside 399, 8-epi-loganic acid 146a, 6′-O-E-p-coumaroyl-8-epi-loganic acid 400, picroside III 401, albidoside 402, globularin 403, dihydrocatalpol 404, catalpol 14 Melittoside 356, 10-O-E-p-coumaroylmelittoside 356a, 10-O-E-feruloylmelittoside 356b, stachysoside E 405, stachysoside G 406 Teucardoside 407, 8-O-acetylharpagide 12a Agnuside 17, eurostoside 408, viteoid I 53, viteoid II 409, iridolactone I 410, pedicularislactone 411, eucommiol 292, 1-oxoeucommiol 412, VR-I 408a Lamiide 207, ipolamiide 121, ipolamiidoside 107

[136]

Catalpol 14, globularicisin 403a, 10-O-Zcinnamoylcatalpol 403a Aucubin 13, gardoside 398, mussaenosidic acid 112, 6-deoxycatalpol 413

[151]

Leonurus persicus

Melittis melissophyllum Nepeta cilicia Otostegia fruticosa Phlomis aurea Physostegia virginiana Premna japonica

Salvia digitaloides

Satureja vulgaris Scutellaria albida ssp. albida

Sideritis trojana

Teucrium yemense Vitex rotundifolia

Wiedemannia orientalis 31. Lentibulariaceae Pinguicula vulgaris Utricularia australis

[137]

[138] [139] [140] [141] [142] [143]

[144]

[145] [146]

[147]

[148] [149]

[150]

[151] (continued)

2.3 Distribution of Iridoids in Plants

27

Table 2.2 (continued) Family, plant species 32. Loasaceae Caiophora coronata Eucnide bartonioides

Loasa acerifolia Mentzelia cordifolia Schismocarpus matudai 33. Loganiaceae Antonia ovata Strychnos nux-vomica 34. Malpighiaceae Stigmaphyllon sagittatum 35. Malvaceae Abutilon pakistanicum 36. Meliaceae Xylocarpus moluccensis 37. Menyanthaceae Menyanthes trifoliata Nymphoides indica Villarsia exaltata 38. Metteniusaceae Apodytes dimidiata 39. Montiniaceae Montinia caryophyllacea 40. Nyssaceae Nyssa ogeche 41. Oleaceae Chionanthus virginicus Fontanesia phillyreoides Forestiera acuminata Forsythia europaea Fraxinus excelsior

Iridoids reported

Reference (s)

Caiophoraenin 414, isoboonein 142 Morroniside 70, kingiside 71, sweroside 67, secologanol 320, loganin 18, 5-hydroxyloganin 415, 8-epi-loganin 96 Acerifolioside 416, tricoloroside methyl ester 417, loganin 18, loganic acid 146 7-Chlorodeutziol 418, mentzefoliol 419, glucosylmentzefoliol 420 Schismoside 285, 8-epi-mussaenoside 422, dihydrorandioside 423

[152] [153]

10-Hydroxyloganin 424, ixoside 26, geniposidic acid 289, 7b-hydroxy-11-methylforsythide 425 Loganin 18, loganic acid 146, deoxyloganin 426, secologanin 64, 7-ketologanin 427

[157]

Galioside 280, monotropein 25, geniposidic acid 289, geniposide 23, scandoside methyl ester 282

[159]

Pakiside A 428, pakiside B 429

[160]

Xylomollin 430

[161]

Loganin 18, dihydrofoliamenthin 74a, menthiafolin 75 Menthiafolin 75, 7-epi-exaltoside (= foliamenthin) 74, 6′′,7′′-dihydro -7-epi-exaltoside 74a Exaltoside 431, 7-epi-exaltoside 74

[162]

Genipin 41, genipin 10-O-acetate 41a

[165]

Montinioside 432

[166]

Grandifloroside 11-methyl ester 326

[167]

Oleuropein 80, excelside B 433 Loganic acid 146, secologanic acid 66, 5-hydroxysecologanol 434, secologanoside 330, fontanesioside 435, swertiamarin 68 Oleuropein 80 Adoxosidic acid 436, forsythide 11-glucosyl ester 437 Ligstroside 79, 10-hydroxyligstroside 438, oleoside 11-methyl ester 439, oleoside dimethyl ester 440, GI-3 441, GI-5 90, excelside A 433a, excelside B 433, nuzhenide 82

[168] [169]

[154] [155] [156]

[158]

[163] [164]

[170] [169] [171]

(continued)

28

2 Occurrence and Distribution of Iridoids

Table 2.2 (continued) Family, plant species

Iridoids reported

Reference (s)

Jasminum nitidum Ligustrum japonicum

Lilacoside 442, fliederoside 443 Ligustaloside A 444, ligustaloside B 445, oleonuzhenide 446, isonuzhenide 447, neonuzhenide 448, ligstroside 79, oleuropein 80, 10-hydroxyligstroside 438, nuzhenide 82, 8-epikingiside 245, 10-hydroxyoleuropein 438a, oleuropeinic acid 449, ligustrosidic acid 450, methylglucooleoside 451 7-Ketologanin 427, 8-epi-kingisidic acid 246, 10-hydroxyoleoside dimethyl ester 438b Myxopyroside 452, 6-O-acetyl-7-O-(E/Z)-pmethoxycinnamoyl ester of myxopyroside 453 Oleuropein 80, ligstroside 79 Nyctanthoside 454, 6b-hydroxyloganin 455, arbortristoside A 456, arbortristoside B 457, arbortristoside C 458, arborside A 459, arborside B 460, arborside C 461, arborside D 462, nyctanthic acid 463 Oleuropein 80, ligstroside 79, oleoside dimethyl ester 440, oleuroside 464 10-Acetoxyligstroside 465, 10-acetoxyoleuropein 465a, nuzhenide 82, GI-3 441 Oleuropein 80, ligstroside 79, 7-epi-loganic acid 162a, 8-epi-kingisidic acid 246, secologanoside 330, secoxyloganin 65 Loganin 18, 7-ketologanin 427, 8-epi-kingisidic acid 246, ligstroside 79, picconioside I 466, secoxyloganin 65 Ligstroside 79, oleuropein 80, syringopicroside 467, fliederoside (= syringolactone A) 443, lilacoside (= syringolactone B) 442, 8-epi-kingiside 245, nuzhenide 82, isoligustroside 468, isooleuropein 469, neooleuropein 470

[172] [173]

Isoaucubin 111 Aucubin 13, shanzhiside methyl ester 103, gardoside methyl ester 97, 8-epi-loganin 96, bartsioside 471, 5-deoxypulchelloside I 471a Aucubin 13, gardoside methyl ester 97, 8-epi-loganin 96, 8-O-acetylharpagide 12a Aucubin 13, bartsioside 471, melampyroside 472, mussaenoside 20, gardoside methyl ester 97, mussaenosidic acid 112, geniposidic acid 289, 8epi-loganin 96 Boschnaside 473, boschnaloside 176a, (4R)4-hydroxymethylboschnialactone 474 Penstemonoside 475, dihydrocornin 266, catalpol 14, aucubin 13

[181] [182]

Menodora robusta Myxopyrum smilacifolium Nestegis sandwicensis Nyctanthes arbor-tristis

Olea europaea Osmanthus fragrans Phillyrea latifolia

Picconia excelsa

Syringa vulgaris

42. Orobanchaceae Aeginetia indica Agalinis communis Aureolaria flava Bellardia trixago

Boschniakia rossica Castilleja rhexifolia

[170]

[174] [170] [175]

[176] [177] [178]

[179]

[180]

[183] [184]

[185] [186] (continued)

2.3 Distribution of Iridoids in Plants

29

Table 2.2 (continued) Family, plant species

Iridoids reported

Reference (s)

Cistanche salsa Euphrasia genargentea

Cistanin 476, cistachlorin 477 Aucubin 13, catalpol 14, mussaenosidic acid 112, melampyroside 472 Lamourouxide I 478 Aucubin 13, 6′-O-glucopyranosylaucubin 479, melampyroside 472, 6′-O-glucosylmelampyroside 472a Aucubin 13, 8-epi-loganin 96, mussaenoside 20, gardoside methyl ester 97, melampyroside 472 7-O-Acetyl-8-epi-, loganic acid 480, 8-Oacetylmussaenosidic acid 112a Aucubin 13, catalpol 14, mussaenoside 20, shanzhiside methyl ester 103, 8-epi-loganin 96, odontoside 481 Aucubin 13, melampyroside 472, gardoside methyl ester 97, shanzhiside methyl ester 103, 8-epiloganin 96 Rehmannioside A 482, rehmannioside B 483, rehmannioside C 484, rehmannioside D 485, rehmaglutin A 486, rehmaglutin B 487, rehmaglutin C 46, rehmaglutin D 488, jioglutolide 489, jioglutoside A 490, jioglutoside B 491 Aucubin 13, mussaenoside 20, melampyroside 472, gardoside methyl ester 97, 8-epi-loganin 96, shanzhiside methyl ester 103, 6′-Obenzoylshanzhiside methyl ester 492 Siphonostegiol 493 Catalpol 14, ajugol 11, 6-O-feruloylajugol 201, 6O-p-coumaroylajugol 199

[187] [188]

Mussaenoside 20 Catalpol 14, paulownioside 494, tomentoside 495, 7-hydroxytomentoside 496

[199] [200]

Shanzhiside methyl ester 103

[200]

Procumbide 497, 6′-O-p-coumaroylprocumbide 498, harpagide 12, harpagoside 499, 8-O-(E/Z)-pcoumaroylharpagide 500, 8-O-feruloylharpagide 501, procumboside 502, pagoside 503, harprocumbide A 504, harprocumbide B 505 Harpagide 12, harpagoside 499, 8-O-ciscinnamoylharpagide 506, 8-O-pcoumaroylharpagide 500 Sesinoside 507

201]

Lamourouxia multifida Lathraea squamaria

Melampyrum arvense Monochasma savatierii Odontites verna ssp. serotina Parentucellia viscosa

Rehmannia glutinosa

Rhinanthus angustifolius ssp. grandiflorus Siphonostegia chinensis Triaenophora rupestris 43. Paulowniaceae Brandisia hancei Paulownia tomentosa 44. Passifloraceae Barteria fistulosa 45. Pedaliaceae Harpagophytum procumbens

Rogeria adenophylla

Sesamum indicum

[189] [190]

[191] [192] [193]

[194]

[195]

[196]

[197] [198]

[202]

[203] (continued)

30

2 Occurrence and Distribution of Iridoids

Table 2.2 (continued) Family, plant species 46. Plantaginaceae Adenosma caeruleum Anarrhinum orientale Angelonia integerrima

Antirrhinum majus Aragoa cundinamarcensis Besseya plantaginea

Chaenorhinum minus Cymbalaria muralis ssp. pilosa Globularia dumulosa

Gratiola officinalis Hemiphragma heterophyllum Hippuris vulgaris Kickxia elatine

Lagotis yunnanensis Linaria vulgaris Littorella uniflora Penstemon fruticosus

Picrorhiza kurroa Plantago subulata

Pseudolysimachion rotundum var. subintegrum Russelia equisetiformis

Iridoids reported

Reference (s)

Aucubin 13, adenosmoside 508 6′-O-Cinnamoylantirrinoside 509, 6-O-nerol-8-Oyl-antirrinoside 109a Angeloside 510, galiridoside 113, harpagide 12, ajugol 11, antirrhide 511, 6b-hydroxyantirrhide 512, daunoside 513, aucubin 13, stegioside II 389 Antirrhinoside 109, 5-O-glucosylantirrhinoside 109b, antirrhide 511, linarioside 514 Aucubin 13, catalpol 14, mussaenoside 20, globularin 403, gardoside methyl ester 97, rehmannioside D 485 Catalpol 14, 8-epi-loganic acid 146a, mussaenoside 20, veronicoside 195a, verproside 195b, Isovanilloylcatalpol 195c Antirrhinoside 109, 10-O-glucosylbartsioside 471a, chaenorrhinoside 515 Muralioside 516, antirrhinoside 109, linarioside 514, linaride 517, antirrhide 511, 8-epi-loganic acid 146a 10-O-Benzoylglobularigenin 518, davisioside 519, dumuloside 520, aucubin 13, melampyroside 472, catalpol 14, 10-O-benzoylcatalpol 202a, alpinoside 521, deacetylalpinoside 522 1b,6b-Di-O-trans-Cinnamoyl-9-O-bD-glucopyranosyl-3-iridene-5b-ol 523 Globularin 403

[204] [205]

Aucubin 13, catalpol 14 Kickxioside 524, 5-O-menthiafoloylkickxioside 525, kickxin 526, antirrhinoside 109, antirride 511, mussaenosidic acid 112, linarioside 514 Lagotisoside D 527, lagotisoside E 528 Antirrhinoside 109, 6-O-(E/Z)-p-coumaroyl antirrhinoside 109c, procumbide 497 Aucubin (= aucuboside) 13, catalpol 14 Aucubin 13, mussaenoside 20, eurostoside 408, geniposidic acid 289, 8-epi-loganin 96, 10-O-foliamenthoylaucubin 529, 10-O-(E/Z)-pmethoxycinnamoylaucubin 530 Pikuroside 531, picroside I 532, picroside II (=amphicoside) 192, 6-O-feruloylcatalpol 194a Aucubin 13, 10-O-acetylaucubin 530a, monomelittoside 533, 10-O-acetylmonomelittoside 534, melittoside 356 Verproside 195b, piscroside C 535, 3bmethoxy-3,4-dihydrocatalposide 536

[215] [216]

10-O-Cinnamoyl sinuatol 537, catalpol 14, specioside 180, verminoside 195, gmelinoside A 538, rehmaglutin B 487, rehmaglutin D 488

[224]

[206]

[207] [208]

[209]

[210] [211]

[212]

[213] [214]

[217] [218] [219] [220]

[221] [222]

[223]

(continued)

2.3 Distribution of Iridoids in Plants

31

Table 2.2 (continued) Family, plant species

Iridoids reported

Reference (s)

Scoparia ericacea

Geniposide 23, geniposidic acid 289, scandoside methyl ester 282, shanzhiside methyl ester 103, caryoptoside 539 Aucubin 13, 8-epi-loganic acid 146a, scrophularioside 540, gardoside 168a, mussaenosidic acid 112, derwentioside 541, derwentioside B 542, derwentioside C 543 Wolfenoside 544, isoscrophularioside 545, globularin 403 Aucubin 13, ajugol 11, gardoside 168a, 8-epiloganic acid 146a, 6-O-a-L (3′′ cinnamoyl)rhamnopyranosylcatalpol 373, 6-O-a-L (4′′-cinnamoyl)-rhamnopyranosylcatalpol 373a

[182]

Adinoside A 546, adinoside B 547, adinoside C 548, adinoside D 549, adinoside E 550, grandifloroside 11-methyl ester 326 Aitchisonide A 551, aitchisonide B 552, deacetylasperulosidic acid 290, nepetanudoside 553 Amagnalactone 554, boschnaloside aglycone 176b 6b-Hydroxy-7-epi-gardoside methyl ester 555, shanzhiside methyl ester 103, ixoside 26 Sweroside 67, 3′-O-caffeoylsweroside 556, loganin 18, loganic acid 146, 8-epi-kingiside 245 Asperulosidic acid 288

[228]

Asperuloside A 557, asperuloside B 558, asperuloside C 559, picconioside II 460a Asperuloside 24, scandoside methyl ester 282, 6′-O-(2-glyceryl) scandoside methyl ester 560 b-Gardiol 561, a-gardiol 562 Diderroside 563, 7-methoxydiderroside 564, 6′-Oacetyldiderroside 565, 8-O-tigloyldiderroside 566, loganetin 230, loganin 18, secoxyloganin 65, kingiside 71 Geniposidic acid 289 Gardenoside 567, scandoside methyl ester 282, 6a-hydroxygeniposide 272, shanzhiside methyl ester 103 Asperuloside 24, deacetylasperuloside 24a Alboside I 568, alboside II 569, alboside III 570, alboside IV 571 Monotropein 25 Vogeloside 234, swertiamarin 68, secologanin 64, asperuloside 24

[234]

Veronica derwentiana

Wolfenia carinthiaca Wolfeniopsis amherstiana

47. Rubiaceae Adina racemosa

Aitchisonia rosea

Alberta magna Alibertia edulis Anthocephalus chinensis Arcytophyllum thymifolium Asperula maximowiczii Borreria verticillata Burchellia bubalina Calycophyllum spruceanum

Canthium gilfillanii Catunaregam tomentosa

Coprosma pyrifolia Chiococca alba Coussarea platyphylla Cruckshanksia pumila

[225]

[226] [227]

[229]

[230] [231] [232] [233]

[235] [236] [237]

[238] [239]

[240] [241] [242] [243] (continued)

32

2 Occurrence and Distribution of Iridoids

Table 2.2 (continued) Family, plant species

Iridoids reported

Reference (s)

Cruciata laevipes

Scandoside 282a, asperuloside 24, asperulosidic acid 288, deacetylasperulosidic acid methyl ester 272, daphylloside 271 Asperuloside 24, asperulosidic acid 288, deacetylasperulosidic acid 290 Dunnisinoside 572, dunnisinin 573 Plumericin 60, duroin 574 Loganin 18, loganic acid 146, 6′-O-Ecaffeoylloganic acid 146b, loganetin 230, cachineside I 175 Geniposidic acid 289, asperulosidic acid 288, deacetylasperulosidic acid 290, monotropein 25, scandoside 282a, 10-hydroxyloganin 424, deacetyldaphylloside 272 Gardenoside 567, galioside 280, geniposide 23, ixoroside 19, scandoside methyl ester 282, 7b, 8bepoxy-8a-dihydrogeniposide 575, 8-epiapodantheroside 576, 10-O-succinoylgeniposide 577, 10-O-acetylgeniposide 578, 6′-Oacetylgeniposide 579, 6′-O-p-coumaroylgeniposide 580 Genameside A 581, genameside B 582, genameside C 583, genameside D 584, geniposide 23, geniposidic acid 289, gardenoside 567, genipin 1-O-gentiobioside 585 Guettardodiol 586, sarracenin 147 Hedycoryside A 587, hedycoryside B 588, hedycoryside C 589, asperuloside 24, scandoside methyl ester 282, geniposide 23, 6ahydroxygeniposide 272, asperulosidic acid 288, deacetylasperuloside 24a, 10-O-benzoylscandoside methyl ester 282b, 10-O-phydroxybenzoylscandoside methyl ester 282c Lamalbide-6,7,8-triacetate 377a, lamiridosin-6,7,8triacetate 590 Floribundane A 591, floribundane B 85

[244]

Ixoside 26, ixoroside 19, geniposidic acid 289 Asperuloside dimer 592, iridolactone II 593, asperuloside 24, paederoside 594, daphylloside 271 Secologanoside 330 Barlerin 105, shanzhiside methyl ester 103, 6-Overatroylshanzhiside methyl ester 103a Yopaaoside A 37, yopaaoside B 595, yopaaoside C 596, 10-O-acetylmonotropein 25a, 6-Oacetylscandoside 597, asperulosidic acid 288, asperuloside 24, deacetylasperuloside 24a, secoxyloganin 65

[256] [257]

Crucianella maritima Dunnia sinensis Duroia hirsuta Emmenopterys henryi

Galium melanantherum

Gardenia jasminoides

Genipa americana

Guettarda grazielae Hedyotis corymbosa (= Oldenlandia corymbosa)

Heinsia crinita Hymenodictyon floribundum Ixora chinensis Lasianthus wallichii

Machaonia brasiliensis Molopanthera paniculata Morinda coreia

[245] [246] [247] [248]

[249]

[250]

[251]

[252] [253]

[254] [255]

[258] [259] [260]

(continued)

2.3 Distribution of Iridoids in Plants

33

Table 2.2 (continued) Family, plant species

Iridoids reported

Reference (s)

Mussaenda incana Myrmecodia tuberosa

Mussaenoside 20, shanzhilactone 43, barlerin 105 Myrmecodoide A 598, myrmecodoide B 599, asperulosidic acid 288, deacetylasperulosidic acid 290 Ixoside 26, Ixoside sodium salt Paederosidic acid dimer I 600, paederosidic acid dimer II 601, paederosidic acid dimer III 602, paederoside B 603, paederoside 594, paederosidic acid 604, paederosidic acid methyl ester 605, 6b-Ob-D-glucosylpaederosidic acid 606, asperuloside 24, asperulosidic acid 288, geniposide 23 Tudoside (= citrifolinin B) 607, gaertneroside 36, 13R-epi-epoxygaertneroside 608, E-uenfoside 609, Z-uenfoside 610 Prismatomerin 611, gaertneroside 36 Asperuloside 24, paederoside 594, paederosidic acid 604 Randinoside 612, galioside 280, deacetylasperulosidic acid methyl ester 272, scandoside methyl ester 282, geniposide 23, gardenoside 567 Macrophylloside 613, macrophyllide 614, gardenogenin A 615, gardenogenin B 616, 6ahydroxygeniposide 272, 6a-O-E/Zferuloylscandoside methyl ester 272a, 6a-O-transp-coumaroylscandoside methyl ester 272b 6b-Methoxygeniposidic acid 597a 3,4-Dihydro-3-methoxypaederoside 617, paederoside 594, paederosidic acid 604, methylpaederosidate 605, monotropein 25, scandoside 282a, 10-acetylscandoside 282d, asperulosidic acid 288, deacetylasperulosidic acid 290, 10-O-benzoyldeacetylasperulosidic acid 290a, 6-epi-paederosidic acid 604a Scyphiphorin A (= hedycoryside C) 589, scyphiphorin B 589a, scyphiphin C 618, shanzhiside methyl ester 103, geniposidic acid 289, hydrophylin A 619, hydrophylin B 620 Loganin 18, secoxyloganin 65, loganic acid 146, sweroside 67 Tarennin 621, tarenninoside A 622, tarenninoside B 623, tarenninoside C 624, tarenninoside D 625, tarenninoside E 626, tarenninoside F 627, tarenninoside G 628, ixoside 26, 10-methylixoside 26a b-Gardiol 561, a-gardiol 562, mollugoside methyl ester 629, formosinoside 630 7-Deoxy-8-epi-loganic acid 163a

[261] [262]

Oxyanthus pallidus Paederia scandens

Pentas lanceolata

Prismatomeris tetrandra Putoria calabrica Randia spinosa

Rothmannia macrophylla

Rubia cordifolia Saprosma scortechinii

Scyphiphora hydrophyllacea

Sickingia williamsii Tarenna attenuata

Tocoyena formosa Uncaria tomentosa

[263] [264]

[265]

[266] [267] [268]

[269]

[270] [271]

[272]

[273] [274]

[275] [276] (continued)

34

2 Occurrence and Distribution of Iridoids

Table 2.2 (continued) Family, plant species

Iridoids reported

Reference (s)

Villaria odorata

Morindolide 631, hydrophylin A 619, hydrophylin B 620 5-Dehydro-8-epi-adoxosidic acid 632, 5dehydro-8-epi-mussaenoside 633, wendoside 634, 8-epi-mussaenoside 635, 10-Odihydroferuloyldeacetyldaphylloside 273a, 10-Overatroyleranthemoside 110a

[277]

6-O-(3″, 4″-Dimethoxycinnamoyl) catalpol 211a

[279]

Sarracenin 147 Sarracenin 147, alatenoside 636, morroniside 70, 7a/7b-7-O-methylmorroniside 263, alpigenoside 211a, kingiside 71

[280] [281]

Harpagoside 499, 6′-O-b-D-glucopyranosyl-8-Oacetylharpagide 499a Aucubin 13, catalpol 14, 6-O-(3′′, 4′′dimethoxycinnamoyl)-catalpol 211a, methylcatalpol 211b Harpagide 12, catalpol 14, caprarioside 637, 3bhydroxymyopochlorin 638, 5-hydroxyglutinoside 639, macfadyenoside 189, 8-O-acetylharpagide 12a, 6b-hydroxyantirrhide 512 Melampyroside 472, verminoside 195, 6-Oferuloylajugol 201, catalpol 14, geniposidic acid 289 Ipolamiide 121, lamiide 207 Aucubin 13, catalpol 14 Altissimoside 640, sweroside 67, eustomoside 323, eustoside 324, secoxyloganin 65, secologanoside 330 Myopochlorin 638a, myobontioside A 641, myobontioside B 642 Aucubin 13, harpagide 12, harpagoside 499, oreosolenoside 372a, scorodioside 372b, catalpol 14, methylcatalpol 211b Aucuboside (= aucubin) 13, bartsioside 471a, 8-Oacetylharpagide 12a, harpagoside 499, scorodioside 372b Aucubin 13 6-O-b-D-Glucosyl catalpol 211c, 6-O-aL-rhamnosylcatalpol 211d, verbaspinoside 370a, pulverulentoside I 370b, buddlejoside A8 527, 6-bD-glucosylaucubin 218a, 6-O-(6′′-O-E-phydroxycinnamoyl)-b-D-glucosylaucubin 218b Zaluzioside 643, catalpol 14, ajugol 11

[282]

Wendlandia tinctoria

48. Salicaceae Homalium ceylanicum 49. Sarraceniaceae Heliamphora pulchella Sarracenia alata

50. Scrophulariaceae Alonsoa meridionalis Buddleja asiatica

Capraria biflora

Eremophila spp.

Hebenstretia dentata Limosella aquatica Manulea altissima

Myoporum bontioides Oreosolen wattii

Scrophularia scorodonia Sutera dissecta Verbascum salviifolium

Zaluzianskya capensis

[278]

[283]

[284]

[285]

[286] [287] [288]

[289] [198]

[290]

[291] [292]

[293] (continued)

2.3 Distribution of Iridoids in Plants

35

Table 2.2 (continued) Family, plant species 51. Stemonuraceae Cantleya corniculata 52. Stilbaceae Retzia capensis

Stilbe ericoides 53. Symplocaceae Symplocos glauca 54. Toricelliaceae Aralidium pinnatifidum Torricellia spp. 55. Umbelliferae Heracleum rapula 56. Verbenaceae Bouchea fluminensis Citharexylum caudatum

Duranta erecta

Lantana camara

Lippia graveolens

Stachytarpheta angustifolia Verbena officinalis

Verbenoxylum reitzii

Iridoids reported

Reference (s)

Cantleyoside 89

[294]

Unedoside 7, stilbericoside 8, retzioside 644, capensioside 645, holmioside 646, 5deoxyholmioside 646a, thunbergioside 116, 5deoxythunbergioside 116a, adoxosidic acid 436 Unedoside 7, stilbericoside 8

[295]

Verbenalin 647, 6b-hydroxyverbenalin 647a

[297]

Griselinoside 334, aralidoside 648 Griselinoside 334, aralidoside 648, torrilliolide 649, torricellate 650

[121] [121, 298]

Rapulaside A 651, rapulaside B 652

[299]

Lamiide 207, lamiidoside 207a, duranterectoside C 207b, durantoside II 209, boucheoside 209a Caudatoside A 653, caudatoside B 654, caudatoside C 655, caudatoside D 656, caudatoside E 657, caudatoside F 658 Lamiide 207, lamiidoside 207a, duranterectoside C 207b, duranterectoside B 207c, duranterectoside D 207d, duranterectoside A 207e, durantoside III 207f, durantoside II 209 Theveside 164, theviridoside 165, lamiidoside 207a, 8-epi-loganin 96, geniposide 23, shanzhiside methyl ester 103 Loganin 18, secologanin 64, dimethylsecologanoside 330a, loganic acid 146, 8epi-loganic acid 146a, caryoptoside 659, caryoptosidic acid 660, lippioside I 661, lippioside II 662 Citrifolinoside 663, serratoside B 664, 6-O-(3″-OE-cinnamoyl)-a-L-rhamnopyranosylcatalpol 373 Verbenalin 647, 3,4-dihydroverbenalin 647b, hastatoside 665, 7-hydroxydehydrohastatoside 666, verbeofflin I 667 Theviridoside 165, ipolamiide 121, 2′-Oapiosylgardoside 398a

[300]

[296]

[301]

[302]

[303]

[304]

[305] [306]

[307] (continued)

36

2 Occurrence and Distribution of Iridoids

Table 2.2 (continued) Family, plant species B. Monocots 57. Cyperaceae Cyperus rotundus

Iridoids reported

Reference (s)

Ipolamiide 121, 6b-hydroxyipolamiide 198, negundoside 698, isooleuropein 469, neonuezhenide 448, nishindaside 668, rotunduside A 669, rotunduside B 670, rotunduside C 671, rotunduside G 672, rotunduside H 673, 10-Ovanilloyltheviridoside 165a, 10-O-phydroxybenzoyltheviridoside 165b, loganic acid 146, 6′-O-(E-p-coumaroyl)-procumbide 498

[308]

Fig. 2.1 Chemical structures of the plant iridoids that are listed in Table 2.2

2.3 Distribution of Iridoids in Plants

Fig. 2.1 (continued)

37

38

Fig. 2.1 (continued)

2 Occurrence and Distribution of Iridoids

2.3 Distribution of Iridoids in Plants

Fig. 2.1 (continued)

39

40

Fig. 2.1 (continued)

2 Occurrence and Distribution of Iridoids

2.3 Distribution of Iridoids in Plants

Fig. 2.1 (continued)

41

42

Fig. 2.1 (continued)

2 Occurrence and Distribution of Iridoids

2.3 Distribution of Iridoids in Plants

Fig. 2.1 (continued)

43

44

Fig. 2.1 (continued)

2 Occurrence and Distribution of Iridoids

2.3 Distribution of Iridoids in Plants

Fig. 2.1 (continued)

45

46

Fig. 2.1 (continued)

2 Occurrence and Distribution of Iridoids

2.3 Distribution of Iridoids in Plants

Fig. 2.1 (continued)

47

48

Fig. 2.1 (continued)

2 Occurrence and Distribution of Iridoids

2.3 Distribution of Iridoids in Plants

Fig. 2.1 (continued)

49

50

Fig. 2.1 (continued)

2 Occurrence and Distribution of Iridoids

2.3 Distribution of Iridoids in Plants

Fig. 2.1 (continued)

51

52

Fig. 2.1 (continued)

2 Occurrence and Distribution of Iridoids

2.3 Distribution of Iridoids in Plants

Fig. 2.1 (continued)

53

54

Fig. 2.1 (continued)

2 Occurrence and Distribution of Iridoids

2.3 Distribution of Iridoids in Plants

Fig. 2.1 (continued)

55

56

Fig. 2.1 (continued)

2 Occurrence and Distribution of Iridoids

2.3 Distribution of Iridoids in Plants

Fig. 2.1 (continued)

57

58

Fig. 2.1 (continued)

2 Occurrence and Distribution of Iridoids

2.3 Distribution of Iridoids in Plants

Fig. 2.1 (continued)

59

60

Fig. 2.1 (continued)

2 Occurrence and Distribution of Iridoids

2.3 Distribution of Iridoids in Plants

Fig. 2.1 (continued)

61

62

Fig. 2.1 (continued)

2 Occurrence and Distribution of Iridoids

2.3 Distribution of Iridoids in Plants

Fig. 2.1 (continued)

63

64

Fig. 2.1 (continued)

2 Occurrence and Distribution of Iridoids

2.3 Distribution of Iridoids in Plants

Fig. 2.1 (continued)

65

66

Fig. 2.1 (continued)

2 Occurrence and Distribution of Iridoids

2.3 Distribution of Iridoids in Plants

Fig. 2.1 (continued)

67

68

Fig. 2.1 (continued)

2 Occurrence and Distribution of Iridoids

2.3 Distribution of Iridoids in Plants

69

Fig. 2.2 Chemical structures of some selected iridoid alkaloids

Till to date, nearly 3000 iridoids have been reported from plant sources [309]. From Table 2.2, it is evident that secoiridoids are abundant in the plants of families, Adoxaceae, Caprifoliaceae, Gentianaceae, Hydrangeaceae, Loganiaceae, Rubiaceae, and Oleaceae, while iridoids are dominant in other plant families. The iridoid lactones are mostly found in the plants of Actinidiaceae, and plumeria-type iridoids are mainly found in Apocynaceae and Rubiaceae. The Valeriana-type iridoids are abundant in Caprifoliaceae. The distribution of iridoids is mainly restricted to plant families that belong to Wettstein’s Tubiflorae [310]. Several iridoid alkaloids have been isolated from some plants of families, Apocynaceae, Gentianaceae, Loganiaceae, and Rubiaceae, for instance, strictosidine 674 from Vinca rosea (Apocynaceae) [311], bahienoside B 675 from Palicourea acuminata (Rubiaceae) [312], gentianine 321, gentianidine 322, and gentioflavine 676 from Erythraea centaurium (Gentianaceae) [313], and alangiside 677 from Alangium lamarckii and Alangium salviifolium [314] (Fig. 2.2).

2.4

Iridoid Content in Plant’s Organs

The concentration of iridoids in different organs of a plant depends on the age, growth condition, and geographical origin. For instance, an HPLC analysis of harpagoside 499 and harpagide 12 content in stems, leaves, and callus of Harpagophytum procumbens shoots of 3-, 6-, and 12-month-old plants grown under both in vitro (in green house tissue culture process) and in vivo (in

70

2 Occurrence and Distribution of Iridoids

stem-propagated process) conditions showed that total iridoid content as the sum of harpagoside and harpagide was highest in the root tubers of 6-month-old plants (4.15 ± 0.52 mg/g DW and 4.18 ± 0.39 mg/g DW, respectively), while it was relatively lower in the root tubers of 3- and 12-month-old plants (2.30 ± 0.38 and 2.54 ± 0.36 mg/g DW; 1.73 ± 0.21 and 2.41 ± 0.43 mg/g DW, respectively). Moreover, the content of harpagoside was found much higher compared to that of harpagide in the leaves, stems, and root tubers of 3-month-old plant grown in in vitro condition (2.66, 1.92, and 2.1 mg/g DW of harpagoside, respectively). A similar trend was also noticed in in vivo derived plants [315]. Levielle and Wilson [316] investigated the iridoid concentration in the aerial parts of H. procumbens and found that the iridoid content of the leaves of 18-month-old in vitro grown plants was 10 times lower than that of the underground parts. Another study on the contents of plantarenaloside 176 and boschnaloside 176a in different parts (shoots, roots, and flowers) of Incarvillea emodi showed that plantarenaloside was the major constituent in shoots (6.78% in terms of dry weight of plant powder), while in flowers, boschnaloside was the major constituent (6.12% DW of plant) [317]. A comparative study on antirrhinoside 109 content in leaves and roots of two related plants Antirrhinum majus L and Linaria vulgaris Mill of family Plantaginaceae indicated that young leaves of these plants contain high concentration of antirrhinoside compared to that of roots. Furthermore, the concentration of antirrhinoside in L. vulgaris roots decreased relative to A. majus roots during budding and flowering stages [318].

2.5

Iridoids in Insects

Several insect specialists in the orders, Coleoptera, Lepidoptera, Hymenoptera, and Hemiptera, feed on iridoid glycosides (IGs) containing plants for the growth of their larvae, and some of them sequester IGs to use them in defensive purpose against their predators as well as to improve their reproduction [319]. For instance, the females of buckeye butterfly, Junonia coenia, feed on IGs to stimulate its oviposition [320], while catalpa moth, Ceratomia catalpae, uses IGs as feeding stimulants [321]. Some aphids such as Acyrthosiphon nipponicus accumulate these IGs in their body and use it in defensive purpose against their predators [322] and ant species of genus Iridomyrmex also use these compounds as defensive secretions,

2.5 Iridoids in Insects

71

Table 2.3 Occurrence of iridoids in different families of insects Family, insect species 1. Aphididae Acyrthosiphon nipponicus 2. Chrysomelidae Chrysomelina populi, Gastrophysa viridula Plagiodera versicolora 3. Chrysopidae Chrysopa oculata 4. Figitidae Leptopilina heterotoma 5. Formicidae Iridomyrmex humilis and other Iridomyrmex spp. 6. Geometridae Meris paradoxa 7. Nymphalidae Euphydryas anicia Euphydryas cynthia Euphydryas phaeton Junonia coenia Thessalia theona 8. Sphingidae Ceratomia catalpae

Iridoids present

References

Paederoside 594

[322]

Chrysomelidial 678

[324]

Chrysomelidial 678, anisomorphal 679

[325]

Iridodial I 680

[326]

(−)-iridomyrmecin 4, (+)-isoiridomyrmecin 5, iridodial 3, iridodial II 681

[327]

Iridomyrmecin 4, isoiridomyrmecin 5

[328]

Antirrhinoside 109

[329]

Macfadienoside 189 Aucubin 13, catalpol 14, 6-O-glucosyl catalpol 211c Aucubin 13 Aucubin 13, catalpol 14 6-Hydroxyipolamiide 198

[330] [331] [183] [332] [333]

Catalpol 14

[334]

Fig. 2.3 Chemical structures of some insect iridoids that are listed in Table 2.3

while parasitoid wasp, Leptopilina, species use these compounds as pheromones [323]. The occurrence of iridoids in some insects is listed in Table 2.3 (Fig. 2.3).

2.6

Iridoid Content in Insect’s Organs

The herbivorous insects usually accumulate the dietary IGs in their midgut. In the midgut, these IGs are either hydrolyzed by b-glucosidases into iridoid aglycones or converted into other iridoids to reduce the toxicity. These modified iridoids are transferred to the hemolymph for use as defensive secretions [335]. The larvae of

72

2 Occurrence and Distribution of Iridoids

the buckeye butterfly (Junonia coenia) feed on catalposide 182 producing plants as diet for better growth and hence store it in digestive tract [336]. The larvae of Chrysomelina species sequester these IGs from food plants or synthesize these compounds in their body and store these deterrent compounds in glandular reservoirs on their back and discharge as droplets against predators [324].

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

13. 14. 15. 16.

17. 18. 19. 20.

21. 22. 23. 24. 25. 26. 27. 28.

Angiosperm Phylogeny Group III (2009) Bot J Linn Soc 161:105 Bentham G, Hooker JD (1862–1883) Genera Plantarum, vol 3. London Engler A, Prantl K (1928) Die Naturlichen Pflanzenfamilien, 2nd edn. Engelmann, Leipzig Takhtajan AL, Crovello TJ, Cronquist A (1986) Floristic Regions of the World. University of California Press, Berkeley Gronquist A (1988) The evolution of flowering plants, 2nd edn. The New York Botanical Garden, Bronx, New York Dahlgren R (1980) Bot J Linn Soc 80:91 Thorne RF (1992) Bot Rev 58:225 Hufford L (1992) Ann Mo Bot Gard 79:218 Downie SR, Palmer JD (1992) Ann Mo Bot Gard 79:266 Albach DC, Soltis PS, Soltis DE, Olmstead RG (2001) Ann Mo Bot Gard 88:163 Jensen SR, Nielsen BJ, Dahlgren R (1975) Bot Not 128:148 Bowers MD (1988) Chemistry and coevolution: iridoid glycosides, plants and herbivorous insects. In: Spencer KC (ed) Chemical mediation of coevolution. Academic Press, New York, pp 133–165 Angiosperm Phylogeny Group IV (2016) Bot J Linn Soc 181:1 Jensen HFW, Jensen SR, Nielsen BJ (1988) Phytochemistry 27:2581 Sun Y, Ouyang J, Deng Z, Li Q, Lin W (2008) Magn Reson Chem 46:638 Damtoft S, Jensen SR, Nielsen BJ (1982) Tetrahedron Lett 23:4155; Suksamrarn A (1986) J Nat Prod 49:179; Byrne LT, Sasse JM, Skelton BW, Suksamrarn A, White AH (1987) Aust j Chem 40:785 Tebou PLF, Mabou FD, Ngnokam D, Harakat D, Voutquenne-Nazabadio KL (2016) Nat Prod Res 30:1611 Jensen HFW, Jensen SR, Nielsen BJ (1987) Phytochemistry 26:3353 Jensen SR, Nielsen BJ (1989) Phytochemistry 28:3059 Sakan T, Isoe S, Hyeon SB, Ono T, Takagi I (1964) Bull Chem Soc Jpn 37:1888; Hyeon SB, Isoe S, Sakan T (1968) Tetrahedron Lett 9:5325; Sakai T, Nakajima K, Sakan T (1980) Bull Chem Soc Jpn 53:3683; Morota T, Nishimura H, Sakai H, Chin H, Sugama K, Katsuhara T, Mitsuhashi H (1989) Phytochemistry 28:2385 Jensen SR, Nielsen BJ (1979) Biochem Syst Ecol 7:103 Wang ZY, Han H, Yang BY, Xia YG, Kuang HX (2011) Molecules 16:3869; Kuang HX, Han H, Yang By, Yang L, Jiang H, Wang QH (2012) Molecules 17:1830 Jensen SR, Nielsen BJ, Norn V (1985) Phytochemistry 24:487 Kupchan SM, Dessertine AL, Blaylock BT, Bryan RF (1974) J Org Chem 39:2477; Abe F, Mori T, Yamauchi T (1984) Chem Pharm Bull 32:2947 Feng J, Cai XH, Du ZZ, Luo XD (2008) Helv Chim Acta 91:2247 Topcu G, Che CT, Cordell GA, Ruangrungsi N (1990) Phytochemistry 29:3197 Miettinen K, Dong L, Navrot N, Schneider T, Burlat V, Pollier J, Memelink J, Werck-Reichhart D (2014) Nat Commun 5:3606 Abe F, Yamauchi T, War ASC (1989) Chem Pharm Bull 37:2639

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Chapter 3

Isolation and Identification of Iridoids

3.1

Introduction

Diverse pharmacological activities of iridoids encouraged several chemists and pharmacologists for isolation of these compounds in large quantities in pure states for use as chemical standards as well as for further pharmacological studies. The separation and isolation of pure iridoid and secoiridoid glycosides and aglycones from crude plant extracts by conventional chromatographic systems such as thin-layer and column chromatographic methods are time consuming and require large amounts of organic solvents, and numerous chromatographic steps resulting in the lower recovery and higher cost for isolation. Moreover, in the long-step preparative thin-layer and column chromatographic processes, partial decomposition of the natural compounds occurs in many cases. Recently developed chromatographic techniques such as high-, medium-, and low-performance liquid chromatographic methods, droplet countercurrent chromatography (DCCC), high-speed countercurrent chromatography (HSCCC), gas—liquid chromatography (GLC) and capillary electrophoresis are frequently utilized in separation and purification of iridoids. It is observed that a single method of separation is not suitable for isolation of iridoid compounds because of their different polarities. Classical techniques such as column and thin-layer chromatographic methods are still useful in many cases. In this chapter, an emphasis is given to the recently developed techniques of separation and isolation of iridoids as well as their identification by spectroscopic techniques.

© Springer Nature Switzerland AG 2019 B. Dinda, Pharmacology and Applications of Naturally Occurring Iridoids, https://doi.org/10.1007/978-3-030-05575-2_3

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3.2

3 Isolation and Identification of Iridoids

Extraction of Iridoids from Plants and Insects

Usually, iridoids are extracted from air-dried powdered plant materials by percolation with 95% ethanol or 85% methanol for 48 h. In few cases, 60% ethanol or hot water or pressurized hot water is effective for efficient extraction of water-soluble iridoids from plant material. The crude alcoholic or aqueous extract is suspended in a little water and successively partitioned with petroleum ether (bp 60–90 °C) or hexane, dichloromethane or chloroform, ethyl acetate, and n-butyl alcohol in turn. Each organic solvent extract is concentrated under reduced pressure in a rotary evaporator, and the concentrated extract is subjected to chromatographic techniques for isolation of pure compounds [1]. For isolation of iridoids from insects, the extraction of iridoids from insects is carried out with methanol. The methanol extract is dissolved in water and extracted with solvent ether. The residue obtained from the aqueous part is dissolved in dry methanol and treated with trimethyl silyl chloride and pyridine for conversion of the iridoids into their less polar trimethylsilyl derivatives. Both the ether extract and silylated extract are subjected to gas chromatography for analysis of the iridoids [2]. Sometimes, the secretion of insect larvae is taken in dry ether, and the ethereal solution is injected into a gas chromatograph for analysis of iridoids [3].

3.3 3.3.1

Isolation Techniques of Iridoids Thin-Layer Chromatography

Thin-layer chromatography (TLC) is the simplest method for quick detection and separation of iridoids from their mixture in both plant and insect extracts. Silica gel GF254 is commonly used adsorbents in glass plates. The fractions obtained from open-column chromatography are often subjected to preparative (prep.) TLC for isolation of pure iridoid compounds. Bolzani et al. [4] purified mollugoside methyl ester 629, a-, and b-gardiol (562 and 561) from the leaves of Tocoyema formosa by prep. TLC using the solvent mixture of benzene–ethyl acetate (1:1) + 1.5% acetic acid and benzene–ethyl acetate (2: 3) + 3% acetic acid in silica gel plates. High-performance thin-layer chromatography (HPTLC), over-pressured layer chromatography (OPLC) and planar electrochromatography (PEC) are also useful for purification of plant iridoids [5]. TLC system is hyphenated with various spectroscopic techniques such as mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy for identification of plant metabolites. TLC system equipped with direct autography technique is useful for screening of antimicrobial constituents present in a mixture. In this technique, the bioactive chemical constituents are visualized directly on a TLC plate after developing in a suspension of microbial culture and spraying the plate with a tetrazolium salt, MTT [6]. Rodriguez et al. [7] applied this method for isolation of antimicrobial iridoids from Swertia

3.3 Isolation Techniques of Iridoids

85

calycina and Alibertia myrciifolia. HPTLC method was applied for quantitative estimation of catalpol glycosides in microgram quantities from the stem bark of Premna integrifolia using a solvent gradient, ethyl acetate–methanol–water–acetic acid (80:12:6:2, v/v) on silica gel 60F254 plates, and vanillin–sulfuric acid as spraying reagent [8]. The iridoids, such as plumieride 34 and isoplumieride 156 from Himatanthus sucuuba, were separated by HPTLC method [9].

3.3.2

Open-Column Chromatography

Column chromatography is very useful technique for preliminary purification and large-scale fractionations of iridoids from crude plant extracts. Silica gel, Diaion HP-20, and Sephadex LH-20 are widely used packing materials for columns. Ersoz et al. [10] separated iridoids and phenyl ethanoid glycosides from an ethanol extract of Euphrasia pectinata on silica gel column using solvent gradients, chloroform–methanol–water (90:10:0.5 to 60:40:4), and methanol. The water-soluble iridoids from aqueous extract of Eucommia ulmoides were separated by column chromatography using Diaion HP-20, MCI gel CHP-20P, and silica gel (Mesh 60) as successive column packing materials [1]. A vacuum liquid chromatography with silica gel column and solvent gradient of methanol–dichloromethane (10:90 to 70:30) was effective for separation of polar iridoids from Strychnos cocculoides [11]. The polar iridoid lactones, plumieride 34, and 15-demethylplumieride 154 were isolated from Plumeria obtusa by repeated column chromatography technique using silica gel, Sephadex LH-20, and RP-8 as packing materials [12].

3.3.3

High-, Medium-, and Low-Performance Liquid Chromatography Techniques

High-performance liquid chromatography (HPLC) is a powerful tool for detection, quantitative estimation, and separation of natural compounds including iridoids from their mixture. The difference between the analytical and preparative methodologies reflects their application in chromatographic separations. Preparative and semi-preparative HPLC techniques are used for isolation and recovery of compounds from their mixtures, while analytical HPLC is used for qualitative and quantitative analyses. The scope and versatility of this technique has been increased recently mainly due to availability of necessary instrumentation and efficiency of versatile column packing materials. A modern HPLC system comprises following basic units: a pump to deliver solvents of definite composition at a high pressure (up to 600 bars), sample injection valve, packed column(s), and one or more detectors. The hardware is usually controlled by a computer system, which allows a high degree of precision.

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A variety of columns with different packing materials, particle size, and dimensions are available in the market. Usually, reverse-phase columns provide an excellent resolution and separation of polar iridoid glycosides. Octadecylsilane particles in reversed-phase mode (ODS, C18) are the most popular column in HPLC separation of iridoids. The mobile phase is usually a mixture of methanol–water or acetonitrile–water containing a catalytic amount of acetic acid, formic acid, trifluoroacetic acid or phosphoric acid (0.02–0.05%) [13]. UV and refractive index (RI) detectors are routinely used in both qualitative and quantitative HPLC analyses of iridoids [14]. The analyses of iridoids with a carbonyl group (–CHO, –COOH, – COOR) at C-4 were usually carried out with a UV detector in the wavelength range of 240–270 nm [14]. The most powerful setup for identification of iridoids in a sample mixture is a coupling setup of HPLC with a mass spectrometer (LC–MS) or with a nuclear magnetic resonance spectrometer (LC–NMR), with or without a UV detector in between. Some of the separations of iridoids from their mixture by HPLC are listed in Table 3.1.

Table 3.1 Separation and isolation of iridoids by HPLC Separed iridoids; plant source

Column

Mobile phase

References

Plumieride 34, 15-demethylplumieride 155, isoplumieride 156; Himatanthus sucuuba Loganin 18, loganic acid 146, aucubin 13, catalpol 14, geniposide 23, geniposidic acid 289, shanzhiside 21, harpagoside 499, gardenoside 563; different plants Aucubin 13, catalpol 14; Paulownia tomentosa Harpagoside 499, 8-O-pcoumaroylharpagide 500; Harpagophytum procumbens, H. zeyheri Valtrate 54, isovaltrate 54a; Valeriana officinalis

LiChrospher C18

Acetonitrile–water (5:95 to 25:75) + 0.05% trifluoroacetic acid

[13]

Cosmosil 5 C18

Aqueous solution of potassium dihydrogenphosphate (20 mM)–acetonitrile (96:4 to 25:75)

[14]

Spherisorb ODS 2 µ-Bondapak C18

Methanol–water

[15]

Methanol–water (57:43)

[16]

Hypersil ODS

Acetonitrile–water–phosphoric acid (20:80:0.05 to 80:20:0.05) Water–methanol (1:0 to 1:1)

[17]

Aucubin 13, gardoside 398, mussaenosidic acid 112, 8-epiloganic acid 146a, scrophularioside 540, derwentioside A 541, derwentioside B 542, derwentioside C 543; Veronica derwentiana

Lobar RP-18

[18]

(continued)

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87

Table 3.1 (continued) Separed iridoids; plant source

Column

Mobile phase

References

Boonein 142a, isoboonein 142; Rauwolfia grandiflora 10-O-Succinoylgeniposide 577, 10-O-acetylgeniposide 578, 6′O-acetylgeniposide 579; Gardenia jasminoides

µ-Bondapak C18 Purospher STAR RP (C18)

Methanol–water (50:50)

[19]

Methanol–water (4:6)

[20]

Table 3.2 Separation and isolation of iridoids by MPLC and LPLC Separated iridoids; plant source

Technique

Column

Mobile phase

References

10-Hydroxyhastatoside 267, 5b,6bdihydroxyadoxoside 125a; Penstemon secundiflorus Melittoside 356, 10-O-Eferuloylmelittoside 356b; Sideritis trojana

MPLC

Lobar RP C-18

[21]

MPLC

LiChroprep C18

MPLC

LiChroprep C18

LPLC

Lobar C-18 (size B)

LPLC

LiChroprep RP-18 (size A)

Water– methanol (25:1 to 6:1) Water– methanol (100:0 to 35:65) Water– methanol (95:5 to 1:1) Water– methanol (3:7 to 1:1) Water– methanol mixture

5b,6b-Dihydroxyboschnaloside 682, 6b-hydroxyboschnaloside 683; Euphrasia pectinata Amphicoside 192, 6′-Omenthiafoloylmussaenosidic acid 684; Veronica bellidioides 5-Deoxysesamoside 685, sesamoside 686, shanzhiside methyl ester 103, lamalbide 377; Phlomis tuberosa

[22]

[9]

[23]

[24]

Medium- and low-pressure liquid chromatography (MPLC and LPLC) techniques have been applied also for separation of plant iridoids. In these chromatographic techniques, the columns and mobile phases are similar to those used in HPLC technique. Some of these separation studies are listed in Table 3.2.

3.3.4

Droplet- and High-Speed Countercurrent Chromatography Techniques

Countercurrent chromatography (CCC) is a simple and efficient liquid–liquid separation chromatography technique for separation and isolation of iridoid glycosides from their mixtures. In this technique, two immiscible liquid phases without a solid support are used, where one liquid phase acts as the stationary phase in the column, while the other as mobile phase, which is pumped through the stationary phase of the column. In the droplet countercurrent chromatography (DCCC),

88

3 Isolation and Identification of Iridoids

a better and effective method of CCC, the stationary phase is held in the column by the force of gravity, while in another sophisticated method, high-speed countercurrent chromatography (HSCCC), it is held by a hydrodynamic centrifugal force (known as Archemedes’ screw force) in the helical coil-shaped column [25]. DCCC is an efficient chromatographic technique that has been developed by Tanimura et al. [26]. In this technique, the separation of compounds from their mixture is achieved due to their different partition coefficients between the two liquid phases. It is carried out by passing the droplets of a mobile liquid phase through a series of columns containing stationary liquid phase. The residue of the extract fraction is dissolved in the stationary phase. The mobile phase liquid, either heavier or lighter than the stationary phase, is used in the separation, depending on the nature and polarity of the compounds to be separated; when lighter, the mobile phase is delivered at the bottom of the columns (ascending mode) and, when heavier, through the top (descending mode). This method is particularly suitable for preparative separation of polar iridoid compounds, such as iridoid glycosides of high oxidative substituents. Usually, heavier liquid in the mobile phase is preferred for separation of polar glycoside mixture. A general account of DCCC has been discussed in detail by Hostettmann highlighting the advantages and limitations of the method [27]. Compounds with greater partition coefficients in the mobile phase liquid, will travel quickly through the column, while compounds that are more soluble in the stationary phase, will linger in their movements. The efficiency of the method depends upon droplet formation and internal diameter of the columns. The choice of mobile phase depends on the internal diameter of the columns. In most cases, chloroform–methanol–water or chloroform–methanol–n-propanol–water mixtures were used as solvent systems in the mobile phase to achieve good separations. Some of the naturally occurring iridoids isolated from their mixture by DCCC technique are listed in Table 3.3. In the DCCC, the separation time of iridoids is long due to slow flow rates of mobile phase and separation efficiency is low because of poor mixing of the liquid phases. Therefore, to improve the mixing of two liquid phases, scientists Ito and Bowman invented a coil planet centrifuge system, known as high-speed CCC (HSCCC) [35]. The HSCCC is also known as multilayer coil countercurrent chromatography (MLCCC) because in this technique, the separation of compounds is achieved in multilayer column units which are interconnected by fine inert Teflon tubes around a holder in multiple layers. The stationary liquid phase is held in the coiled tubular column by a centrifugal force when the immiscible mobile phase passes through it. The chromatograph is allowed to revolve in a speed of 0– 1000 rpm, when the rotation of the coiled column containing two immiscible solvents creates an asymmetrical force resulting in the mixing of two phases and bilateral distribution of these phases, in which the heavier phase occupies the head

3.3 Isolation Techniques of Iridoids

89

Table 3.3 Isolation of iridoids by DCCC Iridoids

Plant source

Mobile phase

References

7-O-E/Z-Feruloyl loganic acid 261

Alangium platanifolium

[28]

Geniposidic acid 289

Canthium gilfillanii

Myopochlorin 638a

Myoporum bentioides

Oleuropein 80

Ligustrum japonicum Premna japonica

Chloroform–methanol– water–n-propanol (9:12:10:2) Chloroform–methanol– water–i-propanol (5:6:4:1) Chloroform–methanol– water–n-propanol (9:12:8:2) n-Butanol–ethanol–water (4:1:5) Chloroform–methanol– water–n-propanol (45:60:40:10)

6-O-a-L-(2″O-pMethoxycinnamoyl)– rhamnopyranosylcatalpol 375c, 6-O-a-L-(3″-O-pmethoxycinnamoyl)– rhamnopyranosylcatalpol 375d Phlomiol 377b, pulchelloside I 687, 6b-hydroxyipolamiide 198, sesamoside 686 Harpagide 12, 8-O-acetylharpagide 12a

[29]

[30]

[31] [32]

Sesamum angolense

Chloroform–methanol–ipropanol–water (5:6:1:4)

[33]

Ajuga pyramidalis

Chloroform–methanol– water (43:37:20)

[34]

Table 3.4 Isolation of iridoids by HSCCC Iridoids

Plant source

Solvent system

References

Geniposide 23

Gardenia jasminoides Cornus officinalis

[37]

Lamiophlomis rotata

Ethyl acetate–n-butanol– water (2:1:3) Dichloromethane– methanol–n-butanol– water–acetic acid (5:5:3:4:0.1) Ethyl acetate–n-butanol– water (5:14:12)

Gardenia jasminoides

n-Butanol–ethanol–water (10:1:10)

[40]

Rehmannia glutinosa Veronica ciliata

Ethyl acetate–n-butanol– water (2:1:3) n-Hexane–n-butanol– water (1.5:5:5)

[41]

Loganin 18, sweroside 67, morroniside 70

Shanzhiside methyl ester 103, phloyoside II 688, chlorotuberoside 689, penstemonoside 475 6b-Hydroxygeniposide 282, geniposidic acid 289, gardenoside 567 Catalpol 14 Catalposide 182, verproside 195b

[38]

[39]

[42]

90

3 Isolation and Identification of Iridoids

of the coil and the lighter phase in the tail end. Depending on the polarity of the compounds to be separated, the mobile phase may be selected as either the upper or the lower layer [36]. Similar to an HPLC system, an HSCCC system consists of a mobile phase reservoir, pump, injection valve, a column, a fraction collector and a data processor [36]. The separated components are usually detected by HPLC-diode array detector (HSCCC-HPLC-DAD). The partition efficiency of this method is high, and purification of compounds occurs within 3–4 h in many cases [36]. This technique is ideal for isolation of iridoid glycosides and their derivatives, secoiridoid glycosides from crude plant extracts. Some iridoid and secoiridoid glycosides isolated by this method are listed in Table 3.4.

3.3.5

Gas–Liquid Chromatography

Direct gas—liquid chromatography (GLC or GC) technique for separation of iridoids is carried out using their TMS derivatives in a GC–MS system, and their separations are monitored with a flame ionization detector (FID). Inouye et al. [43] developed a method for analysis of 33 plant iridoid and secoiridoid glycosides using their TMS derivatives in a Hitachi Gas Chromatograph K-53 equipped with a Hitachi RMU-6E mass spectrometer and different sizes of OV packing columns and a hydrogen FID. In a non-polar 1.5% OV-17 column (1.8 m  4.0 mm) at a column temperature of 270 °C, the iridoids were eluted in the order: aucubin 13, 7-deoxyloganic acid 163, catalpol 14, 7-deoxyloganin 18a, monotropein 25, gardenoside 567, secologanin 64, loganin 18, scandoside 282a, theviridoside 165, geniposide 23, scandoside methyl ester 282, 7-ketologanin 427, morroniside 70, hastatoside 665, forsythide 691 (Fig. 3.1), forsythide 10-methyl ester 692 (Fig. 3.1), verbenalin 647, sweroside 67, gentiopicroside 69, swertiamarin 68, bankakosin 693 (Fig. 3.1), kingiside 71, amaroswerin 328, amarogentin 81, and asperuloside 24. In polar 2% OV-210 and 2% OV-225 columns at column temperatures, 215 and 230 °C, the ketoiridoid compounds, 7-ketologanin 427 and verbenalin 647, and lactonic compounds, sweroside 67, and gentiopicroside 69, showed longer retention times. In a short non-polar 1.5% OV-1 column (0.5 m  3 mm) at column temperature 270 °C, the iridoids, paederoside 594, ligstroside 79, catalposide 182, oleuropein 80, 10-acetoxyligstroside 465, and 10-acetoxyoleuropein 465a were well-separated. Weiss et al. [44] applied this method for identification of hydrocarbons and non-glycosidic iridoids, (−)-iridomyrmecin, (+)-iridomyrmecin and two isomeric forms of iridodial present in the female species of Leptopilina, a genus of parasite wasp, in a GC 2010 gas chromatograph equipped with a QP 2010 plus mass spectrometer using a non-polar capillary column (BPX-5, 30 m  0.25 mm).

3.3 Isolation Techniques of Iridoids

91

Fig. 3.1 Chemical structures of some selected plant iridoids

3.3.6

Capillary Electrophoresis

Capillary electrophoresis, also known as capillary electrochromatography and micellar electrokinetic chromatography is an electrokinetic method for separation of compounds under the influence of an electric field through a capillary silica column in presence of a buffer solution [45]. The compounds are separated according to their electrokinetic mobility through the electrolyte solution. Only a limited application of this technique has been reported in the analysis of plant iridoids. Suomi et al. [46] applied micellar electrokinetic capillary chromatography (MECC) for quantitative estimation of iridoids, catalpol and aucubin in an aqueous extract of Veronica longifolia in a Hewlett-Packard (HP-3DCE) electrocapillary chromatograph

92

3 Isolation and Identification of Iridoids

equipped with a silica capillary column (33.5 cm  50 µm) using a buffer solution (50 mM borate, 180 mM sodium dodecyl sulfate, pH 9.3) and a UV-Vis DAD detector, operated at 200 nm and +10 kV, and isolated higher amounts of these compounds compared to their purification in the conventional column chromatography method. The same group used this technique to analyze a mixture of 11 iridoid glycosides, unedoside 7, harpagide 12, methyl catalpol 211b, catalpol 14, morroniside 70, asperuloside 24, griselinoside 334, loganin 18, 7-ketologanin 427, verbenalin 647, and 10-cinnamoylcatalpol 202b and found good linearity for all these iridoids in different ranges [47]. Wu et al. [48] applied this method for separation of nine iridoid glycosides, geniposide 23, loganin 18, shanzhiside 21, aucubin 13, catalpol 14, harpagoside 499, gardenoside 567, geniposidic acid 289, and loganic acid 146 in a buffer solution of sodium borate and 2,6-di-O-methyl-b-cyclodextrin and found their effective separations except aucubin and catalpol. Both aucubin and catalpol were not separated even on addition of organic solvents or urea and barium ions in the buffer solution. The major advantage of this technique over HPLC separation is that the separation is quick because of electro-osmotic mobility of the iridoids in presence of the electrolyte buffer solution.

3.4 3.4.1

Spectroscopic Methods for Identification of Iridoids UV and IR Spectroscopic Methods

Most of the iridoid glycosides exhibit a UV absorption in the range of 220–245 nm, characteristic of unsaturated enol ether system of the basic iridoid skeleton. An additional absorption in the range of 275–332 nm indicates the presence of a carbonyl and/or aromatic functionalities [49]. The IR spectrum of iridoid glycosides exhibits absorption bands for hydroxyl (near 3400 cm−1), carbonyl (1705–1720 cm−1), olefinic double bond (1635– 1652 cm−1), ester carbonyl (1690–1705 cm−1), and aromatic (1605, 1508 cm−1) functionalities [50].

3.4.2

1

H-NMR Spectroscopy

The 1H-nuclear magnetic resonance (1H-NMR), known as proton magnetic resonance (PMR) spectroscopy, is a well-established method for analysis of the structures of iridoids. It gives the information about the structural environment of the protons in a molecule. Recently available powerful Fourier transform (FT)-NMR spectrometers are very useful for analysis of iridoids using about 1 mg of the sample. Sometimes, the iridoid glycosides are converted into their acetates for NMR study. The most common solvents used for NMR study of iridoid and secoiridoid glycosides are DMSO-d6,

3.4 Spectroscopic Methods for Identification of Iridoids

93

CD3OD, D2O, acetone-d6, and pyridine-d5, and CDCl3 for their acetates. For iridoid aglycones and lactones, CDCl3 is the preferred solvent. The 4-substituted and 4-unsubstituted iridoid glycosides can be distinguished easily from their characteristic chemical shift values of H-3 and H-4 protons. In C-4 methyl- and hydroxymethyl-substituted iridoid glycosides, H-3 appears in the range of 6.05–6.65 ppm as a brs, while in C-4 carboxaldehyde-, carboxyl-, and carboalkoxyl-substituted iridoid glycosides, H-3 appears in the downfield range of 7.05–7.53 ppm as a broad singlet (brs). In C-4-unsubstituted iridoid glycosides, both H-3 and H-4 appear in the upfield region in the range of 6.20–6.53 ppm and 4.88–5.32 ppm, respectively, as a doublet of doublet (dd) or multiplet (m). The enomeric sugar proton, H-1′, appears in the range of 4.56–4.80 ppm as a doublet (d) (J = 7.0–8.0 Hz), while the aglucone H-1 appears in the range of 4.86– 5.45 ppm as a brs or d (J = 1.5–4.0 Hz). In iridoid glycosides with saturated cyclopentane ring, H-6 and H-7 appear in the range of 1.44–2.52 ppm as multiplets, while H-5 and H-9 appear in the range of 2.28–3.10 ppm as doublet of double doublet (ddd) or multiplet. The presence of hydroxyl or acyl group at C-6 or C-7 causes the appearance of the respective H-6 or H-7 in the downfield region in the range of 3.60–4.80 ppm. The presence of a double bond in between C-6 and C-7 in the cyclopentane ring of the iridoid glycosides causes the appearance of H-6 and H-7 in the range of 5.54–6.58 ppm. The secondary methyl group at C-8 in the cyclopentane ring of iridoid glycosides appears in the range of 0.94–1.14 ppm as a doublet (J = 6.5–7.5 Hz), while an a-hydroxyl or a-epoxy tertiary C-8 methyl group appears in the range of 1.20–1.73 ppm as a sharp singlet. The aoxygenated-hydroxymethyl protons at C-8 appear in the range of 3.90–4.54 ppm as sharp doublets (J = 11.5–13.5 Hz). In catalpol derivatives, H-7 with adjacent epoxy group appears in the range of 3.40–3.70 ppm as brs. While, in epoxygaertneroside 608, one of these protons appears in the downfield in the range of 3.98–4.10 ppm. The exomethylene protons in gardoside methyl ester 97 and other related compounds appear in the range of 5.11–5.46 ppm as brs or m. The methyl group with adjacent double bond at C-8 appears in the range of 1.80–1.87 ppm as a sharp singlet [51]. The configuration of hydroxyl groups at C-6 and C-7 can be assigned on the basis of the coupling constants of the adjacent methine protons. For instance, in 6a-hydroxyadoxoside 694, H-6 appears near 4.29 ppm as brs, while in 6bhydroxyadoxoside 695 (Fig. 3.1), it appears near 4.21 ppm as br dd (J = 7.8 and 3.7 Hz) [52]. In 7-epi-loganin 162, H-7 appears at 3.67 ppm as triplet (J = 8.0 Hz), while in loganin 18, it appears at 4.04 ppm as multiplet (m). Possibly, the axial orientation of H-7 in 7-epi-loganin and its effective coupling with neighboring H-6 and H-8 protons make its appearance as triplet [53]. In secoiridoids, H-8 of exocyclic olefinic double bonds in oleosides 439 and 440 appear in the range of 5.82–6.12 ppm as broad quartet (brq) and H-10 methyl protons in the range of 1.60–1.75 ppm as doublet (J = 7.5 Hz) [54]. In secologanin derivatives, olefinic H-10 protons appear as two dd in the range of 5.27–5.36 ppm (J = 17.0 and 1.5 Hz) and 5.23–5.31 ppm (J = 10.0 and 1.5 Hz), and H-8 appears in the range of 5.70–5.77 ppm as ddd (J = 17.0, 10.0 and 9.5 Hz) [55]. The 1H-NMR spectral data of some selected iridoids and secoiridoids are presented in Table 3.5.

94 Table 3.5 H (No.)

3 Isolation and Identification of Iridoids 1

H-NMR spectral data (d ppm, J in Hz) of some selected iridoids and secoiridoids

Ajugol 11 (CD3OD) [56]

Harpagide 12 (CDCl3 + DMSO-d6) [57]

Catalpol 14 (D2O) [58]

Aucubin 13 (CD3OD) [59]

Agluc 1

5.46 (d, 2.3)

5.92 (d, 1.0)

5.02 (d, 9.8)

4.98 (d, 7.1)

3

6.16 (ddd, 6.3, 2.1, 0.5)

6.40 (d, 6.5)

6.33 (dd, 6.0, 1.7)

6.34 (dd, 6.1, 1.9)

4

4.85 (ddd, 6.3, 3.2, 0.7)

4.94 (dd, 6.5, 1.4)

5

2.72 (m)

5.08 (dd, 6.0, 4.6)

5.12 (dd, 6.1, 3.9)

2.25 (m)

2.68 (m)

6

3.92 (dt, 5.2, 2.9)

3.60 (d, 4.4)

4.00 (dd, 8.1, 1.0)

4.43 (dd, 3.4, 1.7)

7

2.04 (dd, 13.4, 5.7) 1.79 (dd, 13.4, 4.7)

2.20 (dd, 16.0, 1.5) 2.01 (dd, 16.0, 4.5)

3.56 (brs)

5.79 (brs)

8 9

2.54 (dd, 9.6, 2.3)

2.72 (s)

2.58 (dd, 9.8, 7.7)

2.92 (dd, t-like, 7.3)

10

1.31 (s)

1.40 (s)

4.21 (d, 13.2) 3.70 (d, 13.2)

4.37 (d, 15.4) 4.19 (d, 15.4)

4.54 (d, 7.9)

4.56 (d, 7.4)

4.81 (d, 8.0)

4.70 (d, 7.8)

11 OAc Glc 1′ 2′

3.20 (dd, 9.2, 8.0)

3.27 (m)

3.18 (dd, 7.8, 9.0)

3′

3.37 (dd, 9.2, 8.0)

3.52 (m)

3.37 (t, 9.0) 3.30 (t, 9.0)

4′

3.27 (dd, 9.1, 8.3)

3.34 (m)

5′

3.30 (m)

3.41 (m)

6′

3.89 (dd, 11.9, 2.0) 3.66 (dd, 11.9, 5.7)

3.80 (dd, 12.4, 6.0) 3.59 (dd, 12.4, 2.5)

3.32 (m) 3.84 (brd) 3.66 (dd, 12.3, 5.5)

3.87 (dd, 11.7, 1.6) 3.67 (dd, 11.7, 5.3)

H (No.)

Eranthemoside 110 (D2O) [60]

Antirride 511 (D2O) [61]

8-O-Acetylshanzhiside 21a (CD3OD) [62]

Scandoside 282a (CD3OD) [63]

Agluc 1

5.52 (d, 1.7)

5.54 (d, 2.5)

5.62 (d, 3.8)

4.86 (d, 8.5)

7.10 (brs)

7.32 (s)

3

6.20 (dd, 6.0, 2.0)

6.19 (dd, 6.3, 1.0)

4

5.13 (dd, 6.0, 3.0)

4.88 (dd, 6.3, 1.1)

5

3.30 (m)

2.83 (m)

3.01 (dd, 9.3, 3.5)

2.92 (dd, 7.5, 7.5)

6

6.11 (dd, 5.5, 3.0)

2.03 (m)

4.13 (m)

4.57 (brd, 5.8)

7

5.69 (dd, 5.5, 2.0)

4.61 (m)

2.24 (dd, 14.4, 6.2) 2.17 (dd, 14.4, 5.3)

5.84 (s)

8 9

2.59 (dd, 8.5, 1.7)

3.07 (m)

2.85 (dd, 9.3, 3.8)

2.79 (dd, 8.2, 8.2)

10

3.68 (s)

5.30 (m) 5.34 (m)

1.55 (s)

4.39 (d, 15.7) 4.20 (d, 15.7)

4.84 (d, 7.0)

4.76 (d, 8.0)

4.65 (d, 7.9)

4.74 (d, 7.9)

3.29 (m)

3.18 (dd, 7.9, 9.0)

3.23–3.43 (m)

11 OAc Glc 1′ 2′

2.00 (s)

(continued)

3.4 Spectroscopic Methods for Identification of Iridoids

95

Table 3.5 (continued) H (No.)

Eranthemoside 110 (D2O) [60]

Antirride 511 (D2O) [61]

8-O-Acetylshanzhiside 21a (CD3OD) [62]

3′

3.48 (m)

3.38 (t, 9.0)

4′

3.38 (m)

3.30 (m)

5′

3.48 (m)

3.32 (m)

6′

3.91 (dd, 12.3, 2.0) 3.71 (dd, 12.4, 6.0)

3.90 (dd, 12.0, 2.1) 3.66 (dd, 12.0, 6.2)

Scandoside 282a (CD3OD) [63]

3.85 (dd, 12.0, 2.0) 3.65 (dd, 12.0, 5.1)

H (No.)

Geniposide 23 (DMSOd6) [64]

Loganin 18 (D2O) [65]

Gardoside methyl ester 97 (D2O) [66]

Paederoside 594 (CD3OD) [67]

Agluc 1

5.11 (d, 6.8)

5.41 (d, 4.0)

5.40 (d, 4.0)

5.94 (d, 1.2)

3

7.45 (s)

7.42 (s)

7.40 (d, 0.5)

7.31 (d, 2.0)

4 5

3.05 (m)

3.07 (m)

3.1–3.0 (m)

3.67 (m)

6

2.67 (m)

2.15 (m), 1.75 (m)

2.0–1.8 (m)

5.56 (brd, 6.5)

7

5.67 (brs)

4.14 (brs)

4.37 (brt, 6.0)

5.74 (brs)

8

1.92 (m)

9

2.63 (m)

2.15 (m)

3.1–3.0 (m)

3.30 (m)

10

4.12 (d, 15.0) 3.96 (brd, 15.0)

1.06 (d, 6.6)

5.30 (brs)

4.92 (dd, 14.3, 1.3) 4.83 (dd, 14.3, 0.9)

11

3.63 (s)

3.72 (s)

3.65 (s)

4.52 (d, 7.8)

4.81 (d, 8.0)

4.85 (d, 8.0)

SMe Glc 1′

2.35 (s) 4.67 (d, 7.9)

2′

2.97 (m)

3.27 (t, 8.0)

3.22 (dd, 8.0, 9.2)

3.20 (dd, 7.9, 9.0)

3′

3.16 (m)

3.49 (t, 8.0)

3.48–3.35 (m)

3.40 (t, 9.0)

4′

3.05 (m)

3.39 (t, 8.0)

3.30 (brt, 11.0)

3.28 (t, 9.0)

5′

3.11 (m)

3.31 (m)

3.48–3.35 (m)

3.35 (m)

6′

3.41 (m) 3.64 (m)

3.73 (d, 12.0) 3.92 (d, 12.0)

3.95 (dd, 13.3, 2.2) 3.62 (dd, 13.3, 6.6)

3.92 (dd, 11.8, 1.9) 3.68 (dd, 11.8, 5.0)

H (No.)

Plumieride 34 (Pyridined5) [68]

Isoplumieride 156 (Pyridine-d5) [68]

Plumericin 60 (CDCl3) [69]

Allamancin 134 (CDCl3) [70]

Agluc 1

5.60 (d, 6.0)

5.84 (d, 1.0)

5.56 (d, 9.8)

5.67 (d, 4.0)

3

7.61 (d, 1.0)

7.66 (d, 1.0)

7.44 (s)

5.40 (d, 8.0)

5

4.00 (ddd, 8.0, 2.0, 1.0)

3.80 (ddd, 8.0, 2.0, 1.0)

4.01 (td, 6.6, 3.6)

3.58 (m)

6

6.46 (dd, 5.0, 2.0)

6.68 (dd, 5.0, 3.0)

5.64 (dd, 3.6, 7.8)

5.93 (m)

7

5.41 (dd, 5.0, 2.0)

5.58 (dd, 5.0, 1.0)

6.04 (d, 7.8)

5.93 (m) 3.07 (dd, 8.0, 4.0)

4

2.78 (dd, 8.0, 5.0)

8 9

3.07 (dd, 8.0, 6.0)

3.25 (dd, 8.0, 1.0)

3.43 (dd, 9.8, 6.6)

10

7.92 (d, 1.0)

7.88 (d, 1.0)

5.10 (s)

11

4.83 (d, 2.0) 2.73 (t, 2.0)

12 13

4.99 (q, 6.0)

4.97 (dq, 1.0, 7.0)

7.16 (q, 8.4)

4.45 (m)

14

1.63 (d, 6.0)

1.67 (d, 7.0)

2.08 (d, 8.4)

1.38 (d, 6.0)

(continued)

96

3 Isolation and Identification of Iridoids

Table 3.5 (continued) H (No.)

Plumieride 34 (Pyridined5) [68]

Isoplumieride 156 (Pyridine-d5) [68]

Plumericin 60 (CDCl3) [69]

Allamancin 134 (CDCl3) [70]

15

3.64 (s)

3.57 (s)

3.77 (s)

3.79 (s)

Glc 1′

5.34 (d, 8.0)

5.21 (d, 8.0)

2′

4.04 (dd, 8.0, 9.0)

4.00 (dd, 8.0, 9.0)

3′

4.24 (t, 9.0)

4.19 (t, 9.0)

4′

4.35 (t, 9.0)

4.24 (t, 9.0)

5′

3.88 (m)

3.84 (m)

6′

4.39 (brs)

4.27 (dd, 12.0, 5.0) 4.40 (dd, 12.0, 2.0)

H (No.)

Secologanoside 330 (D2O) [55]

Swertiamarin 68 (CD3OD) [71]

Gentiopicroside 69 (CD3OD) [72]

7a-O-methylmorroniside 263 (CD3OD) [73]

Agluc 1

5.46 (d, 4.5)

5.73 (d, 1.4)

5.65 (d, 3.0)

5.80 (d, 9.4)

3

7.28 (d, 1.6)

7.64 (s)

7.44 (d, 1.5)

7.52 (brs)

1.90 (dddd, 10.2, 8.8, 10.2, 6.8) 1.74 (dddd, 16.2, 12.0, 16.2, 6.8)

5.61 (m)

2.01 (ddd, 12.9, 4.1, 2.1) 1.17 (td, 12.9, 10.0)

4.31 (dd, 5.6, 1.8) 4.38 (dd, 5.6, 1.8)

5.07 (m) 4.97 (m)

4.49 (dd, 1o,o, 2.1)

4 5

3.17 (m)

6

2.27 (dd, 16.0, 9.5) 2.75 (dd, 16.0, 4.9)

7

2.83 (dt, 12.9, 4.7)

8

5.69 (ddd, 17.0, 10.0, 9.6)

5.45 (ddd, 16.8, 8.5, 8.6)

5.74 (ddd, 17.5, 10.5, 7.0)

3.95 (dq, 6.8, 2.1)

9

2.79 (ddd, 9.6, 4.9, 4.5)

2.92 (dd, 8.0, 1.4)

3.15 (dd, 7.3, 1.5)

1.80 (ddd, 10.0, 4.7, 2.1)

10

5.27 (dd, 10.0, 1.4) 5.30 (dd, 17.0, 1.4)

5.29 (m) 5.40 (m)

5.23 (ddd, 17.1, 5.1, 5.0) 5.20 (ddd, 10.5, 1.5, 1.5)

1.41 (d, 6.8)

11

3.70 (s)

OMe-7

3.50 (s)

Glc 1′

4.80 (d, 8.0)

4.65 (d, 8.1)

4.60 (d, 8.0)

4.79 (d, 7.9)

2′

3.29–3.53 (m)

3.10–3.40 (m)

3.20 (dd, 9.0, 8.0)

3.22 (dd, 9.5, 7.9)

3.30–3.40 (m)

3.38 (t, 9.5)

3.45 (m)

3.28–3.32 (m)

3.85 (dd, 12.0, 2.0) 3.65 (dd, 12.0, 6.0)

3.89 (dd, 12.2, 1.9) 3.67 (dd, 12.2, 6.3)

3′ 4′

3.25 (t, 9.5)

5′ 6′

3.4.3

3.91 (dd, 12.4, 2.0) 3.72 (dd, 12.4, 5.7)

3.89 (dd, 14.2, 1.2) 3.66 (dd, 14.2, 7.0)

13

C-NMR Spectroscopy

The carbon-13 nuclear magnetic resonance (13C-NMR) spectroscopy is the most important and powerful technique for structure elucidation of iridoid aglycones and their glycosides. The isotope, carbon-13, has a natural abundance of only 1.1% and has smaller magnetic moment compared to that of proton and hence requires at least

3.4 Spectroscopic Methods for Identification of Iridoids

97

5 mg of sample for measurement of 13C-NMR spectra in a 400 MHz FT-NMR instrument. The detailed instrumental and theoretical aspects of this technique are available in the textbooks of Levy and Nelson (1972), and Stothers (1972) [74]. The distortionless enhancement by polarization transfer (DEPT) technique is frequently used in the study of 13C-NMR spectrum of a compound to identify the presence of quaternary, methine, methylene, and methyl carbons. It is done by taking three successive 13C-NMR spectra, one containing only the methine carbons, one only the methylene carbons, and the rest only the methyl carbons by changing the flip angle h in DEPT experiments in addition to normal 13C-NMR spectrum of a compound. A DEPT experiment with a flip angle of 45° showed positive signals for methine, methylene, and methyl carbons; experiment with flip angle of 90° showed only methine carbon signals, while with flip angle of 135°, methylene carbons appeared as negative and methine and methyl carbons as positive in the spectrum. The carbon signals of the iridoid compounds are usually assigned from the preferred 1H-decoupled or noise-decoupled CMR spectra. The carbon magnetic resonance (CMR) spectra of iridoid and secoiridoid glycosides are taken in polar solvents such as DMSO-d6, CD3OD, D2O, and pyridine-d5.

3.4.3.1

Substituent Effects

The presence of a substituent, such as hydroxyl, hydroxymethyl, ester, and carbonyl group in both cyclopentane and pyran rings of iridoids causes the changes of the carbon chemical shifts of the attached carbon and nearby carbon atoms in the skeletal rings of the iridoids. Such changes are referred to as ‘substituent effects,’ and knowledge of these effects is useful in the assignment of carbon signals of iridoids of unknown structures. Sticher et al. (1980), Damtoft et al. (1981), and Bianco et al. (1980) have discussed the substitution effects of hydroxyl group at C-6 and C-8 positions on the chemical shifts of neighboring carbons and the effects of acetylation of hydroxyl group of some iridoid glycosides [75]. They considered the iridoid glycosides that were reported up to 1980. As several new iridoid glycosides and derivatives have been reported after 1980, a detailed discussion in this regard is relevant.

3.4.3.2

Substituent Effect of Hydroxyl Group

The analysis of the reported 13C-NMR spectra of several C-6 and C-8 hydroxyl-substituted iridoid glycosides indicates that the position and configuration of hydroxyl group at C-6 and C-8 carbons showed significant shielding and deshielding effects on the neighboring carbon atoms of the cyclopentane ring due to its long range ortho, meta, and para effects. In addition, it exhibits a strong deshielding effect at its a-position (+32.0 to +42.9 ppm) depending on the oxidation state of cyclopentane ring. The strong deshielding effect at the signal of a-carbon occurs in presence of adjacent double bond. For instance, 6b-hydroxy group in

98

3 Isolation and Identification of Iridoids

aucubin 13 showed the a-effect at C-6 by +42.9 ppm, while 6a-hydroxy group in 6epi-aucubin showed the a-effect by +36.5 ppm, compared to that of the respective chemical shift value at C-6 in bartsioside 471. The hydroxyl group at C-6 exhibits both deshielding and shielding effects (b-effect) on C-5 carbon, depending on the substituent on C-5 carbon. When C-5 is attached to hydrogen atom, C-6 hydroxyl group exerts a deshielding effect (about +3.0 to +7.0 ppm), whereas, if C-5 is attached to hydroxyl group, the C-6 hydroxyl group exerts both shielding and deshielding effects on C-5 carbon depending on the configuration of hydroxyl group at C-6. For example, 6b-hydroxy group in antirrhinoside 109 exhibits a weak shielding effect by about −2 ppm, while 6a-hydroxy group in procumbide 497 shows higher deshielding effect on C-5 by about +3.5 ppm [76]. The deshielding effect of hydroxyl group on adjacent b-carbon depends on the coupling interactions of hydroxyl proton with ortho proton. When this interaction is strong (as in the case of C-5 OH and C-9 H), the deshielding effect is strong (about +10.0 ppm). For example, in 5-deoxystasioside (stanside) 690 (Fig. 3.1), C-9 appears at 42.9 ppm, whereas in stansioside 178, C-9 appears at 56.8 ppm [77]. In general, cis-coupling of hydroxyl group with vicinal hydroxyl group exerts shielding effect and its ciscoupling with vicinal hydrogen exerts deshielding effect. The hydroxyl group at C-6 with an adjacent double bond in between C-7 and C-8 exerts an c-effect on neighboring C-4 and C-8 carbons. This effect is relatively stronger with the ahydroxyl group at C-6. For instance, 6b-hydroxyl group in scandoside 282a exerts a weak shielding effect of −1.51 ppm on C-4 and a better deshielding effect of +3.09 ppm on C-8, while 6a-hydroxyl group in deacetylasperulosidic acid 290 exerts a strong shielding effect of −4.26 ppm on C-4 and a strong deshielding effect of +7.10 ppm on C-8. Possibly, the envelope conformations of cyclopentene and 3,4-dehydropyran rings permit efficient chelating interaction of C-6 a-OH group with C-4 carboxyl group in 290 (Fig. 3.2a), and coupling interaction of the double bond with the hydroxyl oxygen lone pair of electron is responsible for this stronger effect. In C-4-unsubstituted iridoid glycoside such as in antirrhinoside 109, 6b-OH group exerts only shielding effect on both C-4 and C-8 by −2.12 and −3.10 ppm, respectively, and in procumbide 497, 6a-OH group exerts also shielding effect relatively stronger than that of 109 on C-4 and a weaker deshielding effect on C-8 by −5.31 and +0.45 ppm, respectively [76]. Possibly, the epoxy function at C-7 and C-8, and the C-5 OH group permits another conformation (Fig. 3.2b), where 6bhydroxyl group exerts only shielding effect on both C-4 and C-8 in antirrhinoside. Therefore, it is inferred that both C-6 a/b-OH group exert shielding effect on C-4 in both C-4-substituted and -unsubstituted iridoid glycosides. The C-6 OH group also exhibits weak deshielding effects on C-3 and C-1; these effects are relatively higher by 6a-OH group. For example, 6b-OH group in scandoside 282a, shows weak deshielding effect on C-3 and C-1 by +0.8 and +0.74 ppm, respectively, while 6aOH group in deacetylasperulosidic acid 290 shows deshielding effect on C-3 and C-1 by +2.44 and +3.47 ppm, respectively [76]. This deshielding effect of C-6 OH group in both antirrhinoside and procumbide is only observed on C-3 by +1.18 and +2.40 ppm, respectively, compared to that of galiridoside 367 [76]. Similarly, in 6b-dihydrocornic acid 696, 6b-OH group exerts deshielding effect only on C-3 by

3.4 Spectroscopic Methods for Identification of Iridoids H H OGlc H O H OH OH H O OH

(a)

(b)

99

HO OGlc O

O OH

H Me

Fig. 3.2 Shielding and deshielding effects of C-6 OH group on C-4 and C-8 in a deacetylasperulosidic acid and b antirrhinoside in 13C-NMR spectra

+1.6 ppm, while 6a-OH group in 6a-dihydrocornic acid 697 (Fig. 3.2), exerts deshielding effect on both C-3 and C-1 by +3.9 and +3.6 ppm, respectively, compared to the chemical shift values at these carbons in loganic acid 146 and deoxyloganin 18a [77, 78]. The presence of epimeric hydroxyl group at C-8 position also induces both shielding and deshielding effects on neighboring carbon atoms in iridoid glycosides. For instance, in galioside 280, C-8a-OH group induces weak deshielding effect on bcarbon, C-9 by +1.72 ppm, while in gardenoside 567, b-OH group at C-8 induces strong deshielding effect on both C-9 and C-7 by +8.7 and +2.25 ppm, respectively, compared to that of adoxoside 125 [76, 79]. The C-8b-hydroxyl group of gardenoside 567 also induces a strong shielding effect on C-1 by −4.2 ppm, compared to that of adoxoside. Possibly, this strong shielding effect occurs from 1,3-betadiaxial interaction of OH group with glycosidic linkage. In case of galioside 280, such shielding effect of C-8 a-OH group on C-1 is less because of the antirelationship with the glycosidic linkage, but shows a strong deshielding effect on C-6 [76].

3.4.3.3

Substituent Effects on Acetylation and Methylation

The acetylation of free hydroxyl groups in both cyclopentane ring and sugar moiety of an iridoid glycoside produces significant changes in carbon chemical shifts of the compound. It can be used to assign the position of –OH group in the skeletal structure. On acetylation, the chemical shift of hydroxylated a-carbon moves to downfield by +2.5 to +11.5 ppm. The lower downfield value (+2.5 to +3.5 ppm) indicates its location at C-6, C-7, C-10 or in sugar moiety, while higher downfield value (+8.0 to +11.5 ppm) indicates its location at C-8. The 6b-acetoxy group produces higher upfield shift, i.e., shielding effect on C-5 and C-7 by −3.5 to −6.5 ppm, while 7b-acetoxy group exerts low upfield shifts on C-6 and C-8 by −2.0 to −3.0 ppm. The methylation of hydroxyl group similarly produces downfield shift of methylated carbon (+1.5 to +2.5 ppm) and upfield shift of adjacent carbons (−3.5 to −6.5 ppm) [80]. The acylation of C-6 hydroxyl group in iridoid glycosides with benzoyl, cinnamoyl, caffeoyl, feruloyl, and isoferuloyl groups produces a downfield shift (+2.0 to +3.0 ppm) of the a-carbon and an upfield shift (−2.0 to −5.0 ppm) to the b-carbons. If the b-carbon contains a tertiary OH group, the chemical shift of the b-carbon is deshielded by about 2.5 ppm due to H-bonded chelation with the acyl carbonyl group [76, 81].

100

3.4.3.4

3 Isolation and Identification of Iridoids

Effects of Keto and Olefinic Groups

The presence of keto function in cyclopentane ring of iridoid glycosides is indicated by appearance of a carbon signal in the range of d 205–225 ppm. The keto group at C-7 in loganin derivatives induces deshielding effects on C-6 and C-8 by 2.5– 4.5 ppm. The appearance of a carbon signal in the range of d 190–195 ppm indicates the presence of a carboxaldehyde group at C-4 position of an iridoid glycoside. The presence of exomethylene double bond at C-8 in iridoid glycosides is indicated by appearance of two sp2-carbon signals in the range of d 150–155 ppm and 110–115 ppm, whereas the appearance of two sp2-carbon signals in the range of 128–140 ppm in iridoid glycosides indicates the presence of an olefinic double bond in between C-6 and C-7. In plumeria-type iridoids, the olefinic carbon signals appear on the range of 130–155 ppm. In secoiridoids, the presence of a double bond in between C-8 and C-10 is indicated by appearance of two sp2-carbon signals in the range of 118–122 ppm and 132–136 ppm; while an olefinic double bond in between C-8 and C-9 is indicated by appearance of two carbon signals in the range of 123–133 ppm [80, 82]. The 13C-NMR spectral data of some selected iridoids and secoiridoids are listed in Table 3.6.

3.4.4

2D-NMR Spectroscopy

The two-dimensional nuclear magnetic resonance (2D-NMR) spectroscopy is extensively used in the assignment of proton and carbon chemical shift values of iridoids and other natural products [88]. Several 2D-NMR experiments such as 1 H–1H-correlation spectroscopy (1H–1H-COSY), 1H–1H-DQF (double-quantum filter)-COSY, nuclear Overhauser enhancement spectroscopy (NOESY), and rotating frame nuclear Overhauser enhancement spectroscopy (ROESY) are frequently used for assignment of chemical shift values of protons in a complex molecular structure of an iridoid glycoside from the study of their spin–spin coupling interactions in space. Similarly, other 2D-NMR experiments such as heteronuclear multiple quantum correlation (HMQC), heteronuclear single quantum correlation (HSQC), and heteronuclear multiple bond correlation (HMBC) experiments are frequently used for assignment of both proton and carbon chemical shift values from their coupling interactions through a single bond in HMQC and HSQC, and through two and three bonds in HMBC spectra. In a few instances, the DQF-COSY is preferred than simple 1H–1H-COSY spectra because in the former, both the diagonal and cross-peak multiplets are in antiphase in both dimensions and thus eliminates strong in-phase diagonal peaks in the spectrum that are found in simple COSY experiment. The most popular two-dimensional NMR experiment is the homonuclear (1H–1H) correlation spectroscopy (1H–1H-COSY), which is used to identify the spin–spin coupling interactions of protons in a molecule. The 2D-COSY spectrum shows the frequencies of the coupling protons, along both the X- and Y-axes as

Agluc 1 3 4 5 6 7 8 9 10 11 OMe Glc 1′ 2′ 3′ 4′ 5′ 6′

C (No.)

Table 3.6

93.3

142.7 108.0 72.4 78.1 47.3 78.3 59.1 25.2

99.2

74.3 77.4 71.6 78.2 62.6

140.4 105.9 41.3 78.2 50.0 79.5 51.8 25.2

99.4

74.1 77.8 71.4 78.0 62.9

Harpagide 12 (CD3OD) [76]

93.8

Ajugol 11 (CD3OD) [56]

74.8 78.5 71.7 77.7 62.9

99.7

141.8 104.0 39.1 79.6 62.6 66.6 43.6 61.6

95.3

Catalpol 14 (CD3OD) [83]

74.8 78.1 71.4 77.8 62.6

99.9

141.5 105.7 46.1 82.7 130.3 148.0 47.9 61.3

97.7

Aucubin 13 (CD3OD) [83]

C-NMR spectral data (in d, ppm) of some selected iridoids and secoiridoids

13

73.6 76.5 70.4 77.0 61.5

98.8

138.8 106.5 38.0 131.6 138.3 85.9 44.7 67.3

94.3

Eranthemoside 110 (D2O) [60]

74.3 77.9a 71.4 77.9a 62.7

99.4

142.9 107.5 74.5 77.3a 66.0 64.2 52.7 17.5

94.9

(continued)

Antirrinoside 109 (CD3OD) [76]

3.4 Spectroscopic Methods for Identification of Iridoids 101

97.5 151.7 113.8 30.6 41.2 74.8 40.9 45.7 12.8 170.5 52.5

99.4

73.6 76.5 70.4 77.1 61.3

95.7 139.4 108.3 30.8 39.0 73.3 152.2 44.0 111.2

98.8

73.3 76.2 70.2 76.8 61.3

Agluc 1 3 4 5 6 7 8 9 10 11 OMe/ SMe/OAc Glc 1′ 2′ 3′ 4′ 5′ 6′

Loganin 18 (D2O) [77]

Antirrhide 511 (D2O) [61]

C (No.)

Table 3.6 continued

73.3 76.6 70.0 77.2 61.0

98.6

95.7 151.6 110.9 34.4 38.0 125.5 144.1 45.9 59.3 166.9 51.0

Geniposide 23 (DMSO-d6) [64]

74.6 78.1 71.3 77.6 62.5

100.2

98.8 154.0 111.0 47.0 82.4 129.9 147.3 45.9 61.1 172.1

Scandoside 282a (CD3OD) [76]

74.7 78.4 71.6 77.9 62.8

100.0

93.3 150.3 106.2 37.5 86.3 128.9 144.3 45.3 61.9 172.2 172.5, 20.8

Asperuloside 24 (CD3OD) [84]

74.6 77.9 71.5 78.3 62.7

100.0

93.3 150.3 106.1 37.5 86.2 129.5 143.8 45.2 64.3 172.6 13.6

(continued)

Paederoside 594 (CD3OD) [67]

102 3 Isolation and Identification of Iridoids

100.8 74.7 78.1 70.8 78.7 62.1

172.9, 22.3

100.6 74.8 77.9 71.7 78.3 62.9

94.7 147.9 111.0 43.6 77.6 46.9 90.1 48.6 22.1 181.0

Agluc 1 3 4 5 6 7 8 9 10 11 12 13 14 15 OMe/Acyl/ OAc Glc 1′ 2′ 3′ 4′ 5′ 6′

Plumieride 34 (Pyridine-d5) [68] 94.1 152.0 109.5 40.1 141.0 129.1 96.4 50.0 149.0 138.7 171.3 62.7 23.0 166.7 51.2

8-O-Acetylshanzhiside 21a (CD3OD) [62]

C (No.)

Table 3.6 continued

101.1 74.7 78.3 71.3 78.4 62.7

92.6 151.7 108.3 38.3 141.3 128.6 94.9 46.2 149.3 140.9 171.5 62.9 22.6 166.8 51.0

Isoplumieride 156 (Pyridine-d5) [68] 102.0 152.8 108.1 38.1 126.2 141.4 105.9 53.5 84.0 51.6 175.9 64.4 22.2 166.7 51.3

Isoallamandicin 137 (Pyridine-d5) [70]

103.2, 44.2, 26.8, 22.6 103.7 75.1 78.1 71.7 78.0 62.9

91.1 138.7 116.7 28.7 35.9 79.2 79.6 48.4 21.9 69.7

8-epi-Valerosidate 28a (CD3OD) [85]

99.5 74.4 77.5 71.6 78.4 62.6

51.7

93.9 154.2 114.4 70.1 77.2 80.5 78.5 56.9 22.3 168.8

(continued)

Phlomiol 377b (CD3OD) [86]

3.4 Spectroscopic Methods for Identification of Iridoids 103

100.0 75.2 78.1 72.2 78.8 63.3 carbon

99.4 152.3 114.8 31.0 38.6 181.4 135.3 46.2 123.1 175.3

Agluc 1 3 4 5 6 7 8 9 10 11 OMe Glc 1′ 2′ 3′ 4′ 5′ 6′ a Indicates the

Oleoside dimethyl ester 440(CD3OD) [86]

95.1 155.0 109.2 31.6 40.9 173.4 124.7 130.4 13.3 168.5 52.1 100.8 74.6 78.2 71.3 77.8 62.6 chemical shift values may be interchanged

Secologanoside 330 (D2O) [55]

C (No.)

Table 3.6 continued

100.2 74.4 77.7 71.4 78.5 62.5

99.0 154.8 108.8 64.2 33.7 65.9 133.8 51.9 121.2 167.9

Swertiamarin 68 (CD3OD) [71]

99.6 74.6 77.8 71.5 78.3 62.6

97.9 153.9 105.9 28.3 25.9 69.2 133.3 43.7 120.8 168.5

Sweroside 67 (CD3OD) [71]

100.2 74.6 78.0 71.6 78.5 62.8

98.6 150.7 105.0 127.0 117.2 70.9 135.0 46.6 118.5 166.4

Gentiopicroside 69 (CD3OD) [72] 97.7 153.1 111.8 29.1 33.3 104.3 135.4 45.1 119.8 169.2 51.7 100.0 74.1 78.1 71.4 77.9 62.6

Vogeloside 234 (CD3OD) [87]

104 3 Isolation and Identification of Iridoids

3.4 Spectroscopic Methods for Identification of Iridoids

105

cross-peaks from the diagonal peaks of protons. The cross-peaks provide an idea of coupling constants, but not the multiplicity of coupling protons. The diagonal peaks correspond to the peaks in a 1D-NMR experiment, while the cross-peaks indicate the coupling between a pair of nuclei. The cross-peaks result from the coupling of two different proton nuclei, which have different chemical environments in a molecule. Each coupling gives two symmetrical peaks above and below the diagonal. The diagonal relationship of the cross-peaks is useful to assign the chemical shift values of the coupling protons. The COSY-90 is the most common COSY experiment, in which both the p1 and p2 pulses tilt the nuclear spin by 90° [89]. For instance, in the 1H–1H-COSY spectrum of lamiide 207 (Fig. 3.3), the contour plots (by solid lines) of the diagonal cross-peaks of d 3.54 (H-7) with d 2.36 (H-6) and d 2.04 (H-6) confirmed the assignment of their chemical shifts. Similarly, the diagonal relationship of cross-peaks of d 4.60 (H-1′) and d 3.20 (H-2′) confirmed their chemical shifts. In the same way, the diagonal cross-peaks of d 3.87 and d 3.68 with the cross-peak of d 3.34 supported the assignment of chemical shifts of H-6′ and H-5′ protons in the sugar moiety of lamiide [90]. In the 1H–1H-COSY spectrum of auroside (=5-hydroxy-8-epi-loganin) 387 (Fig. 3.4), the diagonal relationship of the cross-peaks of d 2.04 and d 2.58 suggested the assignment of H-6 protons. Similarly, the cross-peak from H-6 at d 2.58 showed the diagonal relationship with the cross-peak from H-7 at d 3.56 suggesting the assignment of their chemical shifts. The diagonal relationship of the cross-peaks from H-8 and H-9 confirmed their assignment at d 2.27 and d 2.80, respectively. In the sugar moiety, the cross-peak from H-1′ at d 4.57 with that from H-2′ at d 3.18 supported their chemical assignment. The same diagonal relationship of the cross-peak from pseudo-axial H-6′ at d 3.65 with the cross-peak from H-5′ at d 3.32 confirmed their chemical assignment. The diagonal relationship of the cross-peaks from H-8 and H310 supported their assignment at d 2.27 and d 0.95 ppm, respectively [91]. The HSQC experiment is effective to explore the connectivity of two heteronuclei such as 1H and 13C separated through a single bond. This method gives one peak per pair of coupled nuclei, whose two coordinates are the chemical shifts of the two coupled atoms. The basic scheme of the experiment involves the transfer of magnetization from the proton (1H) to carbon nucleus (13C) via an insensitive nuclei enhanced by polarization transfer (INEPT) step. After a time of decay (t1), the magnetization is transferred back to the proton via a retro-INEPT step and the signal is then recorded in the instrument. The 1H signal is detected in directly measured dimension of each experiment, while the chemical shift of 13C is measured in indirect dimension from the series of experiments [89]. For instance, in the 2D-HSQC spectrum of lamiide 207 (Fig. 3.5) and in the 2D-HSQC spectrum of auroside 387 (Fig. 3.6), the connectivity of each pair of coupled 1H and 13C nuclei is shown by solid lines. The HMBC experiment shows the correlations of protons and carbons that are interconnected by two or three single covalent sigma bonds, and in few cases by four bonds. It does not show one-bond interactions between proton and carbon. This method is very useful to locate missing quaternary carbons that are difficult to locate from normal 13C-NMR spectra. This method is similar to HMQC experiment, but it eliminates signals of large couplings (J = 125–165 Hz), and only focuses the signals

106

3 Isolation and Identification of Iridoids

(a)

H-1`

H-9 H-6`

H-6`

H-7`

H-5`

H-2`

H-6`

H-6`

(b)

H-6` H-6`

H-9

H-2` H-3` H-7` H-6` H-6`

H-1`

Fig. 3.3 a and b Significant 1H–1H-COSY correlations observed in lamiide 207 in CD3OD. Source of the COSY spectrum: Prof. I. Calis

3.4 Spectroscopic Methods for Identification of Iridoids

107

(a)

(b)

Fig. 3.4 a and b Significant 1H–1H-COSY correlations observed in auroside 387 in CD3OD. Source of the COSY spectrum: Prof. I. Calis

in the range of 2–20 Hz, similar to that of proton–proton coupling interactions [88, 89]. Application of 1,1-ADEQUATE (adequate double-quantum transfer experiment) is suitable to identify only the two-bond connectives between protons and carbons

108

3 Isolation and Identification of Iridoids

(a)

(b)

Fig. 3.5 a and b Significant HSQC correlations observed in lamiide 207 in CD3OD. Source of HSQC spectrum: Prof. I. Calis

3.4 Spectroscopic Methods for Identification of Iridoids

H-3’ H-6’

H-6’

H-5’ H-4’ H-2’

H-7

109

H-9

H-6

H- 6 H-8

C- 8

C- 6

C- 9

C- 6’

C- 4’ C- 2’ C- 7

C- 3’ C- 5’

Fig. 3.6 Significant HSQC correlations observed in auroside 387 in CD3OD. Source of HSQC spectrum: Prof. I. Calis

Fig. 3.7 Significant HMBC correlations in lamiide 207 in CD3OD. Source of HMBC spectrum: Prof. I. Calis

110

3 Isolation and Identification of Iridoids

Fig. 3.8 Significant HMBC correlations observed in auroside 387 in CD3OD. Source of HMBC spectrum: Prof. I. Calis

[92]. The 2D HMBC spectra of lamiide 207 and auroside 387 are shown In Figs. 3.7 and 3.8, respectively. In the spectrum of lamiide, two- and three-bond connectives between 13C and 1H are shown in solid lines.

3.4.5

Mass Spectrometry

Mass spectrometry (MS) is a powerful analytical tool in structure elucidation of natural products due to its sensitivity, rapidity and low levels of sample consumption. It provides the information on the molecular formulae and skeletal structures of natural products. Most of the naturally occurring plant iridoids are glycosides. Because of high polarity and thermal sensitivity of these glycosides, hard ionization, electron-impact (EI)-MS technique is not frequently used for their analysis. Recently developed soft ionization techniques such as electrospray ionization (ESI)-MS, fast atom bombardment (FAB)-MS and matrix-assisted laser desorption–ionization–time of flight (MALDI-TOF)-MS are frequently used for analysis of iridoid and secoiridoid glycosides and their derivatives. These techniques are useful to assign the quasi-molecular ions of iridoids. Several groups applied acetate and trimethylsilyl (TMS) derivatives of iridoid glycosides for MS study. In both ESI-MS and FAB-MS, mass fragmentation mechanisms of iridoid glycosides are studied in both positive and negative modes. The HPLC/MS is

3.4 Spectroscopic Methods for Identification of Iridoids

111

promising technique for structural information about the iridoid glycosides without their purification from the herbal extracts. The instrumental and theoretical aspects of MS are available in the textbooks of Biemann (1962) and Beynon et al. (1968) [93].

3.4.5.1

EI-Mass Spectrometry

Bentley et al. [94] investigated the electron-impact mass spectrometry (EI-MS) of some iridoid glycosides and proposed some mass fragmentation rules, which are still in use. In such MS spectra, the molecular ions of iridoid glycosides were not detectable, while their aglucone ion peaks were prominent. These aglucone ions are formed by simultaneous loss of sugar moiety and a transfer of hydrogen from molecular mass ions. The additional mass ions from the fragmentation of glucose moiety at m/z 145, 127, 109, 73, 61, and 60 are often observed in the mass spectra of iridoid glucosides. The aglycone mass ions undergo elimination of water and carbon monoxide to produce fragment ions in most cases. The main mass fragmentation pattern of aucubin 13 [94], harpagide 12 [95] and loganin 18 [96] is presented in Schemes 3.1, 3.2, and 3.3, respectively, as illustrative fragmentation patterns.

3.4.5.2

ESI-Mass Spectrometry

Several groups applied HPLC-ESI-MS/MS and ultra-performance liquid chromatography/quadrupole time-of-flight (UPLC/Q-TOF)-MS/MS techniques for qualitative and quantitative analysis of plant iridoid glycosides [97, 98]. Both positive and negative ions of iridoid glycosides are generated by operating the instrument in positive mode and negative mode, respectively. The positive mode of ESI-MS gives quasi-molecular ions, [M + H]+, [M + Na]+, [M + NH4]+ or [M + K]+ as a base peak of the mass spectrum, while in negative mode, the quasi-molecular anions, [M − H]−, [M − CH3COO]−, [M − HCOO]− or [2M − H]− as base peak. In HPLC-ESI-MS, a small amount of volatile additives such as ammonium acetate (about 0.2 mM) and acetic acid or formic acid (about

Scheme 3.1 EI-mass fragmentation pattern of aucubin

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3 Isolation and Identification of Iridoids

Scheme 3.2 EI-mass fragmentation pattern of harpagide

Scheme 3.3 EI-mass fragmentation pattern of loganin

-

COOMe + HCOO HO

O

OGlc

HO

m/z 433 -H

-

-H COOMe

H

m/z 207 COOMe

HO

-H2O

-H

-H

CHO

m/z 225

-

-

OH

m/z 225

m/z 123

O

HO

m/z 225

CHO

HO

HO

O

-

COOMe -H

-H2O

OH

CHO

CHO

-H OH

-H

-Glc. + H.

O

-

-

COOMe

-

COOMe -H O m/z 101

O m/z 105

Scheme 3.4 ESI-Negative mode mass fragmentation pattern of geniposide

-

3.4 Spectroscopic Methods for Identification of Iridoids

113

0.1%) are added to the mobile phase to generate positive or negative ions. ESI-mass fragmentation pattern of geniposide 23 in negative ion mode is presented in Scheme 3.4 [99].

3.4.6

X-Ray Crystallographic Study

Several groups reported X-ray crystallographic analyses of iridoids for determination of absolute configuration of the chiral carbons present in the iridoids. For instance, Li et al. [100] reported the X-ray diffraction study of aucubin 13 orthorhombic crystals having P212121 space group. In the crystals of aucubin, both cyclopentane and pyran rings have envelope conformations and the Glc moiety has a 4C1-conformation (Fig. 3.9) [100]. Both the pyran and cyclopentane rings have Fig. 3.9 ORTEP drawing of aucubin crystal structure with atomic numbering and thermal ellipsoids at 50% probability. Adapted from Li et al. [100] with permission of Elsevier. Copyright (2009) Elsevier

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3 Isolation and Identification of Iridoids

alternating positive and negative values of torsion angles, 1.6(4)° and 56.0(3)°, and 0.3(3)° and 22.9(2)°, respectively. While, the Cremer–Pople puckering parameters of cyclopentane propane ring were found as Q = 0.242(3) A°, ɸ = 179.0(6)°, and of pyran ring, Q = 0.458(2) A°, h = 54.8(3)°, and ɸ = 70.7(4)°. The dihedral angle between the rings was 135.04°. The absolute configurations of the chiral carbons, C-1, C-5, C-6, and C-9 of aucubin were determined as S, R, S, and S, respectively. The glucose (Glc) moiety has ring puckering parameters of Q = 0.547(2) A°, h = 11.6(2)°, and ɸ = 305.0(13)°. The absolute configurations of the stereogenic carbons C-1′–C-5′ in the glucose moiety were assigned as S, R, S, S, and R, respectively. The crystals have a network of hydrogen-bonding interactions with hydroxyl groups of the compound. Li et al. reported the X-ray crystal structure of triohima A 86, having an unusual d-lactone-containing skeleton, isolated from Triosteum himalayanum. They prepared colorless needle-shaped orthorhombic crystals of 86, of space group of P21, and unit cell parameters, a = 6.1398(13) A°, b = 7.2275(16) A°, c = 23.635(5) A°, and Z = 2. The absolute configuration of the compound was determined as 1S, 5S [101] (Fig. 3.10). X-ray crystal analysis of tetracyclic iridoid lactone, molucidin 399, isolated from Morinda lucida was reported by Karasawa et al. [102]. The single crystals of molucidin prepared from MeOH solution have orthorhombic crystal system of space group P212121 (no 19) with z = 4 and unit cell parameters of a, 4.68040 (10) A°, b, 8.1049(3) A°, and c, 47.3450(15) A°. The absolute configurations of the chiral carbons were determined as 1R, 5S, 8S, 9S, and 10S with an E geometry of C-11–C-13 double bond. It was an enantiomer of the iridoid lactone, oruwacin

Fig. 3.10 ORTEP drawing of triohima A crystal structure with atomic numbering and thermal ellipsoids at 50% probability. Adapted from Li et al. [101] with permission of Elsevier. Copyright (2009) Elsevier

3.4 Spectroscopic Methods for Identification of Iridoids

115

Fig. 3.11 ORTEP drawing of molucidin crystal structure with atomic numbering and thermal ellipsoids at 50% probability. C and O atoms are gray and red colors, respectively. Adapted from Karasawa et al. [102] with permission from Elsevier. Copyright (2015) Elsevier

63, isolated from the same plant, having the absolute stereochemistry of 1S, 5R, 8R, 9R, and 10R (Fig. 3.11). The X-ray crystallographic studies of 8-deoxyshanzhiside 378 [103], torricellate 650 [104], negundoside 698 [105], 5aH-6-epi-dihydrocornin 700 [106], gibboside 701 (Fig. 3.1) [107], secologanic acid 66 [108], methylcatalpol 211b [109], and swerilactones C 818, D 819 [110], and I 820 [111] have also been reported.

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Chapter 4

Chemistry and Biosynthesis of Iridoids

4.1

Introduction

Potential health benefit effects and versatile pharmacological activities of several iridoids and secoiridoids have created interests among synthetic chemists and biotechnologists to make them popular targets of chemical synthesis and biosynthesis. The presence of oxygenated substituents in the cyclopentane ring of iridoids, several groups have been used these compounds as starting materials for regioselective and stereoselective synthesis of potential bioactive alkaloids, prostaglandin analogues and other bioactive natural products. Most of the synthetic studies on iridoids and secoiridoids are based on stereo- and region-selective strategies. Various human-edible fruits are rich in iridoid content. Biotechnologists are trying to improve the yields of these edible fruits cultivars through breeding technology for production of better quality and quantity of such iridoid-bearing fruits. Moreover, the genes that are involved in the synthesis of bioactive iridoids in plants are utilized in the production of these iridoids in large amounts in tissue culture technologies for commercial applications. In this chapter, the synthetic methods of some iridoids and secoiridoids, applications of iridoids in synthesis of prostaglandin analogues, and their biosynthetic studies as well as their roles as chemotaxonomic markers in the study of plant systematic are briefly emphasized.

4.2 4.2.1

Syntheses and Transformations of Bioactive Iridoids Syntheses of Bioactive Iridoids

Despite enormous progress in the field of iridoid pharmacology, the synthetic approaches of the bioactive iridoids are limited due to difficulties associated with © Springer Nature Switzerland AG 2019 B. Dinda, Pharmacology and Applications of Naturally Occurring Iridoids, https://doi.org/10.1007/978-3-030-05575-2_4

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the glycosidation and generation of chiral centers [1]. Buchi et al. reported the synthesis of loganin 18, which represents the first synthesis of an iridoid glycoside [2]. This synthetic plan includes the photochemical [2 + 2] cycloaddition reaction between 2-formylmalonaldehydic acid methyl ester 4.1 and a cyclopentane derivative 4.2 in the key step, followed by methanolysis of the cycloadduct 4.3 and its oxidation to produce the ketoacetal 4.4. The ketoacetal 4.4 on formylation with methyl formate followed by treatment with p-toluene sulfonyl chloride and 1-butanethiol gave n-butylthiomethylene ketone 4.5. The resultant thiomethylene ketone 4.5 on desulfurization with Raney nickel in methanol and consequent basification afforded C-methylketone 4.6 exclusively. The methyl ketone 4.6 on reduction with sodium borohydride gave alcohol, which was converted into a mesylate, which on treatment with tetraethylammonium acetate in acetone produced the desired acetate 4.7 via inversion. The hydrolysis of acetate 4.7 produced loganol acetate 4.8. The loganol acetate 4.8 on glucosidation with 2,3,4,6-tetra-O-acetyl-bD-glucopyranose in the presence of boron trifluoride etherate at low temperature followed by stirring at room temperature afforded loganin pentaacetate 4.9, which on deacetylation gave loganin 18 in an overall yield of 1.4% (Scheme 4.1). Krische and Jones reported the total diastereoselective synthesis of potential antitumor and anti-inflammatory iridoid glycoside, (+)-geniposide 23 via phosphine catalyzed [3 + 2] cycloaddition reaction of ethyl-2,3-butadienoate 4.10 with enone 4.11. The resulting cycloadduct 4.12 was converted into (+)-geniposide in ten steps (Scheme 4.2) [3]. The following steps are involved: the conversion of the cycloadduct into cyanohydrins, which on elimination afforded the a,b-unsaturated nitrile 4.13. The nitrile on reduction with DIBAL-H was converted into allyl alcohol 4.14. Using the Ghaffar-Parkins catalyst, the alcoholic nitrile 4.14 was converted into primary amide 4.15. The nitrosation and hydrolysis of the primary amide 4.15 with sodium nitrite in acetic acid gave a carboxylic acid, which on esterification with TMS-diazomethane afforded methyl ester 4.16. Treatment of 4.16 with Otera’s catalyst, pivaloyl lactol 4.17 was obtained as a 5:1 epimeric mixture at the lactol carbon. Glycosidation of lactol 4.17 with trichloroacetimidate of tetra-O-acetyl glucose in the presence of boron trifluoride etherate produced tetraacetyl derivative of geniposide 4.18. Deprotection of acetyl groups of 4.18 with lithium hydroxide in acetonitrile gave (+)-geniposide 23 in 61% yield. Trost et al. reported the total synthesis of (±)-plumericin 60 and (±)-allamandin 136a from cycloocta-1,3-diene 4.19 in 16 and 17 steps, respectively using a biomimetic strategy (Scheme 4.3) [4]. The authors prepared the ketone 4.20 from cycloocta-1,3-diene in four steps. The ketone 4.20 was converted into vinylcyclopropanol derivative 4.21 by sulfonium cyclopropylide addition with cyclopropyldiphenylsulfonium fluoroborate. The compound 4.21 on treatment with phenylselenylbromide underwent ring expansion of vinylcyclopropanol to give

4.2 Syntheses and Transformations of Bioactive Iridoids

121

Scheme 4.1 Total synthesis of loganin

spiroseleno lactone 4.22. The Baeyer–Villiger ring expansion of 4.22 with m-CPBA gave 4.23, which was converted into bisulfenylated lactone 4.24 with phenyl (phenylthio) sulfonate. The lactone 4.24 on aldol condensation with acetaldehyde in the presence of ethylmagnesium bromide via desulfenylation gave 4.25. The compound 4.25 on oxidative elimination with m-CPBA and subsequent acetylation with acetic anhydride in pyridine afforded allyl acetate 4.26. The allyl acetate 4.26 on oxidation with OsO4 gave a cis-diol, which on periodate cleavage afforded allamcin 4.27 (132). Allamcin on flash vacuum pyrolysis at 500 °C gave an enol ether 4.28, which on acylation with trichloroacetyl chloride gave 4.29. The acyl derivative 4.29 on methanolysis afforded (±)-plumericin 60. Plumericin on acid-catalyzed hydration with aqueous perchloric acid gave (±)-allamandin 130.

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Scheme 4.2 Total synthesis of (+)-geniposide

Demuth et al. reported the first total synthesis of (+)-iridodial 3, a constituent of ants and other insects, from 1,3-cyclohexadiene in 12 steps and in overall 13% yield via the key intermediate, (−)-tricyclo-[3.3.0.02,8]-octane-3-one 4.30 [5]. The overall steps from 4.30 are outlined (Scheme 4.4). The octanone 4.30 was reduced to an endo-alcohol 4.31 with DIBAH. The alcohol 4.31 on treatment with methane sulfonyl chloride and triethylamine gave (+)-endo-mesylate 4.32 as major product through nucleophilic SN2-like reaction. The mesylate 4.32 on treatment with sodium iodide gave an (+)-exo-iodide, which on reaction with Grignard reagent afforded an exo-methylated product 4.33. Vicinal hydroxylation of 4.33 with OsO4 gave the cis-diol 4.34, which on cleavage with aqueous sodium periodate afforded (+)-iridodial 3. The stereoselective total syntheses of (±)-ethylcatalpol 702, and (−)-specionin 181 [6], (−)-7-deoxyloganin 18a [7], semperoside A 310 [8], (+)-isoboonein 142 [9], (−)-brasoside 703 [10], (±)-forsythide aglucone dimethyl ester 704 [11], dolichodial 3a, isoiridomyrmecin 5, nepetalactol 705 and actinidine 706 [12], and iridoid lactone IV 707 [13] (Fig. 4.1) have been reported.

4.2 Syntheses and Transformations of Bioactive Iridoids

Scheme 4.3 Total synthesis of plumericin and allamandin

Scheme 4.4 Total synthesis of (+)-iridodial

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Fig. 4.1 Chemical structures of some plant iridoids that have been synthesized

4.2.2

Transformations of Bioactive Iridoids

In the last four decades, there has been a growing interest in the synthesis of bioactive compounds from readily available bioactive natural products [14]. The plant iridoids play a key role as starting materials in the syntheses of several bioactive compounds because of their abundant occurrence in plants. In the last few years, several papers and patents on the syntheses of potent bioactive prostaglandin analogues have been reported using iridoids, aucubin 13, asperuloside 24, and catalpol 14 as starting materials [15]. Several groups reported the syntheses of different prostaglandin (PG) analogues using aucubin 13 as a starting material. Aucubin was converted into the lactone of hexaacetylaucubin 4.35, following Dalton’s procedure of bromohydrin formation at the double bond in C-3 and C-4 position [16]. Trogolo et al. reported the synthesis of 12-epi-PGF2a analogue, 11-deoxy-11b-methoxy-11a-(hydroxymethyl)-12-epiPGF2a methyl ester 708, from aucubin, via using the lactone of hexaacetylaucubin 4.35 as an intermediate, which is outlined in Scheme 4.5 [17]. The lactone 4.35, on acid-catalyzed methanolysis and basic hydrolysis gave bicyclic acetal 4.36. The bicyclic acetal 4.36 on iodolactonization with iodine in potassium iodide is followed by deiodination with tributyltin hydride. Selective cleavage of acetal protecting methoxy group to hydroxyl group with very dilute HCl in acetonitrile from the intermediate lactone obtained by tin hydride reduction of iodolactone gave the hemiacetal 4.37 in 75% yield. The hemiacetal 4.37 on Emmons-Horner reaction with sodium salt of dimethyl-(2-oxoheptyl)-phosphonate afforded an enone, which on acetylation with acetic anhydride and reduction with (S)-BINAL-H produced 15Sallylic lactone 4.38 as major product. The lactone 4.38 on reduction with DIBAH to a lactol, which on Wittig reaction with (4-carboxybutyl)-triphenyl phosphonium bromide and subsequent esterification with diazomethane gave 708 in a yield of 11%.

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Scheme 4.5 Total synthesis of 12-epi-PGF2a analogue

Scheme 4.6 Synthesis of enone derivative of Corey lactone aldehyde analogue

From aucubin, using similar strategy, a variety of isoprostanes mostly modified at 11-position were prepared by Ohno et al. [18], 11-methyl PGA2 was synthesized by Trogolo et al. [19], and many related prostaglandin analogues including (+)11-deoxy-11a-hydroxymethyl-PGF2a and Corey lactone aldehyde were synthesized by Naruto et al. and Bonini et al. [20]. Berkowitz et al. reported the conversion of asperuloside tetraacetate 4.39 into enone derivative of Corey lactone aldehyde analogue 709 (Scheme 4.6) [21].

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Scheme 4.7 Total synthesis of (15R/15S)-9-epi-15F2c-isoprostane

Compound 4.39 on hydrogenation over rhodium on carbon in ethyl acetate gave a tetrahydro derivative 4.40, which on acid hydrolysis gave a tetracyclic acetal 4.41. The acetal 4.41 on treatment with acetyl chloride in the presence of titanium tetrachloride was converted into a hemiacetal 4.42, which on Wadsworth–Emmons reaction with dimethyl-2-oxoheptyl phosphonate in the presence of n-butyl lithium produced the enone derivative of Corey lactone aldehyde analogue 709. Berkowitz et al. also reported the synthesis of (+)-11-deoxy-11ahydroxymethyl-PGF2a from asperuloside [22]. Weinges et al. reported the synthesis of (15R)- and (15S)-9-epi-15F2c-isoprostane 710 using catalpol 14 as starting material (Scheme 4.7) [23]. Catalpol 14 was converted into the lactol 4.43 in eight steps. The x side chain in the lactol 4.43 was introduced by Horner–Wadsworth–Emmons (HWE) reaction with 2-oxoheptylphosphonate in the presence of sodium hydride. The primary hydroxyl group was protected by p-phenyl benzoyl chloride and keto function was reduced by zinc borohydride to get (15R)- and (15S)-diastereomers of 4.44. These diastereomers after separation were subjected to a sequence of reactions namely protection at C-15 position as DHP ether, saponification of the benzoate, oxidation to the aldehyde, Wittig reaction with 5-phosphoniovaleric acid, and two final deprotections gave the target molecules 710.

4.3 Syntheses and Transformations of Bioactive Secoiridoids

4.3 4.3.1

127

Syntheses and Transformations of Bioactive Secoiridoids Syntheses of Bioactive Secoiridoids

Synthesis of bioactive naturally occurring sarracenin 147, a tricyclic secoiridoid, has been reported by different groups [24–28]. Among these reported groups, Hoye and Richardson reported its synthesis using Paterno–Buchi cycloaddition reaction and completed the synthesis in nine steps and in 18% overall yield of sarracenin from isolated tosylate intermediate (Scheme 4.8) [28]. Paterno–Buchi photocycloaddition of acetaldehyde and cyclopentadiene afforded diastereomeric exo- and endo-oxetanes 4.45 and 4.46 in a ratio of 5:1. The exo-oxetane 4.45 on acid-catalyzed methanolysis with methanolic camphor sulfonic acid followed by tosylation gave a tosylate 4.47. The tosylate 4.47 was converted into malonate derivative 4.48 on treatment with dimethyl-(E)-(2-phenylethenyl)-propanedioate. The malonate 4.48 was decarboxylated to 4.49, which on demethylation with trimethylsilyl iodide gave the alcohol 4.50. The alcohol 4.50 on ozonolysis in methanol, followed by reduction with dimethyl sulfide gave (±)-saracenin in 47% yield. Hutchinson et al. reported the stereoselective total synthesis of (±)-sweroside aglucone-O-methyl ether 711 in seven steps and in an overall yield of 27% from

Scheme 4.8 Total synthesis of sarracenin

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1,4-cyclohexadiene 4.51 and methyl diformyl acetate 4.52. The authors also achieved the synthesis of (±)-secologanin aglucone-O-methyl ether 712 from 711 in 90% overall yield from a straightforward process in three steps (Scheme 4.9) [29]. The authors used the key intermediate 4.53 obtained from [2 + 2]-photoannelation of 4.51 and 4.52 to complete the syntheses of 711 and 712. The photoirradiation of 4.51 and 4.52 with a Hanovia 450 W lamp gave 4.53 as major product, which on acid-catalyzed acetalization in methanol afforded a mixture of epimeric acetals 4.54a and 4.54b in a ratio of 3:2 quantitatively. These acetals on hydroxylation with OsO4 gave a diol mixture 4.55a and 4.55b, which on periodate cleavage yielded dialdehydes 4.56a and 4.56b. Exposure of the unstable dialdehydes with an excess of sodium borohydride in isopropyl alcohol afforded hydroxylactones 4.57a and 4.57b in a ratio of 5.5:3.3. The hydroxylactone 4.57a on

Scheme 4.9 Total synthesis of sweroside aglucone-O-methyl ether and secologanin aglucone-Omethyl ether

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dehydration via conversion into primary alkyl selenide with o-nitrophenyl selenocyanate and oxidation of selenide with hydrogen peroxide followed by elimination reaction produced 711. The compound 711 on saponification with KOH followed by esterification with diazomethane gave 4.58, which on oxidation with DCC in DMSO gave (±)-secologanin aglucone-O-methyl ether 712. Total stereoselective synthesis of (±)-dimethyl secologanoside O-methyl ether 713 (Fig. 4.1) and a general approach for the synthesis of secoiridoids using formal [3 + 3]-cycloaddition reaction have also been reported [30].

4.3.2

Transformations of Bioactive Secoiridoids

Kikuchi et al. prepared secoiridoid aglucones 714 and 715 from secoiridoid glucosides, isoligustroside 468 and isooleuropein 469 from enzymatic hydrolysis with b-glucosidase via formation of intermediates 4.59 and 4.60, respectively. These aglucones exhibited moderate cytotoxicity against 39 human cancer cell lines. These rearranged aglucones are formed via Michael-type addition reaction of dihydropyran ring of the generated aglucone intermediates 4.59 and 4.60 (Scheme 4.10) [31].

Scheme 4.10 Enzymatic hydrolysis of isoligustroside and isooleuropein

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Scheme 4.11 Enzymatic hydrolysis of 10-hydroxyoleoside-type secoiridoid glucosides

Similarly, enzymatic hydrolysis of 10-hydroxyoleoside-type secoiridoid glycosides 4.61–4.63 with b-glucosidase in acetate buffer afforded jasmolactones B, D, and E (716-718) via lactonization and stereospecific alkoxyl transfer from C-7 to C-8 in a concerted process involving an intermediate 4.64 (Scheme 4.11) [32]. It was observed that an acid function at C-7 did not induce such transformation. Jasmolactones B 716 and D 717 exhibited significant coronary vasodilating and cardiotropic activities in isolated guinea pig heart model [33].

4.4

General Biosynthetic Pathway of Plant Iridoids and Secoiridoids

Several pharmacologically active iridoids and secoiridoids from plants have been isolated in minor quantities, and hence, their detailed studies in animal models are not yet done, resulting in the hamper of their commercial applications in pharmaceutical and cosmetic industries as well as in the control of insect-related disease vectors. Their biotechnological production is badly hampered due to fragmentary knowledge on the relevant genes involved in their biosynthetic pathways. Therefore, transcriptome analysis of the putative genes and metabolomes analysis of the gene-derived metabolic products that are involved in iridoid biosynthesis are essential for setting of sustainable biotechnological programme for their production in large quantities to use in pharmaceutical and other industries. Moreover, monoterpenoid indole alkaloids (MIAs) are also a large group of secondary plant metabolites that have potential pharmacological activities. Most of these MIAs are biosynthesized via secologanin pathway. The biosynthesis of plant iridoids has been studied in detail through feeding experiments [34–36]. Two main routes for iridoid biosynthesis have been reported. The route I from iridodial 3 via deoxyloganic acid 163 and loganin 18 to secologanin 64 for biosynthesis of C-4 substituted iridoids, known as secoiridoid pathway and route II from 8-epi-iridodial 719, 8-epi-iridotrial 720, and 8-epi-deoxyloganic acid 163a for biosynthesis of decarboxylated iridoids namely aucubin 13 and

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catalpol 14, known as decarboxylated iridoid pathway [34, 36, 37]. Madagascar periwinkle, Catharanthus roseus has been the best-investigated species in the field of iridoid biosynthesis because it is the source of several potential MIAs including vincristine and vinblastine and their derivatives, which have been used for the treatment of various human cancers for a long time. In route I, biosynthesis of secologanin starts from dimethylallyl pyrophosphate and isopentenyl pyrophosphate via formation of monoterpene,geraniol 721 as an intermediate and involves about ten genes (enzymes) catalyzing successive oxidation, reduction,

Scheme 4.12 Secologanin pathway of iridoid biosynthesis in Catharanthus roseus

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Scheme 4.13 Postulated biosynthetic pathway of decarboxylated iridoids

glycosidation, methylation, and cyclopentane ring cleavage reactions (Scheme 4.12) [38]. Intensive biochemical and genetic studies on MIA biosynthesis in C. roseus revealed the discovery of putative genes involved in this pathway [38– 43]. Most of these studies were done through detailed transcriptomes and metabolomes analyses for characterization of the genes and gene-derived products (metabolites) involved in the biosynthetic pathway. Feeding experiment clearly indicated that secologanin 64 is derived from geraniol 721 [44]. In the study of biosynthesis of secologanin 64 in C. roseus cell culture using 13C-labeled D-glucose as upstream precursor, Contin et al. established that the MEP(2-methyl-D-erythritol 4-phosphate) pathway played a major role in its biosynthesis, while the alternative MVA (mevalonic acid) pathway was involved in a minor way [45]. The biosynthesis of iridoids via route II (Scheme 4.13) is not studied well as detailed information on genetic and molecular levels are not available [46, 47].

4.5

Transcriptome and Metabolome Analyses in Iridoid Biosynthesis

Integrated studies of transcriptome, proteome, and metabolome provide us a precise understanding of biosynthetic pathways. Transcriptomics (gene expression analysis), proteomics (protein analysis), and metabolomics (metabolite analysis) are useful

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techniques for identification of novel functional genes and characterization of the regulatory mechanism and key factors of biosynthetic pathways. Transgenic derivatives of plant tissue cells are generated by treatment of tissue cells’ suspension with plant hormone, methyl jasmonate (MeJA). Selected transgenic lines such as

Fig. 4.2 Complete functional genes involved in secologanin pathway of iridoid biosynthesis in Catharanthus roseus. Colors indicate transcriptional activation (blue) or repression (yellow) relative to untreated samples. Tissue of C. roseus: leaf.Sdlg, seedling. Suspension cells (Cell Sus): O2, ORCA2; O3, ORCA3. Treatments of plant tissue: Not, no treatment; MeJA, methyl jasmonate (6, 12, or 24 h). Genes: GES, geraniol synthase; G8O, geraniol 8-oxidase; IS, iridoid synthase; IO, iridoid oxidase; 7-DLGT, 7-deoxyloganetic acid glucosyl transferase; 7-DLH, 7-deoxyloganic acid hydroxylase; LAMT, loganic acid O-methyl transferase; SGD, strictosidine b-D-glucosidase; SLS, secologanin synthase; STR, strictosidine synthase (13 genes); TDC, tryptophan decarboxylase. Adapted from [38] with permission of Springer Nature. Copyright (2014) Springer Nature

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ORCA 2 and ORCA 3 (jasmonate-responsive transcription factors for activation of target genes for biosynthesis of TIA) are treated with estradiol and the total RNA proteins are isolated. Using pure RNA, RNA sequencing, c-RNA, and single-stranded c-DNA are constructed. With the help of RT-PCR, the mapping of gene products is done and it is compared with the available data set from the Medicinal Plant Genomics Resource Consortium [48–50]. From the cultured plant (C. roseus) tissue cells in presence of stress hormone, MeJA , the proteins are extracted with betaine solution. From the betaine extract, proteins are purified by gel electrophoresis and are identified by LC-MS (HPLC-ESI/MS or HPLC-MALDITOF/MS) study. The MS data of protein/enzymes with their accumulated metabolites provide the information of the genes responsible for production of the specific metabolites. Integrated mapping of gene to gene and gene to metabolic data clearly reveals that the MEP pathway is the major pathway of iridoid biosynthesis in C. roseus [38, 51, 52]. The function of relevant gene is discovered from the culture of the isolated genes in yeast. The gene to metabolite correlation provides the identification of gene function. Thus, all these integrated studies of trancriptomes, proteomes, and metabolomes are essential to identify the genes and their functional metabolites involved in the biosynthetic pathway of iridoids. The detailed study of transcriptome analysis of various tissues of C. roseus resulted in a total of 59,220 unique transcripts with an average length of 1284 bp. Among them, 65% of transcripts have homology with sequences available in various repositories, while the rest 35% are specific of this plant. The gene expression analysis revealed that the leaves and roots are actively involved in the biosynthesis of monoterpenoid indole alkaloids (MIAs) via secologanin pathway [49]. The genes involved in the biosynthesis of iridoids in Catharanthus roseus are shown in Fig. 4.2 [38].

4.6

Biosynthesis of Iridoids in Insects

In insects, biosynthesis of iridoids has been investigated thoroughly and found to proceed along the same principal route that occurs in plants. In insects, mevalonic acid is converted into geraniol 721, which undergoes allylic oxidation to produce 8hydroxygeraniol 722. 8-Hydroxygeraniol on subsequent oxidation affords 8-oxogeranial 724. Cyclization of 8-oxogeranial in the presence of cyclase gives plagiodial 728, which on double-bond isomerisation gives chrysomelidial 678. While, cyclization of 8-oxogeranial with iridoid synthase gives cis-trans-iridodial 725, which affords actinidine 706 in the presence of ammonia (Scheme 4.14) [53–55].

4.7

Biosynthesis of Iridoids in Lamiaceae

Lamiaceae is the sixth largest flowering plant family, and a source of mint and culinary flavors that enjoyed by the people worldwide. This family has a high degree of chemical diversity with specialized compounds including iridoids and

4.7 Biosynthesis of Iridoids in Lamiaceae

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Scheme 4.14 Proposed biosynthetic pathway of iridoids in insects

Scheme 4.15 Postulated biosynthetic pathway of nepetalactone and other iridoids in Nepeta cataria

volatile monoterpenoids. The Lamiaceae consists of about 236 genera and about 6900–7200 species [56]. Several species of some largest genera of this family namely Scutellaria, Salvia, Vitex, Teucrium, and Nepeta are rich in iridoid content. However, only a little work on iridoid biosynthetic study has been reported. Both C-8b and C-8a-methyl iridoids are found in the plants of this family. The genus Nepeta, one of the largest genera of this family, contains iridoid lactones as major iridoid constituents. Biosynthetic studies on Nepeta cataria were carried out by

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Scheme 4.16 Postulated biosynthetic pathway of dolichodial in Teucrium marum

Bellesia et al. with feeding experiments using labeled [8-3H]-8-hydroxygeraniol 722, [8-3H]-8-hydroxycitronellol 729, and [8-3H]-iridodial 725, and found good incorporation of the latter two compounds in nepetalactone 730. On the basis of their findings, they suggested that either 8-hydroxycitronellol or iridodial could be the key biosynthetic precursor of iridoid lactones in Nepeta spp and these lactones were biosynthesized via secologanin pathway (Scheme 4.15) [57]. Later on, this work was repeated by Uesato using the same precursors and found also significant incorporation of iridodial in both nepetalactone 730 (0.6%) and 1,5,9-epi-deoxyloganin 731 (1.2%) and inferred the same biosynthetic pathway [58]. Bellesia et al. also investigated the biosynthetic pathway of Teucrium marum by feeding experiments with [8-3H]-8-hydroxygeraniol 722, [8-3H]-8-hydroxycitronellol 729 and [8-3H]-iridodial 725, and found good incorporation of 729 and 725 in dolichodial 3a in about 5.5 and 0.2%, respectively. On the basis of their findings, they inferred that 8-hydroxycitronellol 729 would be the key biogenetic precursor of dolichodial and formation of dolichodial 3a (Scheme 4.16) [59]. Inouye et al. studied the biosynthesis of iridoids in Lamium amplexicaule on feeding with [2-14C]-mevalonic acid (MVA) 732 and isolated lamioside 22 and ipolamliide 121, labeled at C-3 and C-7 positions. On the basis of these results, they proposed that these iridoids are synthesized in L. amplexicaule through iridodial and its glucoside 725a (Scheme 4.17) [60]. Later on, this group repeated this study in the same plant on feeding with 8hydroxygeraniol 722, iridodial 725 and its glucoside 725a, all labeled with tritium (3H) at C-8 position and found [3-3H]-lamioside 22 and [3-3H]-lamiide 207, albeit with very small incorporations (less than 0.01%) [61]. However, they supported their earlier proposed pathway. The low incorporation of labeled intermediates in the iridoids of Lamium spp creates a doubt on the origin of isoprene units. In order to solve this doubt, Gao et al. studied the biosynthesis of iridoid glucoside, lamalbid 377 in Lamium barbatum on feeding with 13C-labeled intermediates, [2-13C1]-mevalonolactone 733, and [3,4,5-13C3]- 1-deoxy-D-xylulose-5-phosphate 734, which are the intermediates of MVA and MEP (2-methyl-D- erythritol-4-phosphate), respectively. Their feeding results demonstrated that the compound 734 was incorporated into lamalbid 377, whereas the incorporation of 733 was not observed. On the basis of these results, they proposed that lamalbid was biosynthesized through the MEP pathway, whereas the classic MVA pathway was not utilized in its biosynthesis (Scheme 4.18) [62].

4.7 Biosynthesis of Iridoids in Lamiaceae

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Scheme 4.17 Postulated biosynthetic pathways of lamioside and ipolamiide in Lamium amplexicaule

The observed incorporation of 13C at C-11 position in lamalbid was possibly due to free rotation of the C(7)-C(8) single bond in iridodial. The involvement of MEP pathway was also observed by Contin et al. in the biosynthesis of secologanin 64 in Catharanthus roseus cell culture [45]. Therefore, the classical MVA pathway of iridoid biosynthesis may not be ignored. Possibly, the operation of one of the two pathways in a plant depends on the physiological state of the cells. Future study using different cell lines and under different conditions would help us to get a better understanding on the involvement of these MVA and MEPpathways in iridoid biosynthesis in plants.

Scheme 4.18 Postulated biosynthetic pathway of lamalbid in Lamium barbatum

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Scheme 4.19 Postulated biosynthetic pathway of catalpol in Scutellaria albida

Damtoft studied the biosynthesis of catalpol 14 in Scutellaria albida using deuterium labeled 8-epi-deoxyloganic acid 163a and found about 3.5 and 5.5% incorporation of the labeled compound in aucubin 13 and catalpol 14, respectively. On the basis of his findings, he concluded that catalpol was synthesized in S. albida via 8-epi-deoxyloganic acid and aucubin as intermediates (Scheme 4.19) [63].

4.8

Iridoids as Taxonomic and Phylogenic Markers in Plants

Some of the plant iridoids, secondary metabolites of plants, usually function as defence (against herbivores, microbes, or competing plants) and signal compounds (to attract pollinating or seed-dispersing animals). Thus, these metabolites are important for survival and reproductive fitness of these plants. These metabolites represent the adaptive characters of plants to natural selection during evolution. Therefore, a molecular phylogeny of a particular family is constructed to interpret the distribution of some major iridoid compounds that are typical for that family. The distribution of the respective compounds in a family indicates a strong phylogenetic and ecological relationship among the plants of that family. In a referred taxon, certain iridoid metabolites may be absent, although all other neighboring and ancestral taxa express the particular trait. It indicates that the referred taxon switches off the genes for the synthesis of these iridoid metabolites to adjust its lifestyle in a given phylogenic framework [64]. In chemosystematics, iridoids have significant roles in plant classification, phylogeny, and evolution. For instance, iridoids in the plants of family are not much oxygenated and poorly specialized suggesting the primitiveness of the taxon. Thus, the family, Actinidiaceae may be considered as the ancestral of the

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iridoid-producing plant families [65]. The iridoid glycosides, aucubin 13, and catalpol 14 are found in most of the species of genus, Veronica (Plantaginaceae) , and hence, these iridoids are considered as chemotaxonomic markers of Veronica [66]. Iridoids, aucubin, catalpol, and harpagoside 499 are found in many species of Lamiaceae, Verbenaceae, Scrophulariaceae, Loganiaceae, Ericaceae and other families, and thus, the presence of these iridoids is not characteristic of any particular clade [67, 68]. A phylogenetic tree of a family based on just one character such as morphological, anatomical, chemical, or molecular feature reflects the evolution of that particular character in that family, but not the evolution of all the characters of the plants in that family. Therefore, a phylogenetic tree based on the occurrence of iridoids in plants will not reflect the true picture of the phylogeny of all characters of the plants in a family [69]. For instance, the genera, Aucuba, Garrya, and Griselinia share many common morphological and chemical features, including the presence of similar pattern of iridoids and petroselinic acid. However, the study of the segmented genes exhibits the same pattern in Aucuba and Garrya and a contrast pattern in Griselinia, and thus, only former two are included in the family, Garryaceae, while Griselinia is placed in a separate family, Griseliniaceae [70]. The genera, Aucuba and Garrya have also some more common features such as crystal sand, fat bodies in mesophylls, starch-free seeds, and accumulation of petroselinic acid in their seeds [71]. The genus Antirrhinum was placed earlier in the family, Scrophulariaceae by Fischer on the basis of morphological study of plants of this family [72]. Later on, chemosystematic study of the plants of this genus showed that the iridoids present in the plants much differ from the iridoids that found in other tribes of the plants of family, Scrophulariaceae. The molecular systematic study of Scrophulariaceae using DNA gene sequences (rbc L, ndhF, and rps 2) reveals that the genes of Antirrhinum are very much similar to that of Cymbalaria, and hence, Antirrhinum has been placed in the family, Plantaginaceae [73, 74]. Thus, both chemical and molecular basis of plants are useful in the evaluation of their phylogenetic relationships. The previous chemosystematic study of iridoids in Escallonia species suggested its inclusion in Saxifragaceae [75]. However, the study of the DNA sequence from chloroplast genes (atpB, ndhF, and rbcL) together with the morphological data supported its position in a special small family Escalloniaceae [76]. In Asterid IIa, the families Adoxaceae, Caprifoliaceae, Dipsacaceae, and Valerianaceae have close chemical similarity among their reported iridoids. All these families produce iridoids of loganin analogues, and secoiridoids, and all but the Valerianaceae also synthesize iridoid alkaloids [77]. Later on, careful morphological, DNA sequence (rbcL) and nuclear ribosomal internal transcribed spacer (ITS) studies of genera Sambucus (Dipsacaceae) and Viburnum (Caprifoliaceae) reveal a close similarity with Adoxa, and hence, the former two genera are included in Adoxaceae [74, 78]. The chemosystematic study of iridoids in a genus also provides us the phylogenetic relationship among the species in the genus. For instance, Mitova et al. isolated 16 iridoid glucosides, geniposidic acid 289, 10-deacetylasperulosidic acid

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Scheme 4.20 Proposed biosynthetic pathways of iridoids in Galium species

290, scandoside 282a, monotropein 25, asperulosidic acid 288, deacetylasperuloside 24a, asperuloside 24, 6-O-acetylscandoside, VI-iridoid, V2-iridoid, humifusins A 736 and B 736a, loganin 18,10-hydroxyloganin 424, 7-Oacetyl-10-acetoxyloganin and 7b-hydroxy-11-methylforsythide; 2 secoiridoid

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glucosides, 10-hydroxymorroniside 735 and secogalioside 73, and 6 triterperpene saponins from 19 species of Galium L. of Bulgarian origin from 6 sects of Galium, namely Aparinoides, Hylaea, Trachigalium, Galium, Leogalium, and Aparine [79]. They isolated secogalioside from 5 species of Galium mollugo group, and iridoid glucosides, 10-deacetyl asperulosidic acid 290, scandoside 282a, monotropein 25, and asperulosidic acid 288 in all other studied species as well as asperuloside 24 in 17 studied species. On the basis of their findings, they concluded that four iridoid glucosides, 10-deacetylasperulosidic acid, scandoside, monotropein, and asperulosidic acid have evolved in early stages in these species and asperuloside was synthesized at a later stage and secogalioside might be considered as chemotaxonomic marker of G. mollugo group. G. rivale was found to contain five triterpene saponins in addition to these iridoids. It indicated that G. rivale was grown under different habitat conditions, where the habitat conditions stimulate the branching of iridoid biosynthetic route to terpenoid biosynthetic route for production of additional defensive metabolites of terpenoid nature for its survival. They suggested a plausible pathway of iridoids in Galium species (Scheme 4.20). Jensen et al. isolated several iridoid glucosides and caffeoyl phenyl ethanoid glycosides from 34 Plantago species of different countries. Aucubin 13 was found in all these studied species, bartsioside 471 was present in subgenus Psyllium, and catalpol 14 was present in subgen, Albicans. On the basis of their findings, they inferred that aucubin might be considered as chemotaxonomic marker of genus Plantago and other isolated iridoids, bartsioside and catalpol could be the characteristic iridoid metabolite of respective subgen. Psyllium and Albicans [80]. Taskova et al. studied the distribution of iridoid glucosides in 14 Plantago L. species. The iridoid pattern among the studied species showed a good correlation with the morphological features of the species. They observed that aucubin was the major iridoid constituent in P. major [81]. Based on the findings, they proposed that P. major could be the most ancient species, from which all other species of Plantago have been originated. The morphological features of different Plantago species also corroborated this proposed fact [82].

References 1. Partridge JJ, Chadha NK, Uskokoviac MR (1973) J Am Chem Soc 95:532 2. Buchi G, Carlson JA, Powell JR, Jr, Tietze LF (1973) J Am Chem Soc 95:540; Idem (1970) ibid 92:2165 3. Jones RA, Krische MJ (2009) Org Lett 11:1849 4. Trost BM, Balkovec JM, Mao MKT (1986) J Am Chem Soc 108:4974 5. Ritterskamp P, Demuth M, Schaffner K (1984) J Org Chem 49:1155 6. Kim BY, Jacobs PB, Elliott RL, Curran DP (1988) Tetrahedron Lett 44:3079 7. Candish L, Lupton DW (2010) Org Lett 12:4836 8. Piccinini P, Vidari G, Zanoni G (2004) J Am Chem Soc 126:5088 9. Tada M, Inoue S, Miki T, Onogi S, Kaminaga J, Hiraoka J, Kitano Y, Chiba K (1988) Chem Pharm Bull 46:1451 10. Mangion IK, MacMillan DWC (2005) J Am Chem Soc 127:3696

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Liao CC, Wei CP (1989) Tetrahedron Lett 30:2255 Beckett JS, Beckett JD, Hofferberth JE (2010) Org Lett 12:1408 Lee S, Paek SM, Yun H, Kim NJ, Suh YG (2011) Org Lett 13:3344 Hanessian S (1983) Total synthesis of natural products. The ‘Chiron’ approach. Pergamon Press, Oxford Khristoforov VL, Serebryanyl VA (1994) Pharmaceut Chem J 28:412 Dalton DR, Dutta VP, Jones DC (1968) J Am Chem Soc 90:5498 Bernini R, Davini E, Iavarone C, Trogolo C (1986) J Org Chem 51:4600 Naruto M, Ohno K, Naruse N, Takeuchi H (1978) Chem Lett 1423; Ohno k, Naruto M (1979) Ibid 1015; Ohno K, Naruto M (1980) Ibid 175 Davini E, Iavarone C, Mataloni F, Trogolo C (1988) J Org Chem 53:20891 Naruto M, Ohno K, Naruse N, Takeuchi H (1979) Tetrahedron Lett 20:251; Bonini C, Di Fabio R (1982) Ibid 23:5199 Berkowitz WF, Choudhry SC, Hrabie JA (1982) J Org Chem 47:824 Berkowitz WF (1981) Tetrahedron Lett 22:1075 Weinges K, Braun G, Oster B (1983) Liebigs Ann Chem 2197 Whitesell JK, Mathews RS, Minton MA, Helbling AM (1981) J Am Chem Soc 103:3468 Tietze LF, Glusenkamp KH, Nakane M, Hutchinson CR (1982) Angew Chem. Int Ed Engl 21 (70):126 Baldwin SW, Crimmins MT (1982) J Am Chem Soc 104:1132 Takano S, Morikawa K, Hatakeyama S (1983) Tetrahedron Lett 24:401 Hoye TR, Richardson WS (1989) J Org Chem 54:688 Hutchinson CR, Mattes KC, Nakane M, Patridge JJ, Uskokovic MR (1978) Helv Chim Acta 61:1221 Cheng NC, Day HM, Lu WF (1989) J Org Chem 54:4083; Wu S, Zhang Y, Agarwal J, Mathieu E, Thorimbert S, Dechoux L (2015) Tetrahedron 71:7663 Kikuchi M, Yaoita Y, Mano N, Kikuchi M (2011) Chem Biodiver 8:651 Shen YC, Chen CH (1993) Tetrahedron Lett 34:1949 Shen YC, Chen CH (1989) J Nat Prod 52:1060 Jensen SR (1991) In: Harborne JB, Tomas-Barberan FA (eds) Ecological chemistry and biochemistry of plant terpenoids. Clarendon Press, Oxford, pp 133–158 Damtoft S, Jensen SR, Jessen CU, Knudsen TB (1993) Phytochemistry 33:1089 Damtoft S, Jensen SR, Weiergang I (1994) Phytochemistry 35:621; Damtoft S (1994) Ibid 35:1187 Jensen SR, Franzyk H, Wallander E (2002) Phytochemistry 60:213 Miettinen K, Dong L, Navrot N, Schneider T, Burlat V, Pollier J, Woittiez L, Van der Krol S, Lugan R, Ile T, Verpoorte R, Oksman-Caldentey KM, Martinoia E, Bouwmeester H, Goossens A, Memelink J, Werek-Reichhart D (2014) Nat Commun 5:3606 Collu G, Unver N, Peltenburg-Looman AM, Van der Heijden R, Verpoorte R, Memelink J (2001) FEBS Lett 508:215 Loyola-Vargas VM, Galaz-Avalos RM, Ku-Cauich R (2007) Phytochem Rev 6:307 Geu-Flores F, Sherden NH, Courdavault V, Burlat V, Glenn WS, Wu C, Nims E, Cui Y, O’Çonnor SE (2012) Nature 492:138 Verma P, Mathur AK, Srivastava A, Mathur A (2012) Protoplasma 249:255 Irmler S, Schroder G, St-Pierre B, Crouch NP, Hotze M, Schmidt J, Strack D, Matern U, Schroder J (2000) Plant J 24:797 Uesato S, Kanomi S, Iida A, Inouye H, Zenk MH (1986) Phytochemistry 25:839 Contin A, Van der Heijden R, Lafeber AWM, Verpoorte R (1998) FEBS Lett 434:413 Sun P, Song S, Zhou L, Zhang B, Qi J, Li X (2012) Int J Mol Sci 13:13748 Breinholt J, Damtoft S, Demuth H, Jensen SR, Nielsen BJ (1992) Phytochemistry 31:795 Van Moerkerche A, Fabris M, Pollier J, Baart GJE, Rombauts S, Hasnain G, Rischer H, Mimelink J, Oksman-Caldentey KM, Goossens A (2013) Plant Cell Physiol 54:673 Murata J, Roepke J, Gordon H, De Luca V (2008) Plant Cell 20:524; Verma M, Ghangal R, Sharma R, Sinha AK, Jain K (2014) Plos One 9:e103583

15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38.

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Chapter 5

Pharmacology of Iridoids

5.1

Introduction

In many Asian and European countries, medicinal plants have been used for a long time for the treatment of different ailments and diseases. In 400 BC, Greek physician Hippocrates, known as the Father of Medicine, said, ‘Food should be medicine and medicine should be food’ and elaborated on several dietary plants that could be prospective sources of medicine. Iridoids, an important class of secondary plant metabolites, have been found in several dietary folk medicinal plants of angiosperm plant families. These iridoid-producing plants have been used for a long time as bitter tonics, sedatives, cough medicines, hypotensives, antidiabetics, antipyretics, antiarthritis and for treatment of tumor, wounds, and skin disorders. Extensive phytochemical research of these plants reveals that in many plants, iridoids are the major bioactive principles and exhibit potent pharmacological and other biological activities including anti-inflammatory, antioxidant, neuroprotective, cardioprotective, antitumor, hypoglycemic, hypolipidemic, antiallergic, antimalarial, antibacterial, antiviral and insect repellent activities. This chapter summarizes the pharmacological and other biological activities of naturally occurring iridoids in order to bring them in the lime light of research for prospective application as chemotherapeutic agents.

5.2 5.2.1

Pharmacology of Iridoids Anti-inflammatory and Antinociceptive Activities

Inflammation is a manifestation of a wide range of human health disorders including rheumatoid arthritis, atherosclerosis, Alzheimer’s disease (AD), Parkinson’s disease (PD), inflammatory bowel disease, sepsis, asthma, type 2 © Springer Nature Switzerland AG 2019 B. Dinda, Pharmacology and Applications of Naturally Occurring Iridoids, https://doi.org/10.1007/978-3-030-05575-2_5

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diabetes mellitus, cirrhosis, and cancer. Inflammation occurs as a reaction to injury on cell surface from toxic chemicals or microbial infections. Inflammation is evidenced by an increased temperature on the injured site, redness, pain, swelling, and loss of function of the affected area. Examination of a range of inflammatory lesions demonstrates the presence of specific leukocytes in the affected area. So, the body immediately releases several extracellular molecular regulators including cytokines and chemokines to the affected inflammatory site for the remedy of injury [1, 2]. Therefore, a better understanding on these extracellular inflammatory mediators and their effects in different inflammatory-related disorders will help us to identify the immune cell recruitment in a specific inflammation and to select the specific anti-inflammatory drugs for treatment of that inflammatory disorder. Accumulating evidence indicates that cytokines are the key modulators in both acute and chronic inflammations via a complex network of interrelated inflammatory processes. These cytokines play their specific roles depending on the nature of immune response, cell type, and location of the cells. The pro-inflammatory cytokines, interleukin-1 (IL-1), IL-6, IL-17, and tumor necrosis factor-alpha (TNF-a) actively participate in amplification of inflammation and contribute to the development of human inflammatory-related diseases, while cytokines IL-2 and IL-10 negatively modulate these events [3]. For instance, up-regulation of IL-1 and IL-6 has been observed in a variety of inflammatory and autoimmune disorders such as type 1 diabetes, rheumatoid arthritis, lupus nephritis, psoriasis, and systemic sclerosis [4–7]. TNF-a is a potent inflammatory mediator for induction of many signaling cascades for generation of other cytokines and their receptors, which have important roles in chronic inflammations via activation of transcription factor NF-jB [8, 9]. It is closely linked to lipid metabolism, blood coagulation, insulin resistance, and endothelial function as well as in the pathogenesis of rheumatoid arthritis (RA), PD, AD, and Behcet’s disease (oral and genital ulcer) [10–12]. AD brain of animals was found to contain high levels of inflammatory mediators, such as inducible nitric oxide synthase (iNOS), TNF-a, IL-1b, and IL-6, while IL-1b, IL-1a, and TNF-a are found in RA, dermatomyositis, and pemphigus (skin sores). Chemokines (chemotactic cytokines), small heparin-binding proteins are acted on immunoglobulin G proteins. Several (about 44) chemokines have been identified in human genes, and these chemokines are secreted from all forms of tissue inflammations [13]. For instance, in Crohn’s disease (CD) and ulcerative colitis (UC), the interleukin-8 (IL-8) and its receptors are up-regulated [14], while chemokine, MCP-1, is over-expressed in atherosclerosis and MCP-4 in allergic and asthmatic lung inflammations [15, 16]. Other principal inflammatory mediators of eicosanoid family, such as prostaglandins (PGE2, PGF2a, and PGF2) and leukotrienes such as 12-hydroxy eicosatetraenoic acid (12-HETE) and leukotriene-C4 (LTC4), LTB4, LTD4, and LTE4 are frequently generated in several inflammatory diseases including asthma, bronchitis, and myocardial fibrosis [17]. Several Verbascum species have been used to treat urinary tract infections, eczema, and other skin disorders in Turkish traditional medicine [18]. A methanolic extract of Verbascum lasianthum flowers and its isolate aucubin 13 showed significant anti-inflammatory and antinociceptive activities in carrageenan-induced

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147

hind paw edema and p-benzoquinone-induced writhings in mice without inducing any apparent acute toxicity or gastric damage [19]. It has been reported that carrageenan induction in mouse results in the accumulation of inflammatory mediators, TNF-a, NO, PGE2, and myeloperoxidase (MPO). Therefore, aucubin could be effective in amelioration of these inflammatory mediators without any toxic effect. Recio et al. evaluated anti-inflammatory activity of 12 iridoid glucosides, namely lamiide 207, 6-O-(2″-O-acetyl-3″, 4″-di-O-p-methoxycinnamoyl-a-L-rhamnopyranosyl)-catalpol 372h, 6-O-(4″-O-acetyl-2″, 3″-di-O-p-methoxycinnamoyl-a-Lrhamnopyranosyl)-catalpol 372i, catalpol 14, aucubin 13, loganic acid 146, harpagoside 499, 6-O-vanilloylcatalpol (Picroside II) 192, oleuropein 80, shanzhiside methyl ester 103, verbenalin 647, and loganin 18 in carrageenan-induced mouse paw edema and TPA-induced mouse ear edema models. Among the tested iridoids, loganic acid was the most active (44.4% inhibition) in the former test, whereas catalpol derivatives 372h and 372i, aucubin 13, verbenalin 647, and loganin 18 showed the high activities (72.0–80.0% inhibition of edema) in the latter model. On the basis of their findings, the authors suggested that possibly a double bond between C-7 and C-8 in aucubin played a significant role on anti-inflammatory activity. The oxidation of this double bond to an epoxy derivative leads to a remarkable decrease in the activity as observed in catalpol [20]. To elucidate a possible molecular target of anti-inflammatory activity of aucubin, Park and Chang studied the effects of both aucubin and its hydrolyzed product (H–Au) obtained from hydrolysis with b-glucosidase, on the production of TNF-a in RAW 264.7 cells. They observed that only H–Au suppressed the production of both mRNA and proteins of TNF-a in a dose-dependent manner showing an IC50 value of 9.2 µM in TNF-a protein inhibition. Moreover, the H–Au significantly blocked both the inhibitor of NF-kappa B,-alpha (1jB-a) degradation and subsequent translocation of NF-jB from the cytosol to the nuclear fraction in the RAW 267.4 cells. On the basis of these results, they inferred that aucubin, at least in part, exhibited its anti-inflammatory activity via suppression of TNF-a production through its aglucone, H–Au [21]. Ajugol 11 and harpagoside 499, isolated from Verbascum xanthophoeniceum, showed significant anti-inflammatory effect against the production of chemokines, IL-8, MCP-1, and interferon gamma-induced protein-10 (IP-10) in IFN-c-activated normal human keratinocytes. These iridoids could be effective in chronic inflammatory-related skin disorders, such as psoriasis and atopic dermatitis [22]. The roots of Morinda officinalis have been used traditionally to treat rheumatoid arthritis, diabetes, and hypertension in Northeast Asia [23]. To identify the anti-inflammatory principles from this plant, Park et al. isolated two iridoid glucosides, monotropein 25 and deacetylasperulosidic acid 290 from the bioactive butanol fraction of methanolic extract of the roots. The major constituent monotropein on oral administration (30 mg/kg) in carrageenan-induced mice showed significant anti-inflammatory effect through inhibition of paw edema (about 39%) at 3 h, and this effect was comparable to that of reference anti-inflammatory drug, ibuprofen (62% inhibition at a dose of 100 mg/kg). In acetic acid-induced writhings and hot plate assays, pretreatment of monotropein (20 and 30 mg/kg/day, p.o.) to mice showed significant antinociceptive effect through reduction of the number of

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writhings and stretchings caused by acetic acid and increase in the action time to jump off in hot plate assay. The effect of monotropein at the higher dose (30 mg/kg) was comparable to that of positive controls, aspirin (100 mg/kg, p.o.) and morphine (10 mg/kg, p.o.) in writhings and hot plate assays, respectively [23]. To evaluate the molecular mechanism of anti-inflammatory effect of monotropein, Shin et al. investigated the anti-inflammatory effects of monotropein in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and dextran sulfate sodium (DSS)induced colitis in mice. Monotropein was found to inhibit the expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-a and IL-1b mRNA by suppressing the DNA binding of NF-jB in LPS-induced RAW 264.7 macrophages. In DSS-induced colitis model, monotropein reduced the activity of MPO and inflammation-related protein expressions by suppressing the NF-jB activation in colon mucosa. These findings suggested that the anti-inflammatory effects of monotropein were related to the suppression of the expressions of inflammatory mediators via NF-jB inactivation [24]. The aerial parts of Brazilian and Bolivian Bouchea fluminensis are widely used in treatment of digestive disorder and in bowel stimulating agent. Delaporte et al. found significant anti-inflammatory effect of an ethanolic extract from the leaves of this plant. From this ethanolic extract, they isolated lamiide 207 and evaluated its anti-inflammatory efficacy in carrageenan-induced rat paw edema and rat brain phospholipid assays. Pretreatment of lamiide (12.5–100 mg/kg, p.o.) to rats 30 min prior to carrageenan injection reduced the paw edema volume dose-dependently with an ED50 value of 62.3± mg/kg. It reduced the paw edema volume by 64 and 78%, compared to the saline control group at 50 and 100 mg/kg, respectively. In the rat brain phospholipid assay, it exhibited the inhibition of phospholipid peroxidation with an IC50 value of 0.93 ± 0.01 mM. These findings indicate that lamiide possibly exhibits its anti-inflammatory effect partially through scavenging of free radicals from the lipid membrane [25]. South American tea, Stachytarpheta cayennensis is widely used in Brazilian folk medicine to treat chronic liver diseases, gastric problems, flues, cough, and arthritis, while roots are used to treat skin wounds, rheumatism, and back-pain [26]. An ethanolic extract and its butanol fraction extract from the leaves of this plant showed significant inhibition of carrageenan-induced edema formation in rats. The isolated iridoid, ipolamiide 121 and phenyl ethanoid glycoside, acteoside from active butanol extract showed significant inhibitory effect on histamine and bradykinin-induced contractions of isolated guinea pig ileum. Ipolamiide and acteoside also exhibited in vivo anti-inflammatory effect in carrageenan-induced edema volume in rats by inhibition of edema volume by 70.22 and 93.99% at the tested dose of 100 and 150 mg/kg, respectively. The ethanol extract showed no lethal toxicity at a dose of 500 mg/kg in mice. These results indicate the anti-inflammatory effects of the leaf extract and its isolates, ipolamiide and acteoside, in the amelioration of back-pain at least partly, due to inhibition of bradykinin and histamine expressions [27]. It has been reported that bradykinin, histamine, PGE2, and serotonin expressions are up-regulated in arthritic back-pain [28].

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Dried fruits of Kigelia africana are used in African countries to prepare different ointments and lotions for topical application in treatment of psoriasis, eczema, and other skin diseases [29]. Verminoside 195, a major isolated iridoid constituent from the fruits of this plant, showed significant anti-inflammatory effects in inhibition of both iNOS expression and nitric oxide release in LPS-induced J774.A1 macrophage cell line [30]. Indian Ajuga bracteosa is traditionally used in treatment of different inflammatory disorders including hepatitis, pneumonia, rheumatism, and bone diseases [31]. Gautam et al. evaluated the anti-inflammatory effect of an ethanolic extract from the whole plant in TPA-induced ear edema in mice and found significant dose-dependent activity at the tested doses of 0.5 and 1.0 mg/ear. The extract also exhibited strong inhibitory effect against COX-1 and COX-2 enzymes, inhibiting their activity by 78.33 and 68.80%, respectively, in the tested concentration of 50 µg/ml. From this active ethanolic extract, they isolated two iridoids, reptoside 342 and 6-deoxyharpagide 342a, which exhibited moderate inhibitory activity against COX-1 and COX-2, inhibiting their activity of 33.55 and 51.30% by reptoside and of 38.36 and 59.45% by 6-deoxyharpagide, respectively, at the concentration of 50 µg/ml, while other isolated iridoids and other compounds showed weak activity [31]. Aerial parts of South American Mentzelia chilensis have been used in treatment of gastric ulcer and other inflammatory disorders [32]. A crude aqueous extract from the aerial parts of the plant showed anti-inflammatory property in carrageenan-induced rat paw edema assay. From this aqueous extract, isolated iridoid glucoside, mentzeloside (also known as deutzioside) 9 showed significant dose-dependent inhibitory effect in carrageenan-induced rat paw edema assay with an ED50 value of 40.4 µg/kg [32]. Scrophularia auriculata, a Mediterranean plant, has long been used in folk medicine in treatment of inflammatory-related skin diseases. Giner et al. isolated two iridoids, scropolioside A 372c and scrovalentinoside 372e along with triterpenesaponins, verbascosaponins A and B from this plant and evaluated their anti-inflammatory effects against carrageenan-induced rat paw edema and TPA-induced mouse ear edema models. Both the isolated saponins showed significant inhibition of edema in both the tested models, while the iridoids showed significant inhibition of edema only in mouse ear edema model. Both these iridoids were active on the delayed-type hypersensitivity reaction. These iridoids significantly reduced the inflammatory lesion and suppressed the cellular infiltration in mouse model [33]. Several accumulating evidence indicate that leukocyte T cells are mainly involved in delayed hypersensitivity. In order to confirm the response of the iridoids in the last phase of hypersensitivity, this group carried out the study of anti-inflammatory activity of scropolioside A in oxazolone-induced mouse ear edema model and observed significant reduction of edema (79% of inhibition) at 72 h at a dose of 0.5 mg/ear, but exhibited no effect during early stages of the process, that is, at 24 and 48 h. In contrast, this iridoid reduced the edema of mouse paw induced by sheep red blood cells in the earlier stages, 47% at 18 h, 45% at 24 h, and 36% at 48 h at a dose of 10 mg/kg, i.p. In vitro, scropolioside A reduced

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the proliferation of activated T-lymphocytes with 61% inhibition at 100 µM and of an IC50 value of 67.74 µM. In a study of cell cycle modification of T cells, treatment of 372c (100 µM) 18 and 24 h after phytohemagglutinin stimulation of T-lymphocyte cells increased the number of cells in the subG0 phase, whereas treatment 3 h after stimulation increased the number of cells that passed to the S phase. These findings indicate that the inflammatory response of scropolioside A occurs in delayed-type hypersensitivity reactions in mice. Furthermore, this iridoid inhibited the production of PGE2, LTB4, NO, IL-1b, IL-2, TNF-a, and interferon-c (IFNc) in LPS-induced RAW 264.7 macrophages. It also modified the expression of NOS-2 and COX-2 through inhibition of the activity of NF-jB in RAW 264.7 cells. All these findings indicate that scropolioside A could be a potential anti-inflammatory agent in inflammatory disorders, where delayed-type hypersensitivity reactions of skin are implicated [34]. Garg et al. isolated iridoids, scropolioside A 372c, harpagoside 499, koelzioside 372d and 6-O-(3″-O-p-methoxycinnamoyl-a-L-rhamnopyranosyl)-catalpol 375d from Indian Scrophularia koelzii and evaluated their hepatoprotective and immunostimulating activities. All these isolated iridoids showed positive response to these activities. Scropolioside A (6 mg/kg) showed maximum hepatoprotective activity in thioacetamide-induced hepatic damage in rats, and the effect was comparable to that of silymarin used as positive control, while harpagoside (4 mg/kg) showed maximum induction of immune response against sheep red blood cells in macrophage migration index (MMI) test and hemagglutinating antibody (HA) titer and plaque-forming cells (PFC) assays. It clearly indicates that hepatoprotective and immunostimulating activities are complementary to each other and are related to delayed-type hypersensitivity [35]. Ahmed et al. isolated harpagoside 499, koelzioside 372d, and three other iridoids from Scrophularia deserti, native to Kuwait, and evaluated their anti-inflammatory efficacy in carrageenan-induced rat paw edema assay. At the tested dose of 10 mg/kg, both harpagoside and koelzioside inhibited the edema volume by 30 and 26%, respectively, after 3 h of carrageenan injection [36]. Garcia et al. [37] isolated harpagoside 499 from Scrophularia frutescens aqueous extract and observed that it showed low anti-inflammatory activity compared to the aqueous extract in carrageenan-induced rat edema assay. Zhang et al. [38] also reported that harpagoside had no effect on COX-1/2 enzymes, TNF-a release, and NO production in an in vitro assay in LPS-induced RAW 264.7 cells. However, the hydrolyzed product of harpagoside, H–Hg obtained from hydrolysis with b-glucosidase, exhibited significant inhibition of COX-2 enzyme activity in a dose-dependent (2.5–100 µM) manner with an IC50 value of 43.3 µM. Scrophularia scorodonia is widespread in Spain and Africa and is used in folk medicine in treatment of inflammatory-related disorders. Seven iridoids, aucubin 13, harpagide 12, 8-O-acetylharpagide 12a, harpagoside 499, scorodioside 372b, scropolioside B 372f and bartsioside 471 isolated from this plant, were evaluated for their in vitro anti-inflammatory activity in calcium ionophore-stimulated mouse peritoneal macrophages. In the LTC4 assay, only aucubin, harpagoside, and harpagide showed significant effect; the effect of aucubin was higher with an IC50

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value of 70 µM. In PGE2 assay, harpagoside and 8-O-acetylharpagide showed weak inhibitory effect [39]. Harpagoside was found to be a major iridoid constituent in the rhizomes of devil’s claw (Harpagophytum procumbens). Huang et al. reported that harpagoside 499 (20 µM) inhibited the activity of COX-2 and iNOS enzymes in LPS-stimulated human HepG2 hepatocarcinoma cells and RAW 264.7 macrophages through inhibition of NF-jB activation. It inhibited the LPS-induced NF-jB transcriptional activity in transfected RAW 264.7 cells with an IC50 value of 96.4 µM [40]. In another study, an ethanolic extract of H. procumbens roots containing harpagoside as major constituent, on oral administration (100 mg/kg) in carrageenan-induced paw edema in rats, showed significant anti-inflammatory effect by reducing the paw edema in rats. While its major constituent harpagide, on oral administration (5 and 10 mg/kg) in carrageenan-induced paw edema in rats, did not exhibit significant anti-inflammatory effect in rats. Therefore, some other constituents of H. procumbens extract exhibit synergistic effect on the anti-inflammatory effect of harpagoside for the enhanced activity of the extract [41]. Haznagy-Radnai et al. [42] reported that administration of harpagoside 499 (10 mg/kg, i.p.) to carrageenan-induced mice and rats completely abolished the paw swelling. The aqueous and alcoholic extracts of H. procumbens containing up to 30% of harpagoside inhibited the biosynthesis of 5-lipoxygenase (5-LOX) completely at the concentration of 51.8 mg/l in an in vitro assay [43]. Therefore, H. procumbens extracts containing sufficient amount of harpagoside could be effective in prevention and treatment of inflammatory-related disorders. Dried-ripe fruits of Gardenia jasminoides are widely used in traditional medicines in Asian countries as cholagogue, sedative, diuretic, anti-inflammatory, antioedemogenic and antipyretic agents. Geniposide 23 and its aglucone genipin 41 as well as other iridoids have been isolated from the fruits of this plant. Koo et al. evaluated the anti-inflammatory efficacy of geniposide and genipin in different experimental models such as carrageenan-induced rat paw edema, carrageenaninduced air pouch formation, and measurement of nitric oxide content in the exudates. In all these tested models, genipin showed stronger anti-inflammatory effect than geniposide. In the carrageenan-induced rat paw edema assay, administration of geniposide (100 mg/kg) and genipin (50 mg/kg) separately to carrageenan-injected rats showed inhibition of edema by 31.7 and 49.1%, respectively, after 3 h of carrageenan administration. In the carrageenan-induced air pouch model, treatment of geniposide (0.1 mg/pouch) and genipin (0.1 mg/pouch) to carrageenan-injected rats decreased the production of exudates and nitric oxide with the degree of their inhibition, 45.1 and 51.1%, respectively. The lower activity of geniposide in reduction of NO production may be due to its delayed transport into the cells because of the presence of glucose moiety [44]. In an in vitro assay, genipin (50–300 µM) showed dose-dependent potent inhibitory effects on both NO production and iNOS expression in LPS/interferon c (IFN-c)-stimulated RAW 264.7 macrophages. Genipin possibly decreased the NO production through NF-jB inactivation via blocking of IjB-b degradation. Genipin also showed concentration-dependent inhibition of lipid peroxidation induced by Fe2+/ascorbate in rat brain homogenate and exhibited significant

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anti-inflammatory effect through inhibition of croton oil-induced ear edema in mice [45]. Jeon et al. proposed that genipin enhanced its anti-inflammatory effect in the suppression of iNOS and COX-2 enzymes expressions in LPS-induced RAW 264.7 cells by up-regulation of heme oxygenase-1 (HO-1) via an nuclear factor-(erythroid derived-2)-related factor-2 (Nrf2) pathway, in which oxidative stress was not involved. Genipin-induced JNK 1/2-mediated phosphorylation and nuclear translocation of Nrf2. The effect of genipin was reversed on exposure to the PI3-kinase inhibitor, LY294002 or blocking of HO-1 activity [46]. Geniposide (100 mg/kg) showed significant reduction of ankle swelling by 21–34% after 2–5 days of geniposide treatment, compared to that of vehicle control group in ankle sprain model in rats [47]. In an in vitro culture assay, geniposide (25–200 µM) showed significant proliferation of rat hind ankle ligament fibroblasts and collagen synthesis by increasing the collagen content (124.2%) compared to control group. Therefore, geniposide might be a useful candidate in the treatment of ligament injuries [48]. In oral administration of geniposide in rats, geniposide is biotransformed into its aglucone, genipin in the intestine of rats. Therefore, the anti-inflammatory activity of geniposide in animals occurs via its aglucone genipin formation [49]. Geniposide 23 also exhibited anti-inflammatory effects in LPS-stimulated IL-6 and IL-8 production in cultured human umbilical vein endothelial cells (HUVECs) through inhibition of NF-jB activation, degradation of 1jB-a, and phosphorylation of p38MAPK and ERK 1/2 proteins [50]. Geniposide treatment in LPS-stimulated primary mouse mammary epithelial cells showed significant inhibition of the LPS-induced production of cytokines, TNF-a, IL-1b, and IL-6 via inhibition of the expression of toll-like receptor-4 (TLR-4) gene and suppression of phosphorylation of inhibitor of NFkappa B-alpha (IjBa), NF-jB, p38, ERK, and JNK in a dose-dependent manner. Therefore, geniposide could be effective in treatment of inflammation-related mastitis pain [50b]. Lin et al. evaluated anti-inflammatory activity of boschnaloside 176a and 8-epideoxyloganic acid 163a, isolated from Boschniakia rossica and Orobanche caerulescens (Orobanchaceae) on free radical production and b2 integrin expression in human leukocytes, peripheral human neutrophils (PMNs), and mononuclear cells activated by phorbol–12-myristate–13-acetate (PMA) and N-formyl–methionyl– leucyl–phenylalanine (fMLP), respectively. Both these iridoids showed moderate activity in the inhibition of ROS production with IC50 values in the range of 8.9–28.4 µM in PMA-activated PMNs and 19.1–21.1 µM in fMLP-induced mononuclear cells. These iridoids significantly inhibited PMA- and fMLPinduced Mac-1 (a b2 integrin) up-regulation at 50 µM, but not of fMLP-induced intracellular Ca2+ mobilization. These iridoids possibly reduced ROS production through modulation of NOX (NADPH oxidase) activity and/or the radical scavenging effect. These iridoids have no significant cytotoxicity. These iridoids may be suitable anti-inflammatory agents during oxidative stress [51]. North American herb, Castilleja tenuifolia (Orobanchaceae), is frequently used in the treatment of cough, dysentery, and neural, hepatic, and gastrointestinal disorders [52]. The methanolic extract from the aerial parts of the plant showed significant anti-inflammatory effect in TPA-induced mouse ear edema model.

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Iridoids, geniposidic acid 289, aucubin 13 and mussaenoside 20 isolated from this methanolic extract, exhibited significant anti-inflammatory effect in TPA-induced ear edema in mice at a dose of 0.1 mg/ear by showing inhibition of edema by 91.0, 71.5, and 69.0%, respectively, and this effect was comparable to that of positive control indomethacin (83.1% inhibition). Another isolated iridoid, 8-epi-loganin 162, showed weak activity in this assay [53]. Loganin 18 and sweroside 67, major constituents of analgesic herbal medicine, SKLJI, prepared from Lonicera japonica flower buds, showed significant anti-inflammatory and analgesic activities in croton oil-, and arachidonic acid-induced ear edema tests, and acetic acid-induced writhings test in mice and carrageenan-induced paw edema in rats. Both croton oil- and arachidonic acid-induced edema formations increased the expressions of phospholipase A2 (PLA2), PGE2, LTC4, LTB4, and LTD4 via up-regulation of COX-2, 5-LOX, and iNOS. Therefore, these activities of loganin and sweroside were mediated, at least in part, by inhibition of COX-2, 5-LOX, and iNOS expressions [54]. Secoiridoids, oleuropeoside (=oleuropein) 80, and ligstroside 79, isolated from the leaves of Spanish Phillyrea latifolia, showed in vitro anti-inflammatory effect in calcium ionophore-stimulated mouse peritoneal macrophages and human platelets. Both these compounds at the concentration of 100 µM inhibited the release of PGE2 from calcium ionophore A 23187-stimulated mouse peritoneal macrophages with an IC50 value of 47.0 and 48.5 µM, respectively, and their effects were relatively low compared to that of indomethacin (IC50 value of 0.95 µM), while in the same concentration, only ligstroside exhibited the inhibition of TXB2 release from calcium ionophore-induced human platelets with an IC50 value of 122.6 µM. These results indicate that these secoiridoids exert their inhibitory effects preferentially on the COX-1 pathway [55]. Secoiridoid gentiolactone 737 (Fig. 5.1) isolated from Japanese gentian, Gentiana triflora roots, exhibited anti-inflammatory effects by inhibiting the expressions of TNF-a, iNOS, and COX-2 genes in LPS-stimulated RAW 264.7 cells. Gentiolactone inhibited the expressions of these cytokine and enzymes through suppression of NF-jB transcriptional activity without inhibition of IjB degradation [56]. Gentiana lutea is frequently prescribed in herbal medicine in China, Japan, and Korea for treatment of inflammatory skin diseases. In atopic dermatitis patients, the acute skin lesions from defective skin barrier function are caused by impairment of ceramide synthase. In most cases, acute skin lesions are produced from Th-2-driven inflammatory disorders from bacterial and fungal infections, due to secretion of cytokines, such as IL-4, IL-5, IL-13, and IL-31, production of IgE and activation of basophils and mast cells. The ethanolic extract of this plant (GE) and its major isolates, gentiopicroside 69 and amarogentin 81, on treatment in human primary keratinocytes culture, showed significant improvement of human primary keratinocytes (hPKs) on incubation for 2 days. Immunohistochemical staining of the hPKs culture showed that ceramide synthase 3 (CerS3) was increased in GE-treated hPKs. CerS3 activation possibly occurs in GE-treated hPKs through PPARc and/or p38 MAPK signaling because the effect of GE is reduced to background levels by blocking of the p38 MAPK or PPARc pathway. Furthermore, GE and both

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amarogentin and gentiopicroside-induced calcium influx and stimulated in hPKs, the expression of differentiation proteins, such as keratin 10, involucrin, and transglutaminase. These results suggest that the effect of GE is partly mediated by the effects of amarogentin and gentiopicroside. Thus, GE improves the skin lesions, at least in part, through amelioration of impaired epidermal barrier via activation of CerS3 [57]. Swertiamarin 68 isolated from Enicostemma axillare (Gentianaceae) exhibited significant antinociceptive activity in hot plate, tail immersion, and acetic acid-induced writhing tests in mice using paracetamol (100 mg/kg) as positive control. In the hot plate method, treatment of swertiamarin (100 and 200 mg/kg) to mice showed a significant increase in the response time (latency period) after 30 and 45 min of swertiamarin treatment. The observed protection percent after 45 min was 109.42, 147.42, and 157.14% for paracetamol, swertiamarin 100 and 200 mg/kg treated groups, respectively. In the tail immersion test, a significant increase in the tail withdrawal reflex was observed in mice with 150 and 200% protection in swertiamarin (100 and 200 mg/kg)-treated groups, which were higher than that of paracetamol-treated group (138% protection). In the acetic acid-induced writhing test, oral administration of swertiamarin (100 and 200 mg/kg) to mice 30 min prior to the administration of acetic acid reduced the number of writhes to 8.66 ± 0.21 and 7.83 ± 0.60, respectively, compared to the control group of mice (17.83 ± 1.10). This effect was very close to paracetamol-treated group (7.00 ± 0.36 writhes). An acute toxicity study of 68 revealed no clinical signs of toxicity or mortality in doses up to 2000 mg/kg in mice. These findings suggest that swertiamarin possesses both peripheral (in acetic acid-induced writhing test) and central (in hot plate and tail immersion tests) antinociceptive activities. Further research is necessary to evaluate the mechanism of action before clinical application of this secoiridoid [58]. In another study, oral administrations of swertiamarin 68 (100 and 200 mg/kg) to carrageenan-induced edema formation in rats showed significant inhibition of edema volume by 38.60 and 52.50%, respectively, after 5 h of carrageenan induction. The inhibitory activity at higher dose was better than that of positive control diclofenac sodium (100 mg/kg, p.o.; 45.55% inhibition) [59]. Cornuside 262, a bioactive secoiridoid constituent of Corni Fructus, showed significant anti-inflammatory effect in LPS-stimulated RAW 264.7 macrophage cells by suppression of LPS-induced production of nitric oxide (NO), PGE2, TNFa, IL-6, and IL-1b. The mRNA and protein expressions of iNOS and COX-2 enzymes were also decreased by cornuside. Furthermore, cornuside inhibited the nuclear translocation of NF-jB and phosphorylation of IjB-a and activation of MAPKs. Thus, the anti-inflammatory effect of cornuside is related to the down-regulation of iNOS and COX-2 enzymes expressions through inhibition of the activity of NF-jB and negative regulation of ERK 1/2, p38, and JNK 1/2 phosphorylation [60]. In an animal study, intravenous administration of cornuside to cecal ligation and puncture (CLP)-induced sepsis in rats showed significant anti-inflammatory response by reducing lethality and expressions of inflammatory cytokines, TNF-a and IL-6 in myeloid cells and lowering the levels of MPO in lungs, liver, and small intestine [61].

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The roots of Korean Patrinia saniculaefolia have been used in Korean traditional medicine for treatment of inflammation-related disorders such as edema, appendicitis, and abscesses. A valeriana-type iridoid, nordostachin 738 isolated from this plant exhibited significant anti-inflammatory activity in LPS-stimulated RAW 264.7 macrophages. This iridoid (2.5–20 µM) inhibited the production of inflammatory mediators, TNF-a, NO, and PGE2 in a dose-dependent manner with respective IC50 values of 16.2, 12.3, and 20 µM. In addition, this compound decreased the expressions of iNOS and COX-2 enzymes in LPS-induced macrophage cells. The anti-inflammatory activity of the plant could be, at least in part, due to inhibition of TNF-a production and iNOS and COX-2 enzymes expressions [62]. Korean Pseudolysimachion rotundum var. subintegrum (Plantaginaceae) has been used in Korea, China, and European countries for treatment of cough, bronchitis, and asthma. Iridoid, 3b-methoxy-3,4-dihydrocatalposide 536 isolated from this plant, showed significant in vitro anti-inflammatory activity in LPS-stimulated RAW 264.7 macrophage cells by inhibiting the expressions of COX-2 and iNOS enzymes as well as suppression of PGE2 and NO production in a dose-dependent manner. This compound also markedly reduced the LPS-induced elevated expressions of pro-inflammatory genes, IL-6, IL-1b, and TNF-a. Furthermore, the compound 536 inhibited the LPS-induced activation of MAP kinases (ERK, JNK, and p38), NF-jB, and AP-1. The co-treatment of the compound with BAY11-7082 (a NF-jB inhibitor), PD 98059 (a specific ERK-MAPK inhibitor), SP 600125 (a specific JNK-MAPK inhibitor), or SB 203580 (a specific p38-MAPK inhibitor) reversed the activity of the compound in iNOS expression. Similarly, co-treatment of 536 with SP 600125 or SB 203580 reduced the activity in down-regulation of COX-2 expression compared to treatment of compound alone. These findings indicate that the iridoid 536 exerts its anti-inflammatory effects through the blocking of the activities of three MAP kinases, and thereby inhibiting the activities of their transcription factors (NF-jB and AP-1) and related target genes. This iridoid could be a promising candidate to treat inflammatory-related disorders [63]. Catalposide 182, a major constituent of Catalpa ovata, exhibited significant anti-inflammatory effects in inhibition of the production of pro-inflammatory cytokines, TNF-a, IL-1b, and IL-6 and activation of NF-jB in LPS-stimulated RAW 264.7 macrophages. Suppression of the expressions of the inflammatory cytokines and nuclear translocation of p65 subunit of NF-jB probably occur via suppression of LPS binding to LPS receptors of the macrophage membrane by catalposide. LPS, an endotoxin, is the outer membrane component of Gram-negative bacteria, which has a key role in the pathogenesis of endotoxin shock in septic syndrome. Therefore, catalposide could be an effective candidate for adjunctive therapy in Gram-negative bacteria-induced sepsis [64]. The aqueous extract of Tibetan Duyiwei, Lamiophlomis rotata in the form of pills and capsules, is prescribed for treatment of cancer, bone fracture, and neuropathic pain in China. Study in experimental pain models in mice and rats indicated that the aqueous extract of the plant reduced the nociceptive pain responses in the mouse hot plate and acetic acid tests, while the iridoid glycosides fraction of the extract only blocked acetic acid-induced writhing response and formalin-induced

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tonic hyperalgesia (peripheral pain) in mice. The aqueous extract was also found to block formalin-induced tonic hyperalgesia and peripheral nerve injury and bone cancer-induced mechanical allodynia (central pain) by 50–80%, with half-effective doses of 130–250 mg/kg in mice and rats. The herb was not effective in alleviating acute nociceptive pain. The study of the mechanism of antinociception revealed that both the aqueous extract of the plant and its two major isolates, shanzhiside methyl ester 103 and 8-O-acetyl shanzhiside methyl ester (=barlerin) 105, inhibited pain hyperactivity by activation of spinal glucagon type peptide-1 receptors (GLP-1Rs) in both rat and human. The antinociceptive effects of the extract and its isolates, 103 and 105, were blocked by co-administration with exendin (9–39), an antagonist of GLP-1R in mice and rats. In the cellular level, both these iridoid glucosides showed significant protective effects against H2O2-induced oxidative damage in rat PC12 cells and human embryonic kidney 293 (HEK293) cells via GLP-1R activation. The activity of compounds 103 and 105 was very similar to that of spinal GLP-1R peptidic agonist, exenatide. These findings suggest that GLP-1Rs may be potential target molecules for treatment of chronic pain [65]. Plumericin 60 from Amazonian Himatanthus sucuuba inhibited the activity of NF-jB in TNF-a-induced inflammation in HEK 293 luciferase cells with an IC50 value of 1.0 µM. Its inhibitory effect was higher than that of NF-jB inhibitor, parthenolide (IC50, 1.5 µM) used as positive control. The other three structurally related iridoid lactones, plumieridin 155, allamandicin 136 and plumeridoid C 739 isolated from the same plant did not exhibit this inhibitory effect up to tested concentration of 30 µM. Plumericin also suppressed the expressions of VCAM-1, ICAM-1, and E-selectin in TNF-a-induced HUVEC tert cells in a dose-dependent manner. Further study indicated that plumericin at a concentration of 10 µM completely abolished the TNF-a induced activation of IKK and activity of IKK-b in HUVEC cells. Thus, plumericin inhibited the activity of transcription factor NF-jB protein complex through inhibition of the activity of IKK. In animal model, plumericin (3 mg/kg) treatment in thioglycollate-induced peritonitis mice inhibited neutrophil recruitment and this effect was comparable to that of parthenolide in intra-tracheal LPS challenge in mice at similar concentrations. These findings suggest that plumericin could be a lead chemical scaffold for development of new anti-inflammatory drugs [66]. Rehmaglutin B 487 isolated from tropical American Russelia equisetiformis exhibited moderate in vitro anti-inflammatory activity in NO production from LPS-induced murine RAW 264.7 cells with an IC50 value of 52.8 ± 2.0 µM, and this activity was better than that of positive control, NG-monomethyl-L-arginine (L-NMMA). Structurally related compound, rehmaglutin D 488 did not exhibit any inhibitory effect [67].

5.2.2

Anti-arthritic Activity

Arthritis, a common chronic, progressive and disabling autoimmune disease, causes inflammation and pain in the joint tissues around the bone joints (usually in the

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neck, shoulder, thigh, and knee) in humans [68]. Inflammation in the synovial joint in between jointed bones results its thickening due to proliferation of synovial cells and infiltration of leukocytes. This proliferative mass, known as pannus, destroys articular cartilage and bone leading to destruction of connective tissue in joint structure and function. The proliferation of the synovial cells and formation of pannus are the key factors for the destruction of connective tissue and subchondral bone in arthritis [69]. Transgenic mice expressing human TNF-a is the most predictive genetic model for arthritis study [69]. Aqueous and ethanolic extracts from the tuberous roots of H. procumbens (Hp) have been reported to possess significant anti-arthritis property in both animals and humans. Oral administration of the ethanolic extract of Hp tuberous roots to adjuvant-induced arthritis in rats in both acute and chronic phases of arthritis showed significant anti-inflammatory and peripheral analgesic properties in rats. In acute phase, the Hp extract (25, 50, or 100 mg/kg/day) was administered successively to rats for 3 days from day 6 of adjuvant application, and in chronic phase, the Hp extract (100 mg/kg/day) was administered successively to rats for 17 day from 24th day of adjuvant application. The results showed that the extract increased the latency of paw withdrawal in hot plate assay in rats in both phases. The extract also showed significant reduction of right paw edema in the experimental groups, compared to control group [70]. In another animal study, successive oral administration of 50% ethanolic extract of Hp roots (50 mg/kg/day) for 3 weeks to adjuvant-induced chronic arthritis in rats showed significant anti-arthritis activity by reducing the swelling and pain in rats. Harpagoside 499, a major iridoid constituent of Hp extract was found to suppress the production of pro-inflammatory cytokines, IL-6, IL-1b, and TNF-a in LPS-induced mouse macrophage RAW 264.7 cells. Possibly, harpagoside is responsible to exhibit the anti-arthritis efficacy of the Hp extract [71]. In humans, daily intake of the ethanolic extract of Hp roots containing about 50 mg of harpagoside by osteoarthritic patients (n = 75) suffering from pain in low-back, knee, and hip, for 4 weeks, significantly relieved from pain [72]. In another study in humans, daily oral intake of aqueous Hp roots extract in tablets (2.4 g/day, containing about 50 mg of harpagoside) by the patients suffering from hip and knee arthritis for 12 weeks showed markedly improved the relief of pain (about 46%) and other symptoms of osteoarthritis [73]. Daily intake of harpagoside (about 60 mg as a form of Doloteffin trade mark, a standardized devil’s claw extract) by knee osteoarthritis patients up to 54 weeks, showed significant improvement in osteoarthritis [74]. Several groups reported the molecular targets of anti-arthritis action of Hp extract and its major isolate, harpagoside. Fiebich et al. reported that the ethanolic extract of Hp roots prevented the expressions of inflammatory cytokines, TNF-a, IL-6, and IL-1b mRNA in LPS-stimulated human monocytes and COX-2 in LPS-stimulated RAW 264.7 cells through inhibition of LPS-stimulated activity of AP-1 and its binding to response elements [75]. Kim and Park [76] suggested that harpagoside 499, major constituent of Hp extract, activated peroxisome proliferator-activated receptor (PPAR)-c in differential 3T3-L1 cells, leading to the reduction of TNF-a induced mRNA synthesis and protein production of inflammatory cytokines and chemokines such as IL-6, MCP-1, and plasminogen

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activator inhibitor-1 (PAI-1) to ameliorate the severity of arthritis. Schopohi et al. reported that both harpagoside and harpagide 12 in Hp extract decreased TNF-a secretion and ICAM-1 and VCAM-1 mRNA expression in IFN-c/LPS-stimulated human acute monocytic leukemia THP-1 cells. Possibly, reduction of TNF-a, ICAM-1, and VCAM-1 levels prevented the cellular migration of leukocytes to the inflamed tissue to ameliorate the development of arthritis [77]. Human leukocyte elastase plays an important role in digesting bacteria and phagocyte immune complexes. It is migrated from blood to tissue for the repair of connective tissue injury. Its increased expression in chronic inflammatory process causes destruction of cartilage tissue and other matrix proteins. Elastase inhibitors could be an alternative target to treat rheumatic/arthritic disorders [78]. Iridoids, 8-p-coumaroylharpagide 500 and pagoside 503 isolated from the roots of H. procumbens inhibited the elastase activity with IC50 values of 179 µg/ml (331 µM) and 154 µg/ml (260 µM), respectively, which was comparable to that of positive control, caffeic acid (IC50, 475 µM) [79]. Ajuga decumbens (Ad) has long been used for the relief of joint pain, gout, and chronic pelvic inflammation in Iran, Japan, and China. An oral administration of ethanolic Ad extract alone or in combination with glucosamine hydrochloride to experimentally induced osteoarthritis in rabbits for 4–8 weeks significantly enhanced the regeneration of cartilaginous matrix and subchondrial bone in rabbits, and this effect was similar to that of ecdysteroid b-ecdysone [80]. In humans, an oral intake of Ad extract-as diet supplement by knee osteoarthritis subjects (n = 22) for 12 weeks significantly improved the knee-pain and stiffness. Study of molecular targets of anti-osteoarthritic action of the extract indicates that the extract significantly increases the level of procollagen II C-terminal propeptide (PIICP) and reduces the level of matrix metalloproteinase-13 (MMP-13), a biomarker of collagen-degrading enzyme to promote the repair of damaged cartilage tissue in knee joints. Therefore, the Ad extract could be a promising candidate as a functional food for beneficial effect of bone joints health [81]. 8-O-Acetylharpagide 12a and harpagide 12 present in the Ad extract have been reported to possess anti-inflammatory effects. So, further study on this extract is necessary to evaluate the bioactive principles responsible for this anti-arthritis efficacy. Geniposide 23, a major constituent of G. jasminoides fruits, exhibited significant anti-arthritis activity in adjuvant-induced arthritic rats. Treatment of geniposide (60 and 120 mg/kg, i.g.) to adjuvant-induced arthritis (AA)-in rats for 7 days from day 18 to 24 after immunization, significantly suppressed the hind paw swelling and arthritis index, similar to that of anti-arthritis drug, total glycoside mixture of paeony (50 mg/kg). Histopathological study of mesenteric lymph node (MLN) indicates that geniposide exhibits improvement of immune balance by decreasing the level of Th 17 cells cytokines and increasing Treg-cell cytokines level in mesenteric lymph node lymphocytes (MLNLs) and peripheral blood lymphocytes (PBLs). In addition, it decreases the expression of phosphorylated-c-Jun-N-terminal kinase (p-JNK) proteins in MLNL and PBL of AA rats. Reduction of Th 17 cells cytokines down-regulates the expression of inflammatory IL-17 and IL-6 genes and up-regulates the expression of Treg cytokines to increase the expression of TGF-b

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for inhibition of JNK phosphorylation. It has been reported that the JNK signaling in MLNL and PBL played a key role in the pathogenesis of RA. Thus, geniposide attenuated the arthritis in rats through induction of Th 17 cell immune tolerance and down-regulation of p-JNK expression [82]. Wu et al. repeated this study in AA rats to explore the molecular target of action of geniposide 23 in amelioration of severity of arthritis and the pharmacokinetics (PK) of geniposide in rats using the same experimental parameters. The Western blotting of fibroblast-like synoviocytes (FLSs) of AA rats revealed that geniposide promoted the recovery from arthritis and inhibited the colonic inflammation by decreasing the elevated expressions of TNF-a, IL-1b, and IL-6, and increasing the production of IL-10 to down-regulate the expression of p-p38 MAPK-related proteins, p-MKK 3/6, p-p38, and p-MAPK AP-2 in FLSs. Emerging evidence reveals that p-p38 MAPK protein is a key regulator of several pro-inflammatory cytokines in inflammation. The pharmacokinetic study showed that the plasma geniposide concentration in area under drug concentration over time curve (AUC), Cmax and t1/2 of geniposide increased linearly with dosage and was related to its efficacy index. The optimum concentration of geniposide in different animal models and the frequency of dosage are to be evaluated before its clinical trial for treatment of RA [83]. Geniposidic acid 289, a major constituent of Genipa americana, on oral administration (100 and 200 mg/kg/day) for 4 weeks to AA rats, showed significant decrease of paw swelling, arthritis index and levels of inflammatory genes, TNF-a, and IL-1b in AA rats. In an in vitro assay, treatment of geniposidic acid (1–4 µM) in synoviocytes (collected from the synovial of AA rats) culture showed dose-dependent apoptosis of synoviocytes (15.8, 24.3, and 40.7% at 1, 2, and 4 µM treatment, respectively). Study of the molecular target of geniposide in the apoptosis of synoviocytes indicates that it occurs via down-regulation of Bcl-2 and up-regulation of Bax proteins [84]. The flowers of Gentiana macrophylla (GM) have been used in Chinese traditional medicine to cure joint inflammation and rheumatoid arthritis (RA). Oral administration of the GM flowers extract (15 and 30 mg/kg/day, i.g.) for 28 day to collagen-induced arthritic (CA) rats showed significant dose-dependent reduction of paw edema, arthritis scores, and index of spleen and thymus in CA rats compared to the control group. The effect of the higher dose was comparable to that of positive control, dexamethasone. The histopathological assay of the serum samples of joint synovial tissues indicates that the GM extract ameliorates the severity of arthritis by reducing the levels of TNF-a, IL-1b, IL-6, COX-2, and iNOS expressions through inhibition of NF-jB signaling in the effected tissues. The HPLC analysis of the extract indicated the presence of four major iridoids, loganic acid (15%), swertiamarin (9.9%), gentiopicroside (41.5%), and sweroside (13%). Possibly, these iridoids are responsible for this efficacy of the GM extract [85]. In an in vitro assay, swertiamarin 68 (10–50 µg/ml) in IL-1b-induced culture of fibroblast-like synoviocytes, isolated from AA rats, showed significant and dose-dependent down-regulation of pro-inflammatory genes (TNF-a, IL-6, PGE2, COX-2, iNOS, and MMPs) and osteoclastogenic mediator (RANKL) at both the mRNA and protein levels. In addition to these anti-inflammatory and anti-arthritic

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effects, it inhibited the level of p38 MAPK in a dose-dependent manner. Thus, swertiamarin could be an effective drug in treatment of arthritis [86]. In an animal model, swertiamarin 68, isolated from Asian E. axillare, on oral administration (5 and 10 mg/kg/day) for 14 days to AA rats, significantly and dose-dependently inhibited the paw edema and decreased the arthritis scores in rats. Histopathological analysis of molecular action revealed that swertiamarin treatment decreased the release of pro-inflammatory cytokines, IL-1b, TNF-a, and IL-6 and pro-angiogenic enzymes, MMP-9, iNOS, PGE2, PPAR-c, and COX-2, and significantly increased the levels of anti-inflammatory genes, IL-10 and IL-4 in the serum of synovial tissues compared to disease group of rats. Several accumulating evidence indicates that the cytokines, IL-10 and IL-4 are effective in protection of cartilage degradation in AA rats. In addition, swertiamarin significantly inhibited the release of NF-jB p65, p-IjB-a, p-JAK 2, and p-STAT 3 signaling proteins levels in both AA rats and LPS-induced RAW 264.7 macrophage cells. The docking analysis of swertiamarin with target proteins (COX-2, iNOS, PGE2, MMP-9, JNK-2, STAT-3, NF-jB p65, and IjB-a) indicated their good hydrophobic interactions and docked well with NF-jB p65 protein and its residue IjB with low binding energy of −3.51 and −1.58 kcal/mol, respectively. Similarly, this secoiridoid glucoside docked well with JAK-2 and STAT-3 proteins with binding energy of −5.52 and −6.14 kcal/mol, respectively. Thus, swertiamarin possibly inhibited the development of arthritis in rats through modulation of NF-jB/IjB and JAK-2/STAT-3 signaling [87]. Kutkin, an inseparable mixture of iridoid glucosides, picroside I 532 and kutkoside 15, isolated from Indian Picrorhiza kurroa, on oral administration (50, 100, and 200 mg/kg) for 14 days in AA rats and mice, showed significant dose-dependent anti-arthritic effects, 32–51% in rats and 18–70% in mice. Oral administration of kutkin at the same doses in formaldehyde-induced arthritis in rats also dose-dependently ameliorated arthritis by 13–43% in the treated rats. Kutkin on oral administration to both mice and rats in the dose range of 100–2000 mg/kg showed no symptoms of toxicity up to 72 h of treatment. Therefore, kutkin could be an effective drug for treatment of arthritis [88]. Agnuside 17, a major iridoid glucoside of Vitex negundo and other Vitex species, on oral administration (6.25 and 12.5 mg/kg/day) for 21 days to adjuvant-induced polyarthritis in rats, showed significant anti-arthritic activity by reducing the exudates volume and erythrocyte sedimentation rate without developing gastric ulceration and loss in weight in rats. The anti-arthritic effects of agnuside at the higher dose were very close to that of positive control, ibuprofen (50 mg/kg), except gastric perforation. The anti-arthritic activity of agnuside was associated with significant suppression of the expressions of inflammatory mediators, PGE2, LTB4, IL-2, IFN-c, and TNF-a, and up-regulation of the expressions of anti-inflammatory cytokines, IL-4 and IL-10. At the same doses, agnuside administration in carrageenan-induced normal and adrenalectomized rats, histamine and dextran-induced edema in rats, showed significant anti-inflammatory responses by reducing the edema volume through inhibition of vascular permeability and leukocyte migration. Agnuside at an oral dose of 2000 mg/kg in mice over a period of 14 days showed no symptoms of toxicity. Therefore, agnuside might be a prospective drug for treatment of arthritis [89].

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5.2.3

161

Hepatoprotective Activity

Oxidative stress, chronic liver inflammation from viral and chemical toxicity, and accumulation of fats in liver from insulin resistance are the key factors for liver diseases. Several pro-inflammatory cytokines such as TNF-a, IL-1b, and IL-6 and endothelial growth factors are over-expressed by liver kupffer cells in the inflammation site, which in turn initiate inflammation cascade to produce TGF-b1 and other growth factors and chemokines for remedial measure. The growth factor TGF-b1 induces the activation of hepatic stellate cells for transformation into myofibroblasts, which initiate apoptosis of hepatocytes in liver tissues. The pro-inflammatory genes, TNF-a, IL-1b, IL-6, IL-8, and IL-17 are considered as key players to elevate obesity and fat-related inflammation in liver [90]. P. kurroa, locally known as kutki, a perennial herb of Northern Himalayan region in India, is extensively used in Indian traditional medicines for treatment of different types of liver disorders. A crystalline product, known as ‘kutkin’ or ‘picroliv,’ isolated from the rhizomes of this plant, is a mixture of two major iridoid glucosides, picroside I 532 and kutkoside 15 in a ratio of 1:2, along with other minor iridoids and terpenoid constituents [91]. Oral treatment of picroliv (6, 12 and 25 mg/kg/day) for 7 days to 9 weeks to galactosamine hydrochloride/paracetamol/ thioacetamide/carbon tetrachloride/lanthanum chloride/cadmium chloride/alkaloid monocrotaline/ethyl alcohol/Plasmodium berghei infection-induced hepatic injury in rats showed significant hepatoprotective effects. In each of these experiments, the hepatoprotective efficacy of picroliv was assessed from determination of the levels of serum hepatic biomarker enzymes, SGOT, SGPT, and ALP as well as the levels of total cholesterol (TC), triglycerides (TG), albumin content, and bilirubin of liver tissues. In most of these experiments, picroliv significantly ameliorated the necrosis and vascular damage in liver tissues, and reduced the elevated levels of serum SGOT, SGPT, ALP, TC, TG, albumin, and bilirubin contents. In addition, it reduced the lipid peroxidation by increasing the levels of liver tissue membrane bound Na+/K+ ATPase, catalase, GSH, glucose 6-phosphate dehydrogenase (G6PD), succinate dehydrogenase, and SH proteins of liver tissues. These effects of picroliv at higher dose were comparable to that of silymarin (50 mg/kg) used as positive control. Therefore, picroliv might be a prospective candidate for development of hepatoprotective drugs. Several herbal preparations for liver ailments using picroliv as major constituent are available in India and other Asian countries [92–100a]. Most of these studies are based on antioxidant efficacy of picroliv. Future study on molecular target of action of picroliv is sought for its clinical trials in treatment of liver disorders. Swertiamarin 68, a major constituent of Tibetan hepatoprotective herb, Swertia mussotii, on oral treatment (100 and 200 mg/kg/day, i.g.) for 8 weeks in CCl4induced liver injury in rats, showed significant amelioration of liver injury and inflammation via improvement of antioxidant status and induction of hepatic detoxifying enzymes in rats. Swertiamarin significantly protected the injured liver in rats by reducing the elevated levels of serum ALT, AST, and ALP compared to

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control, CCl4-treated group. In addition, it decreased the lipid peroxidation by lowering the levels of MDA and inflammation through down-regulation of the expressions of inflammatory genes, TNF-a, IL-1b, IL-6, and iNOS in the liver tissues. Furthermore, swertiamarin up-regulated the expressions of detoxifying enzymes, CYP2E1 and CYP3A, and the levels of efflux proteins, multidrug resistance-associated proteins-3 (Mrp-3), Mrp-4, HO-1, and NAD(P)H-quinone oxidoreductase-1 (NQO-1) and other antioxidant enzymes, SOD, CAT, GPx, and GSH for detoxification of injured liver tissues [101]. Chen et al. [102] also reported the hepatoprotective activity of swertiamarin 68 in CCl4-induced hepatic injury in rats applying the same dosage of 100 and 200 mg/kg for a period of 8 weeks. Their study on molecular analysis of action reveals that swertiamarin exerts its hepatoprotective activity through down-regulation of the expressions of TGF-b1 and extracellular matrix (ECM) proteins, collagen I and collagen II via reduction of p-Smad 2 and p-Smad 3 proteins expressions. In another study, Jaishree and Badami reported that swertiamarin, a major constituent of E. axillare, on oral treatment (100 and 200 mg/kg) for 8 days in D-galactosamine-induced liver injury in rats, showed significant hepatoprotective activity through restoration of all altered biochemical parameters toward normal in the liver tissues in rats [103]. Swertiamarin 68, secoxyloganic acid (=secologanoside) 330, and an ester of swertiamarin and secoxyloganic acid 740, isolated from Centaurium spicatum, exhibited strong hepatoprotective activity in concanavalin A-induced liver damage in mice at the tested dose of 100 mg/kg, i.g. through reduction of serum elevated SGOT and SGPT levels by 81–96% toward normal values in mice liver tissues. The hepatoprotective activity of these secoiridoids was better than that of hepatoprotective drug, silymarin (50 mg/kg) [104]. Oleuropein 80, a major constituent of olive oil, on both pre- and post-treatments (100 and 200 mg/kg, i.p.) for 3 days in pretreatment and 2 days in post-treatment to CCl4-induced liver injury in mice, showed significant hepatoprotective effect by attenuating oxidative/nitrosative stress and inflammatory response in liver tissues of mice. Oleuropein reduced the oxidative and nitrosative stresses by improving the levels of plasma SOD and GSH and lowering the level of plasma nitrotyrosine. It prevented apoptosis of hepatocytes through inhibition of TGF-b1-induced activation of hepatic stellate cells and caspase-3 via induction of heme oxygenase-1 proteins. It also reduced the inflammatory response in liver tissues through down-regulation of the expressions of plasma TNF-a gene, COX-2 and iNOS proteins, the biomarkers of liver damage [105]. In another study, oleuropein prevented the development of hepatic fibrosis in high-fat diet (HFD)-non-alcoholic steatohepatitis (NASH)-mice. Treatment of oleuropein (0.05%)-supplemented with HFD to NASH mice for 6 months significantly prevented the hepatic fibrosis in mice. The prevention of hepatic fibrosis was associated with the lowering of the elevated levels of plasma TC, TG, AST, ALT, and collagen-type I and alpha smooth muscle actin (a-SMA) proteins in the liver tissues of NASH mice [106]. Therefore, consumption of oleuropein as diet supplement is beneficial for liver health.

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Loganin 18, a major constituent of C. Fructus, exhibited significant hepatoprotective and renal protective effects in type 2 diabetic db/db mice. Oral administration of loganin (20 and 100 mg/kg/day) for 8 weeks to diabetic db/db mice significantly ameliorated hyperglycemia and dyslipidemia in both serum and hepatic tissues of mice through reduction of serum glucose, TC, and TG levels. Loganin reduced the enhanced oxidative stress by decreasing thiobarbituric acid-reactive substances (TBARS) in both liver and kidney, and reactive oxygen species (ROS) in serum, liver, and kidney. Loganin exerted lipid regulatory effects in the liver via suppression of mRNA expressions of acetyl CoA carboxylase (ACC), fatty acid synthase (FAS), and 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR), related to lipid synthesis; down-regulation of the expressions of AGE-related proteins, RAGE, CML, and CEL to reduce inflammation. Loganin also exerted increased expressions of peroxisome proliferator-activated receptoralpha (PPAR-a) and reduced expression of sterol regulatory-element-binding proteins (SREBP1/2) in the nucleus of the hepatocytes. Furthermore, loganin suppressed the elevated expressions of NF-jB, COX-2, and iNOS proteins in hepatic tissues. Thus, loganin exhibits protective effects against hepatic injury and other diabetic complications via lipid regulations and amelioration of AGE-related inflammation [107a]. In another study, oral administration of loganin (100 mg/kg/ day) for 8 weeks to diabetic db/db mice significantly ameliorated the hepatic injury in mice by reducing the hepatic oxidative stress through lowering the elevated levels of hepatic ROS and TBARS toward normal and down-regulating the elevated expressions of hepatic NOX-4 and its regulatory partner p22 phox proteins in hepatic tissue. Accumulating evidence indicated that NADPH oxidase, NOX-4 and its partner p22-phox proteins are actively involved for activation of hepatic stellate cells (HSCs) via a TGFb-Smad2/3-dependent pathway for hepatic fibrosis and hepatocyte apoptosis. Furthermore, loganin reduced hyperglycemia-induced oxidative stress by down-regulation of the expressions of inflammatory mediators, MCP-1, ICAM-1, Nrf-2, HO-1, COX-2, iNOS, and NF-jB in the liver of mice. Loganin also protected the hepatocytes from apoptosis by blocking of cytochrome c release through induction of Bcl-2 proteins and down-regulation of Bax proteins. Thus, loganin ameliorated the hepatic injury through down-regulation of the expressions of oxidative stress-related proteins and ROS in liver [107b]. Morroniside 70, another bioactive constituent of C. Fructus, on oral administration (20 and 100 mg/kg/day) for 8 weeks to type 2 diabetic db/db mice, showed significant hepatoprotective effects in mice through reduction of elevated levels of serum glucose, ALT, AST, ROS, Nrf 2, HO-1, and TBARS. Moreover, morroniside at the higher dose significantly reduced the levels of NF-jB, COX-2, iNOS, MCP-1, and ICAM-1 proteins expressions and down-regulated the expressions of hepatocyte apoptosis-related proteins, Bax and cytochrome c in liver. Thus, morroniside ameliorated diabetic hepatic complications in mice via regulation of oxidative stress, inflammation, and cell apoptosis [108]. Therefore, consumption of C. Fructus as diet supplement is beneficial for prevention of hepatic disorders. Iridoid glycosides (IG) fraction extract rich in paederoside 594 and paederosidic acid 604, isolated from Paederia scandens var. tomentosa, on oral administration

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(10 ml/kg) to CCl4-induced liver injury in rats for 15 days, showed significant hepatoprotective activity via decreasing the oxidative stress in liver tissues in rats. The treatment of IG fraction significantly decreased the levels of MDA, AST, and ALT and increased the levels of GSH, CAT, and SOD, compared to those in control group of rats [109]. Negundoside 698, a major iridoid constituent of V. negundo and other Vitex species, exhibited hepatoprotective effect against CCl4-induced toxicity in cultured human hepatoma HuH-7 cells. The study of molecular target of hepatoprotection revealed that negundoside exerted a protective effect on cytochrome P450 2E1 (CYP2E1)-dependent CCl4-toxicity in HuH-7 cells via reduction of ROS generation, lipid peroxidation, and elevation of the levels of intracellular Ca2+ ions and maintenance of intracellular glutathione homeostasis. The hepatoprotective effect of negundoside against hepatoma HuH-7 cancer cell line at the dose of 100 µg/ml was better than that of silymarin treatment. Furthermore, it inhibited the activity of Ca2+dependent proteases by increasing MMP for protection from caspase-dependent apoptotic cell death [110a]. In animal model experiments, oral treatment of negundoside (20–200 mg/kg) to CCl4 and galactosamine-induced hepatic damage in rats showed significant dose-dependent hepatoprotective effects by reducing the elevated levels of serum ALP, AST, SGOT, bilirubin, TG, and MDA and improving the GSH levels in liver tissues. The hepatoprotective effect of negundoside at higher dose (200 mg/kg) in amelioration of hepatic injury (necrosis) was very similar to that of silymarin (100 mg/kg) treated rats [100b]. Rehmachingiioside F 767, catalpol 14 and ajugol 11, isolated from Chinese Rehmannia chingii showed moderate hepatoprotective effects against N-acetyl-paminophenol (APAP)-induced toxicity in HepG2 cells with cell survival rate in the range of 65.9–69.9% at 10 µM, comparable to that of positive control, bicyclol (66.5% cell survival at the same concentration) [110c].

5.2.4

Neuroprotective Activity

The neurodegenerative Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the greatest challenges of basic science and clinical medicine because of their prevalence, cost, and lack of gene-specific treatments. These diseases have great impacts on the society at large. It has been reported that over four millions of people suffer from AD in the USA and another million have PD. At the age of 85 and above, nearly 50% of people suffer from at least one symptom or sign of Parkinsonism [111]. Mitochondrial dysfunction has a key role in the pathogenesis of these diseases. Mitochondrial dysfunction in these diseases usually occurs from mitochondrial DNA defects. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in mice is the most commonly used animal model for the study of antineurotoxicity of drugs on dopaminergic neurons. It selectively injures the nigrostriatal system. MPTP is metabolized by monoamine oxidase B (MAO-B) to MPP+ (1-methyl-4-phenyl pyridinium ion), which is then taken up by

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dopaminergic neurons via dopaminergic transporter protein and inhibits the activity of mitochondrial complex I (NADH-ubiquinone reductase) of the electron transport chain, leading to the reduction in mitochondrial ATP production. Several evidence from in vitro and in vivo studies indicate that the MPP+ exerts oxidative stress via production of reactive oxygen species (ROS) in neuroblastoma cells. The mitochondrial dysfunction in PD is based on the lowering of the activity of complex I in the substantia nigra from an excessive production of ROS, such as superoxide anion, hydroxyl radical, and H2O2. These ROS damage cellular macromolecules to cause cell necrosis or apoptosis. Antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) play pivotal roles in prevention of cellular damage caused by ROS [111]. In idiopathic PD, about 30–40% decrease in activity of mitochondrial complex I occurs in substantia nigra. It causes a large increase of glutamate-mediated activation of iNOS and formation of ONOO− and ultimately leads to cell death by necrosis or apoptosis. In AD, the decrease in cytochrome oxidase activity occurs from excessive oxidative stress. Creatine and phosphocreatine have important roles to generate ATP in brain through maintenance of mitochondrial membrane potential by Na+–K+ ATPase. Therefore, cytochrome c release from mitochondria or free radical scavengers could be a good approach for treatment of both PD and AD. The molecular hallmark of PD is the extracellular aggregation of a-synuclein as Lewy bodies in the substantia nigra from the loss of dopamine and in AD, the extracellular deposition of amyloid b-proteins (Ab) as senile plaque in the gray matter of brain and intracellular deposition of neurofibrillary tangles (NFT) from accumulation of tau proteins in microglia. The proteases, insulin-degrading enzyme (IDE), neprilysin (NEP), and beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) play significant roles in degradation of Ab-proteins and formation of senile plaque. In brain, the glial cells, such as microglia and astrocytes, are the main sources of IDE secretion and their dysfunction contributes to AD pathology. These glial cells are also primary phagocytes in brain for removal of Ab-proteins through phagocytosis [112]. Rehmannia glutinosa has long been used in Chinese traditional medicine for treatment of age-related diseases. Catalpol 14, a major constituent of the roots of this plant, on pretreatment (0.05–0.5 mM) in MPP+-induced culture of mesencephalic neurons of mice, showed significant dose-dependent neuroprotective effect by increasing the neural viability through improvement of the activity of complex I and mitochondrial membrane potential via reduction of the level of lipid peroxidation and increasing the levels of SOD and GSH [113]. In another in vitro assay, catalpol protected the dopaminergic neurons against LPS-induced neurotoxicity in mesencephalic neuron glia culture. Pretreatment of catalpol (0.05–0.5 mM) in LPS-stimulated mesencephalic neuron glia culture, dose-dependently protected the neurons by reduction of the levels of ROS, TNF-a, and iNOS through suppression of microglial activation [114]. Catalpol was found to protect mesencephalic neurons against MPTP-induced neurotoxicity in mice astrocyte enriched mesencephalic neurons culture, via attenuation of mitochondrial dysfunction and MAO-B activity. Catalpol decreased the activity of MAO-B by improving mitochondrial membrane potential (MMP) and activity of complex I via reduction of the levels of ROS and

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intracellular Ca2+ in the neurons of mice brain [115]. Pretreatment of catalpol (0.5 mM) in H2O2-induced toxicated mice astrocyte culture significantly increased the cell viability by reducing the level of intracellular ROS and increasing the activities of antioxidant enzymes in glutathione redox cycling such as glutathione peroxidase (GPx), glutathione (RSH), and glutathione content. Therefore, the reduction of ROS and improvement of glutathione redox cycling may be one of main protection mechanisms of catalpol in astrocytes [116]. In mimic PD model, pretreatment of catalpol (0.1–10 µM) in LPS-induced PC-12 cells culture showed significant protection of the cells by stimulating the expression of Bcl-2 proteins and reducing the expression of Bax proteins. In addition, catalpol protected the neural cells from apoptosis by decreasing the intracellular Ca2+ concentration and down-regulating the expression of Ca2+-calmodulin-dependent protein kinase II (CaMKII) via blocking of the apoptosis signal-regulating kinase I (ASK-1)p38MAPK signaling cascade. Thus, catalpol protected the PC-12 cells from apoptosis via inactivation of ASK-1 [117]. In an animal model, oral administration of catalpol (15 and 50 mg/kg/day) for 8 weeks in chronic MPTP-toxicated mice showed significant neuroprotection through improvement of tyrosine hydroxylase (TH) neuron number in substantia nigra pars compacta (SNpc), striatal dopamine transporter (DAT) density and striatal glial cell line-derived neurotrophic factor (GDNF) proteins level. In an in vitro assay, catalpol treatment in MPP+-toxicated mesencephalic neuron cells culture showed dose-dependent protective effect on mesencephalic neurons by up-regulation of GDNF mRNA proteins, about double of control group. Therefore, neuroprotective effect of catalpol in MPP+-toxicated neurons is attenuated, at least partially, through elevation of striatal GDNF proteins’ expression [118]. It has been reported that GDNF proteins promote the survival and maintenance of dopaminergic (DA) neurons in substantia nigra during development and adulthood. Both DA neurons and astrocytes express mRNA and proteins of GDNF and its receptor GFR-a1 or tyrosine kinase receptor (RET) for protection of neurons in brain from injury. Due to neurotoxin MPP+ insult in mice, GDNF receptor gene is partially deleted and consequently in the new generation of aged mice, the spontaneous locomotion activity and striatal TH-positive neurons density are reduced to some extent compared to wild type of aged mice. Therefore, MPTP has an important role in locomotion dysfunction in aged mice through deletion of GDNF receptor genes and their ligand [119]. Thus, catalpol might be a prospective drug for treatment of PD. Catalpol 14 was also found to be effective in the treatment of AD. Catalpol on oral administration (20 mg/kg/day) for 30 days in D-galactose-induced AD in aged mice showed significant protection of neural function in the cerebral cortex of the hippocampus in mice by reducing the level of oxidative stress through up-regulation of the expressions of SOD, GSH-Px, and CAT, and reducing the formation of senile plaques, Ab40 and Ab42 in the cerebral cortex of hippocampus in mice. Catalpol reduced the formation of senile plaques via up-regulation of insulin-degrading enzyme (IDE). In addition, catalpol improved the spatial learning and memory impairment in mice, as evident in performance in Morris water maze test and in crossing the hidden platform test as compared to AD group of mice

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[120]. In another study, oral administration of catalpol (5 and 10 mg/kg/day) in dgalactose-toxicated AD mice for 2 weeks showed significant amelioration of cognitive deficit through improvement of the activities of endogenous antioxidant and other enzymes, such as glutamine synthase (GS), GSH, SOD, GSH-Px, Na+/K+ATPase, Ca2+/Mg2+-ATPase, and LDH in brain cortex and hippocampus, and reduction of the elevated levels of CK in liver and spleen of mice [121]. Scopolamine, a blocker of muscarinic acetylcholine (ACh) receptors, induces learning and memory dysfunction through reduction of cholinergic activity in mice. It is used as neurotoxin in the study of stroke model in mice. Administration of catalpol (9 mg/kg/day, i.p.) for 3 days in scopolamine-treated permanent middle cerebral artery occlusion (pMCAO)-induced stroke in mice significantly improved the learning and memory deficit in mice by increasing the levels of ACh and brain-derived neurotrophic factor (BDNF) as well as acetylcholine receptors M1 and M2. In addition, catalpol reduced the expression of acetylcholine esterase (AChE) and increased the activation of choline acetyl transferase (ChAT). The effects of catalpol were very similar to those of nootropic drug, oxiracetam (105 mg/kg), used as positive control [122]. In another study, treatment of catalpol + (5 and 10 mg/kg) in Ab25–35 or Ab25–35 ibotenic acid-induced neurotoxic mice significantly improved the memory deficits by increasing the activity of ChAT and the levels of muscarinic M receptor density and BDNF in the mice brain. In an in vitro assay, pretreatment of catalpol in Ab-induced primary culture of mice forebrain neurons also improved the level of BDNF mRNA by 131 ± 23% compared to control after 48 h of culture. Thus, catalpol ameliorated the cholinergic dysfunction in Ab-induced neurotoxic mice through up-regulation of BDNF [123a]. Xia et al. reported that chronic treatment of catalpol to Ab plus glutamate receptor agonist-induced memory defect in mice for a period of 2 and 3 months significantly improved the learning ability and memory of mice in Y maze avoidance test through elevated expression of BDNF proteins in mice brain. Possibly, BDNF proteins are the important factor in neuroprotective effect of catalpol [123b]. Treatment of catalpol (5 and 10 mg/kg/day) for 21 days to Ab-induced AD in rats showed significant improvement of endocrine function of hypothalamic–pituitary– adrenocortical axis (HPA) by decreasing serum hydrocortisone (HYD) level and increasing serum adrenocorticotropin (ACTH), and corticotropin-releasing hormone (CRH) levels as well as improving the structural damage of hypothalamus. Significant increased expression of CRH up-regulated the expression of hypothalamic BDNF. Therefore, neuroprotective effect of catalpol is closely related to the functioning of HPA [124]. Administration of catalpol (5 mg/kg/day, i.p.) to pMCAO-induced ischemic brain damage in rats for 7 days significantly improved the brain angiogenesis and reduced the ischemic neuronal damage through increased expression of erythropoietin (EPO) and vascular endothelial growth factor (VEGF) in the rat brain without worsening the blood–brain–barrier (BBB)-edema. Possibly, up-regulation of endogenous VEGF and EPO expressions stimulated brain angiogenesis process and healing of ischemic brain [125]. Wan et al. repeated the experiment to evaluate the molecular mechanism of catalpol in neuroprotective and angiogenesis effects in

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pMCAO-induced cerebral stroke in rats. They observed that catalpol increased angiogenesis process in rat brain by increasing the levels of EPO and its receptor, EPOR and VEGF via up-regulation of phosphorylation of JAK-2 and STAT-3 proteins for inhibition of caspase-3-mediated apoptosis of neurons [126]. Neuroplasticity plays a key role in learning and in the ability of understanding new things. Synaptophysin, a glycosylated polypeptide, present in the brain, is involved in physiological and pathological processes in human brain. The synaptophysin level is reduced with aging and causes improper functioning of brain. Treatment of catalpol (5 mg/kg/day, i.p.) for 10 days in aged rats (22–24 months old) significantly improved the synaptophysin level in the dentate granule layer of the hippocampus in rats compared to non-treated aged group. In addition, catalpol increased the levels of protein kinase C (PKC), growth-associated protein-43 (GAP-43), and BDNF proteins in the hippocampus. These results indicate that catalpol ameliorates age-related neuroplasticity loss by increasing the levels of synaptophysin and GAP-43 through up-regulation of PKC and BDNF proteins in the aged rats [127]. This study was repeated by Liu et al. to confirm the improved cognitive deficits of aged rats after catalpol treatment in spatial performance and behavioral responses in open field and Y maze tests. They also supported the involvement of GAP-43-enhanced level in hippocampus of aged rats for amelioration of this cognitive deficit [128a]. Catalposide 182, a major iridoid constituent of C. ovata, exhibited significant neuroprotective effect against H2O2-induced oxidative injury in cultured neuro 2A cells through up-regulation of heme oxygenase-1 (HO-1) protein expression and increased HO-1 activity. The protective effect of catalposide on H2O2-induced neuronal cell death was abrogated by zinc protoporphyrin IX, an inhibitor of HO-1 enzyme, suggesting that catalposide exhibits its neuroprotection through improvement of the activity of the HO-1 enzyme [128b]. Geniposide 23, a major iridoid constituent of G. jasminoides fruits, on treatment to H2O2-induced oxidative damage in PC-12 cells culture showed significant neuroprotective effect by increasing the cell viability compared to control culture (in presence of H2O2 alone). This effect of geniposide was reversed on co-treatment with LY 294002, an inhibitor of phosphatidylinositol-3 kinase (PI3K)-Akt pathway. The molecular target study indicated that geniposide protected the neural cells through increasing the expression of Bcl-2 proteins via PI3K signaling pathway by enhanced phosphorylation of Ajt 308, Ajt 473 and PDK-1 proteins [129]. Geniposide treatment also protected the PC-12 cells from the oxidative damage induced by 3-morpholinosydnonimine in its culture. Geniposide was found to activate glucagon-like peptide-1 (GLP-1) proteins expression in the neural cells to generate cAMP and to enhance the expression of HO-1 proteins. The neuroprotective effect of geniposide was inhibited on co-treatment with H89, a selective inhibitor of PKA proteins. These findings indicate that geniposide protects the PC-12 cells through enhanced HO-1 expression via cAMP-PKA-CREB (cAMP response-element-binding protein) signaling pathway [130]. In an animal model, treatment of geniposide (100 mg/kg/day, i.p.) for 8 days in MPTP-toxicated PD mice showed significant neuroprotective effects by improving the locomotor and

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exploratory activities of mice in open field, behavioral activities, bradykinesia, and balanced movements in rotarod and swim tests. Histopathological studies indicated that geniposide increased the levels of growth factor signaling Bax proteins and TH-positive DA neurons in the substantia nigra pars compacta and reduced the level of apoptosis signaling Bcl-2 X (Bax) proteins in [131]. Several evidence indicate that microRNA-21 has significant role in regulation of a-synuclein and lysosome-associated membrane protein-2A (LAMP-2A) in PD. Lysosomal chaperone-mediated autophagy (CMA) activates LAMP-2A gene to reduce the expression of a-synuclein proteins. MicroRNA-21 (miR-21) in transfected neural cells decreases the levels of LAMP-2A proteins and mRNA and increases the expression of a-synuclein. Over-expression of a-synuclein results its aggregation and deposition as Lewy bodies in extracellular region of neural cells. Lou et al. observed the effect of geniposide on miR-21 expression in amelioration of PD disorder in MPP+-treated human neuroblastoma SH-SY5Y cells and MPTP-treated PD mice. Their observation revealed that the level of miR-21 in both MPP+-toxicated SH-SY5Y cells and mice was significantly higher than that in normal cells and normal mice. Treatment of geniposide (100 mg/kg/day, i.g.) for 21 days to MPTP-toxicated PD mice and to MPP+-toxicated SH-SY5Y cells for 48 h showed significant lowering of miR-21 level and increased levels of protein and mRNA of LAMP-2A and reduction of a-synuclein level. In addition, geniposide increased the number of TH-positive cells in the substantia nigra in mice. Possibly, geniposide abolished the up-regulating effect of miR-21 on a-synuclein in mice by increasing the activity of CMA. Therefore, geniposide exhibited the neuroprotective effects in PD mice by reduction of a-synuclein expression via down-regulation of miR-21 proteins and up-regulation of mRNA and proteins of LAMP-2A expressions [132]. Geniposide 23, one of the major constituents of Chinese herbal ischemic cerebral stroke drug, TongLuo Jiu Nao, protected neural SH-SY5Y cells and rat hippocampal neurons on treatment in their cell culture from Ab42-induced toxicity through inhibition of LDH release from cells and improved the cell viability by about 22% at 100 µM concentration after 24 h of treatment [133]. In an animal model, treatment of geniposide (50 µM) for 14 days in STZ-induced AD rats ameliorated the learning memory deficit by about 40% in Morris water maze test and reduced the tau proteins phosphorylation by about 30%. Co-treatment of wortmannin, a selective PI3K inhibitor along with geniposide in STZ-induced AD rats for 14 days, partially prevented the neuroprotective effect of geniposide in rats. It is reported that glycogen synthase kinase 3 (GSK 3) is involved in the phosphorylation of tau proteins and STZ increases the activity of GSK-3b. The phosphorylated tau proteins are responsible for neural cell death via accumulation of vesicles and Ab proteins in synaptic terminal. Geniposide suppressed the activity of GSK-3b in AD rats via phosphorylation of PI3K proteins and protected the neural cells in rat brain from apoptosis [134]. The study of molecular mechanism of neuroprotection reveals that geniposide binds the glucagon-like peptide-1 receptor (GLP-1R) to protect the brain neurons against oxidative stress and neuronal cell death. Geniposide activates GLP-1R to suppress neuroinflammation through

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PI3K-Akt (protein kinase B)-induced inhibition of GSK-3b activity. Inactivation of GSK-3b inhibits tau phosphorylation and promotes insulin secretion [135]. Later on, Zhang et al. also evaluated the molecular targets of geniposide in neuroprotective effects in STZ-induced insulin-deficient amyloid precursor protein (APP)/ PS1-double transgenic AD mice. Administration of geniposide (5, 10, and 20 mg/kg/day, i.g.) for 4 weeks to insulin-deficient transgenic AD mice dosedependently decreased the phosphorylation of tau proteins to ameliorate the severity of AD in mice. In primary cultured cortical neurons, geniposide treatment (10 µM) enhanced phosphorylation of Akt and reduced phosphorylation of GSK-3b through PI3K signaling pathway. Co-treatment of LY294002 decreased the phosphorylation of Akt. On the basis of their findings, they proposed that geniposide possibly protected and prevented apoptosis of brain cortical neurons by enhancing insulin secretion and reducing phosphorylation of tau proteins through PI3K-Akt-GSK3b pathway in insulin-deficient AD mice [136]. In another study, treatment of geniposide (10 µM) in rat primary cultured cortical neurons as well as in APP/PS1 transgenic mice at the doses of 10, 20, and 40 mg/kg, i.p., for 4 weeks, significantly reduced the formation of neurofibrillary tangles (NFT) in cortical neurons via inducing the expression of leptin receptor, OB-R and enhancing phosphorylation of Akt and reducing phosphorylation of GSK-3b and thereby preventing the phosphorylation of tau proteins. The effect of geniposide on the reduction of tau protein phosphorylation at the dose of 20 mg/kg was better than that of positive control, liraglutide, a human GLP-1 analogue (100 µg/kg, i.p.). Furthermore, co-treatment of leptin antagonist, triple mutant rat recombinant at the dose of 50 ng/ml, suppressed the effect of geniposide on the phosphorylation of tau, Akt, and GSK-3b proteins in rat primary cortical neurons culture. Therefore, the leptin signaling plays a critical role in geniposide-regulated reduction of tau protein phosphorylation and hence, reduction of Ab production in AD. A number of studies have demonstrated that up-regulated leptin expression decreased the expression of BACE-1 and the activity of GSK-3b and boosted cellular metabolism by activating AMPK proteins and sirtuin (SIRT) genes in neurons in hippocampus and other regions of brain [136b]. Treatment of geniposide in Ab1–42-induced cell injury in primary cultured cortical neurons protected the cortical neurons through induction of the expression of insulin-degrading enzyme (IDE) in a dose-dependent manner. Moreover, co-treatment of bacitracin, an inhibitor of IDE, and GLP-1R-short interfering (si)RNA, an antagonist of GLP-1R, decreased the neuroprotection of geniposide in Ab1–42-treated cortical neurons. These findings suggest that geniposide ameliorates the Ab-induced toxicity in cortical neurons in AD, at least in part, through regulation of IDE expression, a major degrading protease of Ab proteins via activation of GLP-1R signaling pathway [136c]. In a study of mechanism of cell signaling transduction pathway for induction of IDE expression by geniposide, Yin et al. reported that geniposide induced the expression of IDE in primary rat cortical neuron culture through enhanced phosphorylation of PPAR-c and metabolic regulator gene, forkhead box O1, FoxO1, followed by acceleration of p-FoxO1 gene from nuclear fraction to the cytosol. This effect of geniposide on up-regulation of IDE expression was inhibited by LY294002 (an inhibitor of PI3K-Akt pathway),

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PPI (inhibitor of c-Src), Gw9662 (antagonist of PPAR-c), H89 (an inhibitor of PKA), and AG1478 (an antagonist of epidermal growth factor receptor, EGFR). Moreover, geniposide activated the activity of IDE promoter in PC 12 cells, suggesting the presence of GLP-1 receptor. On the basis of these findings, the authors proposed that geniposide regulated the phosphorylation of PI3K/Ajt through c-Src and EGFR signaling pathway and enhanced phosphorylation of PPAR-c. The p-PPAR-c was translocated from cytoplasm to nucleus and accelerated the release of p-FoxO1 from nucleus to cytoplasm and enhanced the activity of IDE promoter by binding to functional PPAR-response element, PPRE. Therefore, p-PPAR-c plays a key role in geniposide-induced secretion of IDE from cortical neurons for clearance of Ab in AD pathology [136d]. In animal model, treatment of geniposide (25 mg/kg/day) in STZ-induced diabetic rats for a period of 46 days significantly decreased the level of Ab1–42 in the hippocampus of the diabetic rats through enhanced secretion of IDE in addition to lowering of plasma glucose, TC and TG levels. In neuroblastoma SH-SY5Y cells culture for 24 h, geniposide increased the IDE expression by about 2.5-fold compared to control. Therefore, geniposide could be effective in amelioration of AD complication of diabetic patients [136e]. Calcium ionophore A23187 induces cytotoxicity in neural cells by induction endoplasmic reticulum (ER) stress via increasing the cytosolic Ca2+ concentration and expression of immunoglobulin-binding protein/glucose-regulated protein of 78 kDa (BiP/GRP78) in ER and up-regulation of LDH level. Genipin 41 (20 µM) showed significant neuroprotective effect against A23187-induced cytotoxicity in Neuro2a cells. Genipin protected the neural cells from cytotoxicity by reducing the release of LDH and expression of BiP/GRP78 proteins in the cells. Thus, genipin may be effective in treatment of ER stress-related AD and PD disorders [137]. Loganin 18, a major iridoid constituent of Cornus officinalis fruits, on oral treatment (1 and 2 mg/kg) to scopolamine-induced amnesia in mice, significantly mitigated the memory deficit of mice, as evident from passive avoidance and Morris water maze tests. The effect of loganin at higher dose in passive avoidance test was comparable to that of positive control, donepezil (2 mg/kg). At the higher dose, loganin inhibited the activity of acetyl cholinesterase (AChE) by 45% compared to the control group in the mouse hippocampus [138]. Park et al. repeated this experiment to evaluate the long-term potentiation of memory recovery of mice in organotypic cultured hippocampal tissue on acute administration of loganin (500–1000 ng) and behavioral performance of scopolamine-induced learning and memory impairment in mice on loganin treatment. In the organotypic cultured hippocampal tissue assay, loganin increased the total activity of field excitatory postsynaptic potentials (fEPSPs) after high-frequency stimulation through attenuation of scopolamine-induced cognitive impairment in the hippocampal area for improvement of the memory enhancing effect. In vivo model, treatment of loganin (40 mg/kg, p.o.) to scopolamine-induced amnesic mice significantly recovered the learning and memory deficits, both short-term and long-term in Y maze and Morris water maze tests. In addition, loganin improved the shortening of steps of mice in passive avoidance test. The study of molecular action indicated that loganin reduced the cholinergic muscarinic receptor

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blockade induced by scopolamine through inhibition of the activity of AChE in both cortex and hippocampus and activation of acetylcholine (ACh) receptor system in CNS of mice [139]. In another study, loganin significantly prevented Ab25–35induced injury in PC-12 cells through suppression of ROS generation and attenuation of cell apoptosis. Loganin protected the cells from inflammation through reduction of elevated levels of pro-inflammatory cytokines, TNF-a, COX-2, and iNOS via inactivation of NF-jB proteins and decreased the cell apoptosis through inhibition of phosphorylation of MAPK proteins, ERK 1/2, p38, and JNK, and activation of caspase 3 as well as cell cycle arrest at G0/G1 phase [140a]. Loganin exhibited significant inhibitory effect against the activity of b-secretase (beta-site amyloid precursor protein (APP)-cleaving enzyme-1, BACE-1) at the concentration of 9.2  10−5 M with a Ki value of 5.5  10−5 M and weak activity against a-secretase. The enhanced activity of BACE-1 results the production of Ab proteins via formation of extracellular C-terminal fragment, C99 as intermediate. Therefore, loganin could be an effective drug in treatment of AD disorders [140b]. Loganin isolated from C. Fructus, on intraperitoreal treatment (30 and 50 mg/kg/day) for 7 days in MPTP-induced PD in mice, significantly exhibited neuroprotective effects by decreasing dopamine levels and tyrosine hydroxylase expression in striatum to reduce activation of microglia and astrocytes and decreasing inflammation, autophagy, and apoptosis of dopaminergic neurons in striatum of mice brain. Loganin reduced the inflammation through lowering of TNF-a content and decreased mitochondrial fission through down-regulation of the expression of dynamin-related protein-1 (Drp-1), and improved autophagy process of lysosome for clearance of plaque by increased expression of microtubule associated protein-light chain-3-II (LC-3II) in striatum of mice brain. Drp-1, modulator of mitochondrial dynamics, is responsible for cell death via mitophagy and mitochondrial division, while LC-3II protects the neuronal cells from apoptosis by reducing the acidic vesicles via increasing the autophagy process. Loganin prevented the neuronal cell apoptosis by inhibition of the activity of caspase 3 through suppression of the expressions of NF-jB, p38, and c-Abl-tyrosine kinase proteins. In MPTP-induced PC-12 cells, loganin decreased the acidic vesicle level by 51%. The acidic vesicle level is considered as a biological marker of autophagasomes. These results indicate that loganin exhibits its protective effects on dopaminergic neurons mainly by decreasing inflammation and autophagasomes in striatum of mice brain [140c]. Therefore, loganin could be an effective drug for treatment of PD and AD. Morroniside 70, another major iridoid constituent of C. officinalis fruits, in an in vitro assay, exhibited dose-dependent neuroprotective effect against H2O2induced cytotoxicity in human neuroblastoma SH-SY5Y cells culture at the tested concentration of 1–100 µM by inhibiting the cells from apoptosis through reduction of oxidative stress via elevation of the activity of antioxidant enzyme SOD, reduction of intracellular Ca2+ accumulation, and improvement of mitochondrial membrane potential (MMP) in the cells [141]. Wang et al. in a separate study on neuroprotective effect of morroniside in H2O2-induced SH-SY5Y cells culture observed that morroniside protected the SH-SY5Y cells from H2O2-induced apoptotic death by significant and dose-dependent elevation of intracellular reduced glutathione, GSR expression along with up-regulation of Bcl-2 proteins and

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down-regulation of ROS, and activation of caspase 3 and 9. On the basis of these findings, they proposed that intracellular GSR expression was the key factor in morroniside-mediated cytoprotection of SH-SY5Y cells [142]. Morroniside also protected neuroblastoma SK-N-SH cells against H2O2-induced toxicity in the cell culture in a dose-dependent manner (1, 10, and 100 µM). Morroniside protected the cells against the oxidative damage of H2O2, by reduction of ROS production, improved expressions of antioxidant enzymes, glutathione (GSH) and SOD, improvement of MMP and inhibition of mitochondrial-mediated cell apoptosis through suppression of Bax and stimulation of Bcl-2 mRNA and proteins expressions as well as suppression of caspase 3 enzyme expressions [143]. In an animal model, treatment of morroniside (30, 90, and 270 mg/kg, i.g.) in focal cerebral ischemia-induced brain damage in rats showed significant reduction of infarction volume in ischemic cortex tissues through reduction of malondialdehyde level and caspase 3 activity. In addition, morroniside increased the levels of antioxidant enzymes, GSH and SOD in ischemic cortex tissues of rats [144]. Therefore, morroniside could be a prospective neuroprotective drug. Cornuside 262, another secoiridoid constituent of C. officinalis fruits, on treatment in cultured rat cortical neurons damage-induced by oxygen glucose deprivation, showed significant neuroprotective effects by attenuation of cell apoptosis and mitochondrial energy metabolism through suppression of intracellular Ca2+ elevation and caspase 3 activity and improvement of mitochondrial antioxidant enzymes activities and lowering of mitochondrial malondialdehyde (MDA) content and LDH leakage rate [145]. Oleuropein 80, a major secoiridoid constituent of olive oil, on pretreatment (10, 15, and 20 mg/kg/day) for 10 days in colchicine-induced cognitive dysfunction in rats, showed significant improvement in learning and memory retention of rats in Morris water maze test. The amelioration of cognitive dysfunction of oleuropein was associated with the improvement of the activities of antioxidant enzymes, glutathione peroxidase and CAT, and reduction of the levels of NO and MDA in the hippocampus of rats [146]. Oleuropein aglycone (Ole) 741 present in extra virgin olive oil, on treatment both in vitro culture of human neuroblastoma SH-SY5Y cells at the concentration of 50 µM and in vivo as supplementation with diet (50 mg/kg of diet) for 8 weeks to transgenic TgCRND8 mice, showed significant induction of autophagy for digestion of deposited Ab proteins through activation of AMPK and subsequent inhibition of the activity of cytoplasmic kinase receptor, mammalian target of rapamycin (mTOR). The mTOR proteins are activated in brain neuronal cells in response to different stresses and a key player for inhibition of lysosomal autophagy. Ole activated AMPK proteins through Ca2+-induced activation of calcium/calmodulin-dependent kinase kinase beta (CaMKKb) proteins. The oleuropein aglycone increased the concentration of Ca2+ in cytoplasm through elevated expression of Bcl-2–Beclin-1 protein complex. The oleuropein aglycone also activated sirtuin (SIRT) expression in striatum neurons for induction of lysosomal autophagy to reduce the aggregated Ab peptides from cortex and hippocampus of mice brain for improvement of cognitive deficit. The autophagy effect of Ole was reduced on co-treatment with STO-609 (a CaMKKb inhibitor) or compound C (an

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AMPK inhibitor) in the culture of SH-SY5Y cells. Therefore, consumption of olive oil as food supplement might be beneficial in prevention of AD [147]. Oleuropein also exhibited potent neuroprotective effect against spinal cord injury in rats. Treatment of oleuropein (20 mg/kg, i.p.) in rats immediately and 1 h after spinal cord injury improved the behavioral function of rats compared to the trauma group. Histopathological analysis of spinal cord fluid samples collected after 24 h of oleuropein treatment showed significant decrease of MDA and Bax proteins levels and increase in GSH and Bcl-2 levels. In addition, it significantly reduced the amount of fragmented DNA in TUNEL assay. These findings indicate that the neuroprotective effect of oleuropein is due to its antioxidant efficacy [148]. Oleuropein aglycone was found to inhibit tau proteins fibrillization in vitro generation of both wild-type and P301L transgenic-type tau protein cultures. The activity of the aglycone is better than that of reference tau aggregation inhibitor, methylene blue. These compounds may serve as chemical scaffold for development of new drugs for neurodegenerative taupathies [149]. In another study, intraperitoneal administration of oleuropein (100 mg/kg) in cerebral ischemia and reperfusion injury in mice, 1 h before ischemic injury, showed significant reduction of cerebral infarction volume after 75 min of ischemia and 24 h after reperfusion in mice, compared to ischemia/reperfusion group. The protective effect of oleuropein was associated with its anti-apoptotic effect through up-regulation of Bcl-2 and down-regulation of Bax proteins expressions and inhibition of caspase 3 activity. Thus, oleuropein may be an effective drug for treatment of stroke [150]. The aglucones of secoiridoids, 7-O-butylmorroniside 265, 7R-O-methylmorroniside 263, and 7S-O-methylmorroniside 263 showed significant neuroprotective effect against glutamate-induced toxicity in mouse HT22 hippocampal cells culture with protection of cells up to 78 ± 2.2, 60 ± 3.2, and 50 ± 2.5%, respectively, compared to non-treated control at the concentration of 10 µM, while the aglycone of morroniside 70 and the parent secoiridoids 265 and 263 were inactive under the same tested condition. It indicates that in aglycones of 265 and 263, the presence of alkyl group at C-7 might have a role for their neuroprotective effect [151]. Iridoids, jatadoid A 742, jatamanvaltrate H 743, valerianoid A 744, valerianoid C 745, jatairidoid A 746, jatairidoid B 747, and jatairidoid C 748 isolated from Valeriana jatamansi, showed moderate-to-strong neuroprotective effects against MPP+-induced cell death in human neuroblastoma SH-SY5Y cells culture by inhibiting the cell viability in the range of 50–90.8% at the tested concentration of 30 µM, and their effects were comparable to that of positive control guanosine (90.4% cell viability) [152–154]. Iridoid glycosides, 8-O-E-p-methoxycinnamoyl harpagide 749 and 6′-O-E-pmethoxycinnamoylharpagide 750, isolated from Scrophularia buergeriana roots, exhibited moderate neuroprotective effect against glutamate-induced neurotoxicity in primary cultures of rat cortical neuronal cells with cell viability of 61.8 and 60.9%, respectively, at the tested concentration of 1 µM, while other isolated harpagide derivatives from this plant showed weak activity. Possibly, the presence of E-p-methoxycinnamoyl unit in these iridoids is responsible for their higher activity [155].

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Activators of nerve growth factor (NGF) are promising drugs for treatment of AD and cerebrovascular dementia. Iridoids, gelsemiol 45 and 9-hydroxysemperoside aglucone 751, isolated from Japanese Verbena littoralis, showed significant growth of nerve cells in PC12D cells culture. Gelsemiol (100–300 µM) showed significant increase in the proportion of neurite-bearing cells and the length of neurite in presence of NGF, while 751 (100–300 µM) showed only the elongation of neurite length in presence of NGF [156a]. Secoiridoid glycosides, sweroside 67, swertiamarin 68, gentiopicroside 69, 5′-Ob-D-glucopyranosylameroswerin 752, and n-butyl-epi-vogeloside 753, showed potent neuritogenic activity in PC-12 cell line culture. These secoiridoid compounds are promising starting compounds for the development of potent neurotrophic factor-like iridoid compounds [156b].

5.2.5

Cardioprotective Activity

Coronary artery disease (CAD) is the most common cardiovascular disease throughout the world. It is a complex chronic inflammatory disease and atherosclerosis is its main etiopathogenic process. Atherosclerosis is characterized by accumulation of lipids, fibrous elements, and inflammatory molecules on the walls of large arteries. Hyperlipidemia, hyperglycemia, hypertension, oxidative stress, and psychiatric disorders are the major risk factors of CAD. Inhibition of the activities of angiotensin-converting enzyme (ACE), acetylcholinesterase (AChE), and inflammatory mediators, IL-6, iNOS, and MCP-1 is the key target for prevention of atherosclerosis. ACE plays a key role for hypertension and cardiac failure via vasoconstriction and aldosterone secretion, while AChE is responsible for increased LDL levels in the tissues. Nitric oxide generated from the enzyme iNOS in presence of superoxide anions produces harmful peroxynitrite, which is the key player for cardiomyocytes injury and apoptosis. Creatine kinase (CK)-MB enzyme is considered as biomarker of myocardial injury in heart diseases [157]. Secoiridoid, oleacein 754, isolated from aqueous extracts of both Olea europaea and O. lancea, was found to inhibit the activity of ACE with an IC50 value of 26 µM in an in vitro assay. Other five secoiridoids, oleuropein 80, ligstroside 79, excelsioside 752, oleoside 11 methyl ester 439, and oleoside 439a isolated from these aqueous extracts showed no significant activity; however, their aglucones exhibited ACE inhibition in the range of 64–95% at the tested concentration of 0.33 mg/ml. Oleacein was found to exhibit low toxicity in the brine shrimp lethality assay [158]. Oleuropein 80, a major constituent of olive (O. europaea) leaf, on treatment (100 and 200 mg/kg, i.p.) for 5 days to doxorubicin-induced cardiotoxic rats, showed significant cardioprotective activity through reduction of oxidative stress and lipid peroxidation products. Oleuropein reduces cytoplasmic vacuolization in cardiomyocytes through reduction of cardiotoxicity by decreasing iNOS protein expression and the contents of MDA and conjugated dienes in cardiomyocytes, and reducing the elevated levels of serum creatine phosphokinase (CPK), CK-MB, LDH, AST, and

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ALT. The enzymes, CPK, CK-MB, and LDH are considered as biomarkers of cardiac necrosis and toxicity [159]. In another study in doxorubicin-induced cardiotoxic rats, oleuropein treatment was found to reduce the elevated levels of serum acetate and succinate from cardiomyocytes to ameliorate the cardiotoxicity in rats [160a]. Treatment of oleuropein (1000 and 2000 mg/kg in total, i.p., in 14 days) to doxorubicin (DRX)-induced cardiotoxic rats effectively improved the cardiac geometry and function in rats through improvement of degenerative lesions and left ventricular contractility function as evidenced in transthoracic echocardiography and reduction of plasma inflammatory mediators, IL-6, iNOS, and big-endothelin-1 (Big ET-1) via activation of AMPK kinase proteins. The Big ET-1 level is considered as a biomarker of cardiac function, and its high level indicates the high risk of mortality [160b]. Therefore, consumption of extra virgin olive oil as food supplement is beneficial for prevention of cardiac disorders. Melampyroside 472 and verminoside 195 isolated from Eremophila species showed significant in vitro increase of coronary perfusion rate (CPR) in isolated rat heart with about 41.1 and 39.1% increase of CPR, respectively, at the concentration of 2 mM [161]. In another study, iridoid valtrate 54 and oleuropein 80 showed about 65 and 50% increase in coronary blood flow in isolated rabbit heart at the concentration of 25 µM [162]. These iridoids may be effective in the treatment of CAD. Oxidized low-density lipoproteins (Ox-LDLs) play an important role in the early stages of atherosclerosis and in coronary disease [163]. Iridoid glucosides, geniposidic acid 289, asperulosidic acid 288, deacetylasperulosidic acid 290, scandoside 282a, feretoside (=scandoside methyl ester) 282, and 10-Obenzoylscandoside 283a isolated from Asian Hedyotis diffusa (syn. Oldenlandia diffusa), inhibited the oxidation of LDL in the range of 34.4–63.8%, comparable to that of positive control, probucol (78.1% inhibition) at the tested concentration of 20 µg/ml. Among the tested iridoids, geniposidic acid, scandoside, and deacetylasperulosidic acid have higher inhibitory effects with 63.3, 62.2, and 63.8% inhibition, respectively. These iridoids may be useful in treatment of coronary diseases [164]. A lyophilized extract of P. kurroa roots containing iridoids picrosides I–III (532, 192, and 401) as major constituents, on treatment (200 mg/kg) in isoproterenol (ISP)-induced myocardial infarction in rats, showed significant cardioprotection in rats by attenuation of the elevated level of lipid peroxidation through reduction of myocyte CK-MB and LDH enzymes levels and improving the levels of myocardial antioxidant enzymes CAT, SOD, GSH, and glutathione peroxidase (GSH-Px) [165]. 6′-O-Caffeoylharpagide 755, 6′-O-p-coumaroylharpagide 756, and harpagoside 499 isolated from Scrophularia ningpoensis, exhibited cardioprotective effect on rat cardiac myocytes by inhibiting the increase of Ca2+ ions induced by KCl at 100 µM [166]. Other isolated iridoid glucosides, scrophularianoids A 857 and B 858, from this plant, exhibited moderate cardioprotective effect against H2O2-induced apoptosis of cardiomyocytes [167]. Catalpol 14 on treatment (10 mg/kg, i.p.) for 10 days in ISP-induced myocardial injury in rats showed significant cardioprotective effect through attenuation of oxidative stress by increasing the activity of antioxidant enzyme SOD and reducing

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the levels of MDA, LDH, and CK-MB. In addition, catalpol suppressed the elevated expression of inflammatory cytokines TNF-a and IL-1b [168]. In another study, pretreatment of catalpol (5 mg/kg, i.p.) to myocardial ischemia/reperfusion (I/R) injury in rats improved cardiac functions, reduced myocardial infarction, apoptosis and necrosis of cardiomyocytes through reduction of the contents of serum CK, LDH, iNOS, superoxide anions and peroxynitrite (ONOO−), and increased Akt activation. However, co-treatment of wortmannin, a PI3K inhibitor, with catalpol in I/R-induced heart injury in rats, not only blocked catalpol-induced Akt phosphorylation but also other beneficial effects of catalpol in rats. Therefore, catalpol affords cardioprotection in ischemia-reperfusion induced heart injury in rats through attenuation of peroxynitrite formation via PI3K-Akt signaling pathway [169]. Cornuside 262, a major iridoid constituent of C. Fructus, on treatment (20 and 40 mg/kg, i.v.) in acute myocardial I/R injury in rats induced by coronary occlusion or ISP, showed significant cardioprotection. The cardioprotective effects of cornuside were associated to its inhibition of plasma polymorphonuclear leukocytes (PMNs) infiltration and MPO activity and increase in the activities of antioxidant enzymes SOD and GSH-Px. Furthermore, it decreased the elevated expressions of pro-inflammatory factors, troponin T (Tn-T), TNF-a, and IL-6, and reduced the levels of phosphorylated IjB-a and NF-jB proteins in the heart. Tn-T hormone is a biomarker of myocardial damage. Thus, cornuside could be effective in treatment of early stages of myocardial injury in rats [170]. Loganic acid 146, a major constituent of cornelian cherry (Cornus mas) fruits, showed significant preventive effect in high-fat diet-induced atherosclerosis in rabbits. Oral administration of loganic acid (20 mg/kg/day) for 60 days in cholesterol-rich-diet-induced atherosclerosis in rabbits, significantly exhibited preventive effects on atherosclerosis. Loganic acid decreased intima thickness and intima/media ratio in the thoracic aorta through amelioration of dyslipidemic effects in rabbits by decreasing the levels of ox-LDL and TG, and increasing HDL-cholesterol in plasma through increased expressions of adipogenic transcription factors PPAR-c and -a proteins in the liver of rabbits. Furthermore, loganic acid reduced the inflammation by decreasing the levels of TNF-a and IL-6 in aorta of rabbits. Anthocyanins present in cornelian cherry fruits also exhibited preventive effects in high-fat diet-induced atherosclerosis in rabbits on oral adminstration at the same dose. Thus, cornelian cherry fruits consumption as diet supplement may be effective in prevention of high-fat diet-induced atherosclerosis [171]. An aqueous extract of Chinese Jasminum multiflorum aerial parts exhibited cardioprotective activity by inhibition of the activity of ACE by about 92% of inhibition. Secoiridoid glucosides, 10-hydroxyoleuropein 438b, multifloroside 757, and lactones, jasmolactones B 716 and D 717, isolated from this plant exhibited strong coronary dilating and cardioprotective (chronotropic and enotropic) activities on isolated guinea pig heart preparations at the minimum effective concentration (MEC) in the range of 1.5  10−6 to 2.5  10−5 M, and their effects were comparable to that of isoproterenol (ISP), used as standard (MEC, 4.7  10−7 and 4.7  10−8 M, respectively) [172].

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Valeriana-type iridoids, patriscabioin A 758 and patriscabioin C 759, isolated from Chinese Patrinia scabiosaefolia, showed moderate inhibitory activity on AChE enzyme with IC50 values of 37.6 and 10.5 µM, respectively. The activity of this enzyme is closely related to the deposition of lipids on the walls of arteries of heart in early stages of atherosclerosis [173].

5.2.6

Anti-allergic Activity

Several common allergic diseases such as allergic rhinitis, bronchial asthma, anaphylaxis, atopic and contact dermatitis, chronic urticaria, and hypersensitivity pneumonitis are developed from both genetic and environmental factors. The inflammatory basophil leukocytes, tissue mast cells, and their chemical mediators play a pivotal role in the pathogenesis of these diseases. Lung asthmatic disorder is characterized by reversible obstruction of airways or bronchi. The chronic inflammation in lung bronchi plays a fundamental role in the genesis of this disorder. The airway inflammation is a multicellular process involving mainly eosinophils, neutrophils, CD4+ T-lymphocytes, and mast cells, with eosinophilic infiltration being the most striking feature. Several reports indicate that high eosinophil contents are fundamental factors to airway dysfunction in asthma. Both Th-1 and Th-2 cells are involved in the secretion of immunoregulatory cytokines to initiate inflammation in the airway epithelial NCI-H292 cells. Th-2 cells upregulate the expression of cytokines IL-4 and IL-13 for the release of immunoglobulins (IgE) from plasma cell surface and to activate mast cells. The activated mast cells release histamine, leukotrienes (LTC4), prostaglandins, and cytokines. Th-2 cells also express cytokine IL-5 to release eosinophils, which in turn, release inflammatory mediators IL-3, granulocytemacrophage colony stimulating factor (GM-CSF), eotaxins 1–3 and other growth factors, TGF-b and VEGF. The helper thymus Th-1 cells secret cytokine TNF-a for the activation of NF-jB proteins to release several cytokines including IL-1b, IL-6, IL-3, and IL-8. All these cytokines induce airway hyperresponsiveness and mucus hypersecretion and consequent damage of airway epithelial tissue in both asthma and chronic obstructive pulmonary disease (COPD) patients [174]. Veronica longifolia, a perennial herb in Asian and European countries, has been used in traditional medicine for treatment of bronchitis, cough, and asthma. Iridoid glucoside, verproside 195b isolated from methanol extract of this plant, exhibited anti-asthmatic effect in ovalbumin (OVA)-induced asthmatic mice. Pretreatment of verproside (30 mg/kg, i.g.) in OVA-sensitized asthmatic mice showed significant anti-asthmatic effect by suppression of elevated levels of IgE, IL-4, IL-13, and eosinophils in the plasma and bronchoalveolar lavage fluid (BALF) of mice 48 h after the last OVA challenge. The suppressive effects of verproside on total leukocyte, eosinophils, IL-4 and IL-13 were 79.3 ± 13.1, 86.2 ± 7.2, 64.5 ± 27.7, and 74.9 ± 15.5%, respectively in BALF, compared to control group. These effects were comparable to those of anti-asthmatic drug, montelukast, used as positive control [175].

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In asthma and COPD patients, the over-production and hypersecretion of airway mucus, mainly composed of mucin MUC5AC proteins, are significant risk factors. The over-production of mucus is caused from TNF-a/NF-jB signaling pathway in human airway epithelial NCI-H292 cells. It has been reported that activated TNF-a receptor 1 (TNFR-1) forms a complex TNF-RSC with TNFR-1 associated death domain protein (TRADD) and TGF-b-activated kinase 1 (TAK-1) to initiate the TNF-a/NF-jB signaling cascade. In this activation process, IKK complex acts as a mediator of NF-jB activation and TAK-1 as an activator of IKK. Over-expression of IjB-kinase b (IKKb) from NF-jB activation causes increased expressions of both inflammatory mediators and neutrophilic inflammation in pulmonary epithelial cells. Therefore, inhibition of IKKb and TAK-1 proteins production reduces the production of mucus protein, MUC5AC in airway epithelial cells [176]. In an in vitro assay, verproside (20 µM) significantly reduces the expression levels of TNF-a induced MUC5AC mRNA and proteins by inhibiting both NF-jB transcriptional activity and phosphorylation of its upstream effectors IKKb and TAK-1 in NCI-H292 cells culture. Furthermore, the inhibitory effects of verproside against NF-jB activation as well as IKKb and TAK-1 phosphorylations are reduced to great extent, when combined with BAY11-7802 (an IKK inhibitor) or (5Z)7-oxozeaenol (a TAK-1 inhibitor) compared to its administration alone. The in silico molecular docking studies of TRADD-TRAF 2 complex with verproside also support their effective bindings. These findings indicate that verproside could be a good therapeutic candidate for treatment of asthma and COPD [177]. Korean P. rotundum var. subintegrum has long been used in Asian and European countries for treatment of bronchitis, cough, and asthma. An iridoid glucoside, piscroside C 535 isolated from aerial parts of this plant, exhibited significant suppression of inflammation against cigarette smoke and LPS-induced COPD in mice and TNF-a-stimulated human airway epithelial NCI-H292 cells. Oral treatment of piscroside C (15 and 30 mg/kg) to cigarette smoke and LPS-induced COPD in mice significantly reduced the neutrophil influx in BALF, production of ROS, IL-6 and TNF-a and reduction of the activity of elastase in the lung tissue of COPD in mice. In addition, piscroside C effectively suppressed the phosphorylation of NF-jB and IjB, in order to reduce the recruitment of inflammatory cells into the lung tissue. In consistent with these results of in vivo experiment, piscroside C on pretreatment (2.5 and 20 µM) in a culture of NCI-H292 cells-stimulated by TNF-a, suppressed both mRNA and protein levels of pro-inflammatory cytokines, IL-6, IL-8, and IL-1b as well as TNF-a-induced NF-jB activation by decreasing the phosphorylation of IKKb and TAK-1 in NCI-H292 cells. Thus, piscroside C may be a potential therapeutic candidate for treatment of COPD [178]. Picroliv, a mixture of iridoid glucosides, picroside I 532 and kutkoside 15, isolated from Indian P. kurroa, showed significant anti-allergic and anti-anaphylactic activities in both mice and rat models. Treatment of picroliv (25 mg/kg, p.o.) to OVA-sensitized asthmatic mice and rats for 48 h showed inhibition of passive cutaneous anaphylaxis (PCA) in mice and rats by 82 and 50–85%, respectively, and protected the mast cells from degranulation by 80% after

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4 days of treatment in mice. These inhibitory effects of picroliv were very close to those of anti-allergic drug, disodium cromoglycate (DSCG) (50 mg/kg, i.p.; 82% of PCA inhibition in rats). Picroliv did not exhibit any antihistaminic effect against isolated guinea pig ileum preparation at the tested doses of 1–5 µg/ml [179]. Acylated loganin derivatives, arbortristosides A 456 and C 458, isolated from Indian Nyctanthes arbortristis, exhibited anti-allergic activity by inhibiting PCA and mast cells degranulation in rats, and their activities were comparable to that of positive control, DSCG [180]. Geniposide 23 from G. jasminoides fruits exhibited significant anti-asthmatic effect in OVA-induced asthmatic mice. Intraperitoneal treatment of geniposide to OVA-induced asthmatic mice significantly ameliorated airway hyperresponsiveness and mucus hypersecretion in mice through reduction of elevated expressions of Th-2-associated cytokines and chemokines, IL-4, IL-5, IL-13, reduced eotaxin and VCAM-1, and allergen-specific IgE levels in the lung tissues of mice. These effects of geniposide were comparable to those of anti-asthmatic drug, dexamethasone. Thus, geniposide could be an effective adjuvant therapy for allergic asthma [181]. Secoiridoid glucosides, hydramacrosides A 760 and B 761 of Hydrangea macrophylla var. thunbergii, showed significant inhibitory effect against histamine release from antigen–antibody induced rat mast cells with respective inhibition of 70 ± 3.5 and 78.1 ± 9.5% at 300 µM concentration [182]. Secoiridoid aglucone, 3,4-dihydroxyphenyl ethanol ester of elenolic acid 762, a major constituent of Japanese O. europaea fruits, exhibited anti-allergic activity against suppression of b-hexosaminidase from leukemia RBL-2H3 cells with an IC50 value of 33.5 ± 0.6 µg/ml, while other minor secoiridoids, elenolic acid 763 and oleuropein 80 isolated from the fruits of this plant, showed weak anti-allergic activity with IC50 values of 377.9 and 871.1 µg/ml, respectively. The compound 762 is the major constituent of the fruits, and hence, the anti-allergic efficacy of the olive fruits depends on the efficacy of this compound [183].

5.2.7

Hypoglycemic, Hypolipidemic, and Anti-obesity Activities

Diabetes mellitus type 2, known as type 2 diabetes or T2DM, is characterized by hyperglycemic (high blood sugar) and insulin resistance (IR) from pancreatic b-cells disfunctioning. Various pro-inflammatory mediators such as cytokines and chemokines play a crucial role in the pathogenesis of T2DM. Pro-inflammatory markers such as cytokines, IL-1b, IL-6, and TNF-a, C-reactive proteins (CRPs) and chemokine, MCP-1 are directly or indirectly linked to tissue-specific IR. Several factors, namely oxidative stress, dyslipidemia, chronic inflammation, hypertension, hyperglycemia, and genetic factors, are interlinked for elevated expressions of these pro-inflammatory markers in plasma. The IL-6 gene prevents metabolism of non-oxidative glucose and suppresses the activity of lipoprotein lipase to increase plasma TG level. IL-6 also activates the suppressor of cytokine signaling (SOCS)

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proteins, to block the activation of insulin receptor. The cytokine IL-1b via binding with its receptor (IL-1R1) reduces the expression of insulin receptor substrate-1 (IRS-1) at ERK-dependent level. The inflammatory gene TNF-a expression is elevated in obese animals and modulates the activation of NF-jB and JNK proteins, which on activation impair the activation of IRS-1 and reduce insulin mediated glucose uptake by tissues. Over-expression of MCP-1 in skeletal muscle from muscle inflammation induces local recruitment of macrophages and alters local insulin sensitivity and creates IR. CRP also plays a pivotal role for the pathogenesis of IR by inducing local and systemic inflammation through binding with LDL in atherosclerosis and adiposity. Oxidative stress is a common pathogenic factor for development of tissue-specific IR. Toll-like receptor-4 (TLR 4), an extranuclear cell surface receptor, is expressed in pancreatic b-cells, brain, liver, skeletal muscle, and adipose tissues. In normal condition, TLR 4 regulates insulin sensitivity in these tissues through phosphorylation of IRS serine, but its activity is disordered by ROS and various pro-inflammatory mediators. In skeletal muscle, about 95% of insulin-induced postprandial glucose utilization occurs. The over-expression of TLR4 causes impairment of the translocation of insulin-sensitive glucose transporter-4 (GLUT-4) proteins from cytoplasm to cell membrane in skeletal muscle tissue cells leading to a defect in insulin-stimulated glucose uptake and its disposal. AMP-activated protein kinase (AMPK) on activation increases insulin sensitivity and glucose homeostasis in pancreatic beta cells [184]. Oral administration of aucubin 13 (5 mg/kg/day) for 15 days (twice daily for 5 days followed by single dose daily for 10 days) to STZ-induced diabetic rats showed significant antidiabetic effect by reducing the levels of blood glucose and lipid peroxidation, and improving the activities of antioxidant enzymes, CAT, GSH-Px, and SOD in liver and kidneys of the rats. In addition, aucubin reduced the levels of MDA in both liver and kidneys and improved the number of pancreatic beta cells in the treated diabetic rats [185]. Scropolioside D 372g and 8-O-acetylharpagide 12a, isolated from S. desertii, each on oral administration (10 mg/kg, p.o.) to alloxan-induced diabetic mice, showed antidiabetic effect by lowering the blood glucose level by 34 and 29%, respectively after 2 h of drug administration [36]. Catalpol 14 isolated from R. glutinosa roots, on administration (0.01–0.1 mg/kg, bolus i.v.) to STZ-induced diabetic rats, showed significant antihyperglycemic effect by lowering plasma glucose level of 24.3 ± 2.9% at 0.1 mg/kg dose. This effect was very similar to that of antidiabetic drug, metformin (32 ± 5% lowering of plasma glucose at the dose of 100 mg/kg). The study of molecular mechanism reveals that catalpol increases the glucose utilization by increasing the glycogen synthesis in skeletal muscle and liver of rats [186]. Iridoids, 7-hydroxyeucommiol 764, catalpol 14, specioside 180, and verminoside 195 isolated from African Kigelia pinnata syn. K. africana twigs, exhibited significant stimulation of GLUT 4 translocation from inside to cell surface in cultured skeletal muscle L6-myoblast cells with respective stimulation of 36.3, 50.0, 41.8, and 45.6%, over control at 10 µM. Standard antidiabetic drug, rosiglitazone used as positive control, showed 54% of stimulation activity at the

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same concentration and under identical experimental conditions. The higher activity of catalpol indicates that the skeletal structure of catalpol is critical for this activity, while acylation at C-6 as well as absence of glucose moiety, epoxide linkage, and ring opening in catalpol decreases the activity. These results indicate that catalpol could be a prospective drug for treatment of IR in type 2 diabetes [187]. Asperuloside 24, a major iridoid constituent of edible Eucommia ulmoides leaf, on chronic administration as diet supplementation (0.1–0.3% in HFD) for 3 months to obese-induced diabetic rats, showed strong anti-obesity and antimetabolic syndrome activity by suppressing the body weight, visceral fat weight, food intake and circulating levels of glucose, insulin and lipids (TC and TG/TAG) including non-esterified fatty acids (NEFA), and increasing the plasma adiponectin and PPAR-c mRNA levels in rats. In addition to these, asperuloside increased the level of GLUT-4 in skeletal muscle to improve the level of insulin for glucose metabolism and increased the mRNA levels of citrate synthase, isocitrate dehydrogenase 3a, succinyl CoA synthase, peroxisomal 3-ketoacyl CoA thiolase, and succinate dehydrogenase in the skeletal muscle to increase the glycolytic process, TCA cycle, and electron transport process for utilization of carbohydrates and ketone bodies (acetoacetate, beta-hydroxybutyrate and acetone). Furthermore, RT-PCR analysis of proteins from liver tissues indicated that asperuloside dose-dependently increased the mRNA levels of fatty acid (FA) transport proteins, carnitine palmitoyl transferase 1a (Cpt1a), and acyl-CoA dehydrogenase for activation of lipid metabolism via fatty acid b-oxidation and decreased the mRNA level of fatty acid synthase (FAS) mRNA to reduce the synthesis of fatty acids in the liver of rats. This indicates that uptake of FA in liver increased FA-b-oxidation and ATP production, which in turn decreased the plasma non-esterified fatty acids levels. The increased expressions of mRNA PPARc and adiponectin activate FA b-oxidation in the white adipose tissue (WAT) of rats under HFD conditions to reduce visceral fat weight. Moreover, asperuloside increased the brown adipose tissue (BAT)- uncoupling protein-1 (UCP-1) and UCP-2 mRNA levels to increase non-shivering thermogenesis (heat) by blocking of ATP synthesis and to reduce the food intake through reduction of metabolic rate and to increase BAT weight in liver tissue [188]. Iridoid glucoside, asperulosidic acid 288, isolated from Arcytophyllum thymifolium, exhibited a strong in vitro hypoglycemic activity by inhibition of the activity of a-amylase with an IC50 value of 69.4 ± 3.1 µM. It also showed moderate inhibitory activity against a-glucosidase [189]. Oral administration of geniposide 23 (200 and 400 mg/kg) for 2 weeks to HFDand STZ-induced type 2 diabetic mice, significantly decreased serum blood glucose, TC and TG levels in diabetic mice in a dose-dependent manner. Geniposide also decreased the expression of glycogen phosphorylase (GPase) and glucose 6-phosphatase (G6Pase) at mRNA levels. Thus, geniposide-induced hypoglycemic effect in diabetic mice, at least in part, by inhibition of GPase and G6Pase activities [190]. Possibly, geniposide exhibited its antidiabetic effect after its biotransformation into its aglucone, genipin 41, which exerts antidiabetic effect through inhibition of the expression of uncoupling protein 2 (UCP 2) in pancreatic beta cells. UCP 2, a member of inner mitochondrial membrane anion carrier protein, regulates

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glucose-stimulated insulin secretion. Several lines of evidence indicate that an over-expression of UCP 2 in pancreatic beta cells induces the suppression of glucose-stimulated insulin secretion by the b-cells and develops type 2 diabetes. Moreover, it is reported that pancreatic islets from UCP 2 gene knockout mice restore insulin secretion and increase serum insulin level than those of wild-type mice. Possibly, genipin stimulates insulin secretion in b-cells through improvement of mitochondrial membrane potential to increase the ATP production via closing of KATP channels [191]. In another study, oral diet supplementation of geniposide (0.1 and 0.3% in normal diet) to diabetic TSOD mice for a period of 4 weeks significantly ameliorated the obesity in mice by suppression of body weight, visceral fat accumulation and plasma insulin, glucose, TC and TG levels in mice in a dose-dependent manner. The higher dose of geniposide also increased the ratio of HDL/TC in the plasma of mice. In an in vitro study, genipin treatment (100 µM) in HepG2 cells culture exposed to free fatty acids for 48 h showed significant increase of PPAR-a expression and reduction of TC and TG concentrations in HepG2 cells. These findings indicate that geniposide via genipin formation reduces the fatty acids level in liver of mice through increased expression of fatty acid oxidation related gene, PPAR-a [192]. In an animal model, administration of genipin (25 mg/kg/day, i.p.) for 12 days to 18-month-old SD diabetic rats, significantly ameliorated insulin resistance, and hyperglycemia through inhibition of hepatic oxidative stress and improvement of mitochondrial dysfunction in the rats. Genipin improved insulin sensitivity in rat liver by promoting insulin-stimulated glucose consumption and glycogen synthesis, inhibiting cellular ROS production and increasing the levels of MMP and ATP compared to those of control group of rats. Pretreatment of genipin treatment in LO2 hepatocytes significantly decreased oxidative stress through down-regulation of JNK phosphorylation and up-regulation of Akt activation [193]. In a study of molecular action of genipin in antidiabetic activity, Zhou et al. [194] reported that genipin suppressed the phosphorylation of IRS-1 proteins through up-regulation of JNK activity for insulin-stimulated glucose uptake in 3T3-L1 adipocytes. While Ma et al. reported that genipin stimulated glucose uptake in mouse skeletal muscle cells (C2C12 myoblasts) culture in a time- and dose-dependent manner with maximal effect at 2 h of treatment and at the concentration of 10 µM by increasing insulin secretion through an insulin receptor substrate-1 (IRS-1) and calcium-dependent mechanism. Genipin stimulated glucose uptake in skeletal C2C12 cells by translocation of GLUT4 proteins from cytoplasm to cell surface through inhibition of the activity of uncoupling protein 3 (UCP 3) and increasing the phosphorylation of IRS-1, Akt, and GSK3b. At the same time, it increased ATP levels, closed the cell membrane KATP channels, and increased the concentration of Ca2+ in the cytoplasm. The effect of genipin in glucose uptake was reversed in presence of wortmannin (an inhibitor of PI3K) and calcium chelator EGTA [195]. Loganin 18 and morroniside 70, isolated from C. officinalis fruits, on oral administration (200 mg/kg) for 4 weeks in STZ-induced diabetic mice, significantly ameliorated the diabetic complications by lowering the serum glucose and MDA levels and activity of aldonic reductase (AR), and elevating the activity of SOD in diabetic mice. Treatment of loganin and ursolic acid mixture (1:1) (200 mg/kg) to diabetic mice for

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4 weeks showed better hypoglycemic effect. Furthermore, treatment of loganin and morroniside in HepG2 cells culture showed significant glucose uptake by HepG2 cells after 24 h of incubation. Both these compounds also showed a-glucosidase inhibitory activity with IC50 values of 3.54 ± 0.33 and 2.77 ± 0.19 mg/ml, for loganin and morroniside, respectively [196]. In another study, oral administration of iridoid fraction extract of C. Fructus (20 mg/kg/day, p.o.) for 10 days to diabetic rats ameliorated diabetic-related advanced glycation endproduct (AGE) accumulation in liver and kidney of rats [197]. These findings indicate that either these iridoids or their parent extract of C. Fructus could be effective in prevention of diabetes. Swertiamarin 68 from Indian Enicostemma littorale, on oral administration (50 mg/kg) for 40 days in experimental non-insulin dependent diabetes mellitus (NIDDM) rats, significantly enhanced insulin sensitivity via modulation of carbohydrate and fat metabolism through regulation of the activity of PPAR-c and its regulatory genes. Study of pathogenesis indicated that swertiamarin inhibited the activities of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) and G6Pase to reduce the hepatic cholesterol and glucose levels and improved the levels of GLUT 4, adiponectin, sterol regulatory-element-binding protein-1c (SREBP-1c), and lipoprotein lipase-1 (LPL-1) to normal levels to overcome the insulin resistance in rats [198]. Oleuropein 80 from olive oil, on treatment (3 and 5 mg/kg, i.p.) for 56 days to STZ-induced diabetic rats, showed significant antidiabetic effect by attenuation of oxidative stress through restoration of the activities of hepatic antioxidant enzymes, SOD and CAT as well as by reducing the elevated plasma glucose level [199]. In another study, oral administration of oleuropein (20 mg/kg/day, p.o.) to alloxan-induced diabetic rabbits for a period of 16 weeks significantly lowered the elevated levels of serum MDA and glucose through improvement of the activities of most of the enzymatic and non-enzymatic antioxidants such as SOD, CAT, GSH, and GSH-Px toward normal for amelioration of diabetic complications [200]. Therefore, consumption of extra virgin olive oil as diet supplement might have beneficial effect for prevention of diabetes. The in silico study of some reported antidiabetic iridoid and secoiridoids in insulin-sensitivity-related targets reveals that glycogen phosphorylase a (GPase) is a common target for exhibition of antidiabetic activity through inhibition of glucose release from storage of glycogen in liver and muscle. These iridoid compounds inhibited the activity of the enzyme preferably binding with the enzyme at the site of pyridoxal-5′-phosphate (PLP). Among the tested iridoids, oleuropein, swertiamarin, morroniside, loganin, loganic acid, genipin, anhydrogenipin, and aucubin showed good binding interactions at the PLP site of the enzyme with docking energies in the range of −3.8 and −7.38 kcal/mol [201]. An aqueous extract of Fraxinus excelsior seeds rich in secoiridoid content, on oral administration (20 mg/kg/day) for 15 days to both normal and STZ-induced diabetic rats, exhibited significant hypoglycemic activity by reducing serum glucose levels in both normal and diabetic rats without affecting plasma insulin concentrations [202]. In another study in humans, oral intake of an aqueous extract of F. excelsior seeds (1 g in normal diet daily) by glucose-induced glycemic

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volunteers showed significant hypoglycemic effect by reducing serum glucose level and improving insulin secretion. Nuzhenide 82 and GI3 441 present as major constituents in this extract, possibly exhibited this hypoglycemic effect of the extract [203]. Secoiridoids, nuzhenide 82, GI3 441, excelside B 433, and oleoside dimethyl ester 440, isolated from F. excelsior seeds extract, significantly activated PPAR-a in PPAR reporter cell line system and inhibited adipocyte differentiation in 3T3-L1 cells in the concentration range of 10−4 M, comparable to those of synthetic PPAR-a activator, WY14,643. These findings indicate that F. excelsior extract possibly exhibited its antidiabetic effect, at least in part, through inhibition of adipocyte differentiation and PPAR-a-mediated pathway [204].

5.2.8

Renoprotective Activity

Diabetic nephropathy or diabetic kidney damage is the most common cause of renal disease in Western world and is associated with increased cardiovascular morbidity and mortality. It occurs from induction of vascular injury through a complex process of overlapping of metabolic and hemodynamic factors, including formation of advanced glycation endproducts (AGEs), polyols, activation of enzyme, protein kinase C (PKC), generation of ROS, increased glomerular filtration rate (GFR), activation of angiotensin-converting enzyme (ACE), and angiotensin II hormone. The high GFR and high concentration of albumin in urine are considered as hallmarks of early diabetic nephropathy. Transforming growth factor-beta (TGF-b) is a key player for induction of various cellular metabolic pathways through Smad-3 signaling for accumulation of excess extracellular proteins (ECM) in diabetic kidney resulting glomerulosclerosis, tubulointerstitial fibrosis and renal dysfunction [205]. The activity of AGEs is mediated by interaction with their receptor (RAGE). Thus, inhibition of AGE and RAGE activity is a potential target for treatment of diabetic nephropathy. The enhanced levels of urinary heme oxygenase-1 (HO-1) and creatine are closely related to urinary albumin/creatinine ratio and are considered as biomarkers of diabetic renal injury in early stages [206]. Morroniside 70, a major bioactive constituent of C. Fructus, on oral administration (20 and 100 mg/kg/day) for 20 days in STZ-induced diabetic rats showed significant protective effects against diabetic-induced renal damage by decreasing the elevated levels of serum glucose, glycosylated proteins, urea nitrogen, and urinary albumin and creatinine. At the higher dose, morroniside significantly reduced the enhanced levels of RAGE, CEL, and HO-1 in renal cortex and elevated levels of serum and renal mitochondrial thiobarbituric acid-reactive substances (TBARS). Thus, morroniside exhibits its renal protective effects via inhibition of hyperglycemia and oxidative stress [207]. Loganin 18, another bioactive constituent of C. Fructus, significantly improved diabetic nephropathy in diabetic nephropathic mice. Feeding of loganin as diet supplementation (0.02 and 0.1 g/kg with high AGE food) to STZ and AGE food diet-induced diabetic mice for 12 weeks effectively improved the diabetic-induced renal complications by reducing kidney/body

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weight ratio, urine protein levels, and serum levels of glucose, urea nitrogen, and creatinine in diabetic mice to different degrees compared to the control group. Furthermore, loganin improved the histology of pancreas and kidney by alleviating the disordered arrangement of acinar cells in pancreas and enlarged mesangial region in kidney. In addition, loganin significantly reduced the AGE and MDA levels and increased the levels of SOD in serum and kidney and down-regulated mRNA and protein expressions of RAGE in the kidney of diabetic mice. These protective effects of loganin were very similar to those of positive control, aminoguanidine (0.1 mg/kg). These results indicate that loganin suppresses the AGE–RAGE pathway and reduces oxidative stress in kidney to improve diabetic nephropathy in diabetic mice [208]. Therefore, consumption of C. Fructus as nutraceutical diet might have beneficial effects for elderly diabetic persons.

5.2.9

Antiglycation Activity

The formation and accumulation of advanced glycation endproducts (AGEs) on long-lived plasma proteins and sugars are frequently observed in age-related chronic diseases, such as diabetes, chronic renal failure, neurodegenerative diseases, osteoarthritis, non-diabetic atherosclerosis, and chronic heart failure. These AGE proteins are usually accumulated in vascular basement membranes leading to vascular damage. Cardiovascular and connective tissue disorders are very common in patients of chronic renal diseases from excessive accumulation of AGE in kidney, which lead to kidney failure [209]. Deacetylasperulosidic acid 290 and loganic acid 146, major iridoid constituents of noni (Morinda citrifolia) fruits and other edible fruits, exhibited significant in vitro antiglycation activity by inhibiting the glycation formation in a concentration-dependent manner, with respective IC50 values of 3.55 and 2.69 mM in skin autofluorescence assay using aminoguanidine as positive control [210]. Therefore, consumption of noni fruit juice as diet supplement might be effective in prevention and treatment of AGE-related chronic diseases.

5.2.10 Pancreas Protective Activity Acute pancreatitis (AP) is an inflammatory disease of pancreas and is associated with lung injury in most cases. For this reason, pulmonary injury is considered as a devastating complication of AP. AP is caused by the damage of pancreatic exocrine acinar cells from over-expression of inflammatory mediators, TNF-a, IL-1b, and IL-6, which have been found to be enhanced in both experimental pancreatitis and pancreatitis patients. Acinar cells are the major functional units of pancreas for synthesis, storage, and secretion of digestive enzymes, a-amylase, lipase, and proteases. On activation by GLP-1, it transports these digestive enzymes in the duodenum for digestion of food.

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Damaged acinar cells in the presence of intracellular Ca2+ influx, release inflammatory mediators, to block the secretion of vesicle-associated membrane protein-8 (VAMP-8) from vesicle SNARE proteins, resulting reduction of secretion of digestive enzymes [211]. Loganin 18, a major iridoid constituent of C. Fructus, on oral pretreatment (100 mg/kg) to cerulein-induced AP in mice, showed significant reduction of pancreatic damage and AP-associated lung injury. The antipancreatitis effect of loganin was associated with the reduction of MPO activity, pancreatic weight-to-body weight ratio, and the serum levels of pro-inflammatory cytokines, TNF-a and IL-1b. While the post-treatment of loganin at the same dose failed to improve pancreatic damage and biochemical parameters of AP, but significantly inhibited cerulean-induced activation of NF-jB proteins and elevated levels of inflammatory genes, TNF-a and IL-1b in the pancreas. These findings indicate that loganin exhibits protective effects against AP and its pulmonary complications through inhibition of NF-jB activation and consequent reduction of pro-inflammatory cytokines levels. Therefore, consumption of C. Fructus as diet supplement may be beneficial for prevention and treatment of AP [212].

5.2.11 Antitumor/Anticancer Activity Inflammation has long been associated with the development of cancer in humans. Cancer results from the outgrowth of a clonal population of cells in a tissue. Both cancer cells and their consequent tumor growth are the essential features or hallmarks of cancer. Cancer is induced by inflammatory mediators through genomic changes in DNA such as point mutation, gene deletion and amplification and chromosomal rearrangements leading to irreversible cellular changes in cancer cells. Tumor development is promoted by the survival and clonal expansion of these initiated cancer cells, and subsequently, it is progressed through a substantial growth in tumor size. The key features in cancer-related inflammation (CRI) are the infiltration of leukocytes and tumor-associated macrophages (TAMs), presence of messengers of inflammation, cytokines, and chemokines, such as CCL2 and CXCL8 and occurrence of tissue remodeling and angiogenesis. The important players of CRI are transcription factors, such as nuclear factor kappa-B (NF-jB) and signal transducer activator of transcription 3 (STAT3) and primary inflammatory cytokines, IL-1b, IL-6, and TNF-a. The transcription factor NF-jB protein activation plays a central role for induction of tumorigenesis through induction of expressions of inflammatory cytokines, adhesion molecules, some key enzymes, COX-2 and iNOS, and other growth factors. STAT-3 is a major controller of cancer cell proliferation and survival through regulation of several proteins expressions including Bcl-2. Malignant cells induce matrix metalloproteases (MMPs) to penetrate the extracellular matrix and basement membrane for tumor growth by angiogenesis. Therefore, down-regulations of tissue-specific CRI mediators are the targets for cancer therapy [213]. Aucubin 13, a major constituent of Aucuba japonica, showed significant antitumor effect against human non-small-cell lung cancer A549 cells with an IC50

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value of 12.5 µM after 24 h of treatment. Aucubin exhibited its antiproliferative effect on tumor cells by cell cycle arrest at the G0/G1 phase through induction of the expressions of p53 and p21 proteins in A549 cells. The p53 proteins consequently induced the expression of cell surface receptor protein Fas and its ligand, FasL. Interactions of Fas with FasL, and FasL-induced activation of caspase 8, activated a series of caspase cascades resulting in apoptotic death of cancer cells. Pretreatment of A549 cells with Fas antagonist ZB4 or a caspase 8 inhibitor, Z-IETD-FMK, blocked the apoptotic activity of aucubin suggesting the involvement of the Fas/FasL signaling pathway in the apoptosis in A549 cells [214]. DNA topoisomerases are closely associated in DNA translation, transcription, and replication. Therefore, anticancer drugs that act as inhibitors of DNA topoisomerases in cancer cells could be a promising therapeutic target to combat cancers [215]. Aucubin 13 and geniposide 23 were found to inhibit the activity of DNA topoisomerase 1 in cancer cells via formation of covalent DNA–topoisomerase cleavage complex [216]. In another study, aucubin 13, catalpol 14, geniposide 23, geniposidic acid 289, and harpagoside 499 did not exhibit cytotoxicity in cultured human prostate DU145, breast MDA-MB-231, and multiple myeloma U266 cancer cells at the tested concentration of 150 µM, whereas their hydrolyzed (H)-products showed significant cytotoxicity against these tumor cells at this concentration. Among these H-iridoids, H-aucubin, H-catalpol, H-geniposide, and H-geniposidic acid showed significant toxicity in DU145 cells. In addition, H-geniposide exhibited significant toxicity against MDA-MB-231 cells, while H-catalpol showed significant toxicity on U266 cells. Among these H-iridoids, H-catalpol and H-geniposide exhibited most potent toxic effects on these tumor cells. The study of molecular mechanism of cytotoxicity on these tumor cells indicated that H-geniposide exhibited its cytotoxic effect through suppression of the STAT-3 activation in DU145 cells in a concentration-dependent manner through down-regulation of upstream tyrosine kinases JAK-1 and c-Src levels and cell survival proteins Bcl-2, Bcl-xL, survivin, and cyclin D1 levels. In addition, H-geniposide-induced apoptosis of tumor cells through accumulation in the sub-G1 phase via caspase-3 activation. Several accumulating evidence indicate that STAT 3 activation is closely linked to the growth of a variety of tumor cells including prostate cancer, multiple myeloma, breast cancer, head and neck squamous cell carcinoma, lymphomas and leukemia, brain tumor, nasopharyngeal and pancreatic cancers. Therefore, suppression of STAT 3 activation could be a powerful target in cancer therapy [217]. The study of genipin-induced apoptosis of multiple myeloma U266 and U937 cells by another group revealed that genipin suppressed the activation of STAT 3 by repressing the activation of c-Src, but not JNK-1 and down-regulating the expressions of STAT 3 target genes, Bcl-2, Bcl-xL, survivin, cyclin D1, and VEGF. This effect of genipin is blocked in presence of protein phosphatase inhibitor, pervanadate. Furthermore, genipin potentiated the cytotoxic effect of some chemotherapeutic agents, bortezomib, thalidomide, and paclitaxel in U266 cells [218]. In another study, genipin 41 exhibited significant toxic effect against rat hepatoma FaO and human Hep3B, prostate PC-3 and cervical carcinoma HeLa cells. In HeLa cells, genipin showed toxic and antiproliferative effects in a

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dose-dependent manner with IC50 value of 90 µg/ml. Genipin at a higher dose (90 µg/ml) induced apoptosis in HeLa cells by cell cycle arrest at G1 phase and significantly increasing the expression of p-JNK, phospho-p53 and Bax proteins through activation of JNK [219]. Genipin also exhibited significant antitumor effect against steroidogenic human granulose-like tumor KGN cells. Genipin at 300 µM concentration induced apoptosis of KGN cells by increasing the expression of mitogen-activated protein kinases (MAPKs), p38 and JNK MAPKs and down-regulating the expression of ERK1/2. In addition, genipin elevated the levels of p53 and Bax proteins, and down-regulated the level of Bcl-2 proteins and activity of caspase 3 proteins. These findings indicate that genipin induces apoptosis in tumor cells mainly by activation of mitochondrial pathway [220]. Genipin was found to exhibit strong antitumor effect against human non-small-cell lung cancer H1299 cells with an IC50 value of 351.5 µM. Genipin-induced cell cycle arrest at G2/M phase and apoptosis of the tumor cells by up-regulation of Bax and down-regulation of Bcl-2 proteins, release of cytochrome c, and activation of caspases 9 and 3. Co-treatment of p38 MAPK inhibitor, SB203580, reversed the effects of genipin. This indicates that genipin exhibits apoptosis of H1299 cells through p38 MAPK-mediated activation of Bax proteins via mitochondrial death cascade [221]. Takagi et al. evaluated antitumor efficacy of aucubin 13, scandoside methyl ester 282, geniposide 23, loganin 18, sweroside 67, gentiopicroside 69, and gardenoside 567 and their aglucones, on treatment in mice bearing experimental tumor leukemia 388 cells. None of the iridoid glucosides showed any activity, while most of their aglucones were found to exhibit activity. Among the tested iridoid aglucones, scandoside methyl ester aglucone (SMEH) showed most potent activity at an i.p. dose of 100 mg/kg maximum total/control (T/C) value of 162%. SMEH also showed strong antitumor activity on treatment (5–100 mg/kg, i.p.) to mice bearing Ehrlich ascites carcinoma in a dose-dependent manner. At the dose of 100 mg/kg, all the mice were survived for more than 30 days and this effect was better than that of 5-fluorouracil. Treatment of SMEH in Meth A and Sarcoma 180-infected mice showed significant antitumor activity by increasing the life spans of mice by 81.8 and 94.4%, respectively, at the i.p. dose of 50 mg/kg. Thus, SMEH could be a prospective antitumor drug for future study [222]. Pentaacetylgeniposide 23a, isolated from a modified extract of Gardenia Fructus, exhibited antitumor activity against brain tumor C-6 glioma cells culture through inhibition of DNA synthesis of the cells, but had little effect on RNA and protein synthesis [223]. In an animal model, pretreatment of pentaacetylgeniposide (5 and 10 mg/kg/day, i.p.) for 5 days in rats inoculated with tumor C-6 glioma cells showed inhibition of tumor growth by 41 and 75%, respectively, after 7 weeks and prolonged the latency period of T50 (time for 50% tumor incidence). In post-treatment experiments, the tumor growth inhibition was less. Pentaacetylgeniposide showed no significant toxic effect on oral administration at the tested dose of 10 mg/kg in rats after a period of 7 weeks [224]. All these reported antitumor studies indicate that aucubin, geniposide, and its aglucone genipin and pentaacetyl derivative, and scandoside methyl ester aglucone could be effective drugs in treatment of cancers.

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8-O-Acetylharpagide 12a, a major constituent of A. decumbens, showed significant antitumor effect against mouse-skin tumors. In an in vitro assay, it inhibited the growth of tumor cells on TPA-induced Epstein–Barr virus early antigen in Raji cell culture. In an animal model, treatment of 12a (85 nM) in 7,12-dimethylbenz[a]anthracene (DMBA) and TPA-induced skin tumor promotion in mice showed only 10, 20, and 80% of mice bore papillomas at 8, 10, and 17 weeks of promotion, respectively. Its inhibitory effects were more potent than those of positive control, glycyrrhetic acid. In another experiment, oral treatment of this iridoid (2.54 mg/ mouse/week) to glycerol and 4-nitroquinoline-1-oxide-induced pulmonary tumors in mice significantly reduced the percentage of tumors (0.9 tumors per mouse) after 22 weeks of treatment in mice [225]. In another study, treatment of 12a (0.0025%/ mouse/week, p.o.) for 20 weeks in mice bearing skin carcinogenesis induced by NO donor, (±)-E-methyl-2-[E-hydroxyimino]-5-nitro-6-methoxy-3-hexenamide and TPA, significantly ameliorated the skin carcinogenesis in mice. Furthermore, oral administration of 12a (0.0025%/mouse/week) for 25 weeks to mice with hepatic tumor-induced by N-nitrosodiethylamine and phenobarbital, showed significant reduction of tumor in hepatic tumorigenic mice. Therefore, 8-O-acetylharpagide could be useful in prevention of chemical carcinogenesis [226]. UVB-irradiation-induced transactivation of Activator Protein-1 (AP-1) plays a key role in promotion of skin cancer. Therefore, inhibition of AP-1 activity leads to suppression of skin tumor promotion. Iridoids, citrifolinin A 765 and citrifolinoside 663, isolated from noni leaves, exhibited significant inhibitory effect on UVB-induced AP-1 activity in cultured mouse-skin epidermis JB6-P+ 1–1 cells with respective IC50 value of 69.6 and 29.0 µM. These findings indicate that noni leaf extract may be useful in skin tumor prevention and treatment [227] Phlomiol 377b, isolated from Phlomis younghusbandii, on oral treatment (2.5, 5.0, and 10 mg/kg) for 14 days to tumor bearing mice inoculated with S180 and H22 cells, showed dose-dependent antitumor effect with an inhibitory rate of 28.5– 65.0% and 35.0–74.5%, respectively [228]. Oleuropein 80, a major constituent olive oil, in an in vitro assay, inhibited proliferation and migration of advanced grade human tumor cell lines, erythroleukemia TF1a, renal adenocarcinoma 786O, ductal breast carcinoma T47D, malignant skin melanoma RPMI7951, colorectal adenocarcinoma LoVo, and normal human skin fibroblast NLFib cells culture in a dose-dependent manner. Oleuropein in a concentration of 0.025% almost completely inhibited their cell proliferations after 5 days of treatment and in a concentration of 0.01% completely inhibited the mobility of the cell lines. Oleuropein treatment in a concentration of 0.01% in the breast cancer MCF-7 cell line culture dramatically disrupted the organization of actin filaments within the cells and induced cell rounding after 2 h. In animal model, oral administration of oleuropein (1%/kg in diet/day) for 12 days in mice bearing breast tumor completely regressed the tumors [229]. In another animal study, oral administration of oleuropein (10 and 20 mg/kg, twice daily) for 30 weeks to UVB-irradiation-induced skin tumors in hairless mice, prevented the tumor growth and skin carcinogenesis by decreasing the elevated expressions of matrix metalloproteinases, MMP-2, MMP-9, and MMP-13, and of vascular

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endothelial growth factor (VEGF) and COX-2 [230]. Oleuropein was found to inhibit the proliferation and migration of human lung carcinoma A549 cells culture with an IC50 value of 59.96 µM through reduction of intracellular ROS and MDA levels [231]. Treatment of oleuropein as diet supplement (125 mg/kg of diet) to MCF-7 cells xenografted ovariectomized nude mice for 28 days significantly prevented weight loss and both peripulmonary and parenchymal lung metastasis of breast cancer in xenografted mice [232]. In an in vitro study, oleuropein at the concentration of 200 µg/ml in the MCF-7 breast tumor cells culture for 24 h induced the cell death by cell cycle arrest at G1 phase [233]. All these reported evidence indicate that oleuropein could be a chemopreventive agent in cancers. Prismatomerin 611, isolated from the leaves of Bangladeshi shrub, Prismatomeris tetrandra, showed remarkable in vitro antitumor activity against four mammalian tumor cell lines, L-929, KB-3-1, A-549, and SW-480 with IC50 values of 0.21, 0.41, 1.41, and 0.06 µM, respectively, in SRB protein assay. In addition, this compound induced apoptosis of solid tumor A-498, PC-3, and MCF-7 cell lines with LC50 values in the range of 100–0.6 µM [234]. Iridoid lactone plumericin 60, isolated from Brazilian Allamanda schottii, exhibited moderate toxicity against cancer cell lines, melanoma B16F10, leukemia Nalm6, fibroblast L929, leukemia K562, HeLa and breast MCF-7 cells with respective IC50 value of 3.8 ± 1.7, 92.4 ± 10.7, 161.9 ± 25.5, 111.1 ± 27.6, 24.5 ± 13.4, and 121.7 ± 60.0 µM [235]. In another study, plumericin inhibited the proliferation of leukemia NB4 cells with an ED50 value of 4.35 ± 0.21 µg/ml [236]. Iridoids, plumericin 60, allamandin 130, allamcin 132, and fulvoplumericin 161, isolated from Indonesian Plumeria rubra, showed significant toxicity against leukemic P-388, and human breast, colon, fibrosarcoma HT-1080, lung, KB and melanoma cancer cells with ED50 values in the range of 0.1–4.6 µg/ml. Among them, plumericin, allamandin, and allamcin showed strong cytotoxic effects [237]. Allamandin also exhibited antileukemic effect on treatment in mice bearing leukemic P-388 cells [238]. Plumericin 60, isoplumericin 62, and allamandin 130 exhibited toxic effects against human nasopharyngeal carcinoma 9KB cells with ED50 values of 2.6, 2.7, and 2.1 µg/ml, respectively [239]. Picroliv, a mixture of picroside I 532 and kutkoside 15, on treatment (150 µg/ ml) in cultured chronic myeloid leukemic KBM-5 cells, exhibited antiproliferative effect through inhibition of NF-jB activation. Picroliv induced both antiproliferative effect and apoptosis in leukemic cells by suppression of the expressions of cell survival proteins, survivin, Bcl-2, Bcl-xL, inhibitor of apoptosis protein-1 (IAP-1) and TNF receptor-associated factor-2 (TRAF-2), and proliferative proteins, cyclin D1 and COX-2 and invasive proteins, MMP-9, ICAM-1, and VEGF [240]. In another in vitro study, picroliv inhibited both invasion and migration of breast cancer MCF-7 cells through down-regulation of the expressions of MMPs, MMP-1, MMP-2, MMP-9, and MMP-13 in the cancer cells [241]. An oral administration of picroliv (100 and 200 mg/kg/day, p.o.) in 20-methylcholanthrene (20-MC)-induced sarcoma in mice for 200 days, inhibited sarcoma development by 47 and 53%, respectively. All the control animals died after day 170 of 20-MC administration, while 60 and 66% of animals survived in the picroliv-treated groups [242].

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Verminoside 195, veronicoside 195a, and amphicoside 192, isolated from Veronica thymoides ssp. pseudocinerea, exhibited significant toxic effect against human cancer cell lines, Hep-2, rhabdomyosarcoma RD and transgenic murine L-20B cells in the concentration range of 36–173 µg/ml [243]. Another iridoids, 4b-hydroxy-6-O-(p-hydroxybenzoyl)-tetrahydrolinaride 766 and 10-O-protocatechuylcatalpol 767, isolated from Veronica americana, showed potent toxic effect against human tumor cell lines, colon HF-6 and prostate PC-3 cells with respective IC50 values of 0.031 and 0.066 µM against HF-6 cells and of 0.721 and 0.801 µM against PC-3 cells. Their cytotoxic effects against HF-6 cells were better than camptothecin (IC50, 0.315 µM) used as positive control. Possibly, acyl group present in these compounds plays a significant role for their cytotoxic effect [173]. Aglucones of oleuropein 80 and ligstroside 79 exhibited moderate toxicity against disease-oriented 39 human cancer cell lines with GI50 values in the range of 16–88 µM. The aglucone of ligstroside also inhibited the activity of epidermal growth factor receptor (EGFR) tyrosine kinase, a key enzyme in the growth of cancer cells, showing inhibition of activity by above 50% at a concentration of 10 µM [244]. Iridoids, nudifloside 768 and linearoside 769, isolated from Callicarpa nudiflora, showed moderate cytotoxic effect against human leukemia K562 cell line, with respective IC50 value of 20.7 and 36.0 µg/ml after 72 h of incubation [245]. An iridoid glucoside, 10-O-acetylmacrophyllide 770, isolated from Thai Rothmannia wittii, was found to exhibit weak cytotoxic effect against human small-cell lung cancer NCI-H187 cells (IC50 valueof 6.82 µg/ml) [246]. Acevaltrate 771, isolated from V. jatamansi, showed significant cytotoxic effect against lung adenocarcinoma A549, metastatic prostate cancer PC-3M, colon cancer HCT-8, and hepatoma Bcl7402 cell lines with IC50 values of 2.9, 1.4, 1.0, and 1.7 µM, respectively, while other isolated iridoids from this plants, namely didrovaltrate acetoxyhydrin 772, IVHD-valtrate 241, 5-hydroxydidrovaltrate 773, and valtrate 54 exhibited strong-to-moderate cytotoxicity against these cell lines with IC50 values in the range of 1.0–7.4 µM. These iridoids and their extract could be effective in treatment of cancers [247]. Volvaltrate B 238, another iridoid constituent of V. jatamansi and other Valeriana species showed moderate in vitro cytotoxicity against human cancer A549, PC-3M, HCT-8, and Bel-7402 cell lines with respective IC50 value of 8.5, 2.0, 3.2, and 6.1 µM in an MTT assay [248a]. Valejatanin A 774, isolated from V. jatamansi, showed moderate cytotoxic effect against cancer HT29, K562, and B16 cell lines (respective IC50 value of 22.2, 15.3, and 3.5 µg/ml) [248b]. Iridoid derivatives, patriridosides G 775 and H 776, isolated from Patrinia scabra, exhibited moderate cytotoxicity against human gastric carcinoma MNK-45 cells with respective IC50 value of 8.7 and 9.4 µM [249]. Valeriana-type iridoids, patriscabioins A 758, C 759, and E 777 isolated from another Patrinia species, P. scabiosaefolia, showed strong cytotoxic effects against human tumor cell lines, HL-60, SMMC-7721, and SW-480 cells with respective IC50 values of 1.4 ± 0.02, 9.9 ± 1.52, and 1.2 ± 0.05 µM against HL-60 cells, 7.2 ± 0.29, 13.8 ± 0.17, and 7.1 ± 0.38 µM against SMMC-7721 cells, and 7.1 ± 0.35, 10.0 ± 0.28, and

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18.2 ± 0.19 µM against SW-480 cells. Their cytotoxic effects were comparable to that of cisplatin (IC50 value of 2.8 ± 0.12, 5.9 ± 0.17, and 7.6 ± 0.54 µM against HL-60, SMMC-7721, and SW-480 cell lines, respectively) [250]. 11-Methylixoside 778, isolated from Randia dumetorum, exhibited weak cytotoxic effect against human skin melanoma SK-MEL-2 cell line with an IC50 value of 63.1 µg/ml [251]. Cornifin B 267, isolated from C. officinalis leaves, showed moderate cytotoxic effect against human lung cancer A549 cell line with an IC50 value of 29.1 µM [252]. Iridolactones, triohimas A-C 86, 235, and 236, isolated from Chinese Triosteum himalayanum, showed moderate in vitro antileukemic effect against lymphocytic leukemic L1210 cell line by inhibiting proliferation of leukemic cells by 13, 11, and 18%, respectively, at the concentration of 50 µM [253]. Valeriana-type iridoids, luzonoids A-D 57, 779, 780, and 781 and their glucosides, luzonosides A 33 and B 782, isolated from Viburnum luzonicum, exhibited moderate cytotoxic effect against human epithelial cancer HeLa S3 cell line with IC50 values in the range of 3–7 µM [254]. Iridoid derivatives, luzonials A 783 and B 784, isolated from this plant, exhibited strong cytotoxic effect against HeLa S3 cells with respective IC50 value of 3.50 and 1.93 µM after 72 h of treatment [255]. Plumieride pentaacetate 34a prepared from plumieride 34 showed more cytotoxic effect against radiation-induced fibrosarcoma (RIF) tumor cells with an ED50 value of 11.8 µg/ml, compared to its parent compound, plumieride (ED50, 49.5 µg/ ml). Possibly, the acyl moieties in 34a have important roles for higher efficacy of the compound [256]. The n-butanol extract of Tibetan Pterocephalus hookeri containing dimeric iridoids, sylvestrosides I, III, and IV 221, 222, and 785, cantleyoside 89, and laciniatoside II 786, on oral administration (200 and 500 mg/kg) to hepatoma xenografted mice for 20 days, significantly and dose-dependently ameliorated the tumor by reducing the tumor weight without affecting on body weight and spleen index in mice. The study on molecular mechanism of antitumor effect revealed that the extract inhibited the phosphorylation of PDK1 and Akt and increased the expression of Bax and decreased Bcl-2 proteins levels in the tumor tissue to reduce the tumor volume. The extract also exhibited moderate-to-weak activity against the proliferation of other tumor cell lines, esophageal carcinoma ECA-109, colorectal adenocarcinoma Caco-2, cervic carcinoma HeLa, chronic myelogenous leukemia K562, breast adenocarcinoma MCF-7, and lung carcinoma A549 cells with IC50 values in the range of 102.2–318.2 µg/ml. Further study on the evaluation of antitumor efficacy of the iridoid constituents of the extract will be useful for their application in treatment of tumors [257]. Iridoids, catalposide 182, verproside 195b, veratroylcatalpol 195d, and aquaticoside C 787, isolated from different Veronica species, exhibited cytostatic activity against human sarcoma RD cells [258].

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5.2.12 Anticolitis Activity Ulcerative colitis (UC) is a chronic inflammatory disease of the colon that affects the rectum, a variable length of contiguous colon. The disease is characterized by abdominal pain, rectal bleeding, and frequent diarrhea during the period of severity of the disease and consequent weight loss. The pathogenic mechanism of UC is believed to be severe intestinal mucosal tissue inflammation due to an aberrant immune response, which activates neutrophils and enhances the formation of ROS and several pro-inflammatory cytokines such as TNF-a, IL-1b, IL-6, IL-8, and INFc via NF-jB activation. NF-jB-mediated expressions of TGF-b1, ICAM-1, and IL-8 play key roles in mucosal tissue injury and apoptosis of intestinal epithelial cells (IECs) via activation of MAPKs. Accumulating evidence indicates that the inhibition of ERK and p38 MAPK kinase pathway attenuated TNF-a-induced IL-8 secretion in human colon adenocarcinoma HT-29 cells [259]. Folium syringae leaves have long been used in traditional Chinese medicine to treat intestinal disorders such as acute enteritis and bacillary dysentery. Iridoid glycosides (IGs) extract fraction from F. syringae leaves containing syringopicroside 467 as major constituent (55.7%), on administration (160 and 240 mg/kg, p.o.) to 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats, showed significant amelioration of colon tissue damage. The histological study of colon epithelial tissue indicated that the extract significantly reduced the activity of MPO and lowered the elevated levels of MDA and NO, and of inflammatory genes, NF-jB p65, TNF-a, and IL-6 toward normal levels in the colon epithelial tissue of rats in a dose-dependent manner. The effects of the higher dose were superior to those of positive control, salicylazosulfapyridine (150 mg/kg). These results indicate that the extract ameliorates the colon tissue damage in colitis rats through improvement of antioxidant status by down-regulation of NF-jB p65 proteins expression [260]. In another study, administration of IGs extract fraction (160 and 240 mg/kg/twice daily, p.o.) to dextran sulfate sodium (DSS)-induced colitis in rats for 14 days significantly ameliorated the macroscopic damage and histological changes in colon tissue of rats. The IGs extract significantly reduced the epithelial cells apoptosis through reduction of the activity of MPO and lowering of the elevated levels of pro-inflammatory mediators, TNF-a, IL-8, COX-2, and TGF-b1. In addition, the extract blocked the activation of NF-jB transcription factor through inhibition of NF-jB p65 mRNA expression, IjBa phosphorylation/degradation, and IKKb activity and down-regulation of the proteins and mRNA expressions of Fas and FasL, Bax, caspase 3, and activated Bcl-2 proteins in colon epithelial cells in rats. These findings indicate that the IGs extract exhibits its protective effects on colitis in rats through inhibition of colon epithelial cells apoptosis via blockade of NF-jB signal pathway [261]. The IGs extract fraction of F. syringae leaves could be an effective drug in treatment of colitis after detailed study of its toxicity and side effects in long-term use. Catalposide 182, a major constituent of C. ovata, on pretreatment in TNF-a induced human epithelial HT-29 cells culture, significantly inhibited TNF-a-induced

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IL-8 mRNA accumulation and secretion and down-regulated both p38 kinase and ERK1/2 proteins activation in HT-29 cells. Furthermore, catalposide inhibited TNFa-induced NF-jB activation and IjBa degradation in HT-29 cells. These findings indicate that catalposide protected the epithelial HT-29 cells from apoptosis by lowering the levels of cell-apoptosis-related pro-inflammatory cytokine genes via inhibition of NF-jB activation [262]. These findings were also observed in an in vivo model. Intrarectal administration of catalposide (10 µg/mouse/day) to TNBS-induced colitis in mice for consecutive 3 days, dramatically reduced the weight loss, colonic damage, and mucosal ulceration in mice. Furthermore, catalposide suppressed the expression levels of TNF-a, IL-1b, and ICAM-1 and inhibited the activity of NF-jB through inhibition of translocation of NF-jB p65 proteins in the nucleus of the epithelial cells in colitis mice. Thus, catalposide may be effective in treatment of intestinal bowel disease (IBD) in humans. The extract of C. ovata has long been used in Korean herbal formulation for treatment of colonic inflammation [262].

5.2.13 Gastroprotective Activity Gastric ulcer, a common digestive disease is caused from multiple pathogenic factors such as microbial infection from Helicobacter pylori, extensive consumption of alcohol and drugs and oxidative stress. This disease is closely associated with the decrease of gastric mucosal defensive factors such as heat-shock protein 70 (HSP-70), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), calcitonin gene-related peptide (CGRP), and activities of COX-1, COX-2, and SOD in the gastric tissue. The pathogenic factors induce gastric mucosal injury through elevation of pro-inflammatory cytokines levels and reduction of some gastric mucosal defensive factors [263]. Aucubin 13 from E. ulmoides seeds, on prophylactic oral administration (40 and 80 mg/kg) for 3 days to ethanol-induced gastric mucosal injury in mice showed significant gastroprotective effect in reduction of lesions of mucosal tissue in mice. The gastroprotective effect of aucubin was associated to the histological changes in mucosal tissue such as reduction of the activity of MPO, down-regulation of the elevated levels of MDA and inflammatory genes, TNF-a and IL-6, and up-regulation of the activity of antioxidant enzymes, GSH and SOD. In addition, aucubin normalized the levels of HSP-70, EGF, VEGF, and COX-1 proteins to improve the defensive factors of gastric mucosal tissue in mice. The protective effect of aucubin was very close to that of cimetidine (100 mg/kg) used as positive control. These findings indicate that aucubin exhibits its gastroprotective effect through improvement of antioxidant status and reduction of inflammation in the mucosal tissue of mice [264a]. Secoiridoid glucosides, amarogentin 81 and ameroswerin 328, isolated from G. lutea roots, on oral administration (5 mg/kg) to ethanol-induced gastritis in rats, showed remarkable suppressive effects (33.7 and 45.4%, respectively) on gastric lesions in rats.

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Their gastroprotective effects were reversed by gastritic ulcer inducing indomethacin (5 mg/kg) pretreatment. Several studies demonstrated that indomethacin induces gastric ulceration by inhibiting the prostaglandin synthesis and reducing the release of COX-1, PGE2 and mucin in gastric juice. These results suggest that therapeutic effects of compounds 81 and 328 on gastric lesions are associated with enhanced mucosal defensive factors via the prostaglandin pathway in the cell membrane [264b]. Geniposide 23 and genipin 41, important bioactive constituents of G. Fructus, exhibited inhibitory effect against H. pylori growth in both gastric adenocarcinoma AGS cells and H. pylori-infected C57BL/6 mice. Genipin showed stronger activity than geniposide. Genipin inhibited the growth of H. pylori in infected AGS cells through reduction of vacuolating cytotoxin, vacA and cytotoxin-associated gene A, cagA genes via lowering of levels of inflammatory mediators, such as IL-8 and IFNc. In the in vivo experiments, geniposide and genipin, on treatment in H. pyloriinfected C57BL/6 mice, showed significant suppressive effects on the vacA gene expression in mice through lowering the elevated levels of serum IFN-c, IL-1b, immunoglobulins A and M, and down-regulation of inflammatory marker, COX-2 enzyme. Thus, both geniposide and genipin, and their source, G. Fructus, could be effective in prevention of gastric inflammation from H. pylori infection [264c].

5.2.14 Wound-Healing Activity Wound-healing is a process of making new collagen matrix tissue at the site of injured tissue. Acute wound-healing is characterized in four overlapping phases; hemostasis, inflammation, proliferation, and remodeling. The hemostasis phase begins immediately after wounding, with vascular constriction and fibrin clot formation. The clot and surrounding wound tissue release pro-inflammatory cytokines and growth factors such as transforming growth factor (TGF)-b, platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and epidermal growth factor (EGF) for the control of bleeding. Once the bleeding is controlled, the inflammatory phase starts with migration of inflammatory cells to the wound site, which is characterized by sequential infiltration of neutrophils, macrophages, and lymphocytes to clear the invading microbes and cellular debris. The proliferative phase follows after inflammatory phase for epithelial migration and proliferation. The fibroblasts migrate into the site of injury and produce collagen, glycosaminoglycans, and proteoglycans for formation of new extracellular matrix. The newly formed collagen matrix then starts cross-linking and organizes as new tissue in the remodeling phase [265]. Several herbal drugs are effective in wound-healing process. The decoction of roots and leaves of Buddleia scordioides is traditionally used in many countries for treatment of ulcer and wound dressing. Catalpol 14 and methylcatalpol isolated from this plant, on oral administration (50 mg/kg) to chloroform and histamine-induced microvascular skin permeability in rabbits, protected the activity of increased vascular permeability of both chloroform and histamine in the microvascular skin of rabbits by 52.9 and 65.8%, respectively.

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Their protective activities were comparatively lower than that of vasoprotective drug, troxerutin (50 mg/kg) having 71.3% inhibition. Thus, these iridoids could be useful in the dressing of wounds in the wound angiogenesis stage to prevent suppuration from oxidative damage and to increase collagen deposit by improving capillary function through reduction of abnormal leakage [266]. Acylated catalpols, scropolioside A 372c, scrovalentinoside 372e, and scrophuloside A4 372h isolated from Scrophularia nodosa seeds, showed in vitro wound-healing activity by stimulating the growth of human dermal fibroblasts in a concentration range of 100–0.78 µg/ml. Compound 372c showed the highest activity at the concentration of 25 µg/ml, while compounds 372e and 372h showed highest stimulation at 0.78 µg/ml [267]. Aucubin 13, a common iridoid glucoside isolated from several plants, on topical administration (0.1% solution) on either side of buccal mucosa of mice for 3 days, showed significant wound-healing effect by promoting early re-epithelization and collagen matrix formation compared to control group. Future study on the mechanism of action will be useful for its application as a wound-healing drug [268]. Sweroside 67 and swertiamarin 68, isolated from G. lutea, exhibited significant wound-healing activity in cultured chicken embryonic fibroblasts by stimulation of collagen production and mitotic activity. Their stimulating activity on collagen production and mitotic activity in fibroblasts were comparable to that of skin wound-healing drug, dexpanthenol [269]. Genipin 41, on application (50 mg/ml) in wound dressing nanofibers, silk fibroin and hydroxybutyl chitosan, in excision model of rats, showed significant wound-healing effect by stimulating the proliferation of fibroblast cells and collagen formation in the nanofibers. Possibly, genipin improves the wound-healing process via remodeling of collagen matrix tissue through stimulation of cross-linkage process [270].

5.2.15 Choleretic Activity The impairment of bile production and its excretion from liver into duodenum is known as cholestatic liver disorder. Jaundice, bile duct stone, biliary cirrhosis are the diseases from cholestatic liver disorder. These disorders result in the accumulation of biles in liver and damage of liver tissue. Several factors such as drugs, xenobiotics, sepsis, mechanical aberrations, genetic defects, and dysregulation of immune system are responsible for cholestatic disorders. Chronic inflammatory processes in liver tissue lead to the injury of cholangiocytes and hepatocytes, which in turn, secret cytokines and chemokines such as TNF-a, IL-1, and IFN-c that recruit and activate immune cells for repairing of the injury. The inflammatory disorders such as RA, diabetes, IBD, multiple sclerosis are closely related with the functional disorders of cholangiocytes and hepatocytes in bile uptake and its excretion. Therefore, new therapies might be developed to ameliorate the functional disorders of cholangiocytes and hepatocytes for treatment of these diseases [271].

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Picroliv, an iridoid mixture of picroside I and kutkoside, isolated from Indian P. kurroa, on oral administration (1.5–12 mg/kg) for 7 days to conscious rats and anaesthetised guinea pig, showed dose-dependent choleretic effect by inducing the increase of bile volume and the contents of bile salts and acids. It was found to be more effective than the well-known hepatoprotective drug, silymarin. Picroliv also exhibited a marked anticholestatic effect against paracetamol- and ethynylestradiolinduced cholestasis [272]. Genipin 41, a metabolite of geniposide, on administration (0.2 µM/min/100 g) to bile duct cannulation in colchicine-induced cholestasis in rats, showed significant increase of bile flow and biliary excretion. Genipin was found to stimulate the activity of multidrug resistance protein-2 (Mrp2) in the bile canalicular membrane to increase the biliary excretion. These findings indicate that colchicine-sensitive vascular transport has no role on genipin-induced activation of Mrp-2 in the canacular membrane of rats [273]. In another experiment, genipin treatment (0.5 µM/min/100 g) to estradiol-17b-glucuronide-induced cholestasis in rats protected the cholestasis in rats by changing the conformation of the substrate of P-glycoprotein (P-gp) and stimulation of Mrp-2 proteins in bile canaliculi [274]. An equimolar amount of patrinoside 29 and its aglucone, or 11-deoxypatrinoside aglucone 788, on oral administration (1 g/kg) to rats accelerated the bile secretion. Their choleretic activities nearly paralleled with that of isovaleric acid level excreted in the bile. This indicates that the hemiacetal moiety of these iridoid compounds plays an important role in exerting choleretic effects, possibly after saponification at C-1 position in the liver of rats [275]. Cyclopentanoid iridoid, a-iridodiol 117, a major iridoid constituent of Actinida polygama, on administration in both lymphokine-induced cholestasis in rats and normal rats, significantly exhibited choleretic effect by increasing the bile flow and excretion [276].

5.2.16 Ocular Hypotensive and Antifibrogenic Activities The glaucomas, most common eye diseases, are a group of optic neuropathies characterized by progressive neurodegeneration of the ganglion cells in the retina of eyes. The retinal ganglion cells, one type of retinal neurons to provide a final output of retina on visual information to the brain through projection of long axons to form the optic nerve. The mitochondrial dysfunction from elevated intraocular pressure in glaucoma leads to morphological changes in ganglion cells and ultimately results cells death and loss of vision. Thus, the loss of ganglion cells is closely related to the level of intraocular pressure, which is increased from several factors including diabetic complications. The reduction of intraocular pressure is the only proven method to treat this disease [277]. Loganic acid 146, a major constituent of cornelian cherry fruits, on direct administration of a single dose (0.7% containing 0.15% sodium hyaluronate) into conjunctival sac of rabbits, decreased the mean value of intraocular pressure

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(IOP) by about 15% after 1 h. This effect was less than that of antiglaucoma drug timolol (35% decrease of IOP), used as positive control. Possibly, loganic acid exhibits this effect through reduction of NO level in aqueous humor of rabbit eye because an increased level of NO is observed in the pathogenesis of glaucoma. Loganic acid was reported to inhibit LPS-induced NO production [278a]. Therefore, dietary consumption of cornelian cherry fruits may be effective in prevention of glaucoma of diabetic patients. In glaucoma filtration surgery, the prevention of subconjunctival scar formation is essential for successful trabeculotomy. Both conjunctival epithelium and fibroblasts are considered to be the source of TGFb in healing bleb. Genipin, on treatment in cultured human sub conjunctival fibroblast cells, was found to suppress injury-induced subconjunctival fibroblast migration and its proliferation and decreased collagen type 1 protein level, TGFb1 and a-SMA mRNA and protein expression through inhibition of Smad 2 signaling. Therefore, genipin could be useful in trabeculotomy [278b]. In another study, genipin, an active constituent of herbal medicine, inchin-ko-to, on treatment in cultured mouse lens epithelial a-TN4 cell line, showed antifibrogenic activity by suppression of the proliferation and migration of the cells and expression of a-smooth muscle actin (a-SMA), the hall mark of myofibroblast formation, through inhibition of Smad and p38 MAPK phosphorylation. Furthermore, genipin suppressed the mRNA expression of TGF-b 1 and connective tissue growth factor (CTGF) proteins. Genipin was not cytotoxic to the cells as evident from the treatment of the cells with genipin for 48 h did not increase the release of nuclear matrix protein (NMP)-41/7, death biomarker proteins to the medium. Therefore, genipin could be a chemo preventing drug in prevention of secondary cataract, posterior capsule opacification, a defect of eye lens due to formation of a hazy membrane behind the intraocular lens [278c].

5.2.17 Antioxidant Activity The oxidative damages of human tissues from excessive generation of reactive oxygen species (ROS) are the major causes for the development of various inflammatory-related diseases such as cancer, diabetes, rheumatoid arthritis, neurological and cardiovascular diseases. Therefore, antioxidant compounds could be effective drugs for prevention and treatment of these diseases. Several naturally occurring iridoids have been reported to possess strong antioxidant properties and act as powerful radical scavengers for reduction of oxidative stress in injured tissues [279]. Ultraviolet (UV) radiation has deleterious effects on human skin, such as sunburn, immune suppression, skin cancer, and photoaging. UVB (280–320 nm) radiation is most hazardous to human health. UVB-irradiation-induced skin cancer and other skin disorders occur from generation of ROS, such as superoxide anion ∙ radical (O−∙ 2 ), hydroxyl radical (OH ), hydrogen peroxide, and singlet oxygen in skin cells. These generated ROS synthesize various matrix metalloproteinases

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(MMPs), such as MMP-1, MMP-8, and MMP-13, most of them are capable to attack native fibrillar collagens. Among them, MMP-1 plays a key role for induction of skin aging through degradation of extracellular matrix tissue of skin. Aucubin 13 isolated from E. ulmoides exhibited significant photoprotective effect against UVB-irradiation-induced injury on human skin fibroblast HS68 cell line on pretreatment at the doses of 0.01, 0.1, and 1 µg/ml. At the higher tested dose, aucubin inhibited the production of MMP-1 by 57% and this effect was comparable to that of vitamin C. Aucubin exhibited this inhibitory effect on MMP-1 production through reduction of ROS generation and improvement of GSH levels in skin fibroblast cells [280]. In both 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide anion radical scavenging assays, aucubigenin, aglucone of aucubin showed more antioxidant activity than aucubin with IC50 value of 2.35 and 2.60 mg/ml, while IC50 value of aucubin was not found. In contrast, in hydroxyl radical assay, aucubin exhibited better antioxidant activity than aucubigenin with 41.4% of radical scavenging effect, compared to 6.4% scavenging effect of aucubigenin at the tested concentration of 2.5 mg/ml. Better antioxidant efficacy of aucubigenin in both DPPH and superoxide anion radical scavenging assays may be rationalized for the presence of free hydroxyl group at C-1 position, which provides greater stability of the radicals after proton abstraction [281]. Harpagide 12 and 8-O-acetylharpagide 12a, constituents of H. procumbens and other plants, exhibited weak antioxidant activity in DPPH radical scavenging assay with IC50 value of 173.5 and 294.9 µg/ml, respectively [282]. In another study, antioxidant efficacy of harpagoside 499 and harpagide 12, major constituents of H. procumbens, was evaluated in DPPH, oxygen radical absorbance capacity (ORAC), and hydroxyl radical averting capacity (HORAC) assays. In DPPH assay, both harpagoside and harpagide were almost ineffective at concentrations lower than 50 µg/ml and showed weak inhibition at 200 µg/ml, while the crude methanol extract of Hp showed about 70.6% inhibition at the concentration of 200 µg/ml. Harpagide was relatively better antioxidant than harpagoside in both DPPH and ORAC assays, while in HORAC assay, harpagoside showed better (about 2 times higher) activity than harpagide. Possibly, acyl moiety in harpagoside plays a crucial role in HORAC assay for its higher activity, because this assay measures the hydroxyl radical prevention activity of the tested sample [283]. Other harpagide derivatives, 2′-O-b-D-glucopyranosyl-6′-O-(p-methoxycinnamoyl)-harpagide 789 and 6′-O-(p-methoxycinnamoyl)-harpagide 750 isolated from Mediterranean Teucrium chamaedrys, showed strong antioxidant effect against 2-deoxyribose with IC50 values of 12.9 and 13.2 µM, respectively, and their activity was better than that of positive control, trolox (IC50, 18.0 µM). Possibly, pmethoxycinnamoyl moiety in their molecules plays a significant role to exhibit their high efficacy via stabilization of the radical through extended conjugation. These iridoids exhibited weak antioxidant capacity against oxidative damage of bovine serum albumin (BSA) proteins [284]. Verminoside 195 and specioside 180, isolated from Spathodea campanulata, exhibited strong and moderate antioxidant activity in DPPH assay with EC50 value of 2.04 and 17.44 µg/ml, respectively, while other isolated iridoid ajugol 11 from this

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plant, showed no activity in this assay. The antioxidant effect of verminoside was very close to that of standard antioxidant drug, ascorbic acid, having an EC50 value of 2.18 µg/ml [285]. In another study, verminoside 195, minecoside 194, amphicoside 192, and specioside 180, isolated from Korean Veronica peregrina, exhibited moderate antioxidant activity in ORAC assay, compared to that of trolox [286]. Iridoids, linearin 790 and canthiumoside 791 isolated from African Canthium subcordatum (formerly known as Psydrax subcordata), exhibited significant antioxidant activity in DPPH radical scavenging assay with an EC50 value of 1.12 and 2.03 µg/ml, respectively, and their activities were comparable to that of vitamin C (EC50, 1.74 µg/ml). While other isolated iridoids from this plant showed weak activity in this assay [287]. 2′-O-Caffeoylloganic acid 792 from Chinese Gentiana loureirii, showed moderate radical scavenging activity in DPPH assay with an IC50 value of 18.54 µM, comparable to that of vitamin C (IC50, 13.74 µM) [288]. 7-epi-7-O-E-Caffeoylloganic acid 793, secoiridoids, griffithosides C 794 and D 795 from Japanese Fraxinus griffithii, exhibited moderate radical scavenging activity against DPPH radical with their IC50 values of 17.4, 42.4, and 26.4 µM, respectively. The activity of loganic acid derivative, 793, was very close to that of trolox (IC50, 15.4 µM). Possibly, the acyl moiety in 793 plays a key role in its enhanced activity via stabilization of the radical [289]. 10-O-Caffeoylscandoside methyl ester 796 and 10-O-caffeoyldaphylloside 273b from Wendlandia formosana showed strong radical scavenging activity in DPPH and hydroxyl radical assays with IC50 values of 2.56 and 2.40 µg/ml in DPPH and of 0.337 and 0.144 µg/ml, respectively, in hydroxyl radicals. They exhibited weak activity in peroxynitrite assay. Their activities against DPPH and hydroxyl radicals were comparable to those of positive control, BHT (IC50 values of 2.86 and 0.151 µg/ml, respectively); while other isolated iridoids from this plant, scandoside methyl ester 282, 6-methoxyscandoside methyl ester 797, and methyl deacetylasperulosidate 272 showed moderate-to-weak activities in all these assays [290]. The C-9 iridoid glycosides, monomelittoside 533, melittoside 356 and 5-allosyloxyaucubin 798, isolated from Stachys lavandulifolia, exhibited moderate antioxidant activities in DPPH, ABTS, b-carotene bleaching and FRAP assay models. Among them, monomelittoside showed comparatively better antioxidant activity in these assays having IC50 value of 118.1, 87.2, 29.8 µg/ml, and 8.4 µM Fe (II)/g in DPPH, ABTS, b-carotene bleaching and FRAP assays, respectively [291]. Chlorinated iridoid glucosides, longifoliosides A 799 and B 800 from V. longifolia, exhibited moderate radical scavenging activities against DPPH, superoxide (NBT), and nitric oxide with IC50 values of 27 and 19 µg/ml against DPPH, 92 and 199 µg/ml against superoxide, and 149 and 285 µg/ml against nitric oxide, respectively [292]. Oleuropein 80, a major constituent of extra virgin olive oil, showed moderate nitric oxide radical scavenging activity from decomposition of sodium nitroprusside with about 50% inhibition at 75 µM; and from peroxynitrite in the aL antiproteinase inactivation assay with 80% reduction at 1 mM [293]. Oleuropein

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also exhibited strong radical scavenging activity against DPPH with an IC50 value of 40.4 µM, better than that of L-ascorbic acid (IC50, 50.3 µM) [294]. Iridoids, 6′-O-trans-caffeoylnegundoside 801, 2′-O-p-hydroxybenzoyl-6′-Otrans-caffeoylgardoside 802 and 2′-O-p-hydroxybenzoyl-6′-O-trans-caffeoyl-8-epiloganic acid 803 from Indian Vitex altissima, exhibited strong antioxidant activity in both superoxide (NBT) and DPPH radical scavenging assays with respective IC50 value of 24.3, 32.0, and 31.9 µM in superoxide and of 15.2, 10.9, and 11.4 µM in DPPH assays. Their antioxidant efficacies were better than the known reference antioxidant, 3,5-diisobutyl-4-hydroxytoluene (BHT), (IC50, 381 and 19 µM in superoxide and DPPH assays, respectively). Possibly, the acyl moiety in glucose unit in these compounds plays a key role for their high activity through stabilization of free radicals [295].

5.2.18 Antibacterial and Antifungal Activities Several human infectious diseases are caused from pathogenic bacterial and fungal infections. Among them, the most common are: amebiasis from Entamoeba histolytica, anthrax from Bacillus spp., candiasis from Candida albicans and other Candida spp., cholera from Vibrio cholera and other Vibrio spp., diphtheria from Corynebacterium diphtheriae, food poisonings from Clostridium and Staphylococcus spp., granulomatous (osteomyelitis) from fungi, Penicillium, Aspergillus, and Burkholderia spp., gonorrhea from Neisseria gonorrhoeae, meningitis from N. meningitidis and S. pneumonia, nasal sinuses from Aspergillus spp., pneumonia from S. pneumonia and Klebsiella pneumoniae, bacillary dysentery from Shigella spp., tuberculosis from Mycobacterium tuberculosis, typhoid from Salmonella typhi and other Salmonella spp., syphilis from Treponema pallidum, ringworms from Trichophyton spp., urinary tract infections from Escherichia coli, Enterococcus, and Pseudomonas spp., and peptic ulcer from H. pylori. Several fungi such as Fusarium spp., Rhizopus spp., and Rhizoctonia spp. are frequently involved in several crop diseases [296]. Plumericin 60, a major constituent of Momordica charantia vine (bitter gourd), exhibited significant antibacterial activity against E. coli, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis (Ef), Salmonella typhimurium, Streptococcus mutans, and Bacillus subtilis (Bs) with minimum inhibitory concentration (MIC) values of 250, 125, 500, 250, 250, 250, 250, and 125 µg/ml in broth dilution assay. The MIC values of Ef and Bs were much lower than that of positive control, antibiotic cloxacillin (MIC, 1000 and 500 µg/ml, respectively) [236]. In another study, plumericin 60 and isoplumericin 62, isolated from Indian Plumeria bicolor, exhibited strong in vitro antimycobacterial activity against M. tuberculosis H37Rv strain and its four multidrug-resistant (MDR) strains with MIC values of 2.1 ± 0.12 and 1.3 ± 0.15 to 2.0 ± 0.14 µg/ml for plumericin, and 2.4 ± 0.08 and 2.0 ± 0.07 to 2.6 ± 0.09 µg/ml for isoplumericin, respectively. Both plumericin and isoplumericin were 60–80 times

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more active than the standard drug rifampicin against four MDR strains [297]. Thus, both these iridoid lactones could be lead compounds for development of potential antituberculosis drugs. Furthermore, dietary consumption of bitter gourd may have beneficial effect for health. Loganin 18, loganic acid 146, secologanin 64, and cantleyoside dimethyl acetal 89a, isolated from Greek antiseptic plant, Pterocephalus perennis ssp. perennis, showed moderate antibacterial and antifungal activities against S. aureus, S. epidermidis, E. coli, Enterobacter cloacae, K. pneumoniae, P. aeruginosa, C. albicans, Candida tropicalis, and C. glabrata at the concentration of 0.1 mg/ml in disk diffusion assay, while another isolated iridoid, cantleyoside 89, showed weak activity against the tested bacteria [298]. In a study of antibacterial activity of iridoid aglucones, it was observed that the activity of an iridoid aglucone depends on the substituent at C-8 position. For instance, aglucones of aucubin 13 and galioside 280 obtained after hydrolysis with b-glucosidase showed strong antibacterial activity against S. aureus, while aglucone of gardenoside 567 was inactive against S. aureus. Possibly, the conformation of hydroxymethyl group at C-8 has a significant role in the antibacterial activity of the iridoid aglucones [299]. Ixoroside 19, boschnaloside 176a, 8-epi-loganic acid 146a, and aucubin 13 from Chinese Pedicularis kansuensis ssp. albiflora, exhibited strong antibacterial activity against E. coli and S. aureus [300]. A butanol extract of M. citrifolia fruits consisting of deacetylasperulosidic acid 290 and asperulosidic acid 288 as major constituents exhibited moderate antimicrobial activity against C. albicans, E. coli, and S. aureus. The fungus C. albicans was most sensitive to the extract, and its growth was completely arrested at the concentration of 0.8 mg/ml of the extract, while at the same concentration, the most of E. coli growth was suppressed [301]. Phloyoside I 804, pulchelloside I 687 and phlomiol 377b from Iranian Eremostachys laciniata showed moderate antibacterial activity against Bacillus cereus, Citrobacter freundii, penicillin-resistant E. coli, Proteus mirabilis, P. aeruginosa, and S. aureus with MIC values in the range of 0.05–0.50 mg/ml in a broth dilution assay. Among them, pulchelloside I was most active against B. cereus, penicillin-resistant E. coli, P. mirabilis, and S. aureus with MIC value of 0.05 mg/ml [302]. Shanzhiside methyl ester 103 from Barteria fistulosa (Passifloraceae) exhibited strong antibacterial activity against E. faecalis with an MIC value of 16 µg/ml and weak antifungal activity against Aspergillus fumigatus and Cryptococcus neoformans with MIC values of 63 and 250 µg/ml, respectively [303]. Oleuropein 80, a major iridoid constituent of O. europaea, showed moderate antibacterial activity against Lactobacillus plantarum, B. cereus, and Salmonella enteritidis [304]. In another study, oleuropein exhibited moderate and weak antimycoplasmal activity against Mycoplasma fermentans, M. hominis, M. pneumonia, and M. pirum with MIC values of 20, 20, 160, and 320 mg/l, respectively.

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Mycoplasma bacteria are vaginal pathogens, and M. hominis causes infection in newborn babies. Therefore, dietary consumption of olive oil may have beneficial effect of pregnant mothers [305a]. Dialdehydic forms of decarboxymethyl ligstroside aglycone 805 and decarbomethoxy oleuropein aglycone 806 from Manzanilla virgin olive oil exhibited significant antibacterial activity against peptic ulcer causing bacterium, H. pylori. The former secoiridoid aglycone showed strong bactericidal activity and killed all the H. pylori cells in a concentration of 1.3 µg/ml. These aglycones are present in high concentration in the virgin olive oil, and hence, this olive oil could be a chemopreventive agent peptic ulcer or gastric cancer [305b]. Linearin 790 and canthiumoside 791 from African Canthium subcordatum fruits extract showed strong antibacterial activity against three strains of V. cholerae, Shigella flexneri, and S. aureus with MIC values in the range of 8–64 µg/ml, while other isolated iridoids from this plant showed weak activity against these strains. Among the tested bacteria, S. aureus was the most sensitive to these compounds [287a]. Two iridoids, 7-O-caffeoylsylvestroside I 807 and 7-O-p-coumaroylsylvestroside I 808, isolated from Scabiosa stellata, showed strong antibacterial activity against E. faecalis with MIC value of 31.2 µg/ml and weak activity against S. epidermidis (MIC value of 62.5 µg/ml) [287b]. Gentiopicrin 69 from G. lutea exhibited moderate antibacterial activity against E. coli, S. typhimurium and S. aureus with MIC values of 0.12, 0.15, and 0.15 mg/ml, respectively, and weak activity against B. subtilis, P. mirabilis, Streptococcus faecalis, E. cloacae, and S. enteritidis with MIC value of 0.19 mg/ml [306]. Noriridoid, hydrophylin B 620 from Philippines Villaria odorata, showed moderate antibacterial activity against S. aureus, E. coli, and P. aeruginosa with MIC values in the range of 125–250 µg/ml in a broth dilution assay [307]. Sarracenin 147 from Nigerian Strychnos spinosa exhibited strong antibacterial and antifungal activities against S. aureus, Streptococcus pyogenes, Shigella dysenteriae, K. pneumonia, C. albicans, and other Candida species, C. tropicalis, C. thrusei, and C. stellatoidea with minimum bactericidal/fungicidal concentration (MBC/MFC) value in the range of 5–10 µg/ml and MIC value in the range of 1.25–2.5 µg/ml. Therefore, sarracenin could be a prospective drug for treatment of skin diseases [308]. Iridoids, rehmaglutin D 488, mussaenin A 809, 1b-methoxymussaenin A 810, 1a-methoxy-4-epi-mussaenin A 811, and 1b-methoxy-4-epi-mussaenin A 812 from Chinese Cymbaria mongolica exhibited strong antibacterial activity against B. subtilis, E. coli, and S. aureus, and their activity was very close to that of positive control, chloramphenicol; while other isolated iridoids from this plant showed weak activity against these bacterial strains [309]. Iridodial b-monoenol acetate 813 from Nepeta leucophylla showed strong antifungal activity against Penicillium citrinum and Aspergillus fumigates, while actinidine 706 from Nepeta clarkei showed strong antifungal activity against Aspergillus ochraceus. Both these compounds also exhibited moderate antibacterial activity against Bacillus anthracis and S. pyogenes [310]. Cis- and trans-nepetalactones A 814 and B 815 of Nepeta cataria inhibited the growth of Gram-negative bacterium, H. pylori at the concentration of 128 and

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64 µg/ml, respectively. These iridoid lactones may be useful in treatment of chronic gastritis disorder [311]. In another study, an essential oil fraction of catnip, N. cataria, containing nepetalactones A and B as major constituents (6 and 70.4%, respectively), exhibited significant antimicrobial activity against ten bacteria, K. pneumonia, B. subtilis, B. macerans, Brucella abortus, E. coli, Proteus vulgaris, S. aureus, S. epidermidis, S. pyogenes, and Burkholdria cepacia, and 12 fungi, Alternaria alternate, Aspergillus flavus, A. versicolor, Fusarium oxysporum, F. solani, F. tabacinum, Penicillium spp., Rhizopus spp., Rhizoctonia solani, Sclerotinia sclerotiorum, Trichophyton rubrum, and T. mentagrophytes, one yeast, C. albicans with MIC values in the range of 12.50–250 µl/ml. These findings indicate that both the oil and their major isolates of N. cataria could be useful in food and pharmaceutical preparations [312]. Swertiamarin 68 and amerogentin 81, major iridoid constituents of Indian Swertia chirata, exhibited moderate antibacterial activity against E. coli, P. aeruginosa, and B. subtilis [313]. Sweroside 67, a major constituent of Anthocleista spp. and Blackstonia perfoliata, showed significant antibacterial activity against B. cereus, B. subtilis, C. freundii, E. coli, and S. epidermidis [314].

5.2.19 Antiviral Activity Viruses are the most common cause of several respiratory and gastrointestinal infectious diseases. Viruses cause tonsillitis, colds, croup, bronchiolitis, influenza, pneumonia, and other respiratory tract infections. Herpes simplex virus (HSV) 1/2 infections result cold sores, encephalitis, meningitis, and genital infections. Respiratory syncytial virus (RSV) is the key player in lung infections and is the leading cause of bronchiolitis and pneumonia in infants and young children. Several evidence indicate that it secrets the cytokine IL-1b at the infected site to induce inflammation. Influenza and flu-like infections are caused by influenza A and B viruses and vesicular stomatitis virus (VSV). Rotavirus, astrovirus, Norwalk-like virus (NLV), and calciviruses are involved in gastrointestinal infections. Hepatic A, B, and C viruses (HAV, HBV, and HCV) are the major cause of chronic hepatitis. Toll-like receptors (TLRs) recognize these viruses and activate the innate immune responses. Although several synthetic antiviral drugs are available in the market, their clinical utility has declined because of adverse effects and widespread development of resistance [315]. Iridoids, 8-O-acetylharpagide 12a, harpagoside 499, and scorodioside 372b from S. scorodonia, exhibited in vitro antiviral activity against VSV showing cellular viability of 32.1, 43.3, and 47.8%, respectively, at the concentration of 500 µg/ml. At the same concentration, scorodioside also exhibited moderate in vitro antiviral activity against HSV-1 with cell viability of 30.6% [316]. The hot aqueous extract of dried leaves and roots of Barleria prionitis is used orally to treat bronchitis and cough in Asian countries. An inseparable iridoid

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mixture of cis- and trans-p-coumaroyl isomers of 6-O-p-coumaroyl-8-O-acetylshanzhiside methyl ester 104a, isolated from this plant, showed potent in vitro antiviral activity against RSV with an EC50 value of 2.46 µg/ml and an IC50 value of 42.2 µg/ml. This mixture was moderately cytotoxic to Hep-2 cells. Barlerin (8O-acetylshanzhiside methylester) 105, isolated from this plant, was inactive in these assays. This indicates that the presence of p-coumaroyl moiety at C-6 position in 104a was possibly responsible for this activity [317]. Iridoid, ipolamiidoside 107 isolated from Barleria lupulina, showed weak anti-HSV-1 activity with an IC50 value of 41.1 µg/ml [318]. Several evidence indicate that hepatitis C virus in co-infections with hepatitis B virus or alone lead to liver cirrhosis and hepatocellular carcinoma (HCC), and about 500 millions of people are infected with it [319]. There is a 9.6% of relative risk of HCC for males, who have hepatitis B surface antigen (HBsAg)-positive alone and a 60.2% of relative risk for males, who are positive for HBsAg and hepatitis B e antigen (HBeAg) [320]. Current treatment of HCV and HBV mainly depends on administration of interferon alone or in combination of synthetic nucleoside analog, ribavirin or telaprevir. Such treatments are often associated with several side effects such as depression, psychoses, anemia, nausea, and diarrhea [321]. In Dominican Republic, an herbal mixture containing aqueous extracts of three herbs including the flowering tops of Lamium album has been used for treatment of HCV infections. The aqueous extract of L. album was active against HCV in an HCVpp (HCV pseudoparticle) entry assay. From the methanol extract of L. album, Zhang et al. isolated an iridoid glucoside, lamalbide 377, which was inactive against HCVpp. However, its aglucones, lamiridosins A and B 816, isolated as an inseparable mixture, was found to be significantly active against HCVpp with an IC50 value of 2.31 µM in an in vitro assay. This epimeric iridoid aglucone mixture of lamiridosins A and B was almost non-toxic to Hep G 2.2.2 cells up to a tested concentration of 50 µg/ml. The study of the ability of lamiridosins A/B in inhibition of the entry of vesicular stomatitis virus-glycoprotein (VSV-G)/HCV proteins into Huh 7 cells indicates that they only block HCV viral entry and hence this epimeric mixture is a selective antiviral agent against HCV. Zhang et al. also evaluated the anti-HCV activity of another 12 iridoid glucosides and found no significant activity in the concentration of 20 µg/ml. However, the aglucones of some of them, namely shanzhiside methyl ester 103, loganin 18, loganic acid 146, verbenalin 647, eurostoside 408, and picroside II 192, exhibited significant anti-HCVpp activity with inhibitions in the range of 21.9–49% and anti-infection activity against HCVpp infections in Huh 7 cells after 24 h of incubation process in the range of 41.4– 61.2% at the concentration of 20 µg/ml. Further study on these iridoid aglucones is needed to maximize their anti-HCV activity [322]. Aucubin 13 was not active against HBV, but its aglucone suppressed the HBV DNA replication in a HepG 2.2.15 cells culture. Aucubin showed no toxicity in a broad range of tested concentrations. Therefore, aucubin may be effective in treatment of HBV infections in its aglucone form [323]. Chinese herb, Swertia mileensis, locally known as ‘Qing-Ye-Dan’, has been used in traditional Chinese medicine to treat viral hepatitis. Qing-Ye-Dan tablets

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prepared from aqueous extract of this plant are used to cure acute hepatitis with high levels of plasma alanine transaminase (ALT) and aspartate transaminase (AST) with curing rate up to 95.3% among 422 patients and 96.8% among 93 patients, respectively, according to the published clinical reports [324]. In vitro anti-HBV screening of the 50 and 90% ethanol extracts of S. mileensis whole plant showed strong inhibitory effect against HBsAg with IC50 value of 0.61 and 0.33 mg/ml, respectively [325]. Chen et al. isolated 11 unusual secoiridoid dimeric and trimeric lactones, swerilactones and evaluated their in vitro anti-HBV activity against HBV-transfected HepG 2.2.15 cell line. Among them, swerilactones A, C, D, and I (817–820) showed significant inhibitory activity against the secretion of HBsAg with IC50 values of 3.66, 1.24, 2.96, and 0.44 mM, respectively, in HBV-transfected HepG 2.2.15 cells culture. Swerilactones H and I (821 and 820) exhibited potent anti-HBV activity against HBV DNA replication with IC50 values of 1.53 and 2.58 µM in HBV-transfected HepG 2.2.15 cell line culture. The antiviral activity of swerilactone H was very close to that of antiviral drug, lamivudine (IC50, 1.00 µM). Further study on their mode of action and in animal models will be useful for their application in clinical trials [326]. Oleuropein 80, a major constituent of olive oil and few Jasminum species, exhibited in vitro anti-HBV activity against HBsAg secretion in HBV-infected HepG 2.2.15 cell line culture in a dose-dependent manner with an IC50 value of 23.2 µg/ml. In bird model, intraperitoneal administration of oleuropein (80 mg/kg, twice daily) in HBV-infected ducks significantly reduced the viral infection [327]. In another study, oleuropein exhibited antiviral activity against fish rhabdovirus, viral hemorrhagic septicemia virus (VHSV) by reducing the viral infectivity to 30% and inhibiting cell-to-cell membrane fusion in VHSV-infected cells [328]. Oleuropein was effective inhibitor of HIV-1 against viral fusion core formation in a dose-dependent manner with an ED50 value of 66 nM. Docking study indicates that oleuropein binds the integrase active site (HIV-gp41 fusion domain) of the virus through strong H-bonding and van der Waals contacts to inhibit its integration [329]. Oleuropein also exhibited in vitro antiviral activity against RSV and parainfluenza type 3 (para 3) virus with IC50 values of 23.4 and 11.7 µg/ml, respectively, in virus-infected HepG 2 cells culture. Other secoiridoids, ligstroside 79, lucidumoside C 822, and oleoside dimethyl ester 440, showed moderate antiviral activity against para 3 virus with IC50 values of 15.6, 20.8, and 20.8 µg/ml, respectively, in the same assay. Their antiviral activity was relatively less than that of RSV drug, ribavirin (IC50 value of 2.6 µg/ml) [330]. In animal model study, oral administration of oleuropein (0.05–3 mg/kg) in herpes mononucleosis-virus, hepatitis-virus, rotavirus, canine parvovirus, and feline leukemia virus-infected animals significantly ameliorated the viral infections [331]. Therefore, oleuropein could be a prospective chemopreventive drug for viral infections. 6′-O-Cinnamoylmussaenosidic acid 823 and 8-O-cinnamoyl mussaenosidic acid 112b from Saudi Arabian Anarrhinum orientale, showed weak antiviral activity against HCV protease (NS3/4A) with IC50 values of 100 and 109 µM, respectively. The positive control, HCV-I2, showed an IC50 of 1.65 µM [332].

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A vaccine consisting of iridoids, picrosides I and II in a ratio of 1:2 in combination with alum and recombinant HBsAg proteins has been patented by an Indian group for treatment against HBsAg and typhoid antigens [333].

5.2.20 Anti-amoebic Activity Amoebiasis is a parasitic disease of humans caused by waterborne transmission of parasite, E. histolytica. The parasite enters the human body through drinking water and penetrates the wall of colon and secretes histolytic enzymes on colon cells to feed upon it. Its aggravation develops ulcer in colon and abscesses in liver, lung, and brain. The commonly used amoebicide drug, metronidazole, develops adverse gastrointestinal disturbances such as nausea and diarrhea and mutagenic effects on intestinal bacteria [334]. In DR Congo, the aqueous decoction of fresh leaves of Morinda morindoides has long been used for treatment of malaria, intestinal worms, and amoebiasis [335]. The in vitro assay of the aqueous decoction and 80% methanolic extract of the leaves of M. morindoides against E. histolytica showed significant anti-amoebic activity with IC50 values of 3.1 ± 1.7 and 1.7 ± 0.6 µg/ml, respectively. From this bioactive methanol extract, few flavonoids and iridoids were isolated and assayed their anti-amoebic activity. The isolated flavonoids showed weak-to-moderate activity, while five isolated iridoids, gaertneroside 36, acetylgaertneroside 36a, gaertneric acid 824, methoxygaertneroside 825, and epoxygaertneroside 608, showed good anti-amoebic activity against E. histolytica with IC50 values of 4.3 ± 1.8, 5.4 ± 1.4, 7.1 ± 1.4, 2.3 ± 0.7, and 1.3 ± 0.4 µg/ml, respectively. Their activities were less compared to that of the parent extract and positive control, metronidazole (IC50, 0.04 ± 0.02 µg/ml). The synergistic effect of the isolated iridoids and flavonoids from the extract accounts for the higher activity of the extract compared to the activity of each of the isolated constituents. The presence of a methoxy group at C-3″ position in methoxygaertneroside and an epoxy function between C-6 and C-7 in epoxygaertneroside plays an important role in higher activity of these iridoids. These iridoids have no toxicity against MT-4 cells in the tested concentration of 250 µg/ml. These iridoids might be useful to develop potent anti-amoebic drugs [336]. Verminoside 195, specioside 180, and minecoside 194 from African K. pinnata exhibited strong anti-amoebic activity against E. histolytica with IC50 values of 0.19, 0.39, and 0.74 µg/ml, respectively. Verminoside was found to be more active than that of the positive control, commonly used anti-amoebic drug, metronidazole (IC50 value of 0.33 µg/ml). This plant has been used in African traditional medicine for treatment of dysentery and diarrhea [337].

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5.2.21 Antimalarial Activity Malaria, an endemic parasitic disease of humans, is caused by the protozoan parasites, Plasmodium species, which are transmitted in humans through blood-sucking female Anopheles mosquito. Several hundred million clinical cases of malaria are reported in each year with mortality of 1–3 million, and most of the victims are the young children from sub-Saharan Africa. The pathogenesis of this disease is not clear. Increasing cyclic fever, recurrent headaches, fatigue, nausea, and musculoskeletal pain are the common clinical signs along with hepatosplenomegaly, thrombocytopenia, and anemia as the disease develops. Over 75% of malarial infections are from Plasmodium falciparum, and the rest are from less virulent P. vivax, P. malariae, and P. ovale. Only a few effective drugs, namely chloroquine, primaquine, and artemisinin, are available in the market. All these available antimalarial drugs target the intraerythrocyte stages of P. falciparum parasite development in host liver of humans. So, there is an urgent need for development of novel antimalarials. Several new molecular targets to inhibit the growth of the parasite have recently developed. Among them, the protein kinase, JAK-2, digestive vacuole, and vestigial mitochondrion are the excellent drug targets to inhibit the parasite growth [338]. Tamura et al. isolated a phenylpropanoid-conjugated iridoid, 6′-O-acetyl methoxygaertneroside 826 and its four congeners 827–830 from the leaves of African antimalarial plant, M. morindoides, and evaluated their antimalarial efficacies. Except congener 828, all other isolated iridoids showed potent antimalarial activity against cycloguanil-resistance P. falciparum strain with IC50 values of 0.1, 4.1, 0.8, and 0.04 µM for 826, 827, 829, and 830, respectively. They prepared the potent congeners in high yields from the most abundant plant constituent 827 by oxidation. The parent iridoid 826 and its congeners showed little cytotoxicity (4.3– 13.4%) against human carcinoma KB-3-1 cells at the tested concentration of 150 µM. The ketonic functionality at C-13 position in the iridoid congener 830 plays an important role to enhance the antimalarial potency of the congener. Detail study of these iridoids in animal models will be fruitful for their utilization in treatment of malaria [339]. Swertiamarin 68 isolated from Indian E. littorale showed moderate in vitro antiplasmodial activity against chloroquine-sensitive P. falciparum strain, MRC-20 with an IC50 value of 12 µg/ml [340]. The stem bark of Heinsia crinita has long been used in DR Congo for treatment of malaria. The dichloromethane extract of the stem bark of this plant showed significant in vitro antiplasmodial activity against P. falciparum with an IC50 value of 29.2 ± 1.39 µg/ml. From this dichloromethane extract, two isolated iridoids, lamalbide 6,7,8-triacetate 831 and its aglucone, lamiridosin 6,7,8-triacetate 832 showed moderate and strong antiplasmodial effects against P. falciparum with IC50 values of 16.39 ± 0.43 and 0.44 ± 1.12 µg/ml, respectively. The ethanolic extract of the stem bark of this plant, on oral administration (200 and 300 mg/kg/day) for 3 days to P. berghei-infected mice, showed moderate antiplasmodial activity in

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mice through inhibition of parasitic growth by 27.84 ± 2.75 and 48.54 ± 3.76%, respectively. The crude extracts and isolates have no cytotoxicity against normal human fetal lung fibroblast WI-38 cells at the concentration of 100 µg/ml. Therefore, lamiridosin-6,7,8-triacetate 832 might be utilized as a lead drug for development of potent synthetic antiplasmodial drugs [341]. The stem bark of Himatanthus articulatus has been used in Amazon for treatment of malaria. The dichloromethane fraction of the ethanolic extract of the stem bark of this plant showed antiplasmodial activity against chloroquine-resistant P. falciparum W2 clone with an IC50 value of 22.9 ± 0.2 µg/ml. Pretreatment of ethanolic extract (200 mg/kg/day) for 10 days to P. berghei-infected mice significantly reduced the parasitemia by 35.4%. The extract showed little toxicity to HepG2 A16 cells in the tested concentration (CC50 > 1000 µg/ml). An oral dose of extract (5000 mg/kg) to mice for 14 days showed no adverse effects in mice. Possibly, some iridoid and other constituents present in the extract may be effective in the reduction of parasitemia [342].

5.2.22 Antileishmanial Activity Leishmaniasis, a vector-borne parasitic disease, is caused by transmission of Leishmania species in humans by phlebotomine sandflies. The disease is endemic in the large areas of tropics, subtropics, and Mediterranean basin, and mostly among the poor and neglected populations in East Africa and Indian subcontinent. Leishmaniasis consists of four main clinical varieties: cutaneous leishmaniasis (CL), muco-cutaneous leishmaniasis (MCL), visceral leishmaniasis (VL, also known as kala-azar), and post-kala-azar dermal leishmaniasis (PKDL). In CL, the patients have one or more nodules or ulcers in the skin and are infected by Leishmania major, L. tropica, L. amazonensis, L. panamensis, L. mexicana, and L. aethiopica. In MCL, the patients suffer from progressive ulcerations of mucosa, extending from nose and mouth to the pharynx and larynx, and are infected mostly by Leishmania braziliensis. In VL, the patients suffer from fever, fatigue, weakness, loss of appetite, and weight, and are infected by Leishmania donovani and L. infantum. In most cases, VL is complicated with HIV co-infections. It is more harmful, about 5 lakh new cases and more than fifty thousand deaths are reported in each year from this disease. The infections of L. donovani as extracellular promastigote forms are transmitted in humans by female sandflies, and once transmitted, the parasites are internalized by the dendritic cells and macrophages in dermis as intracellular amastigote forms. In PKDL, the patients suffer from nodular rashes and have complications of VL. Several lines of evidence indicate that cytokine IL-10 is over-expressed in most cases of VL. Earlier prescribed drugs, pentavalent antimonials, sodium stibogluconate (= pentostam) and meglumine antimoniate, and most conventional amphotericin B have been replaced by more efficient drugs, miltefosine, paromomycin, pentamidine, rifampicin, and liposomal amphotericin B for treatment of different forms of leishmaniasis [343].

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Plumericin 62, a major iridoid constituent of Peruvian H. sucuuba, exhibited strong antileishmanial activity against Leishmania amazonensis infections in macrophages with an IC50 value of 0.9 µM, and its effect was similar to that of reference drug, amphotericin B (IC50, 1.0 µM). This finding supports the traditional use of this plant for treatment of CL in Peru [344]. Iridoids, molucidin 699, and ML-F52 833 isolated from Morinda lucida, exhibited good in vitro antileishmanial activity against Leishmania hertigi with IC50 values of 4.24 and 3.38 µM after 48 h of treatment and against field strain of Ghana, Leishmania enrietii (010) promatigotes with MIC of 4.17 and 2.60 µM, respectively, after 96 h. Their activity was relatively less than that of the positive control, commonly used antileishmanial drug, amphotericin B (IC50 value of 0.1 µg/ml). With respect to toxicity against four human normal skin fibroblast, NBIRGB, lung fibroblast HF-19, lung Hs888Lu, and Chang liver cell lines, the selective index (SI) values of molucidin and ML-F52 were in the range of 1.67– 2.20 and 1.4–5.36, respectively. The study of the parasite morphology indicates that the compound ML-F52 significantly increases the ratio of normal (N) and kinetoplast (K), 2N/2K to inhibit the cytokinesis of parasite cells. Another iridoid, ML-2-3 834, isolated from this plant, showed no activity against these strains. This suggests that an ester function at C-14 in both iridoids, molucidin and ML-F52, may play a key role in the activity of the compounds. These compounds could be promising lead compounds for development of antileishmanial drugs [345]. Secoiridoid amarogentin 81, a major constituent of Indian S. chirata, exhibited significant antileishmanial activity against L. donovani by inhibiting the catalytic activity of DNA topoisomerase I interaction of the parasite through formation of binary complex with DNA at the concentration of 60 µM [346]. In animal model, administration of free amarogentin and its vesicular liposomal and niosomal forms (2.5 mg/kg in every 3 days) for 15 days to L. donovani-infected hamsters reduced the parasite load by 34, 69, and 90%, respectively, in the spleen of hamsters. These findings indicate that both liposomal and niosomal forms have more leishmanicidal property than the free form. Amarogentin showed no toxicity to normal liver function of hamster. Therefore, amarogentin could be a prospective drug for clinical application in treatment of visceral leishmaniasis [347]. Scrolepidoside 835, isolated from Turkish Scrophularia lepidota roots, showed moderate in vitro antileishmanial activity against the amastigote form of L. donovani (IC50 value of 6.1 µg/ml) [348]. The n-butanol fraction of ethanolic extract of Indian N. arbortristis seeds showed significant antileishmanial activity against L. donovani amastigotes in both in vitro and in vivo assays. From this bioactive butanol fraction, four isolated iridoid glucosides, arbortristosides A, B, and C (456, 457 and 458) and 6b-hydroxyloganin 455 showed dose-dependent (30–100 µg/ml) in vitro antileishmanial activity against L. donovani amastigotes in macrophage cultures. The major iridoid, arbortristoside A, on oral administration (100 mg/kg/day) for 5 days to L. donovani-infected hamsters, showed 79.68 ± 21.68% inhibition of parasite load in spleen after 28 days of treatment. The positive control, sodium stibogluconate treatment (10 mg/kg/day) for 5 days to L. donovani-infected

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hamsters produced 93.51% inhibition of parasite load in spleen after 28 days. Therefore, arbortristoside A might be useful as lead compound for development of potent synthetic antileishmanial drugs [349]. Picroliv, a standardized mixture of picroside I 532 and kutkoside 15, isolated from P. kurroa, was found to increase non-specific immune response and to induce a high degree of protection against the infections of L. donovani promastigotes in hamsters. Picroliv was also reported to prevent liver damage in animals associated with the use of sodium stibogluconate. On the basis of these findings, picroliv may be considered as an adjuvant to increase the efficacy of leishmanicidal drugs [350].

5.2.23 Antitrypanosomal Activity Human African trypanosomiasis (HAT), also known as sleeping sickness, is a re-emerging parasitic disease in sub-Saharan Africa with about 70 million individuals are at the risk of infections and American trypanosomiasis, also known as chagas disease affects millions of people in tropical and subtropical America. HAT is induced in human host from the bite of tsetse flies (Glossina spp.) vector of parasitic protozoans, Trypanosoma brucei, T. b. gambiense, and T. b. rhodesiense; T. b. gambiense is responsible for 98% of reported cases of HAT, while T. b. rhodesiense is responsible for rest 2% cases of HAT. HAT infects human host in two stages: infection of the lymph and blood systems followed by invasion of brain parenchyma and cerebrospinal fluid. The infection in brain causes mental changes and gradually leads to coma and death. Accumulating evidence on pathogenesis of HAT indicates that CNS showed increased levels of TNF-a, macrophage inflammatory protein-1 (MIP-1), IL-1a, IL-4, IL-6, and IFN-c. The cytokine IFN-c controls the parasite growth rate and plays a crucial role in affecting the sleeping cycles of the host. American trypanosomiasis (AT) is induced in humans via the bite of triatomid bugs, vector of the parasitic protozoan, Trypanosoma cruzi. In humans, AT infection causes fever, swelling, and damage of heart and brain. Chemoth erapeutic agents to combat these diseases are limited. The drugs suramin, pentamidine, melarsoprol, eflornithine in combination with nifurtimox are currently used for treatment of these diseases. Some natural products showed potent trypanocidal property and could be used as lead structures for drug design by synthetic modifications and optimizations of bioactivity for treatment of these diseases [351]. The ethanolic extracts of Turkish S. lepidota aerial parts and roots showed significant activity against T. b. rhodesiense trypomastigotes and T. cruzi amastigotes in an in vitro assay [352]. From this plant, isolated iridoids, catalpol 14, 6-O-methylcatalpol 192c, aucubin 13, 6-O-b-D-xylopyranosylaucubin 836, ajugol 11, ajugoside 11a, 3,4-dihydromethylcatalpol 404a, scrolepidoside 835, and ningpogenin 837 showed weak-to-moderate trypanocidal activity against T. b. rhodesiense with IC50 values in the range of 49–193 µM. None of these compounds showed activity against T. cruzi. Among them, scrolepidoside was most active against T. b. rhodesiense with IC50 value of 49 µM [348]. In silico docking

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calculations of the reported antitrypanosomal iridoids against T. brucei strain with its selected growth enzymes, trypanothione reductase, rhodesain, farnesyl diphosphate synthase, and triose-phosphate isomerase indicate that ningpogenin has extensive interactions with these target enzymes. Hence, ningpogenin could be a lead drug for synthesis of active compounds to combat T. brucei [353] Secoiridoids, diderroside 563, 7-methoxydiderroside 564, 6'-O-acetyldiderroside 565, and secoxyloganin 65, isolated from the bark of Amazonian Calycophyllum spruceanum, exhibited moderate activity against T. cruzi trypomastigotes with IC50 values in the range of 123–184 µM [354]. Tetracyclic iridoids, molucidin 699, ML-F52 833 and ML-2-3 834 (Fig. 5.1), isolated from Ghanaian antitrypanosomal plant, M. lucida, exhibited potent in vitro antitrypanosomal activity against T. brucei with their respective IC50 values of 1.27, 0.43, and 3.75 after 48 h of incubation. The study of the molecular mechanism revealed that both ML-F52 and ML-2-3 induced strong apoptosis of Trypanosoma parasite cells at the minimum concentration of 0.78 and 6.25 µM, respectively, through inhibition of paraflagellar rod-2 (PFR-2) protein expression and cell cycle alternation at G0/G1 phase in parasite flagellum in the cultured parasite cells. Accumulating evidence reveals that PFR-2 protein plays a key role in flagellum function. In an animal model, intraperitoneal administration of each compound (30 mg/kg/day) for 5 days to T. b. brucei-infected BALB/c mice showed that only ML-F52 completely cleared the trypanosome parasites and ensured survival of mice after 20 days of post-infection. These findings indicate that ML-F52 might be a lead compound for development of new chemotherapeutic agents against trypanosome [355].

5.2.24 Molluscicidal Activity Human schistosomiasis, known as snail fever and bilharzia, is a parasitic disease caused from the infections of trematode fluke worms of genus Schistosoma. Freshwater snails are infected with different species of Schistosoma, namely S. mansoni, S. japonicum, S. haematobium and release these parasites in water. Contamination of this water in drinking or bathing, these parasites enter in the body and colonize in human blood vessels. Most common symptoms of this infection are fever, abdominal pain and gland enlargement, diarrhea, bloody stool, and blood in urine. Prolonged infections results liver damage and kidney failure. The presence of parasite eggs in urine or stool is the common diagnosis of this disease. This disease is most common in Africa, Asia, and South America and about 230 million people are affected and about 2 lakh people die from it in each year. The best method for prevention of this disease is to improve the access of clean water for human use by reduction of the number of infected snails. Only an isoquinolinone drug, praziquantel, is widely used for treatment of this disease [356]. Oruwacin 63, isolated from African M. lucida, exhibited strong molluscicidal activity against different species of fresh water snails, Bulinus globusus, B. rohlfsii,

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Biomphalaria pfeifferi, and Lymnaea natalensis with LD90 values in the range of 1.3–5.3 mg/l. B. globusus and its sister species, B. rohlfsii are the intermediate hosts of S. haematobium, while B. pfeifferi is the intermediate host of S. mansoni and L. natalensis is the intermediate host of liver fluke, Fasciola gigantica. Therefore, oruwacin could be used as an effective molluscicidal agent [357]. Secoiridoids, oleuropein 80 and ligstroside 79, isolated from olive fruits, showed moderate activity against Biomphalaria glabrata snails with LD50 values of 250 and 100 ppm, respectively. B. glabrata is the intermediate host of S. mansoni [358]. Genipin 41 and its 10-acetate 41a, isolated from Madagascar molluscicidal plant, Apodytes dimidiota, showed moderate molluscicidal activity against Bulinus africanus snails with LD50 values of 25.27 and 21.72 ppm, respectively [359]. Plumericin 60 and isoplumericin 62, isolated from Thai P. rubra, exhibited significant molluscicidal activity against Biomphalaria glabrata with LD100 value for both of them is 6.25 ppm [360].

5.2.25 Anti-osteoporotic Activity Osteoporosis, a porous bone disease, is characterized by deterioration of bone mass and microarchitecture, resulting in increased bone fragility and propensity to fracture. It occurs mostly among elder men and women of ages above 60 years. Worldwide, about 9 million osteoporotic fractures are reported each year. In elder women, osteoporotic fractures mainly occur as a consequence of estrogen deficiency after menopause. Osteoblasts, osteocytes, and osteoclasts are three main types of bone cells. Osteoblasts are bone-forming cells and are embedded within the bone material as osteocytes (about 90–95% of cells in bone) and remain as bone-lining cells. Osteoclasts are multinucleated cells for bone resorption. Both osteoblasts and osteoclasts work together in a co-ordinated fashion at specific sites on the surface of trabecular bone. Osteocytes play a key role in modeling and remodeling of bone through maintenance of bone mass. An imbalance between the functions of osteoblasts and osteoclasts results in bone loss. Various pathways such as receptor activator of nuclear factor kappa-B (RANK) and its ligand (RANKL), known as RANK-RANKL and wingless-type integration site (Wnt) protein signaling pathways are involved in the regulation of the activities of osteoblasts and osteoclasts. Therefore, the main targets of anti-osteoporotic drugs are the regulation of these signaling. For instance, down-regulation of RANKL expression reduces the activity of osteoclasts and up-regulation of Wnt proteins expression increases the activity of osteoblasts in bone formation. Accumulating evidence indicates that the activation of glycolipoproteins Wnt/b-catenin signaling increases the formation of bone mass through renewal of stem cells, stimulation of preosteoblast replication, induction of osteoblastogenesis, and inhibition of osteoblast and osteocyte apoptosis and increasing the activity of low-density lipoprotein receptor-related protein-5 (LRP-5). Several studies on pathogenesis of bone loss indicate that the levels of calcium, vitamin D, and phosphate are lowered in bone tissues.

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MC3T3-E1, a clonal osteoblastic cell line, is frequently used in the study of anti-osteoporotic activity of drugs. At present, several drugs such as estrogen, raloxifene, biphosphonates, vitamin D, calcitonin, denosumab, teriparatide (parathyroid hormone), strontium ranelate, and cathepsin-K inhibitors have been used for prevention and treatment of osteoporosis. In most cases, undesirable side effects are observed in long-term use. Therefore, new drugs from natural resources are desirable [361]. Korean herbal medicine, ‘Yukmi-jihang-tang’ and Chinese medicine, ‘Liuweidihuang wan’ containing C. Fructus as major constituent, are frequently prescribed to treat osteoporosis disorders in post-menopausal women and elderly men in chronic diabetes [362]. Loganin 18 and morroniside 70, isolated from C. Fructus, exhibited significant anti-osteoporotic activity in an in vitro assay in osteoblastic MC3T3-E1 cell line culture. Treatment of both loganin and morroniside in cultured MC3T3-E1 cell line for 96 h, improved the differentiation of osteoblasts through increased secretion of alkaline phosphatase, osteocalcin and collagen-type 1 and inhibited the apoptosis of osteoblasts through down-regulation of the expressions of caspase-3, caspase-9, and RANKL proteins and up-regulation of the expression of Bcl-2 proteins. The down-regulation of RANKL significantly decreases the number of osteoclasts for suppression of bone resorption. These compounds have no proliferative effects on MC3T3-E1 cells. Thus, loganin and morroniside either alone or in combination showed the protection of osteoblasts through inhibition of their apoptosis. Possibly, these iridoids are the active principles of the prescribed drugs [363]. Ligustrum lucidum fruits (LLF) has long been used in China for treatment of osteoporosis disorders in post-menopausal problems in women and other age-related disorders such as insomnia, rheumatic pain, and low back-pain. LLF is one of the medicinal herbs officially approved by the Ministry of Health, P. R. China, as a dietary supplement [364]. Both ethanolic and aqueous extracts of LLF have been found to improve the bone properties by enhancing the mineralization process in osteoblast cells, maintaining calcium balance and serum parathyroid levels [365]. Wang et al. isolated four secoiridoid glucosides, oleoside dimethyl ester 440, oleoside-7-ethyl-11-methylester 439a, nuzhenide 82, and GI3 441 and four phenolics, tyrosol, tyrosyl acetate, hydroxytyrosol, and salidroside from aqueous extract of LLF and evaluated their anti-osteoporotic effects in osteoblastic-like UMR-106 cell line culture. Among the isolated iridoids, only nuzhenide and GI3 promoted the activity of ALP, while oleoside dimethylester, oleoside-7-ethyl-11-methyl ester, and nuzhenide significantly promoted the proliferation of the osteoblastic cells. Nuzhenide, the major isolated iridoid constituent of LLF, showed significant anti-osteoporotic effect. Further, anti-osteoporotic study of this compound in animal model could be useful for its application in treatment of osteoporosis [366]. South African H. procumbens var. sublobatum, known as devil’s claw, has long been used for treatment of patients with osteoarthritis, rheumatism, inflammation, and stomach disorders. Harpagide 12, a major iridoid constituent of the roots of this plant, exhibited significant anti-osteoporotic activity by regulation of bone mass

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formation in osteoblast MC3T3-E1 cells culture and ovariectomized (OVX)induced bone loss in mice. OVX-mouse model is widely used for the study of post-menopausal osteoporosis mimicking estrogen deficiency. Treatment of harpagide in cultured MC3T3-E1 cell line culture, harpagide improved the bone properties by stimulating the process of differentiation and maturation of osteoblast cells and suppressing the process of RANKL-induced differentiation of osteoclast cells. In the differentiation process, harpagide enhanced the mRNA expressions of ALP, osteopontin (OPN), and osteoprotegerin (OPG) and decreased the mRNA expressions of osteocalcin (OCN) and RANKL via increasing the activation of ERK phosphorylation in a concentration-dependent manner. Furthermore, harpagide decreased the expression of tartrate-resistant acid phosphatase (TRAP), a marker enzyme for the differentiation of osteoclasts. In animal model, oral administration of harpagide (2, 5, and 10 mg/kg/day) for 12 weeks to OVX-induced bone loss in mice, significantly improved the recovery of bone mineral density, trabecular bone volume, and trabecular number in femur bones in mice in a dose-dependent manner. In addition to these effects, harpagide prevented the deterioration of trabecular microarchitecture and effectively decreased the elevated serum levels of biochemical markers of bone loss, namely ALP, OCN, C-terminal telopeptide (CTx), and TRAP to the levels in mice comparable to that in sham group. Thus, harpagide might be a promising drug for improvement of age-related bone destruction disorders [367]. Harpagoside 499, another major iridoid constituent of H. procumbens var. sublobatum radix, also exhibited significant anti-osteoporotic activity in both in vitro and in vivo models. Treatment of harpagoside in cultured osteoblastic MC3T3-E1 cell line significantly induced the bone formation by stimulating osteoblast cells proliferation, alkaline phosphatase activity, and mineralization through bone morphogenetic protein-2 (BMP-2)-induced Wnt/b-catenin signaling pathway and suppression of RANKL-induced osteoclastogenesis. The study of the differentiation of the osteoblasts in harpagoside-treated MC3T3-E1 cells culture indicated that harpagoside significantly increased the mRNA expression of BMP-2 and runt-related transcription factor-2 (Runx-2) gene in a concentrationdependent manner. Harpagoside also increased the expression of b-catenin proteins and suppressed the expression of Dickkoft-1 (DKK-1), an inhibitor of canonical Wnt pathway and phosphorylation of b-catenin. Several lines of evidence have demonstrated that BMP-2 proteins are the fundamental component in bone formation and repair of bone injury, and Runx-2 gene is the master regulator of bone development and osteoblast differentiation. In an animal model, oral administration of harpagoside (2, 5 and 10 mg/kg/day) for 14 weeks in OVX-induced bone loss in mice significantly increased the bone mineral density of femur and restored the OVX-induced destruction of trabecular bone in mice. Furthermore, harpagoside protected the bone loss in mice by stimulating osteoblast differentiation and inhibition of osteoclast-induced bone resorption through lowering of the elevated levels of bone turnover markers, OCN, CTx, and TRAP proteins toward normal levels. Thus, harpagoside could be a potential candidate for management of post-menopausal osteoporosis [368].

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5.2.26 Antidepressant Activity Metacognitive awareness, a cognitive set comes from mental and stress-related disorders, in which negative thoughts/feelings are experienced as mental events, is the main cause of depression. Therefore, the cognitive therapy (CT) to reduce this metacognitive awareness is the best method for prevention and treatment of depression. Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in mammalian central nervous system-activating neurons through a number of receptor sites. Among these receptor sites, GABAA receptor plays an important role in neuronal inhibition and excitation in mammals, thus regulates many physiological and psychological processes. Most of the antidepressant drugs bind at this site to reduce depression by inducing sedative (tranquillizing), hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, and muscle-relaxant properties. The main symptoms of depression arise from functional deficiency of brain monoaminergic transmitters, norepinephrine (NE), serotonin (5-hydroxytryptamine, 5-HT), and/or dopamine (DA). Therefore, increasing the levels of brain NE and 5-HT or DA through inhibiting the activity of monoamine oxidase (MAO) could be a target for prevention of depression. A metabolite of serotonin, 5-hydroxyindole acetic acid (5-HIAA), is considered as a biomarker of depression. Selective serotonin reuptake inhibitors are currently considered as first-choice therapy of depression. Brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) proteins are found to enhance the function and growth of serotonin containing neurons in brain. Hence, improvement of BDNF and NT-3 levels in brain could be a prospective target for treatment of depression. Over-expression of some inflammatory cytokines, such as IL-1 and TNF-a, induces stress-like effects on CNS in regulation of major symptoms of depression, such as in sleep, food intake, cognition, and thinking. Therefore, reduction of inflammation in brain is another target of antidepressant drugs [369]. Fructus Gardeniae (G. jasminoides fruits) has long been used in Chinese traditional medicine to treat depression, anxiety, insomnia, psychosis, and other mental disorders. Geniposide 23, isolated as major constituent of F. Gardeniae, exhibited significant antidepressive effects in mouse force swimming test (FST) and tail suspension test (TST). Administration of geniposide (10 mg/kg, i.p.) to mice significantly decreased the immobility times in both FST and TST, and these effects were comparable to those of antidepressant drug, desipramine (20 mg/kg, i.p.). Geniposide exhibited the antidepressant effects by increasing the levels of serotonin and 5-HIAA in striatum and serotonin level in the hippocampus of mice brain. This antidepressant effect of geniposide was increased in presence of desipramine (a monoamine reuptake inhibitor) and fluoxetine (a selective serotonin uptake inhibitor), but did not alter in presence of clorgyline (a selective MAO-A inhibitor) and maprotiline hydrochloride (a selective noradrenaline uptake inhibitor). These findings suggest that geniposide exerts its antidepressant effect through increasing the serotonin levels in both striatum and hippocampus in mice [370]. In another study, genipin 41, aglucone of geniposide, on administration (50, 100 and 200 mg/kg, i.g.)

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in mice for 7 days, significantly exhibited antidepressive effect by reducing the duration of immobility times in both FST and TST. Histopathological study revealed that genipin elevated the contents of norepinephrine (NE) and serotonin (5-HT) in mice hippocampi significantly. The contents of NE and 5-HT in mice hippocampi were decreased on treatment of reserpine, inhibitor of 5-HT and catecholamines (2 mg/kg, i.p.). These results suggest that the antidepressant effect of genipin, at least in part, is due to regulation of NE and 5-HT levels in hippocampus of mice [371]. In Chinese traditional medicine, ‘Yueju’ pills are frequently prescribed to treat depression and anxiety for its rapid antidepressant effect. The pill consists of a mixture of five antidepressant herbs, Cyperus rotundus, Ligusticum chuanxiong, G. Fructus (GF), Atractylodes lancea, and Massa fermentata. The screening of the ethanolic extracts of each of the constituent herbs of ‘Yueju’ in the mice TST model indicated that only GJ extract exhibited significant antidepressant effect, comparable to that of antidepressant drug, ketamine. Its ant-depressant response started at 2 h and continued for over 20 h. During this response, an up-regulation of BDNF proteins expression in the hippocampus of mice was observed at different time points. These findings suggest that rapid antidepressant effect of GJ is associated with elevated expression of BDNF in the hippocampus. Iridoid constituents, geniposide and genipin of GJ, did not exhibit such rapid antidepressant effects significantly. Possibly, some other constituents of GJ exhibit synergistic effect with the effects of geniposide and genipin to exert high activity of the GJ extract [372]. Iridoid glucosides, rotundusides G 672 and H 673, isolated from C. rotundus rhizomes, on oral administration (50 mg/kg, i.g.) to mice, significantly exhibited antidepressant activity in both FST and TST screenings with reduction of immobility times of 62.2 and 59.4%, respectively, in FST model and of 56.7 and 52.2%, respectively, in TST model. Their effects were very close to that of antidepressant drug, fluoxetine (20 mg/kg) with reduction of immobility times of 62.9 and 60.8% in FST and TST models, respectively. Other isolated iridoid glucosides from this plant showed weak activity [373]. Valeriana wallichi extracts are used in Indian ayurvedic medicine as antidepressant drugs. In a study of antidepressant activity of dichloromethane extract of this plant (40 mg/kg, single dose) in mice, the extract significantly reduced the immobility time of mice in the FST screening. Valepotriates, a mixture of valtrate 54, didrovaltrate 55, and acevaltrate 771 in a ratio of 2:2:1, present as major constituents in the extract, possibly exert this antidepressant effect by significantly increasing the levels of NE and DA in mouse forebrain [374]. An ethanolic extract of Valeriana officinalis root, on oral administration (300 and 600 mg/kg/day) for 30 days to rats, did not influence blood pressure, weight of heart, lungs, liver, spleen, stomach, testes, and kidneys of rats. Hence, these doses are safe for rats [375]. A valepotriates (VAL)-rich fraction from Brazilian Valeriana glechomifolia showed synergistic interactions with antidepressant drugs, imipramine (IMI), desipramine (DES), and bupropion (BUP) in FST of mice by reducing the immobility period in a dose-dependent manner without altering mouse locomotor activity. The ED50 values of VAL, BUP, and VAL + BUP are 2.34, 9.12, and 0.8 mg/kg, respectively, in mice FST test. Their strong synergistic action suggests

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that they do not act on the same site of the neurotransporters. Reported evidence indicates that IMI binds to both serotonin and noradrenaline transporters and thereby prevents the uptake of serotonin and noradrenaline, while DES selectively acts on noradrenaline transporter and BUP acts on both dopaminergic and noradrenaline transporters. Further study on the mechanism of action of valepotriates could provide a promising avenue for the search of herbal antidepressant agents [376].

5.2.27 Anxiolytic Activity Anxiety is a state of mental disorders of a person mainly from depression, panic, premenstrual dysphoric, and obsessive–compulsive disorders. Primary inhibitory neurotransmitter, GABA in CNS and neurotransmitters, serotonin, dopamine, norepinephrine, and glutamate in brain neurons are actively involved for this disorder. Several lines of evidence indicate that inhibition of reuptake of these neurotransmitters reduces the symptoms of anxiety. Several selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, sertraline, citalopram, paroxetine, vilazodone are considered as the first line of therapy for anxiety disorders. Occasionally, serotonin–norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine and duloxetine, are used as anti-anxiety drugs [377]. Valtrate 54, a major constituent of V. jatamansi rhizomes, on oral administration (10 and 20 mg/kg/day) for 10 days to rats, exhibited significant anxiolytic effect in rats by increasing the time and entry percentage in the open arms in the elevated plus maze (EPM) test and increasing the number of central entries in open field test (OFT). The higher dose was not much effective. The effect in lower dose was comparable to that of positive control, diazepam (1 mg/kg, p.o.) in both EPM and OFT. Valtrate significantly reduced the serum corticosterone level in rats. Possibly, valtrate induces its anxiolytic effect in rats by reducing the level of stress hormone, corticosterone via modulation of the activity of GABAergic neurotransmitter in CNS [378]. G. Fructus is a component herb of ‘Kamishoyosan’ (KSS), a Japanese traditional kampo medicine for treatment of mental disorders in menopausal women. Both G. Fructus and its major constituent, geniposide 23, on oral administration (50– 200 mg/kg and 20 and 40 mg/kg, respectively) to mice, showed increased social interaction (SI) time in mice demonstrating its dose-dependent anxiolytic effect. The anxiolytic effect of KSS on SI time in mice was significantly blocked by gamma-amino butyric acid A/benzodiazepine (GABAA/BZP) receptor antagonist flumazenil. Moreover, 5a-reductase inhibitor or blocker of dihydrotestosterone, finasteride, markedly blocked the effect of KSS. These findings indicate that the anxiolytic effects of KSS and its bioactive constituent geniposide are mediated by GABAA/BZP receptor stimulation-induced neurosteroid synthesis [379].

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5.2.28 Anticonvulsant Activity Epilepsy, a group of neurological disorders, is characterized by contraction of chest muscles followed by vigorous shakings (convulsions) of the body for a short-to-long period. These convulsions are generated by excessive and abnormal neuronal activity in the cortex of the brain. The abnormalities of GABAergic function in CNS (known as seizures) have been observed in both genetic and acquired animal models of epilepsy. The most generalized seizures are tonic and clonic seizures, which occur from electric shock, brain injury or infection, stroke, low blood sugar levels, kidney damage, etc. Several pharmacological approaches have been developed for inhibition of enhanced GABAergic function through use of GABA agonists, GABA-transaminase inhibitors, GABA uptake inhibitors and the action by binding at the GABA/benzodiazepine allosteric receptor site. Experimental evidence indicates that some anticonvulsant drugs (ACDs) act as sodium channel blockers of the axons (e.g. phenytoin, valproate) and prevent post-titanic potentiation and reduce the spread of seizures. These drugs reduce the release of excitatory glutamate neurotransmitter in axons for inhibition of convulsions. Anticonvulsants, benzodiazepines work by binding at GABAA receptor site and reduce neuronal excitations in brain by increasing the frequency of chloride channel openings, and barbiturates reduce the neuronal excitations by increasing the opening time of chloride channels [380]. In Colombia, Valeriana pavonii extracts have long been used to treat insomnia and anxiety. A dichloromethane fraction from an ethanolic extract of this plant, on oral administration (35 mg/kg) in maximal electroshock (MES)-induced crisis-like tonic-clonic seizure in mice showed 90% of protection against the seizures. Three valepotriate hydrines, valtrate acetoxyhydrin 838 (Fig. 5.2), valtrate isovaleroyloxyhydrine 839, and valtrate chlorohydrine 840 isolated from this active dichloromethane fraction, in an in vitro GABAA/BDZ-binding site assay, showed respective 11, 14, and 34% inhibition of the binding of 3H-flunitrazepam to BDZ-bs at 300 µM. These findings indicate that these compounds do not bind at the GABAA receptor site. Future study on the molecular action of these metabolites will be useful for their applications as anticonvulsant agents [381]. In another study, an aqueous extract of Valeriana officinalis rich in iridoids content, on intraperitoneal administration (500 mg/kg) to amygdale-kindled (electroshock)-induced tonic-clonic seizure in rats, showed significant anticonvulsant effect in rats by reducing the seizure activity such as decrease of after discharge duration (ADD) and duration of stage (S5D) and significant increase of the latency to the onset of bilateral forelimb clonuses (S4L). Pretreatment of 8-cyclopentyltheophylline (CPT), a selective adenosine A1 receptor antagonist, before administration of the extract, significantly decreased the anticonvulsant effect. These findings indicate that the extract exhibits its anticonvulsant effect through activation of adenosine system [382]. Future study on the anticonvulsant activity of isolated iridoids from this extract will be useful for their application.

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West African Feretia apodanthera has been used in Cameroonian’s folk medicine to treat epilepsy, infantile convulsions, anxiety, psychoses, etc. An aqueous extract of the plant, on administration (150–200 mg/kg, i.p.) to pentylenetetrazole-induced kindled mice, significantly reduced the progression of kindling through attenuation of oxidative stress and cognitive impairment in kindled mice [383]. An iridoid glucosides fraction from this aqueous extract, containing five iridoids, feretoside (=scandoside methyl ester) 282, gardenoside567, geniposide 23, apodantheroside 841, and deacetylasperulosidic acid 290 in a ratio of 29, 18, 14, 23, and 16%, respectively, on administration (30–90 mg/kg, i.p.) to pentylenetetrazole-induced kindled mice, significantly increased the latency to myoclonic jerks and clonic seizures as well as generalized tonic–clonic seizures through improvement of seizure mean stage and reduction of the number of myoclonic jerks in mice. This iridoid glucosides fraction significantly attenuated the GABAergic system by increasing brain GABA and glutathione concentrations through reduction of kindling-induced oxidative stress in mice. The anticonvulsant effect of this iridoid fraction extract was comparable to that of anticonvulsant drug, sodium valproate. The iridoid fraction extract also protected mice against bicuculline-induced motor seizures at the same doses. Thus, bioactive iridoids from this plant could be effective in treatment of epilepsy disorders [384]. Swertiamarin 68, a major constituent of Indian S. chirata, on administration (75 and 100 mg/kg, i.p.) to pentylenetetrazole-induced seizures in rats, significantly reduced the convulsion (70% reduction at the higher dose). Swertiamarin also exhibited anticonvulsant effect against phenytoin-induced convulsion in rats at the higher dose (100 mg/kg) and against mangiferin-induced electroshock in rats at the lower dose (50 mg/kg). Swertiamarin exhibits its anticonvulsant effect through inhibition of GABAergic function in brain. Future study on the mechanism of action of swertiamarin is required for its application as anticonvulsant agent [385a]. Oleuropein 80, a major bioactive constituent of olive oil, on intraperitoneal administration (10, 20, and 30 mg/kg) at 60 min prior to pentylenetetrazole (PTZ)induced clonic seizures in male NMRI mice, showed significant dose-dependent anticonvulsant effect by reducing the PTZ-induced seizure threshold in mice. Co-treatment of naltrexone (10 mg/kg, i.p.), an opioid receptor antagonist, L-NAME (10 mg/kg, i.p.), a non-specific inhibitor of NOS, and 7-nitroindazole (30 mg/kg, i.p.), a selective inhibitor of neuronal NOS, blocked the anticonvulsant activity of oleuropein; while co-treatment of L-arginine (30 and 60 mg/kg, i.p.) potentiated the anticonvulsant activity of oleuropein. These findings suggest that both opioidergic system and neuronal NOS might be involved in the anticonvulsant property of oleuropein. Possibly, the anticonvulsant effect of oleuropein is mediated through NO-dependent mechanism via modulation of the activity of opioidergic receptors in Ca2+ channel expression [385b].

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5.2.29 Antispasmodic Activity Antispasmodic or spasmolytic or smooth muscle-relaxant activities of the drugs are useful to suppress the muscle spasms of stomach, intestine, uterine, and other tissues to ameliorate intestinal motility impairment, menstrual, and bronchial disorders. Antispasmodic drugs act as calcium antagonists, antihistaminic, anticholinergic, and anti-a-adrenergic agents for their spasmolytic activities. A new class of antispasmodic drugs has been developed to improve colonic motility through up-regulation of T-type calcium channels [386]. Peracetates of penstemonoside 475a, aucubin 13a, and catalpol 14a exhibited in vitro antispasmodic activity by antagonizing the uterine muscular contractions induced by acetylcholine and calcium, similar to that of papaverine. The antagonism is non-competitive against acetylcholine, pD2 values in the range of 5.59– 5.74; similar to that of papaverine (pD2 of 5.32), and competitive against calcium, pA2 values in the range of 6.34–6.60; similar to that of papaverine, pA2 of 6.23. Their antispasmodic activity is possibly related to an inhibitory effect on extracellular or intracellular Ca2+ influx or both [387]. Catalpol peracetate 14a (100 µM) also inhibited the contractions of isolated guinea pig ileum induced by acetylcholine by 37% [388]. North American Viburnum prunifolium has been used in American ethnomedicine for its spasmolytic, sedative, and anti-asthmatic properties. An aqueous infusion or decoction of root and stem bark of this plant is frequently used in the treatment of menstrual cramps and postpartum bleeding and as an anti-abortive agent [389]. The ethyl acetate and butanol fractions from a methanolic extract of the stem bark of this plant at the tested concentration of 100 and 250 µg/ml, respectively, showed significant relaxant and spasmolytic effect against rabbit jejunum spontaneous contractions and carbachol-induced contractions of guinea pig trachea. Iridoids, 2′-O-acetyldihydropenstemide 842, 2′-O-trans-p-coumaroyldihydropenstemide 843, and 2′-O-acetylpatrinoside 844 isolated from these fractions, showed significant relaxant activity on rabbit jejunum spontaneous contractions and spasmolytic activity on carbachol-induced contractions of isolated guinea pig trachea in the concentration range of 2  10−5 to 4  10−4 M, while other isolated iridoid, patrinoside 29 was inactive. Propranolol, an inhibitor of b-adrenergic receptors, at the concentration of 10−6 M antagonised both the relaxant and spasmolytic effects of these iridoids; while isoprenaline, a b-adrenergic stimulator (agonist), enhanced the effects of these iridoids. These findings suggest that these iridoids exhibit their relaxant and spasmolytic effects through an interaction with b-adrenergic system. Adrenergic b2 receptor agonists are frequently used for smooth muscle relaxation for dilation of bronchial passages, uterine muscle, and release of insulin. These are primarily used as bronchodilators in treatment of asthma and other pulmonary disorders. Therefore, these iridoids may be effective in treatment of menstrual disorders and asthma [390]. 8-O-Acetylharpagide 12a, a major constituent of Ajuga reptans, showed significant in vitro relaxant activity on isolated guinea pig colon and guinea pig spinal

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cord in a dose-dependent manner with pD2 value of 5.7 and 5.4, respectively, in the concentration range of 10−3–10−5 g/ml. This effect was similar to that of noradrenaline (pD2 of 4.2) and was antagonized by phentolamine, an a-adrenergic blocker [391]. Loganin 18 and sweroside 67, isolated from Sickingia williamsi, showed moderate relaxant activity on isolated guinea pig ileum by inhibiting the electrically induced contractions in a dose-dependent manner with ED50 value of 100 and 400 µM, respectively. This inhibition occurred for 2–4 min after administration of the compound and lasted for 15 min [392]. Valtrate 54 and dihydrovaltrate (didrovaltrate) 55 exerted a spasmolytic effect against histamine-induced spasms of isolated guinea pig ileum, and their effect was about 25–33% that of papaverine [393]. Gentiopicroside 69, a major constituent of Gentiana spathacea, showed spasmolytic effect on isolated guinea pig ileum with an IC50 value of 2.8 µg/ml, and its effect was comparable to that of positive control, nifedipine, a calcium entry blocker (IC50 value of 0.19 µg/ml). Gentiopicroside also blocked significantly the contractions induced by histamine, acetylcholine, BaCl2 and KCl on the ileum by showing inhibition of 19–52.4%. These findings indicate that gentiopicroside exhibits its spasmolytic effect on smooth muscle cells by interaction with calcium influx because both KCl and BaCl2 induce contractions mainly through an increase of Ca2+ influx [394]. Swertiamarin 68 showed significant antispasmodic effect by antagonizing the contractions of isolated guinea pig ileum induced by acetylcholine, barium chloride, and histamine as well as antagonizing pituitrin and acetylcholine induced excitations of rabbit small intestine and uterine [395]. In an in vivo study, swertiamarin on oral administration (300 mg/kg) to rats significantly inhibited the proximal colon contractions in rats induced by carbachol. The inhibitory effect of swertiamarin was similar to that of atropine (0.5 mg/kg, p.o.), but the effect of atropine was much more (about 600 times higher). Thus, swertiamarin could be an effective antispasmodic drug [396].

5.2.30 Melanogenesis Inhibitory Activity Human melanogenesis is a type of hyperpigmentation disorder due to over-production of melanin in the outermost layer of skin in some areas. It is a complex process and frequently occurs from an excessive exposure to UV irradiation or from endocrine and neuronal cells disorders. Melanogenesis inhibitors inhibit the activity of key enzyme, tyrosinase through down-regulation of the activity of microphthalmia-associated transcription factor (MATF), a master regulator of the activity of melanocytes. There is a great demand of plant-derived melanogenesis inhibitors for application as skin-whitening agents in pharmaceutical

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and cosmetic industries. Usually, a-melanocyte-stimulating hormone (a-MSH)stimulated murine melanoma B16 cell line is used for in vitro assay of melanosis inhibition study [397]. Iridoids, asperulosidic acid 288, scandoside methyl ester 282, and 9-epi-6amethoxygeniposidic acid 845, isolated from noni fruits, Indian mulberry (M. citrifolia), exhibited potent melanosis inhibitory activity in a-MSH-stimulated B16 melanoma cell line culture with 38–45% reduction of melanin content at 100 µM. The activity of these compounds was superior to that of arbutin (29.6% reduction of melanin content at 100 µM), a commercial melanogenesis inhibitor, frequently used in cosmetic industry. These iridoids were almost non-toxic to melanoma cells, showing 91–107% of cell viability at 100 µM. Thus, these iridoids could be potential melanogenesis inhibitors [398]. Geniposide analogues, 6′-O-p-coumaroylgeniposide 846 and 10-O-(4″-Omethylsuccinoyl)-geniposide 847, isolated from G. Fructus, showed strong and moderate melanogenesis inhibitory activity in cultured a-MSH-stimulated B16 melanoma cell line with respective 41 and 21.6% reduction of melanin content at 30 µM. These iridoids were almost non-toxic to melanoma cells showing 102.8 and 90% of cell viability at 30 µM [399].

5.2.31 Antiaging Activity Skin aging is a common skin disorder in elder persons. It is caused from enhanced elastase activity in the fibrous connective tissues of dermis resulting in the reduction of skin elasticity and appearance of wrinkle and stretch mark. Elastin, an essential structural extracellular matrix protein, provides elasticity and resilience to many connective tissues, such as dermis, aorta, lung, and cartilage through cross-linking chains. Human neutrophil elastase and other elastases such as elastase MMP-12 and cathepsin G, located in the azurophil granules of polymorphonuclear leukocytes, on activation from continuous exposure to sunlight or microbial infection, are able to break down the elastin connective tissue proteins of skin. Thus, inhibition of elastase activity particularly human leukocyte elastase and cathepsin G could be a target for protection of skin aging. Elastase inhibitors have potential application in cosmetic industry [400]. 6-O-(E)-p-Methoxycinnamoylscandoside methyl ester 848, isolated from H. diffusa showed strong in vitro elastase inhibitory activity against human neutrophil elastase with an IC50 value of 18 µM. The docking study demonstrates that the pmethoxy group in the aromatic ring and the double bond in the acyl moiety of the iridoid appear to influence its activity [401].

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5.2.32 Immunomodulatory Activity The immunosuppressive therapy is an alternative target for treatment of various autoimmune disorders, such as psoriasis, lupus, rheumatoid arthritis, and ulcerative colitis. Immunosuppressive drugs reduce the activity of autoimmune disorders through reduction of T-regulatory cells and macrophages via suppression of the activity of inflammatory cytokines for restoration of normal homeostasis of regulatory T cells in immunotherapy [402]. Geniposide 23, 6a-hydroxygeniposide 272, ixoroside 19, and shanzhiside 21, isolated from G. Fructus, showed significant immunosuppressive effect against secretion of cytokine IL-2 from PMA and anti-CD28 monoclonal antibody-co-stimulated activation of human peripheral blood T cells at the concentration of 50 µg/ml. Among them, shanzhiside and ixoroside were more active. Possibly, a hydroxyl group at C-8 position of these iridoids is responsible for their enhanced activity. These compounds might be useful in the treatment of psoriasis and ulcerative colitis, where over-expression of IL-2 promotes the differentiation of immature T cells into regulatory T cells, which suppress the activities of other T cells and are primed to damage the normal healthy cells in the tissues [403]. Picroliv, isolated from Indian P. kurroa, showed significant immuno stimulating effect against multidrug-resistant Plasmodium yoelii-infected BALB/c mice. Oral administration of picroliv (1 mg/kg) for 14 days to P. yoelii-infected BALB/c mice, followed by chloroquine treatment (8 mg/kg, i.p.) for 3 days resulted in the complete suppression of P. yoelii on day 16 of post-infection, while administration of chloroquine only at the same dose to P. yoelii-infected BALB/c mice for 3 days, resulted in the death of animals on day 12 of post-infection. These findings indicate that picroliv increases the efficacy of chloroquine against drug-resistant malaria P. yoelii strain in mice [404]. Arbortristosides A 456 and C 458, isolated from Indian N. arbortristis, on oral administration (5 mg/kg/day) for 7 days to C. albicans-infected Balb/c mice, showed significant protection of mice against systemic candidiasis by improving median survival time (MST) of 17 days and reducing the colony-forming unit (CFU) of C. albicans in mice. Furthermore, these iridoids increased the humoral and delayed-type hypersensitivity (DTH) response to sheep red blood cells and macrophage migration index (MMI) in Balb/c mice. Arbortristoside C showed more protective (77.7%) and curative than arbortristoside A. The combined therapy of arbortristoside A or C with anticandidiasis drug, ketoconazole, did not improve protection of mice [405].

5.2.33 Anti-angiogenic Activity Treatment of oleuropein 80 (0.1–50 µM) in PMA-stimulated human vascular endothelial cells culture reduced the endothelial cell tube formation on matrigel and

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migration in wound-healing assays. This reduced activity on angiogenesis of oleuropein is associated with inhibition of PMA-induced COX-2 and MMP-9 proteins expressions in cultured endothelial cells via reduction of NF-jB activation [406]. Geniposide 23, isolated from G. Fructus, exhibited anti-angiogenic activity by inhibiting the growth of transformed NIH3T3 cell line culture in a dose-dependent manner in the tested concentration range of 25–100 µM [407].

5.2.34 Antimutagenic Activity A large number of air pollutants from industrial and vehicle exhausts, such as polycyclic aromatic hydrocarbons (PAHs) initiate carcinogenesis in human tissues through mutation of DNA and/or chromosomal damage leading to the development of lung, skin, and bladder cancers [408]. Harpagoside 499, a major constituent of H. procumbens and other plants, on preand co-treatments (10 µg/ml) in 1-nitropyrene (1-NPy)-stimulated culture of human peripheral lymphocytes, showed significant reduction of mutagenic activity of 1-NPy by 43 and 101%, respectively. 1-NPy is one of the most abundant particulates in diesel exhausts. Therefore, dietary consumption of harpagoside and H. procumbens extract as food supplements might have beneficial effect in prevention of mutagenic disorders from air pollution [409].

5.2.35 Estrogenic Activity Sex hormone, estrogen, plays an important role in the growth, differentiation, and function of many targets in female and male reproductive and other organs. The insufficient secretion of estrogen from endocrine gland results in premenstrual and menopausal disorders in women as well as arteriosclerosis and heart diseases in humans; while over-secretion causes development of breast and prostate cancers [410]. Fructus Viticis (fruits of Vitex rotundifolia) is frequently prescribed in traditional Chinese medicine to relieve aches, bloating, and other symptoms relating to menstruation. The ethanolic extract of V. rotundifolia (VRE), and its isolates, iridoid, agnuside 17 and diterpene, rotundifuran, showed significant estrogenic activity in a culture of estrogen receptor (ER)-positive breast cancer MCF-7 cells. VRE, agnuside and rotundifuran in their respective concentration of 200 µg/ml, 10−7 and 10−5 M, showed significant stimulating effect on the proliferation of MCF-7 cells by up-regulating the expressions of estrogen receptor ERa, ER-regulated mRNA levels of progesterone receptor and estrogen regulated gene, pS2, a small cysteine-rich protein and potential biomarker of human breast cancer. Their stimulating effects were reversed on co-administration of a specific estrogen

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receptor antagonist, ICI 182,780. These findings indicate that both VRE and its isolates exert their stimulating effects on the proliferation of MCF-7 cells through modulation of estrogen receptors. Further study on physiological significance of VRE and its active isolates in prevention of premenstrual syndrome will be useful for application in these disorders [411]. Catalpol 14, on oral administration (1, 3 and 5 mg/kg/day, p.o.) for a period of 4-week to 14-month-old senile female rats, showed significant amelioration of behavior through increasing the levels of serum 17b-estradiol and progesterone levels and reducing the levels of serum follicle-stimulating hormone and luteinizing hormone in rats. These findings suggest that catalpol ameliorates the behavioral problems in senile rats by maintaining the hormonal rebalance in sex organs. Thus, catalpol could be an effective drug in treatment of post-menopausal disorders in women [412].

5.2.36 Purgative Activity Inoue et al. evaluated the purgative activities of 12 iridoids, namely geniposide 23, verbenalin 647, plumieride 34, geniposidic acid 289, monotropein 25, deoxyloganin 18a, deoxygeniposide 849 (Fig. 5.2), deacetylasperulosidic acid methyl ester 272, asperuloside 24, deacetylasperulosidic acid 290, aucubin 13 and catalpol 14, in mouse model and observed their relative biological potency in terms of 50% cathartic dose (ED50). Their findings indicate that the presence of free hydroxyl group at C-11 position significantly reduced the purgative activity. Thus, geniposidic acid, deacetylasperulosidic acid, and monotropein are weaker purgatives compared to geniposide and deacetylasperulosidic acid methyl ester. Moreover, a hydroxyl-/oxy group at C-6 position exerts delayed action, as indicated by slower onset of diarrhea in asperuloside, aucubin, catalpol, and deacetylasperulosidic acid methyl ester [413]. In another study, geniposide was found to exhibit diarrhea in mice only after an oral administration to mice after a charcoal meal, and not through parenteral injection. After an oral administration of geniposide in mice, its aglucone genipin 41 was detected in cecum and colon of the large intestine of mice. Furthermore, direct injection of genipin into cecum of mice showed better effect compared to geniposide injection. These findings suggest that geniposide exerts its purgative effect by acting as a propulsive agent in large intestine of mice for movement and evacuation of a charcoal meal via its aglucone, genipin [414].

5.2.37 Spermicidal Activity Plumieride 34, on oral administration (15 mg/rat/day) to male rats for a period of 60 days, showed significant spermicidal effect by reducing the spermatids production by 87.26% through decreasing the population of preleptotene and

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pachytene spermatocytes in miotic phase by 64.26 and 55.13%, respectively. Plumieride also reduced the weights of testes, epididymides, seminal vesicle, and ventral prostate in rats. Furthermore, it reduced the number of Leydig cells and completely suppressed the fertility of male rats. Plumieride did not produce any significant change in RBC and WBC counts in blood and other side effects in rats. Thus, plumieride could be a prospective antifertility drug [415].

5.2.38 Nematocidal and Insecticidal Activities Sweroside 67, isolated from Alstonia scholaris, on treatment at the concentration of 1%, showed potent nematocidal activity against plant root-knot parasitic nematode, Meloidogyne incognita larvae with mortality rate of 80% after 24 h and 92% after 48 h, comparable to that of herbal nematocide, Azadiracta indica extract having mortality rate of 88 and 90% after 24 and 48 h, respectively, at the same concentration [416]. Isolated iridoids from different Galium species, namely geniposidic acid 289, monotropein 25, and scandoside 282a, showed significant insecticidal activity against termite, Kalotermes flavicolis (Kelotermidae), while deacetyldaphylloside 272 and 10-hydroxyloganin 424 were effective against ant, Crematogaster scutellaris (Formicidae) [417].

5.2.39 Repellent and Antifeedant Activities Two chemotype essential oils A and B consist of 91.95% of cis-nepetalactone 814 and 8.05% of trans-caryophyllene and of cis- and trans-nepetalactones 814 and 815 in a ratio of 16.98 and 69.85% and 13.19% of trans-caryophyllene, respectively, isolated from catmint plant, N. cataria, exhibited significant repellent activity against sub-Saharan mosquitoes, Anopheles gambiae and Culex quinquefasciatus; ixodid tick, Rhipicephalus appendiculatus and red-poultry mite, Dermanyssus gallinae. The oils A and B showed high repellent activity against A. gambiae with RD50 values of 0.081 and 0.091 mg cm−2, respectively, comparable to that of synthetic repellent, N,N-diethyl-meta-toluamide (DEET) (RD50 of 0.12 mg cm−2), while showed lower repellent activity against C. quinquefasciatus with RD50 values of 0.34 and 0.074 mg cm−2, respectively. In the climbing assay of R. appendiculatus, the oils A and B showed high repellent activity with RD50 values of 0.005 and 0.0012 mg cm−2, respectively. Both these oils showed significant reduction of D. gallinae trap capture. These oils exhibited greater repellent activity compared to pure nepetalactone isomers. Possibly, synergistic effect of the nepetalactone isomers and trans-caryophyllene is responsible for this higher activity of the oils. Thus, these essential oils from Nepeta spp. could be effective for protection of human and livestock pathogens vectors [418].

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Xylomollin 430, isolated from bitter fruits of Xylocarpus moluscensis, showed significant antifeedant activity against African worm, Spodoptera exempta at the 100 ppm level [419]. Ipolamiide 121, a major iridoid constituent (about 10%) of South African Stachytarpheta mutabilis, exhibited potent antifeedant activity against crop pest, Locusta migratoria through inhibition of feeding of almost 100% at the concentration of 0.2% dry weight in impregnated filter paper with 5% dry weight of sucrose as feeding substance. This compound also exhibited weak antifeedant activity against caterpillar, Spodoptera littoralis and acridid, Schistocerea gregaria [420]. Specionin 181, a major constituent of Catalpa speciosa, exhibited strong antifeedant activity against spruce budworm, Choristoneura fumiferana at the concentration levels of 50–100 ppm [421]. Oleuropein 80, a major iridoid constituent of privet tree (Ligustrum obtusifolium), exhibited antinutritive value for herbivore insects by decreasing the nutritive lysine content of plant proteins via hydrolysis with plant b-glucosidase to a bitter aldehyde, followed by binding of the aldehyde with lysine of plant proteins [422]. Checkerspot butterflies, Euphydryas species, fed on iridoid containing plants to sequester bitter iridoid glycosides in different organs, showed antifeedant activity against birds because of bitter taste of adult flies and their larvae [423a].

5.2.40 Miscellaneous Activity Geniposide 23, major constituent of G. Fructus and American Genipa, is commercially utilized as natural red-colored dyes in foodstuff, meat products, beverages and other alcoholic drinks, and cosmetics and hair dyeing. This iridoid is deesterified at C-4 position by treatment of dilute aqueous sodium hydroxide, and the resultant product, geniposidic acid, is dissolved in acetate buffer at pH 4.5 and treated with b-glucosidase and amino acids such as glycine or alanine in different concentrations to get red-colored dyes of various intensities [423b]. 8-O-Acetylharpagide 12a, a major iridoid constituent of A. decumbens, exhibited moderate ecdysteroid agonist property with an EC50 value of 22 µM. It induces differentiation of Drosophila Kc cells. Possibly, this iridoid plays a significant role as natural defense in plants [423c] (Fig. 5.1).

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Fig. 5.1 Chemical structures of some bioactive plant iridoids

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Fig. 5.1 (continued)

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Fig. 5.1 (continued)

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Fig. 5.1 (continued)

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Fig. 5.1 (continued)

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Fig. 5.1 (continued)

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5.3 Iridoids in Insect Physiology

5.3 5.3.1

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Iridoids in Insect Physiology Iridoids in Growth and Adaptation of Insects

Antirrhinoside 109, a major iridoid constituent of Antirrhinum majus leaves, was found to enhance the growth of fourth instar cabbage looper, Trichoplusia ni, when fed on the young leaves of the plant. Possibly, this iridoid was metabolized by the insects, as antirrhinoside was not detected in their bodies and feces (frass) in both TLC and HPLC analyses. While the fourth instar gypsy moths, Lymantria dispar, reject the feeding of young leaves of the plant. When a diet containing antirrhinoside at a concentration of 3.3% was allowed to feed, the growth of the gypsy moths was reduced relative to control. These findings indicate that antirrhinoside plays metabolic growth in some specific insects on fed [424]. Catalposide 182, a major iridoid glucoside of C. ovata, showed dose-dependent growth response on the larvae of southern army worm, Spodoptera eridania (Noctnidae), when fed on artificial diets containing different amounts of catalposide. Low levels of catalposide decreased growth, intermediate levels showed gradual increase in growth with increasing the dosage, and at the highest dose (7.2%) dramatically reduced the growth of the larvae. Such physiological effects of iridoids on insects may be utilized in pest-control strategy [425]. In a study on the effects of iridoid containing host plants on the digestive metabolism of herbivore insects, larvae of Spilosoma virginica (Arctiidae) were reared in three different plant species, Taraxacum officinale (no iridoid glycosides), Plantago major (low iridoid glycoside content), and P. lanceolata (high iridoid glycoside content). The study of the glucosidase activity of the midgut of the reared larvae from different plant species indicated that the activity of glucosidase in the midgut of the larvae reared on P. lanceolata was decreased significantly. Possibly, the larvae reared in P. lanceolata decreased the activity of glucosidase to enhance tolerance of the caterpillar with more toxic plant iridoid glycosides [426]. Specialist herbivore insect, Euphydryas aurinia butterflies, chooses the leaves of host plant, Lonicera implexa for oviposition and laid eggs to get defense against pathogenic fungi. The leaves of bore egg clusters had higher concentration of iridoid glycosides (over 15-fold) compared to unused leaves of the same plant. These findings indicate that high concentration of iridoid glycosides of the leaves protects the eggs from microbial infections and predators [427]. The larvae of some privet tree specialist caterpillars, such as Eri silkworms, Samia ricini, secrete high concentration of lysine in their digestive juices to inhibit the decrease of lysine content in plant proteins caused by oleuropein for minimization the cost of adaptation [428]. While other privet tree specialist butterflies, Artopoetes pryeri and other privet specialists secret high concentration of GABA or b-alanine and glycine in their digestive juices to compensate the lysine decrease in plant proteins to minimize the cost of adaptation [429].

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5 Pharmacology of Iridoids

Iridoids as Defensive Chemicals in Insects

Five flea beetle Longitarsus species (Chrysomelidae), L. australis, L. lewisii, L. melanocephalus, L. nigrofasciatus, and L. tabidus, feed on iridoid containing host plant, P. lanceolata and sequester selectively iridoid glucosides, catalpol and aucubin, from the plant in concentrations between 0.40 and 1.55% of their dry weights and use these iridoid glucosides as chemical defense against predators. While other iridoids, harpagide, 8-O-acetylharpagide, ajugol, 8-epi-loganic acid, gardoside, and geniposidic acid present in the host plant, could not be detected in the beetles [430]. The larvae of Arctiine moths, Spilosoma congrua and Parasemia plantaginis, feed on host plant, P. lanceolata to take up selectively aucubin 13 and catalpol 14 from the host plant. They biotransform aucubin into catalpol in their body and excrete most of this accumulated catalpol as a defensive toxin against their predators and pathogens. Thus, iridoid glycosides play defensive role for survival of larvae in the development stages of the moths [431a]. Lepidoptera insect herbivore, Euphydryas chalcedona fed on host plant, Castilleja integra to sequester catalpol 14 from the host plant and use it in defense against its predators [431b]. The larvae of leaf beetles, Phaedon cochleariae and P. armoraciae and Gastrophysa viridula, synthesize toxic volatile iridoids, chrysomelidial 678 and epichrysomelidial 850 in their gland and secrete these volatile iridoids to repel their enemies [432]. Several ant species of genus, Iridomyrmex produce iridodial 3, dolichodial 3a, iridolactones, iridomyrmecin 4, and isoiridomyrmecin 5 for their defensive purpose [433]. The phasmid, Graeffea crouani (coconut stick insect) and the pseudophasmid, Anisomorpha buprestoides (southern walking stick) produce iridodials, anisomorphal 679 and nepetalactones for utilization as defensive secretions [434]. The long-horn beetles, Chloridolum loochooanum and rove beetles, Philonthus spp., such as P. sanguinolentus, P. rectangulus, P. chalceus, P. nitidus also produce iridodials, chrysomelidial 678, plagiodial 728, and actinidine 706 for utilization as defensive chemicals [435]. The larvae of Plagiodera versicolora, fed on willow trees, use plagiodial 728 and plagiolactone 851 as defensive secretions [436]. Taiwanese plasmid, Megacrania tsudai, uses actinidine as major defensive chemical [437].

5.3.3

Iridoids as Sex Pheromones in Insects

The females of parasitic wasp, Leptopilina heterotoma, use volatile iridoid compound, (−)-iridomyrmecin 852 to use as a chemical signal (about 80% of the secretion) in order to avoid interference with con- and heterospecific competitors, such as L. boulardi and L. clavipes and as a main component of species-specific sex pheromone, while the male counterpart produce only enantiomeric (+)-isoiridomyrmecin 853 as defensive secretion against their enemies. The females

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239

secrete in high amount when under attack and in low amount to attract males and to trigger the courtship behavior. Future study on their genetic mechanism on the production of these iridoids would be useful to develop molecular biology on chemosensory organ [438]. In another study, it was observed that the females of L. clavipes also secrete (−)-iridomyrmecin as sex pheromone in low concentrations to attract males [439]. A global pest, the rosy apple aphid, Dysaphis plantaginea oviparae (sexual females) releases volatile iridoids, (1R, 4aS, 7S, 7aR)-nepetalactol 854 and (4aS, 7S, 7aR)-nepetalactone 814 as sex pheromones in a ratio of 3.7:1, in high levels during photophase (day-light phase) and in low levels during scotophase (dark phase) for calling to adult males for mating. The pheromone release was greatest on the eighth day of adult stadium, with up to 8.4 ng of pheromone released per ovipara per hour. The oviparae of other aphids, such as vetch aphid, Megoura viciae; greenbug, Schizaphis graminum; black bean aphid, Aphis fabae and pea aphid, Acyrthosiphon pisum release these nepetalactol and nepetalactone or their diasteroisomers in different ratios and levels for mating. Better understanding on the mechanism of biosynthesis and regulation of these sex pheromones will help to explore the physiological and evolutionary aspects of aphid biology and the aphid management [440]. The oviparae of damson hop aphid, Phorodon humuli release only nepetalactol diastereoisomers, (1S, 4aR, 7S, 7aS)-nepetalactol 855 and (1R, 4aR, 7S, 7aS)nepetalactol 856 as volatile sex pheromones for mating to adult males [441]

5.3.4

Iridoids in Chemical Signals in Insects

It has been reported that the secretions of venom iridoids by worker ants are used in different purposes. The secretion at low level sends an alarm message about the presence of an enemy to other members of its own family, while secretion at high concentrations sends the message to its fellow workers to be aggressive and to appear in retreat behavior, and also to repel the foe. A sting-bearing ant normally uses its venom offensively to kill the prey for food [442]. Argentine ant workers, Linepithemia humile, secrete dolichodial 3a and iridomyrmecin 4 from their cuticle as chemical communication signals to other fellow ant workers of their family when they are alive or freshly killed [443].

5.3.5

Iridoids as Allelochemicals in Insects

Feeding of catalpol 14 as diet by a red flour beetle pest, Tribolium castaneum adults showed a significant reduction of digestion of ingested food. Moreover, catalpol produced a series of morphological deformations, such as deficiencies in normal cuticle deposition, deformation of wings and abnormal disposition of legs and wings on topical application in T. castaneum larvae. It also exhibited strong

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inhibitory activity against taq DNA polymerase with an IC50 value of 47.8 µM, while other tested iridoids, harpagide 12 and 8-O-acetylharpagide 12a showed weak activity. Possibly, these allelochemical effects of catalpol in larvae and adults of T. castaneum are related to mutation in DNA synthesis [444] (Fig. 5.2).

Fig. 5.2 Chemical structures of some bioactive plant and insect iridoids

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Chapter 6

Pharmacokinetics of Iridoids

6.1

Introduction

Natural products are the most widely used low-cost drugs for commercial application in pharmaceutical industries. Several herbal products are utilized for treatment of various diseases because of their relatively better efficacy, safety and other qualities, as well as of their low-cost and local availability compared to related synthetic drugs. The low-cost and readily available herbal drugs are selected for commercial application after getting adequate evidence on efficacy, safety, and effective dosages from extensive clinical studies in animals and humans. The search for new drugs can be divided into two main phases: discovery and development from an industrial perspective. The former phase consists of evaluation of target enzymes or receptors for a particular disease and use of a variety of semiempirical structure–activity relationships after modification of the chemical structure of a natural drug to optimize their in vitro activity against a disease. A good in vitro activity cannot be granted to good in vivo activity unless a drug has good bioavailability, least toxicity, a desirable duration of action, a greater metabolic clearance, and least side effects. Pharmacokinetics and drug metabolism have key roles in determination of in vivo drug action. So, in the development phase of a new drug, the efforts are taken on the evaluation of short- and long-term toxicities and efficacy of the drug via detail studies on pharmacokinetics and metabolism. It will help to get an effective turnover rate from a drug. Conventionally, the metabolism of new drugs in humans is studied using radiotracer techniques to evaluate the clinical absorption and disposition of the drug and its metabolites. This metabolism study should be performed initially in microbes and various drug metabolizing enzymes for identification of enzymes responsible in drug metabolism and to evaluate drug–drug interactions. Bioavailability of a drug depends on its lipophilicity, that is its solubility and permeability in lipid membrane. In general, a drug of good partition coefficient between aqueous and lipid medium,

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and of high permeability in intestinal and other tissues membrane, absorbs readily at the site of action and exhibits high clearance of the drug and its metabolites [1]. Microbial and mammalian metabolism of some bioactive iridoids and their disposition as well as metabolism of iridoids in insects are highlighted in this chapter.

6.2

Microbial Metabolism of Iridoids

The microbes in human gastrointestinal tract play key roles in metabolic transformation of food and drugs in production of their metabolites for use as dietary components, nutrients, and therapeutic agents. Thus, the study of human gastrointestinal microbial metabolism of a new drug is essential to evaluate the active metabolites of the drug in its development phase. Gentiopicroside 69, one of the important bioactive constituents of some medicinal Gentiana species, has been explored to exhibit several pharmacological activities. The study of metabolism of this secoiridoid glucoside by 24 strains of intestinal bacteria in an anaerobic incubation process, showed at least five metabolites, namely erythrocentaurin 861, gentiopicral 862, 5-hydroxymethyliso chromen-1-one 863, 5-hydroxymethylisochroman-1-one 864, and trans5,6-dihydro-5-hydroxymethyl-6-methyl-1H,3H-pyrano[3,4-c]-pyran-1-one 865 (Scheme 6.1). Among these microbial strains, a Gram-negative coccus, Veillonella parvula ssp. parvula produced all these metabolites in appreciable amounts under the screening condition of 22 h of incubation process. These metabolites are possibly derived via formation of gentiopicroside aglucone and subsequent its ring opening

Scheme 6.1 Metabolism of gentiopicroside by human intestinal bacteria

6.2 Microbial Metabolism of Iridoids

257

and followed by rearrangement and redox processes (Scheme 6.1). Gentiopicral has been reported to exhibit significant antibacterial, antifungal, and antitumor activities. Possibly, the bioactivity of orally administered gentiopicroside in animal models is due to synergistic activity of its bioactive metabolites, produced by the intestinal microbes [2]. In another study, fermentation of endophytic fungus, Penicillium crustosum 2T01Y01 strain with gentiopicroside for 6 d, produced seven metabolites—five of them were identified as 5a-hydroxymethyl-6b-methyl-3,4,5, 6-tetrahydropyrano[3,4-c]-pyran-(8H)-1-one 866, (Z)-4-(1-hydroxybut-3-en-2-yl)5,6-dihydropyran-2-one 867, (E)-4-(1-hydroxymethylbut-3-en-2-yl)-5,6-dihydro pyran-2-one 868, 5a-hydroxymethyl-6b-methyl-1H,3H-5,6-dihydropyrano[3,4-c]pyran)-1-one 865, 5a-hydroxymethyl-6a-methyl-5,6-dihydropyrano-[3,4-c]-pyran(3H)-1-one 869, and the rest two was tentatively identified as 864 and 5-hydroxymethyl-3,4,5,6-tetrahydroisochromen-1-one 870. These metabolites are possibly formed via formation of an aglucone from gentiopicroside and subsequent its ring opening, reduction, oxidation, and decarboxylation processes (Scheme 6.2). The in vitro bioassay of three metabolites, 865, 866, and 869 and parent compound 69 against H2O2-induced injury in human hepatic HL-7702 cell line, showed significant protective effect by the metabolites, but the parent compound was inactive at the tested concentration of 20 µM. These findings suggest that the metabolites are the active principles. This fungus is very common in plant-derived food and plants, and hence, further study in animal model is required to substantiate the biological functions of these metabolites [3]. The asexual fungal parasite, Cordyceps sinensis on incubation with gentiopicroside, produced two metabolites, 865 and a pyridine monoterpene alkaloid 871 (Scheme 6.2) [4].

Scheme 6.2 Metabolism of gentiopicroside by fungi, Penicillium and Cordyceps spp

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6 Pharmacokinetics of Iridoids

Geniposide 23, a major bioactive constituent of Gardenia Fructus, is transformed into genipin 41 and genipinine 872 by 25 strains of human intestinal bacteria, such as Peptostreptococcus anaerobius, Klebsiella pneumoniae, Fusobacterium nucleatum, and Bacteroides fragilis ssp. thetaotus in an anaerobic culture. Genipinine is possibly formed via ring opening of genipin and amination of the resultant aldehyde (Scheme 6.3) [5]. However, Kobashi et al. reported that human intestinal anaerobic bacteria, Eubacterium spp A44 transformed geniposide into genipin only [6]. Gardenoside 567, another bioactive iridoid of Gardenia fruits, is transformed into a- and b-gardenogenins 873 and gardenine 874 by 25 strains of human intestinal bacteria (Scheme 6.4) [5]. Aucubin 13, on anaerobic incubation with 24 strains of human intestinal bacteria and human feces bacteria, was transformed into pyridine monoterpene alkaloids, aucubinines A 875 (major) and B 876 along with its aglycone, aucubigenin 877 (Scheme 6.5). Among these bacterial strains, K. pneumoniae, Bifidobacterium breve, B. pseudolongum, Peptostreptococcus intermedius, and B. fragilis, showed potent ability in transforming aucubin into aucubinine A on incubation [7]. Harpagide 12, harpagoside 499 and 8-O-p-coumaroylharpagide 500, isolated from Harpagophytum procumbens and H. zeyheri, were metabolized into aucubinine B 876 by human fecal flora and by some isolated bacteria from this flora.

Scheme 6.3 Metabolism of geniposide by human intestinal bacteria

Scheme 6.4 Metabolism of gardenoside by human intestinal bacteria

6.2 Microbial Metabolism of Iridoids

259

Scheme 6.5 Metabolism of aucubin by human intestinal bacteria

The incubation of these iridoids with almond b-glucosidase in the presence of ammonium acetate also produced this metabolite 876 [8]. Swertiamarin 68, on treatment in a culture of fungus Aspergillus niger, was transformed into two metabolites, erythrocentaurin 861 and (Z)5-ethylidene-8-hydroxy-3,4,5,6,7,8-hexahydro-1H-pyrano [3,4-c]-pyridine-1-one 871 (Scheme 6.6) [9]. In another study, swertiamarin on treatment with human intestinal bacteria for 48 h was transformed into three metabolites, erythrocentaurin 861, 5-hydroxymethylisochroman-1-one 864, and gentianine 878 via formation of its aglycone (Scheme 6.7) [10].

Scheme 6.6 Metabolism of swertiamarin by Aspergillus spp

Scheme 6.7 Metabolism of swertiamarin by human intestinal bacteria

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6 Pharmacokinetics of Iridoids

The metabolite gentianine was reported to exhibit antidiabetic effect through up-regulation of PPAR-c gene expression in 3T3-L1 cells [11]. Gentianine also exhibited strong anti-inflammatory activity against adjuvant-induced arthritis in rats through down-regulation of pro-inflammatory cytokines, IL-1b, IL-6, and TNF-a via suppression of Rho GTPase/NF-jB and TGF-b/Smad-3 signaling pathways [12]. Thus, most of the pharmacological activities of swertiamarin in animal models are due to the activities of its metabolites. Catalpol 14, on treatment in an anaerobic culture of human intestinal bacteria for 36 h, was transformed into four metabolites—two of them were identified as catalpol aglycone 879 and nitrogen-containing catalpol aglycone 880 (Scheme 6.8). The culture of pure isolated bacteria from human feces, such as Bacteroides spp and Enterococcus spp with catalpol, also afforded these metabolites [13]. Loganin 18 in an anaerobic culture of human intestinal bacteria for a period of 20 h was transformed into two metabolites, loganin aglucone 230 and 3-hydroxy-1-methyl ether of dihydrologanin aglucone 881 (Scheme 6.9) [14]. Oleuropein 80, a major bioactive secoiridoid of extra virgin olive oil, on fermentation with human fecal microbiota for 48 h, was transformed into four metabolites, oleuropein aglycone 882, elenolic acid 883, hydroxytyrosol 884, and hydroxytyrosol acetate 885 (Scheme 6.10). The bacterial strains of Lactobacillus, Bifidobacterium, and Enterococcus, common inhibitants of human colon, were shown to hydrolyze oleuropein into its aglycone, which on subsequent hydrolysis and carboxylation produced other metabolites (Scheme 6.10). Among the tested bacterial strains, the most effective strains were Lactobacillus paracasei and L. plantarum [15].

Scheme 6.8 Metabolism of catalpol by human intestinal bacteria

Scheme 6.9 Metabolism of loganin by human intestinal bacteria

6.3 Mammalian Metabolism of Iridoids

261

Scheme 6.10 Metabolism of oleuropein by human fecal microbiota

6.3

Mammalian Metabolism of Iridoids

The pharmacokinetic and bioavailability of aucubin 13, a promising hepatoprotective and antitumor drug, were evaluated by intravenous (i.v.), oral (p.o.), intraperitoneal (i.p.), and hepatoportal (p.v.) administration in rats [16]. Aucubin was administered at the dosage of 40, 50, 100, 200, and 400 mg/kg for i.v. study and 100 mg/kg for p.o., p.v., and i.p. studies in rats. A linear pharmacokinetic behavior was observed after i.v. administration of different tested dosages of aucubin. In the i.v. dose of 40 mg/kg, the half-life in the post-distributive phase (t1/2, b), total body plasma clearance (CLt), and volume of distribution (Vdss) of aucubin were 42.5 min, 7.2 ml/min/kg, and 346.9 ml/kg, respectively. There was no significant difference in the parameters in cases of increasing the i.v. dosage. Due to low partition of aucubin in plasma to blood, only 18.5 ± 1.3% of aucubin was found in the blood cells. Plasma protein binding of aucubin was only 9%. The bioavailability of aucubin after administration of a dose of 100 mg/kg in p.v., i.p., and p.o. routes were 83.5, 76.8, and 19.3%, respectively. The pH-stability profile at 37 °C indicated that aucubin is sensitive at lower pH (1–2) with half-lives of 5.02, 5.78, and 14.84 h at pH 1.2, 1.6, and 2.0, respectively, while at pH above 3.0, the degradation of aucubin was negligible (half-lives were more than several days). The low oral bioavailability of aucubin may be attributed to its instability in acidic gastric fluid, poor GI absorption due to low lipophilicity (low availability in lipid membrane), and metabolism by b-glucosidase in the GI mucosa and liver. Thus, further study on the improvement of the bioavailability of aucubin in nano and other techniques is required to increase the efficacy of the drug in clinical trials in humans [16]. The pharmacokinetics of bioactive verproside 195b, a catalpol derivative, was evaluated in rats after i.v. and p.o. administration [17]. The i.v. administration of verproside (2, 5 and 10 mg/kg) in rats showed short half-lives (t1/2) (12.2– 16.6 min), high systemic clearance (CL) (56.7–86.2 ml/min/kg), low renal clearance (2.8–4.1 ml/min/kg), almost constant volume of distribution at the steady

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6 Pharmacokinetics of Iridoids

state, AUC (532–768 ml/kg), and low GI absorption (0.32–0.71%). This systemic clearance (CL) was reduced, and AUC was increased significantly at the higher dosage compared to the lower dosage. The reduced CL (56.7 ml/min/kg) of verproside at higher dosage is possibly due to formation of metabolites, isovanilloylcatalpol 886 and dihydroxybenzoic acid 887. In oral administration of verproside (50 and 100 mg/kg) in rats, the Cmax was increased nonlinearly (23.5– 83.4 ng/ml). The extent of recovered verproside from GI tract at 24 h after oral administration was low (0.01–0.28%). The absolute oral bioavailability of verproside was 0.3 and 0.5% in 50 and 100 mg/kg dosage, respectively. The low oral bioavailability of verproside suggests that it might be metabolized extensively and quickly. The same group repeated this pharmacokinetic study for the search of other metabolites and other information on pharmacokinetics of verproside [18]. The LC-HRMS analysis of bile and urine samples collected at 6 h after administration of verproside (10 mg/kg, i.v.) in rats, resulted in the identification of 21 metabolites along with unchanged verproside. These metabolites are possibly formed via Omethylation and hydrolysis of the ester linkage followed by glucuronidation and sulfation (Scheme 6.11). These metabolites were identified as verproside glucuronide and sulfates, picroside II 192 and isovanilloylcatalpol 886 and their glucuronides and sulfates, 3,4-dihydroxybenzoic acid 887, 3-methoxy-4-hydroxybenzoic acid 888 and 3-hydroxy-4-methoxybenzoic acid 889 and their glucuronides and sulfates. Only a little amount of verproside was recovered in bile (0.77% of the dose) and urine (4.48% of the dose). The O-methylation of verproside to picroside II and isovanilloylcatalpol followed by their glucuronidation and sulfation was the major metabolic pathway in rats. The in vivo bioactivity of verproside in animal model is possibly due to the activity of these metabolites [18].

Scheme 6.11 Metabolism of verproside in rats

6.3 Mammalian Metabolism of Iridoids

263

The pharmacokinetics and distribution of catalpol 14 in both rat plasma and cerebrospinal fluid (CSF) were evaluated [19]. Administration of catalpol (6 mg/kg, i.v.) in rats resulted in the rapid transport of catalpol into CSF of rats with a Cmax of 676 ng/ml of fluid after 5 min of drug administration. Catalpol was slowly eliminated from the CSF with a half-life (t1/2) of 1.5 h. Only 5.8% of plasma catalpol is able to penetrate the blood–brain barriers (BBBs), which is effective in therapeutic efficacy of catalpol in neurodegenerative disorders. The maximum catalpol concentration (Cmax) in rat plasma was 23,617 ng/ml of fluid with a half-life (t1/2) of 0.71 h [19]. The tissue distribution of loganin 18 in rats was evaluated by Li et al. on oral administration of loganin (20 mg/kg) in rats [20]. The highest level of loganin was observed in kidney, followed by in stomach, small intestine, and liver. The lowest level was found in brain. The maximum concentration levels were attained at 90 min in most of the tissues. The maximum concentrations of loganin at 90 min after drug administration were 6.35, 2.31, 1.93, 1.39, 1.29, 1.23, and 0.28 µg/ml in the plasma fluid and in the respective tissue of kidney, stomach, plasma, small intestine, liver, lungs, and brain. There was no long-term accumulation of loganin in kidney, as it was not found in kidney after 360 min of drug administration. The lowest level of loganin in brain is due to its difficulty in crossing the BBBs because of its polar nature [20]. In another experiment, Li et al. observed the metabolism of loganin in rats [14]. In an oral administration of loganin (100 mg/kg) in rats, the metabolites in urine and feces were investigated after 24 h of loganin administration. Loganin and its aglycone 230 were detected in urine, while 3-hydroxy-1-methyl ether of dihydrologanin aglycone 881 was only found in feces [14]. A comparative pharmacokinetics of 8-O-acetylharpagide 12a and harpagide 12 in rats was evaluated by Li et al. after oral administration of these iridoids in pure forms and mixture from Ajuga decumbens extract [21]. An oral administration of 8-Oacetylharpagide (12 mg/kg) and harpagide (3 mg/kg) in rats showed their concentrations in rat plasma Cmax 1447.2 and 338.8 ng/ml, Tmax 0.83 and 0.21 h, t1/2 3.37 and 2.34 h, AUC0!t 1635 and 604 h/ng/ml, and AUC0!œ 1674 and 806 h/ng/ml, respectively, while in an oral administration of an aqueous extract of A. decumbens (30 mg/kg, equivalent to 12 mg/kg of 8-O-acetylharpagide and 3 mg/kg of harpagide) in rats, their respective pharmacokinetic parameters in rat plasma were Cmax 1383 and 496.5 ng/ml, Tmax 0.39 and 0.39 h, t1/2 2.88 and 2.67 h, AUC0!t 1279.6 and 866.9 h/ng/ml, and AUC0!œ 1503 and 958 h/ng/ml. Both these iridoids were quickly absorbed by oral route and showed similar pharmacokinetic parameters except Tmax when dosed as pure forms and extract. 8-O-Acetylharpagide was possibly metabolized to harpagide in rat plasma and affected the pharmacokinetic profiles of harpagide when dosed as a mixture of the extract. The metabolites of harpagide were not found in rat plasma [21]. Several groups reported the pharmacokinetics of geniposide 23 and genipin 41, important bioactive constituents of Gardenia fruits. Ueno et al. reported that in an oral administration of Gardenia fruit extract (1200 mg/kg, corresponding to 216.4 mg/kg of geniposide) in mice, the plasma geniposide level reached a maximum concentration at 30 min (about 103.1 µg/ml) and gradually decreased, while a

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6 Pharmacokinetics of Iridoids

very small amount of genipin was detected in the mice plasma, and its concentration at 60 min was 0.07 µg/ml [22]. Later on, Hou et al. reported that in an oral administration of genipin or Gardenia fruit decoction in rats, genipin sulfate was found as major metabolite in the blood plasma of rats, whereas the parent forms of genipin and geniposide from the fruit decoction were not detected in rat plasma. An i.v. administration of genipin (50 mg/kg) in rats, the plasma clearance, and volume of distribution of genipin and genipin sulfate were 89.5 ± 6.7 and 230.3 ± 25.9 ml/min, and 1148.4 ± 187.3 and 32,617.0 ± 7987.4 ml, respectively. It indicates that genipin sulfate emerged instantaneously and genipin declined rapidly via rapid hepatic sulfation. In an oral administration of genipin (200 mg/kg) in rats, only genipin sulfate was found in rat plasma, genipin and genipin glucuronide were not detected. Furthermore, seven among the nine rats receiving this dose of genipin became weaker and subsequently died (mortality of 78%). In another in vivo study, in an oral administration of Gardenia fruits (GF) decoction (10 and 20 g/kg, corresponding to 490 and 980 mg/kg of geniposide) in rats, only genipin sulfate was found in rat plasma, whereas geniposide, genipin, and genipin glucuronide were not detected in the rat plasma. The plasma concentration (Cmax) of genipin sulfate was 4.2 ± 0.6 and 8.8 ± 0.6 nM/ml in the oral 10 and 20 g/kg dosage of GF, respectively. The applied dosages of GF produced no adverse toxicity in rats. These results indicate that geniposide acts as a prodrug of genipin through gradual hydrolysis by intestinal bacteria. These results indicate the dosages of genipin to be used in food and medical preparations in industries with caution because of its toxicity in higher dosage [23]. Recently, it has been observed that a long-term oral intake of geniposide as herbal medicines by patients caused an idiopathic mesenteric phlebosclerosis (IMP), a rare fibrotic degeneration disease of veins, characterized by thickening of the walls of right hemicolon and calcification of mesenteric veins. Possibly, geniposide is converted into its metabolite genipin, which plays a key role in the manifestation of this disease via intermolecular cross-linking complex formation with the collagen fibers at the effected veins [24]. In another study, Wang et al. reported the pharmacokinetics, bioavailability, and tissue distribution of geniposide in rats [25]. In an oral administration of geniposide (100 mg/kg) in rats, the maximum concentration of geniposide in rat plasma, Cmax of 1.40 ± 0.24 µg/ml, occurred at 1 h, and plasma geniposide was eliminated nearly completely within 12 h, with a half-life of elimination phase, t1/2 of 3.55 ± 0.69 h. The AUC0!œ values of geniposide were 6.99 ± 1.27 and 6.76 ± 1.23 h/µg/ml after i.v. administration of 10 mg/kg and p.o. administration of 100 mg/kg of geniposide in rats, respectively. The absolute oral bioavailability of geniposide was 9.67%. After p.o. administration of geniposide (100 mg/kg) in rats, the AUC0!4h values of geniposide in rat tissues were in the order of kidney > spleen > liver > heart > lungs > brain. The low bioavailability of geniposide might be attributed, partly because of its metabolism in intestine and liver of rats through hydrolysis and sulfation reactions with b-glucosidase and sulfatase, respectively, before entering the blood circulation. Geniposide showed no toxicity in rats on oral administration at a dose of 200 mg/kg. Future study on the improvement of bioavailability of

6.3 Mammalian Metabolism of Iridoids

265

geniposide is essential in the direction of solid–liquid nanoparticles system or other methods before its clinical trials in humans [25]. The pharmacokinetics, bioavailability, and tissue distribution of agnuside 17, a major bioactive constituent of several Vitex species, were evaluated [26]. An oral administration of agnuside (53 mg/kg) in mice showed maximal concentrations of agnuside in mice plasma and tissues within 30–45 min, the most abundant in intestine, followed by kidney, liver, spleen, brain, lungs, and heart. Agnuside was cleared off from all the tissues within 8 h except brain, where the levels were detected up to 24 h. After oral dosing, the plasma concentration (Cmax), half-life (t1/2), systemic clearance (CL), and volume of distribution (Vd) of agnuside in mice were 422.3 ± 101.7 ng/ml, 0.19 ± 0.2 h, 95.7 ± 48.2 g/h/kg, and 143.0 ± 79 l/kg, respectively. The agnuside concentration (Cmax) in mice plasma was found to be 62,852.3 ± 16,013.9 ng/ml in an i.v. administration of agnuside (5.3 mg/kg). The plasma concentration of agnuside declined quickly, signifying its rapid distribution in the tissues. The high Vd value could be inferred for its extensive distribution in the tissues rather than in plasma. The mean absolute bioavailability of agnuside was 0.7%. This low oral bioavailability of agnuside could be attributed to its low permeability, fast metabolism from intestinal bacteria. The higher levels of agnuside in intestine and kidney suggest that these organs have prominent roles for excretion of this drug. The identified target tissues of agnuside might be useful in the explanation of its pharmacological action in animal models [26]. In an animal model, oral administration of swertiamarin 68 (200 mg/kg) in rats resulted in the formation of metabolite, gentiandiol 890 in rat plasma. Possibly, swertiamarin is metabolized to gentiandiol via formation of its aglycone and gentianine 878 as intermediates (Scheme 6.12). In an in vitro culture of rat liver microsomes with gentianine, gentiandiol was produced. This indicates that gentiandiol is likely metabolized in rat liver and excreted via urine [27]. The pharmacokinetics of sweroside 67, a major bioactive constituent of Lonicera japonica, was evaluated in rat model [28]. An oral administration of sweroside

Scheme 6.12 Metabolism of swertiamarin in rats

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6 Pharmacokinetics of Iridoids

(1 mg/kg, i.v. and 500 mg/kg, p.o.) in rats showed plasma Cmax of 1.18 and 0.32 µg/ml at 30 min, t1/2 of 23.27 and 64.34 min, and AUC0!240 min of 12.34 and 19.09 µg/ml/min of sweroside for i.v. and p.o. dosage in rats, respectively. The absolute oral bioavailability of sweroside was about 0.31%. The low oral bioavailability might be due to rapid metabolism and intestinal bacterial biotransformation. The recovered amounts of sweroside in feces were much higher than in plasma. About 43.38% of sweroside was accumulated in the feces within 72 h after oral administration. The hepatoprotective efficacy of sweroside may be explained from its hepatic uptake and biliary excretion (31.2% of total dosage in bile) in feces via bile formation in rats [28]. The pharmacokinetics of morroniside 70 in rats was evaluated after administration of a single intravenous (5 mg/kg) and oral (10, 20, and 40 mg/kg) dose of morroniside in rats. The level of morroniside in rat plasma (Cmax) was higher (36.54 µg/ml) in i.v. administration compared to that of oral administration (Cmax, 1.29 and 1.48 µg/ml in 20 and 40 mg/kg dosage, respectively). The maximum concentration of morroniside in rat plasma is attained at 60 min of oral administration in rats. Morroniside was absorbed and eliminated rapidly in rats, as it was detected in plasma at 15 min of oral administration and was not detected in the tissues after 5 h. The half-life of morroniside was 103.9 and 90.2 min for 20 and 40 mg/kg dosage, respectively. The absolute oral bioavailability of morroniside was 7.0, 6.1, and 3.6% for 10, 20, and 40 mg/kg dosage, respectively. The distribution of morroniside in the tissues of rats at 60 min after the oral dose of 20 mg/kg was found to be 2.94, 2.44, 1.29, and 0.35 µg/ml in small intestine, kidney, plasma, and stomach, respectively. It was not detected in brain, possibly due to its difficulty to cross the BBBs because of its high polarity [29]. The pharmacokinetics of oleuropein 80 in rats was evaluated after administration of a single dose (100 mg/kg) of oleuropein in rats. Analysis of rat plasma at 2 h of oral administration showed the presence of unchanged oleuropein (200 ng/ml) along with a small amount of its metabolite, hydroxytyrosol, whereas in urine, both these compounds were detected as their glucuronides [30]. The noni (Morinda citrifolia) fruits juice is consumed as dietary supplement for maintenance of good health in many countries including USA. The juice contains different types of iridoids, of which deacetylasperulosidic acid (DAA) 290 and asperulosidic acid 288 are the major iridoid constituents and make up over 90% of total iridoid content of the juice. The pharmacokinetic of DAA in mouse model was evaluated. An oral administration of tritium labeled DAA (25 mg/kg) in mice showed rapid absorption and excretion of DAA via kidney with a half-life of 30 min. The highest concentrations of 3H were observed in blood at all time points. The radioactivity (tritium) was present in all the tissue organs with highest concentrations in kidney and liver. An HPLC analysis of serum and urine samples showed only a single peak with a retention time identical with that of DAA. The short half-life of excretion suggests that the absorption of DAA takes place in the upper parts of intestine, which avoids the contact of the compound with intestinal bacteria for biotransformation. More than 20% of the radioactivity was excreted via feces after 24 h. In an in vitro study, treatment of DAA in human intestinal bacterial culture for a period of 24 h,

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267

showed a rapid breakdown of the molecule and formation of several metabolites as indicated in HPLC analysis. The aglucone of DAA was the major metabolite, and other minor metabolites were not identified [31].

6.4

Mammalian Disposition of Iridoids

Most of the herbal medicinal formulations are the combination of multiple herbs and have very complex chemical compositions. The pharmacokinetics and disposition studies are the crucial steps for identification of chemical basis responsible for their therapeutic actions. In many cases, phytochemical constituents and their active metabolites in the living system exhibit synergistic pharmacological effects, and thus, evaluation of their pharmacokinetic compatibility will lead to understand the therapeutic action of the herbal medicine. A herbal medicine with high levels of systemic exposure of bioactive constituents in different tissues and better disposition of the bioactive constituents and their metabolites from the tissues would be a potential drug for clinical trials in humans [32]. Re Du Ning injection in China, prepared from a combination of extracts from three herbal plant parts, Gardenia jasminoides fruits, Lonicera japonica flower buds, and Artemisia annua aerial part, is frequently prescribed in the treatment of viral infections in upper respiratory tract. Iridoids, organic acids, and flavonoids are most likely the important bioactive constituents of this herbal injection because of the reported pharmacological activities of these plant metabolites, such as antiviral, anti-inflammatory, and antioxidant activities of pure isolates [33]. Cheng et al. reported the pharmacokinetics and disposition of the major circulating chemical compounds in rats that received this injection intravenously [34]. Re Du Ning injection was reported to contain 19 iridoids (content levels 0.01–27.93 mM), 16 organic acids (0.04–19.06 mM), and 11 flavonoids (‹ 0.08 mM). After administration of the injection (2 ml/kg via the tail veins) in rats, the iridoids, namely geniposide (56.8%), secologanic acid (21.4%), secoxyloganin (6.6%), genipin-1-bgentiobioside (3.2%), geniposidic acid (2.8%), and shanzhiside (1.8%) and the organic acids, namely chlorogenic acid, quinic acid, cryptochlorogenic acid, and neochlorogenic acid were found as major circulating compounds in rat plasma with mean elimination half-lives of 0.2–0.9 h, whereas other plasma compounds were at low exposure levels. These major circulating compounds have small apparent volumes of distribution (0.03–0.34 l/kg). Most of the iridoids were eliminated predominantly via renal excretion as unchanged compounds. The mean total plasma clearance (CLt) and mean distribution volumes at steady state (VSS) of the iridoids were 0.2–1.6 ± 0.2 l/h/kg and 0.2–0.4 l/kg, respectively. The iridoids were poorly bound to rat plasma proteins as evident from the fractions of iridoids unbound plasma proteins in the range of 75.2–99.0%. Among the major circulating iridoids, geniposide 23, secoxyloganin 65, genipin-1-b-gentiobioside 585, sweroside 67, and shanzhiside 21 were eliminated in urine, with fractions of doses of 64.0–87.5%,

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Scheme 6.13 Metabolism of geniposide and secologanin in rats

whereas the fraction of geniposidic acid 289 was 334.8%. Possibly, a major part of geniposide was hydrolyzed to geniposidic acid by microsomal P450 enzymes (Scheme 6.13). In contrast, the renal excretion of secoiridoid, secologanin was only 7.3%. A reduced metabolite 891 of secologanin was detected in rat plasma, urine, and bile samples. The metabolism of secologanin was probably mediated by carbonyl reductase enzyme in rat liver cytosol (Scheme 6.13). Iridoids, geniposide 23, secologanic acid 66, secoxyloganin 65 and geniposidic acid 289 exhibited high levels of systemic exposure (Cmax 11.3 ± 2.4 – 71.7 ± 6.4 µM), whereas sweroside 67, genipin-1-b-gentiobioside 585 and shanzhiside 21 were at lower levels of systemic exposure (Cmax 4.6 ± 0.2 – 6.7 ± 0.9 µM). Possibly, these iridoids play a key role in the efficacy of this injection [34].

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Chapter 7

Applications of Iridoids in Pharmaceutical, Cosmetic, and Insecticide Industries

7.1

Introduction

A widely grown edible fruits and vegetables in different countries are rich in iridoid and phenolic contents. Bioactive iridoids present in these fruits and vegetables could be useful in commercial preparation of nutraceutical diet supplements and herbal drugs for prevention and treatment of various ailments and diseases. Recently, the Complementary and Alternative Medicine (CAM) is expanding rapidly to provide low-cost herbal drugs of minimum adverse effects from pharmaceutical industry based on conventional allopathic scientific methods, indigenous medical practices, and local health traditions as key components. Moreover, the plant extracts having insecticidal and insect hormonal iridoids could be utilized in the preparation of herbal insecticides in the management of disease bearing harmful insects in a local community to provide a better lifestyle of the people in the community and to protect the people from the endemic disease hazards. Furthermore, the plant extracts rich in colored dye producing iridoids and melanogenesis inhibitory iridoids could be useful in cosmetic industries.

7.2

Applications of Iridoids in Pharmaceutical, Cosmetic, and Insecticide Industries

In several developing and underdeveloped countries, most of ordinary people are suffering from various diseases due to malnutrition. Therefore, consumption of nutritional foods in their routine diets could be useful in prevention of various diseases and maintenance of good health and would be a prospective target for development of socio-economy of the countries. The noni (Morinda citrifolia) fruits are widely grown in India and several islands in adjoining USA. These fruits are rich in a variety of iridoid glycosides and © Springer Nature Switzerland AG 2019 B. Dinda, Pharmacology and Applications of Naturally Occurring Iridoids, https://doi.org/10.1007/978-3-030-05575-2_7

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flavonoids. Many of these constituents have good antioxidant, hypoglycemic and hypolipidemic, and antitumor activities. A variety of beneficial effects of this fruit are reported. In one study, consumption of noni fruit juice (30 ml/d) as diet supplement for about 3 weeks has significantly improved glycemic effect in diabetic patients [1]. Cornelian cherry (Cornus mas fruits) are grown wild and cultivated in different European countries. Its sister, Corni Fructus (Cornus officinalis fruits) are extensively grown in Japan and China and other Asian countries. Both these Cornus fruits are rich in iridoid content. Regular consumption of these fruits as diet supplement could be useful in prevention and treatment of cardiovascular and diabetic problems. The herbal formulation, ‘ÇDAP,’ known as, ‘Supungsunkihwan,’ containing Corni Fructus and other three herbs, is frequently prescribed in Korean traditional medicine for the treatment of obesity. This formulation effectively ameliorates obesity through reduction of lipid accumulation via expression of major adipogenesis factors, PPAR-c, C/EBP-a, and lipin-1 as well as activation of AMPK-a phosphorylation. Major iridoids, loganin, morroniside, cornuside, and some anthocyanins present in the fruits have been found to exhibit these effects through induction of PPAR-c, C/EBP-a, lipin-1, PPAR-a genes activation and up-regulation of AMPK phosphorylation [2]. The commercial herbal product, locally called, ‘Tochu-Cha,’ in Japan, composed of roasted Eucommia ulmoides leaves, has been extensively used as soft drink for good health of diabetic patients. Iridoid, asperuloside present as a major constituent (45.2 mg/g of dry leaf) in the leaves, exhibited significant anti-obesity effect in high-fat diet rats by stimulating insulin-induced glucose uptake and improving metabolic functions in liver, skeletal muscle, and plasma through expression of metabolic genes [3]. The dried chaste berry (Vitex agnus-castus fruits) and its aqueous extract are used as a dietary supplement in many European countries to improve menstrual disorders and premenstrual syndrome, such as cyclical mastalgia and corpus luteum insufficiency. The estrogen-stimulating constituents namely iridoid, agnuside, and flavonoids of the fruits are effective in amelioration of these disorders [4]. Chaste berry fruit extract along with Valeriana root extract and extracts of other herbs has been formulated under the trade name ‘Fem EstroPlex’ in China and USA for the treatment of menopausal disorders in women [5]. The dried radix of Devil’s claw (Harpagophytum procumbens) has long been used in various herbal formulations in Germany and other European and African countries for the relief from osteoarthritis and low-back pain. About 60 pharmaceutical products in Germany are now available based on Devil’s claw as an ingredient. In USA, few clinical trials on the extracts of H. procumbens for the treatment of hip and knee arthritis are in process. The major iridoid constituent, harpagoside of the radix, has been found to exhibit significant anti-osteoarthritis activity in both animal and human models [6]. Dried roots of Rehmannia glutinosa has long been used in traditional Chinese medicine under various trade names, such as ‘Liuwei Dihuang Wan’ and ‘Sheng Di Huang’ for the treatment of kidney and adrenal glands disorders. In Western herbal medicine, an adrenal tonic containing the root extract of R. glutinosa is used for

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treatment of menopause and impotence. Several accumulating evidence indicate that iridoid glycosides, catalpol, rehmannin, and geniposide present as major constituents in the roots, exhibited significant cortical hormone stimulating and anti-inflammatory activities to ameliorate these disorders [7]. Dried fruits of Gardenia jasminoides are frequently used in Japan and China as tea to get relief from several health disorders, such as anxiety, insomnia, tiredness from dampness and heat. Chinese herbal formulation, ‘Yinchenhao Tang,’ consists of G. jasminoides fruits, Artemisia annua and Rheum palmatum, has been prescribed to treat jaundice syndrome and liver disorders. Major iridoid constituents, geniposide (about 70%) and gardenoside and other constituents, namely chlorogenic acid and ursolic acid of G. jasminoides, are the bioactive constituents of this formulation [8]. Honey-suckle tea (Lonicera japonica loose dried buds) is widely consumed in China and European countries for the relief from asthma, feverish condition, and diarrheal dysentery. Several iridoid and secoiridoid constituents such as catalpol, loganin, secoxyloganin, sweroside and morroniside of flower buds are effective to ameliorate these disorders [9]. The aqueous extract of the whole plant of Swertia chirayita is orally consumed in India for improvement of hepatic and gastric disorders. Some secoiridoid glycosides, namely swertiamarin and amerogentin as well as some xanthones, isolated as major constituents from this plant, are reported to ameliorate these hepatic and gastric disorders. In India, herbal formulations, such as ‘Ayush 64,’ ‘Mensturyl syrup D-400,’ ‘Sudarshan Churna,’ and ‘Melicon V ointment’ containing S. chirayita extract in different concentrations along with other herb extracts are available in the market for treatment of leishmanial fever, skin diseases, rheumatic inflammation, and intestinal parasites [10]. The entire plant of Ajuga decumbens has been used in Japan and China in different herbal formulations to treat chronic bronchitis, and pain and swelling in knee joints. Iridoid, 8-O-acetylharpagide, and cyasterone are the major active principles of this plant. A cosmetic preparation containing the extracts of A. decumbens and A. reptans as ingredients has been patented for topical application on human dry skins to enhance the productivity of hyaluronic acid by skin tissue for prevention of dermal aging. Aucubin and harpagoside of these extracts are the active principles [11]. Consumption of extra virgin olive oil from Olea europaea in daily diet has been found to improve the lipid profile and reduce cardiovascular morbidity in persons suffering from cardiovascular disorders. In a study, oral administration of olive leaf extract, rich in secoiridoid, oleuropein, and other phenolics, in high-lipid diet atherosclerotic rabbits, significantly reduced the sizes of atherosclerotic lesions and thickness of the aortic intima of the rabbits compared to the control group via decreasing the levels of atherosclerotic markers, including serum TG, TC, LDL, HDL, and MDA and down-regulating the expressions of MCP-1, VCAM-1, NF-jB, and TNF-a [12]. Consumption of the extract of Indian Picrorhiza kurroa rhizome in powder form is well recognized for healthy liver functioning. Iridoids, picrosides I and II, major constituents of the rhizomes of P. kurroa, were found to be effective in protection of liver in different liver toxicities in animal models. A commonly used Ayurvedic

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formulation—‘Arogyavardhini’—containing 50% of P. kurroa extract was found to be effective in a double-blind trial in viral hepatitis. Other herbal formulations, namely ‘Picroliv,’ ‘Picrosil,’ ‘Livotrit,’ ‘Livarin,’ ‘Livfit,’ ‘LivRx,’ mainly based on P. kurroa extract are available in the market for treatment of liver disorders in different complications [13]. Dried roots and rhizomes of Valeriana officinalis are orally consumed by the people in the USA and European countries in insomnia and other sleep-related disorders. Iridoids, valepotriates as well as valeric acid, major constituents of the roots and rhizomes, are the active principles. In European countries, more than 80 commercial preparations containing Valeriana extract along with the extracts of other herbs, such as ‘Valmane,’ ‘Baldrisedone,’ ‘Valdispert,’ ‘Relarian,’ are used for treatment of insomnia and other related disorders [14]. Both fresh and dried ripe fruits of Ligustrum lucidum are supplemented in regular diets in China for treatment of menopausal and rheumatic disorders, insomnia, and age-related complications. Chinese herbal formulation, ‘Dan-zhi-xiao-yao-san’ containing L. lucidum and Eclipta prostrata is frequently prescribed in Taiwan for treatment of menopausal syndrome. Another herbal preparation, ‘Equiguard,’ containing L. lucidum as an ingredient, is prescribed as a dietary supplement for treatment of prostate cancer and kidney disorders. The fruit powders are supplemented in the diets of hens to improve the quality of eggs and quantity of meet in poultry farming. The antioxidant and anti-inflammatory secoiridoids and phenolics constituents of L. lucidum fruits, are the active principles [15]. Young shoots, leaves, and flowers of Lamium album, commonly known as white dead nettle in Asian and European countries, are consumed as teas and vegetables to ameliorate menstrual disorders, skin and upper abdominal inflammations, sore throat, musculoskeletal disorders and to improve fat metabolism. Several iridoids and phenolics including flavonoids and phenylethanoids present in the plant exhibit these beneficial activities through their potential antioxidant, anti-inflammatory, antiviral, and hormone secretion efficacies [16]. Seeds and fruits of Fraxinus excelsior are used as dietary supplements in food and condiments for the relief from type 2 diabetes, arthritis, and cardiovascular disorders. The seed extract of F. excelsior is commercially used under the trade name ‘Fraxi Pure,’ for treatment of obesity and hyperglycemia. Several secoiridoids, such as nuzhenide, GI-3, excelside B, have been found to exhibit potential hypoglycemic activity through inhibition of adipocyte differentiation and PPAR-a gene activation [17]. The ethanolic extract of Gentiana lutea has been used orally in India and some European countries for treatment of digestive disorders, such as loss of appetite, dyspepsia, and feeling of fullness. Possibly bitter iridoids, gentiopicroside, and amerogentin as well as other phenolics of the G. lutea extract increase the gastric secretion in mouth and stomach and exhibit antibacterial activity against Helicobacter pylori and improve the antioxidant status in liver and other tissues to ameliorate the digestive disorders [18].

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A mixture of dried catnip, Nepeta cataria, chamomile flowers, fennel seeds, and lavender blossoms has been used as mother’s milk tea for mothers after postpartum to reduce the jumpiness and anxiety, quick angering, and frequent weeping [19]. Dried leaves of Morinda lucida are used in Cameroon and Nigeria as teas for treatment of malarial fever and as tonic for young children. Antimalarial iridoids and anthraquinones and growth-stimulating steroids, major constituents of the leaves, are the active principles [20]. Folium syringae leaves have been used in Chinese traditional medicine for the treatment of acute enteritis, bacillary dysentery, hepatitis, and upper respiratory tract infection. Several iridoids present as major constituents of F. syringae leaves are the active principles [21]. A herbal formulation containing the extracts of Ligustrum japonicum fruits and Sanguisorba officinalis as ingredients has been patented for effective treatment of burn injury and chronic wounds. The iridoids from L. japonicum and terpenoid saponins from S. officinalis are the most active constituents of this formulation [22]. Different parts of Indian Nyctanthes arbor-tristis (night jasmine) are used in traditional medicine for the treatment of skin diseases, coughs, and muscular pains. Two commercial herbal formulations, namely ‘Lupin’ and ‘Harshiangar oil,’ using the extract of this plant as an ingredient have been available for treatment of pain and inflammations in arthritis, joint and knee pains, and menstrual pain. Some iridoids, such as loganin derivatives, arbortristosides are most active principles due to their anti-inflammatory efficacy [23]. The whole plant extract of Hedyotis corymbosa has been prescribed in both Indian and Chinese traditional medicines for treatment of liver disorders. A Chinese preparation called, ‘Pch-hue-juwa-chin-cao,’ containing H. corymbosa as a part of it, is frequently prescribed for treatment of hepatitis [24]. In Indian ethnomedicine, a decoction prepared from a mixture of Vitex negundo leaf, Sapindus laurifolius fruit, and Leucas aspara leaf is used for treatment of sore nose. An Ayurvedic formulation, ‘Nirgundi oil,’ containing V. negungo extract as major constituent, is prescribed to use orally for treatment of arthritis, sciatica, respiratory diseases like cough, asthma, bronchitis, and in female menopausal disorders. The iridoids, agnuside, negundoside, aurostoside, and aucubin, and flavonoids, casticin and vitexin, are the major bioactive constituents of the oil [25]. A cosmetic preparation using Ajuga turkestanica extract as major constituent has been patented for treatment of dry skin and protection of skin from strong sunlight and to improve the hydration of the skin. Iridoids, harpagide and 8-O-acetylharpagide, and ecdysteroids, ecdysterone, turkesterone, and 22-acetylcyasterone from the extract of A. turkestanica are the major bioactive chemicals of this preparation [26]. Cornelian cherry fruits (Cornus mas fruits) are used in cosmetic industry in some European countries. An iridoid-rich fraction from an aqueous ethanol (1:1) extract of cornelian cherry fruits was found to exhibit skin-whitening property in tyrosinase activity inhibition assay. The isolated iridoids from this bioactive fraction could be useful as novel ingredients in cosmetic industry [27].

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The mother tincture of Gelsemium sempervirens is frequently used in the treatment of neurological disorders for improvement of memory and cognitive impairment in Indian Homeopathic and Ayurvedic systems. Several iridoids and alkaloids present in the mother tincture of G. sempervirens could be prospective neuroprotective drugs [28]. The fruit extract of Kigelia pinnata has been used in Asia and Europe in the production of commercial skin-care products for protection from sun burn and treatment of skin diseases and wounds as well as skin-tightening agent. Possibly, the antimicrobial and anti-inflammatory catalpol derivatives of the fruit extract are the major active principles of these skin-care products [29]. Different Veronica species are used in the USA and Europe as teas to ameliorate various ailments. Native Americans use V. americana as an expectorant tea to alleviate bronchial congestion associated with asthma and allergies. In Austria and other European countries, V. officinalis (locally known as speedwell) and V. chamaedrys are used as teas for amelioration of nerve, respiratory, and cardiovascular disorders. The major iridoid constituents, aucubin, catalpol, and catalposide, are the active principles for the efficacy of these plants [30]. The essential oil of N. cataria has been identified as an effective mosquito repellent. Three major isolated bioactive compounds from the catnip’s oil extracted from N. cataria cultivated in Burundi were identified as 4aa, 7a, 7ab-nepetalactone (72%), b-caryophyllene (10%), and trans-b-ocimene (4%). The major constituent of the oil, nepetalactone is the active constituent of the oil and its activity is similar to that of DEET repellent, and its hydrogenated form, dihydronepetalactone, is two times more active than DEET, when formulated with isopropyl alcohol (1% w/v). Among 41 different essential oils applied on skin as mosquito repellent, the catnip’s oil offered protection for 480 min. Moreover, catnip’s oil exhibits a more favorable safety profile than DEET. In a study of its effectiveness, out of 60 individual volunteers, 55 faced no mosquito bites. The catnip’s oil has a pungent odor. An epidemiological study is required to establish its clinical efficacy before commercial application as mosquito repellent in most of the malaria endemic countries. Accumulating evidence indicates that the anopheles mosquitoes developed resistance to DEET. Moreover, catnip’s oil is a better spatial repellent than DEET. Furthermore, among the available vaccines for malaria prevention, only RTS, S vaccine reduced the malaria episode by 58%. The most effective and commonly used drug artesunate exhibits toxicity to children at high doses. The malaria-prone communities prefer essential oil-based mosquito repellent for safety in their day-time activities. Therefore, the development of essential oil-based mosquito repellent is the thrust area of natural products research [31]. Earlier, Science Daily based on the information from American Chemical Society reported that catnip essential oil was about ten times more effective in repelling mosquitoes than DEET, the most commercially used insect repellent [32]. Catnip essential oil was also effective in repelling housefly (Musca domestica), German cockroach (Blattella germanica), and house mosquito (Culex pipiens), and this activity was comparable to that of DEET. Schultz et al. reported that catnip essential

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oil contained two major iridoid lactones, Z,E-nepetalactone 780 and E,Z-nepetalactone 781. German cockroaches were more responsive to the E,Z-isomer, while houseflies were more sensitive to Z,E-isomer of nepetalactone, compared to catnip essential oil [33].

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Plant Species Index

A Abelia grandiflora, 21 Abutilon pakistanicum, 27 Acalypha indica, 23 Acicarpha tribuloides, 21 Actinidia polygama, 19 Adenosma caeruleum, 30 Adina racemosa, 31 Adinocalymma marginatum, 20 Adoxa moschatellina, 19 Aegenetia indica, 28 Agalinis communis, 28 Aitchisonia rosea, 31 Ajuga bracteosa, 149 decumbens, 158, 190, 229, 263, 273 pyramidalis, 89 reptans, 25, 222, 273 Alangium platanifoliumvar.trilobum, 22 Alberta magna, 31 Alibertia edulis, 31 myrciifolia, 85 Allamanda neriifolia, 19 schottii, 191 Alonsoa meridionalis, 34 Alstonia scholaris, 19, 228 Alyxia reinwardtii, 20 Anarrhinum orientale, 30, 207 Andrographis laxiflora, 19 Andromeda polifolia, 23 Angelonia integerrima, 30 Anthocephalus chinensis, 31 Anthocleista djalonensis, 24

Antirrhinum majus, 30, 70, 237 Antonia ovata, 27 Apodytes dimidiata, 27 Aragoa cundinamarcensis, 30 Aralidium pinnatifidum, 35 Arbutus unedo, 23 Arcytophyllum thymifolium, 31, 182 Argylia radiata, 20 Asperula maximowiczii, 31 Aster auriculatus, 20 Astianthus viminalis, 20 Aucuba japonica, 23, 187 Aureolaria flava, 28 Avicennia marina, 19 B Barleria lupulina, 206 prionitis, 205 Barteria fistulosa, 29, 203 Bellardia trixago, 28 Besseya plantaginea, 30 Betonica officinalis, 25 Bhesa paniculata, 22 Blackstonia perfoliata, 24, 205 Borreria verticillata, 31 Boschniakia rossica, 28, 152 Bouchea fluminensis, 35, 148 Brandisia hancei, 29 Brillantaisa owariensis, 19 Buddleja asiatica, 34 globosa, 21 Burchellia bubalina, 31

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280 C Caiophora coronata, 27 Callicarpa formosanavar.formosana, 25 nudiflora, 192 Calycophyllum spruceanum, 31, 213 Campsidium valdivianum, 20 Campsis grandiflora, 20 Canthium gilfillanii, 31 subcordatum, 201, 204 Cantleya corniculata, 35 Capraria biflora, 34 Caryopteris clandonensis, 25 Castilleja integra, 238 rhexifolia, 28 tenuifolia, 152 Catalpa ovata, 155, 168, 194, 195, 237 speciosa, 20, 229 Catharanthus roseus, 20, 131, 133, 134, 137 Catunaregam tomentosa, 31 Centaurium littorale, 24 spicatum, 162 Centranthus longiflorus ssp. longiflorus, 21 Cerbera manghas, 20 Chaenorhinum minus, 30 Chamaeranthemum gaudichaudii, 19 Chelonanthus chelonoides, 24 Chilopsis linearis, 20 Chiococca alba, 31 Chionanthus virginicus, 27 Cistanche salsa, 29 Citharexylum caudatum, 35 Citronella gongonha, 22 Clerodendrum thomsonae, 25 Coprosma pyrifolia, 31 Cornus mas, 177, 272, 275 officinalis, 22, 171–173, 183, 193, 272 Coussarea platyphylla, 31 Coutoubea spicata, 24 Craibiodendron henryi, 23 Crescentia cujete, 20 Crucianella maritima, 32 Cruciata laevipes, 32 Cruckshanksia pumila, 31 Curtia tenuifolia, 24 Cybistax antisyphilitica, 20 Cymbalaria muralis ssp. pilosa, 30 Cymbaria mongolica, 204 Cyperus rotundus, 36, 218

Plant Species Index D Daphniphyllum angustifolium, 22 Deplanchea speciosa, 20 Desfontaina spinosa, 22 Deutzia scabra, 24 Dipsacus asperoides, 21 Dolichandra cynanchoides, 21 Dunnia sinensis, 32 Duranta erecta, 35 Duroia hirsuta, 32 E Eccremocarpus scaber, 20 Emmenopterys henryi, 32 Enicostemma axillare, 154, 162 Eranthemum pulchellum, 19 Eremophila, 34, 176 Eriophyton wallichii, 25 Erymostachys glabra, 25 laciniata, 203 Erythraea centaurium, 24 Escallonia myrtoidea, 23 Eucnide bartonioides, 27 Eucommia ulmoides, 23, 85, 182, 195, 200, 272 Euphrasia genargentea, 29 pectinata, 85 Eustoma russellianum, 24 Exacum tetragonum, 24 F Fagraea fragrans, 24 Feretia apodanthera, 221 Folium syringae, 194, 275 Fontanesia phillyreoides, 27 Forestiera acuminata, 27 Forsythia europaea, 27 Fouquieria diguetii, 23 Fraxinus excelsior, 27, 184, 185, 274 griffithii, 201 G Galeopsis tetrahit, 25 Galium melanantherum, 32 Gardenia jasminoides, 32, 151, 158, 168, 180, 217, 267, 273 Garrya elliptica, 23 Gelsemium sempervirens, 23, 276 Genipa americana, 32, 159 Gentiana decumbens, 24

Plant Species Index loureirii, 201 lutea, 153, 195, 197, 204, 274 macrophylla, 159 spathacea, 223 triflora, 153 Globularia dumulosa, 30 Gmelina philippensis, 25 Gonocaryum calleryanum, 22 Gratiola officinalis, 30 Griselinia littoralis, 24 Guettarda grazielae, 32 H Halenia campanulata, 24 Harpagophytum procumbens, 29, 69, 151, 157, 158, 200, 215, 216, 226, 258, 272 zeyheri, 258 Hebenstretia dentata, 34 Hedyotis corymbosa, 32, 275 diffusa, 176, 224 Heinsia crinita, 209 Heliamphora, 34 Hemiphragma heterophyllum, 30 Heracleum rapula, 35 Himatanthus articulatus, 210 sucuuba, 20, 85, 156, 211 Hippuris vulgaris, 30 Holmskioldia sanguinea, 25 Homalium ceylanicum, 34 Hunteria umbellata, 20 Hydrangea macrophyllavar.thunbergii, 180 paniculata, 24 Hygrophila polysperma, 19 Hymenodictyon floribundum, 32 I Incarvillea emodi, 21, 70 Ixora chinensis, 32 J Jasminium multiflorum, 177 nitidum, 28 K Kickxia elatine, 30 Kigelia africana, 149, 181

281 pinnata, 21, 181, 208, 276 Kirengeshoma palmata, 25 L Lagotis yunnanensis, 30 Lamiophlomis rotata, 155 Lamium album, 206, 274 amplexicaule, 25, 136 Lamourouxia multifida, 29 Lantana camara, 35 Lasianthus wallichii, 32 Lathraea squamaria, 29 Leonurus persicus, 26 Ligustrum lucidum, 274 obtusifolium, 229 Limosella aquatica, 34 Linaria vulgaris, 30, 70 Lippia graveolens, 35 Lisianthius seemanii, 24 Littorella uniflora, 30 Loasa acerifolia, 27 Lomatogonium carinthiacum, 24 Lonicera implexa, 237 japonica, 153, 265, 267, 273 morrowii, 21 M Macfadyena cynanchoides, 21 Machaonia brasiliensis, 32 Manulea altissima, 34 Maytenus laevis, 22 Melampyrum arvense, 29 Melittis melissophyllum, 26 Memora peregrina, 21 Menodora robusta, 28 Mentzelia chilensis, 149 cordifolia, 27 Menyanthes trifoliata, 27 Molopanthera paniculata, 32 Momordica charantia, 22, 202 Monochasma savatierii, 29 Montinia caryophyllacea, 27 Morina nepalensis, 21 Morinda citrifolia, 186, 203, 224, 266, 271 coreia, 32 lucida, 114, 211, 213, 275 morindoides, 208, 209

282 Mussaenda incana, 33 Myoporum bontioides, 34 Myrmecodia tuberosa, 33 Myxopyrum smilacifolium, 28 N Nelsonia canescens, 19 Nepeta cataria, 135, 204, 205, 228, 275, 276 cilicia, 26 leucophylla, 204 Nerium indicum, 20 Nestegis sandwicensis, 28 Nyctanthes arbor-tristis, 28, 180, 211, 225, 275 Nymphoides indica, 27 Nyssa ogeche, 27 O Odontites verna ssp. serotina, 29 Oldenlandia corymbosa, 32 diffusa, 176 Olea europaea, 28, 175, 180, 203 lancea, 175 Ophiocolea floribunda, 21 Oreosolen wattii, 34 Orobanche caerulescens, 152 Osmanthus fragrans, 28 Otostegia fruticosa, 26 Oxyanthus pallidus, 33 P Paederia scandensvar.tomentosa, 163 Parentucellia viscosa, 29 Parkia javanica, 23 Patrinia saniculaefolia, 155 scabiosaefolia, 178, 192 scabra, 192 villosa, 21 Paulownia tomentosa, 29 Pedicularis kansuensisssp.albiflora, 203 Penstemon fruticosus, 30 secundiflorus, 87 Pentas lanceolata, 33 Perichlaena richardii, 21 Phaulopsis imbricata, 19 Phillyrea latifolia, 28, 153

Plant Species Index Phlomis aurea, 26 tuberosa, 87 younghusbandii, 190 Phyllarthron madagascariense, 21 Physostegia virginiana, 26 Picconia excelsa, 28 Picrorhiza kurroa, 30, 160, 161, 176, 179, 198, 212, 225, 273 Pinguicula vulgaris, 26 Pithecoctenium crucigerum, 21 Plantago lanceolata, 237, 238 major, 141, 237 subulata, 30 Plumeria bicolor, 202 obtusa, 85 rubra, 20, 191, 214 Podranea ricasoliana, 21 Poraqueiba sericea, 25 Potalia amara, 24 Premna integrifolia, 85 japonica, 26 Prismatomeris tetrandra, 33, 191 Pseudocalymma elegans, 21 Pseudolysimachion rotundumvar.subintegrum, 30, 155, 179 Pterocephalus hookeri, 193 perennisssp.perennis, 203 Putoria calabrica, 33 Pyrola japonica, 23 R Radermachera sinica, 21 Randia dumetorum, 193 spinosa, 33 Rauwolfia grandiflora, 87 serpentina, 20 Rehmannia chingii, 164 glutinosa, 29, 165, 181, 272 Retzia capensis, 35 Rhinanthus angustifoliusssp.grandiflorus, 29 Rogeria adenophylla, 29 Rothmannia macrophylla, 33

Plant Species Index wittii, 192 Rubia cordifolia, 33 Russelia equisetiformis, 31, 156 S Sabatia elliottii, 24 Salvia digitaloides, 26 Sambucus williamsii, 19 Saprosma scortechinii, 33 Satureja vulgaris, 26 Scabiosa variifolia, 22 Scaevola racemigera, 24 Schismocarpus matudai, 27 Scoparia ericacea, 31 Scrophularia auriculata, 149 buergeriana, 174 deserti, 150, 181 frutescens, 150 koelzii, 150 lepidota, 211, 212 ningpoensis, 176 nodosa, 197 scorodonia, 34, 150, 205 Scutellaria albidassp.albida, 26 Scyphiphora hydrophyllacea, 33 Sesamum angolense, 89 indicum, 29 Sickingia williamsii, 33, 223 Sideritis trojana, 26 Siphonostegia chinensis, 29 Spathodea campanulata, 200 Stachys lavandulifolia, 201 Stachytarpheta angustifolia, 35 cayennensis, 148 mutabilis, 229 Stilbe ericoides, 35 Strychnos cocculoides, 85 nux-vomica, 27 spinosa, 204 Sutera dissecta, 34 Swertia calycina, 85 chirayita, 273 mileensis, 206 mussotii, 161 Symphoricarpos albus, 22 Symplocos glauca, 35 Syringa vulgaris, 28

283 T Tabebuia rosea, 21 Tachiadenus longiflorus, 24 Tarenna attenuata, 33 Tecoma stans, 21 Tecomella undulata, 21 Teucrium chamaedrys, 200 yemense, 26 Thevetia peruviana, 20 Thunbergia alata, 19 mysorensis, 19 Tocoyena formosa, 33 Torricellia, 35 Triaenophora rupestris, 29 Triosteum himalayanum, 114, 193 pinnatifidum, 22 Tripterospermum japonicum, 24 Trochocarpa laurina, 23 U Uncaria tomentosa, 33 Utricularia australis, 26 V Vaccinium bracteatum, 23 Valeriana glechomifolia, 218 jatamansi, 174, 192, 219 officinalis, 22, 218, 274, 276 pavonii, 220 wallichi, 218 Verbascum lasianthum, 146 salviifolium, 34 xanthophoeniceum, 147 Verbena littoralis, 175 officinalis, 35 Verbenoxylum reitzii, 35 Veronica americana, 192, 276 bellidioides, 87 ciliata, 89 derwentiana, 31 longifolia, 91, 178, 201 peregrina, 201 thymoidesssp.pseudocinerea, 192 Viburnum betulifolium, 19

284

Plant Species Index

luzonicum, 193 prunifolium, 222 Villaria odorata, 34, 204 Villarsia exaltata, 27 Vitex aitissima, 202 negundo, 160, 164, 275 rotundifolia, 26, 226

tinctoria, 64 Wiedemannia orientalis, 26 Winchia calophylla, 20 Wolfenia carinthiaca, 31 Wolfeniopsis amherstiana, 31

W Weigela subsessilis, 22 Wendlandia formosana, 201

Z Zaluzianskya capensis, 34

X Xylocarpus moluccensis, 27

Index

A Abelioside A 223, 21 Abelioside B 224, 21 Acerifolioside 416, 27 10-Acetoxyligtroside 465, 28, 90 10-Acetoxyoleuropein 465a, 28, 90 6-O-Acetylajugol 199a, 26 10-O-Acetylaucubin 530a, 30 Acetylbarlerin 106, 19 8-O-Acetylclandonoside 353a, 25 2′-O-Acetyldihydropenstemide 843, 222 Acetylgaertneroside 36a, 208 6-O-Acetylgeniposide 579, 32 10-O-Acetylgeniposide 578, 32 8-O-Acetylharpagide 12a, 25, 28, 34, 150, 158, 190, 200, 205, 222, 229, 240, 263 7-O-Acetylloganic acid 204, 21, 22 7-O-Acetyl-8-epi-loganic acid 480, 29 10-O-Acetylmacrophyllide 770, 192 10-O-Acetylmonotropein 25a, 32 8-O-Acetylmussaenosidic acid 112a, 29 2′-O-Acetylpatrinoside 844, 222 6-O-Acetylscandoside 597, 32 10-O-Acetylscandoside 282d, 33 8-O-Acetylshanzhiside 21a, 94, 95, 103 1 H-,13C-NMR data, 94, 95, 103 6-O-Acetylshanzhiside methyl ester 104, 26 Acevaltrate 771, 192, 218 Actinidine 706, synthesis, 122, 134, 204 Adenosmoside 508, 30 Adinoside A 546, 31 Adinoside B 547, 31 Adinoside C 548, 31 Adinoside D 549, 31 Adinoside E 550, 31

Adoxoside 125, 19, 99 Adoxosidic acid 436, 27, 35 Agnuside 17, 20, 26, 160, 226, 265 AHD-valtrate 56, 8 Aitchisonide A 551, 31 Aitchisonide B 552, 31 Ajugol 11, 20, 22, 25, 29, 30, 34, 147, 164, 200, 212 1 H-, 13C-NMR data, 94, 101 Ajugoside 11a, 23, 25, 212 Ajureptoside 343, 25 Ajureptoside A 344, 25 Ajureptoside B 345, 25 Ajureptoside C 346, 25 Ajureptoside D 347, 25 Alangiside 677, 69 Alatenoside 636, 34 Albidoside 402, 26 Alboside I 244, 21 Alboside II 569, 31 Alboside III 570, 31 Alboside IV 571, 31 Allamandicin 136, 19, 156 Allamcidin A 61, 9 Allamcin 132, 19, 191 Allamancin 134, 19 1 H-NMR data, 95, 96 Allamandin 136a, 120 Allobetonicoside 348, 25 3-O-Allopyranosylcerberidol 148, 20 3-O-Allopyranosylepoxycerberidol 151, 20 3-O-Allopyranosylcyclocerberidol 153, 20 5-Allosyloxyaucubin 798, 201 Alpigenoside 211a, 34 Alpinoside 521, 30

© Springer Nature Switzerland AG 2019 B. Dinda, Pharmacology and Applications of Naturally Occurring Iridoids, https://doi.org/10.1007/978-3-030-05575-2

285

286 Altissimoside 640, 34 Alyxialactone 143, 19 4-epi-Alyxialactone 144, 20 Amagnalactone 554, 31 Amarogentin 81, 90, 153, 195, 211 Ameroswerin 328, 24, 195 Amphicoside 192, 21, 192, 201 Andromedoside 278, 23 Angeloside 510, 30 Anisomorphal 679, 238 Anthirrinoside 109, 19 13 C-NMR data, 101 Antirrhide 511, 30 1 H-, 13C-NMR data, 102 2′-Apiosylgardoside 398a, 35 Apodantheroside 841, 221 Aquaticoside C 787, 193 Aralidoside 648, 35 Arborside A 459, 28 Arborside B 460, 28 Arborside C 461, 28 Arborside D 462, 28 Arbortristoside A 456, 28 Arbortristoside B 457, 28 Arbortristoside C 458, 28 Argylioside 169, 20 Asperuloside A 557, 31 Asperuloside B 558, 31 Asperuloside C 559, 31 Asperuloside 24, 23, 31, 90, 92, 124, 140, 141, 182, 227 13 C-NMR data, 102 Asperuloside dimer 592, 32 Asperulosidic acid 288, 23, 31, 140, 141, 176, 182, 203, 224, 266 Aucubin 13, 20, 23, 25, 26, 28, 30, 34, 90, 92, 98, 113, 124, 130, 138, 139, 141, 146, 150, 153, 181, 187–189, 195, 197, 200, 203, 206, 212, 238, 258, 261 as chemotaxonomic marker, 141 1 H-, 13C-NMR data, 94, 101 EIMS- fragmentation pattern, 111, 113 Aucubin peracetate 13a, 222 Aucuboside 13, 30, 34 Auroside 387, 26, 107, 109, 110 1 H-1H-COSY, HSQC, HMBC spectra, 105, 107, 109, 110 B Bahienoside B 675, 69 Bankakosin 693, 90 Barlerin 105, 19, 25, 32 Bartsioside 471, 28, 98, 141, 150 10-O-Benzoylcatalpol 202a, 30

Index 10-O-Benzoyldeacetyl asperulosidic acid 290a, 33 10-O-Benzoyl 10-O-deacetyldaphylloside 274, 22 10-O-Benzoylglobularigenin 518, 30 7-O-Benzoylloganic acid 260, 22 10-O-Benzoylgalioside 281, 23 6-O-Benzoylphlorigidoside B 350, 25 10-O-Benzoylscandoside 283a, 176 10-O-Benzoylscandoside methyl ester 282b, 32 3,10-Bis-O-allopyranosylcerberidol 149, 20 5,7-Bisdeoxycynanchoside 197, 21 Boonein 142a, 87 Boschnaloside 176a, 21, 28, 70, 152, 203 Boschnaloside aglycone 176b, 31 Boschnaside 473, 28 Boucheoside 209a, 35 (−)-Brasoside 703, synthesis, 122 Buddlejoside A8 527, 34 7-O-Butylmorroniside 265, 22, 174 C Cachineside I 175, 20, 32 Cachinol 173, 20 6-O-Caffeoylajugol 200, 21 10-O-Caffeoylcatalpol 202, 21 6′-O-Caffeoylharpagide 755, 176 2′-O-Caffeoylloganic acid 792, 201 7-epi-7-O-Caffeoylloganic acid 793, 201 6′-O-Caffeoylnegundoside 801, 202 10-O-Caffeoylscandoside methyl ester 796, 201 (7R)-7-Caffeoyloxysweroside 256, 22 (7S)-7-caffeoyloxysweroside 257, 22 3′-O-Caffeoylsweroside 556, 31 7-O-Caffeoylsylvestroside I 807, 204 Caiophoraenin 414, 27 Canthiumoside 791, 201, 204 Caprarioside 637, 34 Catalpol 14, 19, 20, 25, 26, 28, 30, 34, 90, 92, 124, 126, 131, 138, 139, 141, 147, 164–166, 176, 181, 188, 196, 212, 227, 238, 239, 260, 263 1 H-,13C-NMR data, 94, 101 Catalpol peracetate 14a, 222 Catalposide 182, 20, 72, 90, 155, 168, 193, 194, 237 Cantleyoside 89, 21, 24, 35, 193, 203 Cantleyoside dimethyl acetal 89a, 203 Caryoptoside 539, 31 Caryoptosidic acid 660, 35 Caudatoside A 653, 35 Caudatoside B 654, 35 Caudatoside C 655, 35

Index Caudatoside D 656, 35 Caudatoside E 657, 35 Caudatoside F 658, 35 Centauroside 92, 24 Cerberidol 47, 20 Chaenorrhinoside 515, 30 Chelonanthoside 318, 24 7-Chlorodeutziol 418, 27 Chlorotuberoside 689, 89 Chrysomelidial 678, 71, 134, 238 epi-Chrysomelidial 850, 238 6′-O-Cinnamoylantirrinoside 509, 30 10-O-Z-cinnamoylcatalpol 403a, 26 8-O-cis-Cinnamoylharpagide 506, 29 6′-O-Cinnamoylmussaenosidic acid 825, 207 3′′-O-Cinnamoyl-6-O-rhamnosylcatalpol 373, 25, 31, 35 4′′-O-Cinnamoyl-6-O-rhamnosylcatalpol 373a, 31 10-O-Cinnamoylsinuatol 537, 30 Cistachlorin 477, 29 Cistanin 476, 29 Citrifolinin A 765, 190 Citrifolinin B 607, 33 Citrifolinoside 663, 35, 190 Clandonensine 354, 25 Clandonoside 353, 25 Clandonoside II 355, 25 Cornifin B 267, 193 Cornuside 262, 22, 154, 173, 177 6-O-Coumaroylajugol 199, 21, 29 6-O-(E/Z)-p-Coumaroylantirrhinoside 109c, 30 10-O-p-Coumaroyl-10-O-deacetylasperuloside 276, 22 10-O-p-Coumaroyl-10-O-deacetyldaphylloside 273, 22 10-O-(E/Z)-p-Coumaroyldeacetylasperulosidic acid 284, 23 2′-O-(E)-p-Coumaroyldihydropenstemide 843, 222 6′-O-E-p-Coumaroyl-8-epiloganic acid 400, 26 6′-O-E-p-Coumaroylgardoside 399, 26 6′-O-p-Coumaroylgeniposide 846, 224 8-O-p-Coumaroylharpagide 500, 29, 258 6′-O-p-Coumaroylharpagide 756, 176 10-O-(E/Z)-p-Coumaroyl-6ahydroxy-dihydromonotropein 286, 23 10-O-Ep-Coumaroylmelittoside 356a, 26 10-O-(E/Z)-p-Coumaroylscandoside 283, 23 6a-O-p-Coumaroylscandoside methyl ester 272b, 33 7-O-p-Coumaroylloganin 258, 24 6′-O-p-Coumaroylprocumbide 498, 29

287 7-O-p-Coumaroylsylvestroside I 808, 204 Crescentin I 186, 20 Crescentin II 187, 20 Crescentin III 188, 20 Crescentoside A 183, 20 Crescentoside B 184, 20 Crescentoside C 185, 20 Cyclocerberidol 152, 20 Cynanchoside 196, 21 D Daphcalycinosidine A 38, 7 Daphcalycinosidine B 39, 7 Daphylloside 271, 22, 23, 32 Daunoside 513, 30 Davisioside 519, 30 DCCC of iridoids, 88 Deacetylalpinoside 522, 30 Deacetylasperuloside 24a, 31, 140 Deacetylasperulosidic acid 290, 23, 31, 98, 147, 176, 186, 203, 221, 227 10-O-Deacetylasperulosidic acid methyl ester 272, 22 Deacetyldaphylloside 272, 32, 228 Decapetaloside 131, 19 Decentapicrin A 315, 24 Decentapicrin B 316, 24 Decentapicrin C 317, 24 5-Dehydro-8-epi-adoxosidic acid 632, 34 5-Dehydro-8-epi-mussaenoside 633, 34 Dehydroiridomyrmecin 122, 19 15-Demethylisoplumieride 157, 20 15-Demethylplumieride 154, 20, 85 11-Demethoxy-11-ethoxydaphylloside 275, 22 1-Deoxyeucommiol 293, 23 6-Deoxyharpagide 342a, 149 5-Deoxyholmioside 646a, 35 4′- Deoxykanokoside A 226, 21 5-Deoxylamiol 376a, 26 5-Deoxylamioside 22a, 25, 26 6-Deoxylamioside 22b, 25 7-Deoxy-8-epi-loganic acid 163a, 33, 130, 138, 152 10-Deoxygeniposidic acid 289a, 26 7-Deoxyloganic acid 163, 20, 21, 90 Deoxyloganin 426, 27 1, 5, 9-epi-Deoxyloganin 731 , 136 11-Deoxy-11b-methoxy-11a-(hydroxymethyl)12-epi-PGF2a methyl ester 708, synthesis from aucubin, 124 11-Deoxypatrinoside aglucone 788, 198 5-Deoxypulchelloside I 471a, 28 5-Deoxysesamoside 685, 87

288 8-Deoxyshanzhiside 378, 26, 115 5-Deoxystansioside 214, 21 5-Deoxythunbergioside 116a, 35 1-Deoxy-D-xylulose-5-phosphate 734 in biosynthesis of lamalbid, 136 Derwentioside A 541, 31 Derwentioside B 542, 31 Derwentioside C 543, 31 Desfontainic acid 78, 10 a/b-Deutziogenin 336, 24 Deutziol 335, 24 Deutzioside 9, 24 1b,6b-Di-O-cinnamoyl-9-O-bD-glucopyranosyl-3-iridene-5b-ol 523, 30 Diderroside 563, 31 Didrovaltrate 55, 218 Didrovaltrate acetoxyhydrin 776, 192 Dienone derivative of Corey lactone aldehyde analogue 709 synthesis from asperuloside, 126 (8S)- 7,8-Dihydroaucubin 114 , 19 Dihydrocatalpol 404, 26 6b-Dihydrocornic acid 696, 98 6a-Dihydrocornic acid 697, 98 b-Dihydrocornin 266, 22, 28 5aH-6-epi-Dihydrocornin 700, 115 6′′, 7′′-Dihydro-7-epi-exaltoside 74a, 27 3,4-Dihydro-3b-ethoxyasperuloside 299, 23 3,4-Dihydro-3b-ethoxy-deacetylasperuloside 300, 23 10-O-Dihydroferuloyl deacetyldaphylloside 273a, 34 Dihydrofoliamenthin 74a, 27 Dihydroplumericin 159, 20 Dihydroplumericinic acid 160, 20 Dihydrorandioside 423, 27 6-Dihydroverbenalin 647a, 35 3,4-Dihydroverbenalin 647b, 35 5b, 6b-Dihydroxyadoxoside 125a, 87 5b, 6b-Dihydroxyboschnaloside 682, 87 6-O-(3′′, 4′′-Dimethoxycinnamoyl)-catalpol 211a, 34 Dimethylsecologanoside 259, 22 (±)-Dimethylsecologanoside-O-methyl ether 713, synthesis synthesis, 129 Dipsanoside A 95, 12 Dolichodial 3a, 122, 136, 238, 239 Dumuloside 520, 30

Index Dunnisinin 573, 32 Dunnisinoside 572, 32 Durantoside II 209, 21, 35 E Eccremocarpol A 190, 20 Eccremocarpol B 191, 20 EIMS of iridoids, 111 Elenolic acid 763, 180 Elenolic acid ester 762, 180 Eranthemoside 110, 19, 94, 95, 101 1 H-, 13C-NMR data, 94, 104 Epoxycerberidol 150, 20 (13R)-epi-Epoxygartneroside 608, 33 7,8-Epoxy-8-epi-loganic acid 383, 26 ESIMS of iridoids, 111 Ester of swertiamarin and secoxyloganic acid 740, 162 (±)- Ethylcatalpol 702, synthesis, 122 7a/7b-O-Ethylmorroniside 264, 22 Eucommiol 292, 23, 26 epi-Eucommiol 294, 23 Eucommoside I 295, 23 Eucommioside II 295a, 23 Eucomoside A 296, 23 Eucomoside B 297, 23 Eucomoside C 298, 23 Eurostoside 408, 26, 30, 206 Eustomorusside 325, 24 Eustomoside 323, 24, 34 Eustoside 324, 24, 34 7-epi-Exaltoside 74, 27 Exaltoside 431, 27 Excelside A 433a, 27 Excelside B 433, 27, 185 Excelsioside 752, 175 F Fagraldehyde 51, 24 6-O-Feruloylajugol 201, 21, 29, 34 6-O-Feruloylcatalpol 194a, 30 7-O-(E/Z)-Feruloylloganic acid 261, 22 10-O-Feruloylmelittoside 356b, 26 Fliederoside 443, 28 Floribundane A 591, 32 Floribundane B 85, 32 Foliamenthin 74, 27 10-O-Foliamenthoylaucubin 529, 30 Fontanesioside 435, 27 Forsythide 691, 90

Index Forsythide 10-methyl ester 692, 90 (±)-Forsythide aglucone dimethyl ester 704, synthesis, 122 Forsythide 11-glucosyl ester 437, 27 G Gaertneric acid 824, 208 Gaertneroside 36, 33, 208 Galioside 280, 23, 23, 27, 32, 99, 203 Galioside 10-acetate 280a, 23 Galiridoside 113, 19, 25, 26, 30 Gardaloside 27, 5 Gardenogenin A 615, 63 Gardenogenin B 616, 63 Gardenoside 567, 63, 90, 92, 99, 189, 203, 258 a-Gardiol 562, 63 b-Gardiol 561, 63 Gardoside 398, 57, 59 Gardoside methyl ester 97, 19, 28, 30, 93 1 H-NMR data, 93–95 Gelsemide 308, 23 Gelsemide 7-O-glucoside 309, 23 Gelsemiol 45, 23, 175 Gelsemiol-1-O-glucoside 312, 23 Gelsemiol 3-O-glucoside 313, 23 Genameside A 581, 32 Genameside B 582, 32 Genameside C 583, 32 Genameside D 584, 32 General structure of iridoid 6, 3 General structure of secoiridoid 6a, 3 Genipin 41, 23, 27, 151, 171, 182, 188, 196–198, 214, 217, 227, 258, 263 Genipin 10-O-acetate 41a, 27 Genipin 1-O-gentiobioside 585, 32 Genipinic acid 49, 8 Geniposide 23, 23, 27, 31–33, 35, 86, 89, 90, 92, 95, 102, 113, 120, 151, 152, 158, 159, 168, 169, 180, 182, 188, 189, 196, 217, 219, 221, 225–227, 229, 258, 263, 267, 268 1 H-, 13C-NMR data, 95, 102 ESIMS-fragmentation pattern, 111–113 Geniposide pentaacetate 23a, 189 Geniposidic acid 289, 23, 27, 28, 31, 33, 92, 139, 153, 159, 176, 188, 227, 228, 268 Gentianidine 322, 24, 69 Gentianine 321, 24, 69 Gentiolactone 737, 153 Gentiopicrin 69, 24, 204 Gentiopicroside 69, 26, 24, 26, 90, 153, 175, 189, 223, 256

289 1 H-, 13C-NMR data, 96, 101 Geraniol 721, 131, 132, 134 GI-5 90, 27 Gibboside 701, 115 Globularin 403, 26, 30 Globularicisin 403a, 26 Glucologanin 231, 22 6′-O-b-D-Glucopyranosylasperuloside 287, 23 10-O-Glucosylbartsioside 471a, 30 6-O-b-D-Glucosylcatalpol 211c, 34 6′-O-Glucosylmelampyroside 472a, 29 5′-O-b-D-Glucopyranosylameroswerin 752, 175 6′-O-Glucopyranosylaucubin 479, 29 2′-O-b-D-Glucopyranosyl-6′-O(p-methoxycinnamoyl)-harpagide 789, 200 6′-O-b-D-Glucopyranosylmorroniside 332, 24 Glucosylmentzefoliol 420, 27 6′-O-(2-Glyceryl)-scandoside methyl ester 560, 31 Gmelinoiridoside 371, 25 Gonocaryoside A 248, 22 Gonocaryoside B 249, 22 Gonocaryoside C 250, 22 Gonocaryoside D 251, 22 Gonocaryoside E 252, 22 Grandifloroside 233, 22 Grandifloroside methyl ester 326, 24 Griffithoside C 794, 201 Griffithoside D 795, 201 Griselinoside 334, 24, 35, 92 GSIR-1 314, 23 Guettardodiol 586, 32

H Harpagide 12, 25, 29, 34, 69, 92, 150, 158, 200, 215, 240, 258, 263 1 H-, 13C-NMR data, 94, 101 EIMS-fragmentation pattern, 111 Harpagoside 499, 29, 34, 69, 92, 139, 147, 150, 151, 157, 176, 188, 200, 205, 216, 226, 258 Harprocumbide A 504, 29 Harprocumbide B 505, 29 Hastatoside 665, 35, 90 IVHD-valtrate 241, 192 Hedycoryside A 587, 32 Hedycoryside B 588, 32 Hedycoryside C 589, 32 Holmioside 646, 35 HPLC of iridoids

290 columns, solvents, 85, 86 HPTLC of iridoids, 85 HSCCC of iridoids columns, solvents, 83, 88–90 Hydramacroside A 760, 180 Hydramacroside B 761, 180 Hydrophylin A 619, 33 Hydrophylin B 620, 33, 204 6a-Hydroxyadoxoside 694, 93 6b-Hydroxyadoxoside 695, 93 6b-Hydroxyantirrhide 512, 30, 34 6-O-p-Hydroxybenzoylajugol 254, 22 6′-O-m-Hydroxybenzoylloganin 258a, 24 10-O-p-Hydroxybenzoylscandoside methyl ester 282c, 32 4b-Hydroxy-6-O-(p-hydroxybenzoyl)tetrahydrolinaride 766, 192 10-O-p-Hydroxybenzoyltheviridoside 165b, 36 6b-Hydroxyboschnaloside 683, 87 6-O-(6′′-O-E-p-Hydroxycinnamoyl)-bD-glucosylaucubin 218b, 34 [8-3H]-8-Hydroxycitronellol 729, 136 as biosynthetic precursor, 136 7-Hydroxydehydrohastatoside 666, 35 5-Hydroxydidrovaltrate 773, 192 7-Hydroxyeucommiol 764, 181 6b-Hydroxy-7-epi-gardoside methyl ester 555, 31 6a-Hydroxygeniposide 272, 31, 225 8-Hydroxygeraniol 722, 134, 136 5-Hydroxyglutinoside 639, 34 6b-Hydroxyipolamiide 198, 21, 36 10-Hydroxyligstroside 438, 28 6b-Hydroxyloganin 455, 28, 211 10-Hydroxyloganin 424, 27, 32, 140, 228 10-Hydroxymorroniside 735, 141 3b-Hydroxymyopochlorin 638, 34 10-Hydroxyoleuropein 438a, 28 10-Hydroxyoleoside dimethyl ester 438b, 28 5-Hydroxysecologanol 434, 27 9-Hydroxysemperoside 311, 23 9-Hydroxysemperoside aglucone 751, 175 6b-Hydroxysplendoside 305, 23 6b-Hydroxysplendoside 10-acetate 305a, 23 7b-Hydroxysplendoside 306, 23 6b-Hydroxysweroside 340, 25 7-Hydroxytomentoside 496, 29 I Ipolamiide 121, 20, 25, 34, 35, 136, 148, 229 Ipolamiidoside 107, 19, 25, 206 Iridane skeleton 1, 1 Iridodial 3, 1, 122, 130, 238 8-epi-Iridodial 719, 130

Index cis-trans-Iridodial 725, 134 Iridodial b-monoenol acetate 813, 204 a-Iridodiol 117, 19, 198 b-Iridodiol 118, 19 cis-Iridodiol 119, 19 Iridoid lactone IV 707, synthesis, 122 Iridoid structure 2, 2 Iridoids of Acanthaceae, 19 Actinidiaceae, 19, 68, 138 Adoxaceae, 19, 69, 139 Apocynaceae, 19, 69 Asteraceae, 20 Bignoniaceae, 20 Buddlejaceae, 18, 21 Calyceraceae, 21 Caprifoliaceae, 18, 21, 69, 139 Cardiopteridaceae, 22 Celastraceae, 22 Centroplacaceae, 22 Columelliaceae, 22 Cornaceae, 22 Cucurbitaceae, 22 Cyperaceae, 17, 36 Daphniphyllaceae, 22 Ericaceae, 23, 139 Escalloniaceae, 55, 139 Eucommiaceae, 23 Euphorbiaceae, 23 Fabaceae, 23 Fouquieriaceae, 23 Garryaceae, 23, 139 Gelsemiaceae, 23 Gentianaceae, 24, 69 Goodeniaceae, 24 Griseliniaceae, 24, 139 Hydrangeaceae, 24, 69 Icacinaceae, 25 Lamiaceae, 25, 134, 139 Lentibulariaceae, 26 Loasaceae, 27 Loganiaceae, 18, 27, 69, 139 Malpighiaceae, 27 Malvaceae, 27 Meliaceae, 27 Menyanthaceae, 27 Metteniusaceae, 27 Montiniaceae, 27 Nyssaceae, 27 Oleaceae, 27, 69 Orobanchaceae, 28 Paulowniaceae, 29 Passifloraceae, 29 Pedaliaceae, 29

Index Plantaginaceae, 18, 29, 70, 139 Rubiaceae, 31, 69 Salicaceae, 34 Sarraceniaceae, 34 Scrophulariaceae, 18, 34, 139 Stemonuraceae, 35 Stilbaceae, 35 Symplocaceae, 35 Toricelliaceae, 35 Umbelliferae, 35 Verbenaceae, 35, 139 Iridolactone I 410, 26 Iridomyrmecin 4, 1, 19, 238, 239 cis-trans-Iridodial 725, 134 8-epi-Iridodial 719, 130 Iridotrial 727, 131 8-epi-Iridotrial 720, 130 Isoallamandicin 137, 19 13 C-NMR data, 103 Isoaucubin 111, 19, 28 Isoboonein 142, 19, 27, 122 Isodihydronepetalactone 301, 23 Iso-dehydromyrmecin 123, 19 6-O-a-L-(2′′-O-Isoferuloyl) rhamnopyranosylcatalpol 375a, 25 6-O-a-L-(3′′-O-Isoferuloyl)rhamnopyranosylcatalpol 375b, 25 Isoiridomyrmecin 5, 23, 122, 238 Isoligustroside 468, 28, 129 Isoligustroside aglucone 714, preparation, 129 Iso-neonepetalactone 124, 19 Isonuzhenide 447, 28 Isooleuropein 469, 28, 36, 129 Isooleuropein aglucone 715, preparation, 129 Isoplumericin 62, 20, 191, 202, 214 Isoplumieride 156, 20, 85, 86, 95, 96, 106 1 H-, 13C-NMR data, 95, 96, 103 (15R)-, (15S)-9-epi-15F2c-Isoprostane 710, synthesis from catalpol, 126 Isoscrophularioside 545, 62 Isosweroside 72, 9 Isovaltrate 54a, 86 Isovanilloylcatalpol 195c, 30 Ixoroside 19, 32, 203, 225 Ixoside 26, 27, 31 Ixoside sodium salt 26b, 33 J Jasminin 76, 10 Jasmolactone B 716, 130, 177 pharmacology of, 177 semisynthesis from secoiridoid, 130 Jasmolactone D 717, 130 pharmacology of, 177

291 semisynthesis from secoiridoid, 130 Jasmolactone E 718, 130 semisynthesis from secoiridoid, 130 Jatadoid A 742, 174 Jatairidoid A 746, 174 Jatairidoid B 747, 174 Jatairidoid C 748, 174 Jatamanvaltrate C 58, 22 Jatamanvaltrate H 743, 174 Javanicoside A 302, 23 Javanicoside B 303, 23 Jiofuran 48, 8 Jioglutolide 489, 29 Jioglutoside A 490, 29 Jioglutoside B 491, 29 K Kanokoside A 225, 21 Kanokoside C 227, 21 7-Ketologanin 427, 27, 28, 90, 92 Kickxioside 524, 30 Kingiside 71, 21, 22, 27, 31, 34, 90 8-epi-Kingiside 245, 22, 28, 31 Kingisidic acid 247, 22 8-epi-Kingisidic acid 246, 22, 28 Koelzioside 372d, 150 Kutkoside 15, 160, 161, 179, 191, 212 L Laciniatoside II 786, 193 Lagotisoside D 527, 30 Lagotisoside E 528, 30 Lamalbide 377, 25, 206 Lamarbide-6,7,8-triacetate 590, 32 Lamiidoside 207a, 35 Lamiide 207, 21, 25, 34, 35, 136, 147, 148 1 H-1H-COSY, HSQC, HMBC spectra, 105, 106, 108–110 Lamiol 376, 25 Lamiolactone 380, 26 Lamiophlomiol A 381, 26 Lamiophlomiol B 382, 26 Lamiophlomiside 205, 26 Lamioside 22, 25, 136 Lamiridosin A/B 40, 206 Lamiridosin-6,7,8-triacetate 590a, 32 Langaside 329, 24 Ligstroside 79, 27, 153, 175, 192, 214 Ligustaloside A 444, 28 Ligustaloside B 445, 28 Ligustrohemiacetal A 88, 11 Lilacoside 442, 28 Linaride 517, 30 Linarioside 514, 30

292 Linearin 796, 201 Linearoside 769, 192 Lippioside I 661, 35 Lippioside II 662, 35 Lisianthioside 327, 24 Loganetin 230, 22 Loganic acid 146, 20–22, 24, 27, 31, 32, 35, 36, 92, 99, 147, 177, 186, 198, 203, 206 Loganic acid-6′-O-b-D-glucoside 217, 21, 24 Loganin 18, 19, 21, 22, 24, 25, 27, 31, 35, 90, 92, 93, 111, 120, 130, 140, 147, 153, 163, 171, 183, 185, 187, 189, 203, 206, 215, 223, 260, 263 1 H-, 13C-NMR data, 95, 102 EIMS-fragmentation pattern, 111 7-epi-Loganin 162, 20, 93 8-epi-Loganin 96, 19, 26, 27, 28, 30, 35 8-epi-Loganic acid 146a, 25, 30, 35, 203 Logmalicid A 269, 22 Logmalicid B 270, 22 Longifolioside A 799, 201 Longifolioside B 800, 201 Loniceroside 64, 21 Lonijaposide A 83, 11 Lonijaposide B 84, 11 Lucidumoside C 822, 207 Lamourouxide I 478, 29 Luzonial A 783, 193 Luzonial B 784, 193 Luzonoid A 57, 193 Luzonoid B 785, 193 Luzonoid C 786, 193 Luzonoside A 33, 193 Luzonoside B 782, 193 M Macfadienoside 189, 20 Macrophyllide 614, 33 Macrophylloside 613, 33 Marinoid A 98, 19 Marinoid B 99, 19 Marinoid C 100, 19 Marinoid D 101, 19 Marinoid E 102, 19 MECC of iridoids, 91 Melampyroside 472, 28, 30, 34, 176 Melittoside 356, 25, 30, 201 Menthiafolin 75, 27 5-O-Menthiafoloylkickxioside 525, 30 6′-O-Menthiafoloylmussaenosidic acid 684, 87 6-O-p-Methoxycinnamoylaucubin 218, 21 6-O-p-Methoxycinnamoylcatalpol 219, 21 10-O-(E/Z)-p-Methoxycinnamoylaucubin 530, 30

Index 8-O-E-p-Methoxycinnamoyl harpagide 749, 174 6′-O-E-p-Methoxycinnamoylharpagide 750, 174, 200 6-O-a-L-(2″-O-p-Methoxycinnamoyl)rhamnopyranosylcatalpol 375c, 89 6-O-a-L-(3″-O-p-Methoxycinnamoyl)rhamnopyranosylcatalpol 375d, 89 6-O-E-p-Methoxycinnamoylscandoside methyl ester 848, 224 7-Methoxydiderroside 564, 31, 213 3b-Methoxy-3,4-dihydrocatalposide 536, 30, 155 Methoxygaertneroside 825, 208 6b-Methoxygeniposidic acid 597a, 33 9-epi-6a-Methoxygeniposidic acid 845, 208 1b-Methoxymussaenin A 810, 204 1a-Methoxy-4-epi-mussaenin A 811, 204 1b-Methoxy-4-epi-mussaenin A 812, 204 7a-Methoxysweroside 234, 24, 104 3-O-Methylallamancin 135, 19 3-O-Methylallamcin 133, 19 4-Methylantirrinoside 396, 26 1-O-Methylcachinol 174, 20 6-O-Methylcatalpol 211b, 34 Methylglucooleoside 451, 28 10-Methylixoside 26a, 33 11-Methylixoside 778, 193 7a/b-O-Methylmorroniside 263, 22 7a/7b-7-O-Methylmorroniside 263, 34 1 H-NMR data, 96 Methylpaederosidate 605, 33 10-O-(4″-O-Methylsuccinoyl)-geniposide 847, 224 [2-14C]-Mevalonic acid 732, 136 as biosynthetic precursor ofLamiumiridoids, 136 [2-13C1]-Mevalonolactone 733, 136 as biosynthetic precursor ofLamiumiridoids, 136 Mentzetriol 44, 7 Mentzefoliol 419, 27 Minecoside 194, 21, 201, 208 ML-2-3 834, 211 ML-F52 833, 211, 213 Mollugoside methyl ester 629, 33, 84 Molucidin 699, 211, 213 Monomelittoside 533, 30, 201 Monotropein 25, 23, 27, 31, 90, 140, 147, 227, 228 Morindolide 631, 34 Morroniside 70, 19, 21, 24, 27, 34, 90, 92, 163, 172, 174, 183, 185, 215, 266 Multifloroside 757, 177

Index Muralioside 516, 30 Mussaenin A 812, 204 Mussaenoside 20, 19, 28–30, 153 Mussaenosidic acid 112, 19, 26, 28, 30 Myobontioside A 641, 34 Myobontioside B 642, 34 Myopochlorin 638a, 34 Myrmecodoide A 598, 33 Myrmecodoide B 599, 33 Myxopyroside 452, 28 N Naucledal 87, 22 Negundoside 698, 36, 115, 164 Nemoroside 210, 21 Neomatatabiol 42, 7 (+)-Neomatatabiol 120, 19 Nepetacilicioside 385, 26 Nepetalactol 705, synthesis, 122 Nepetalactone 730, biosynthesis, 136 Nepetanudoside 553, 31 Neonuzhenide 448, 28 Neooleuropein 470, 28 (1R, 4aS, 7S, 7aR)-Nepetalactol 854, 239 (1S, 4aR, 7S, 7aS)-Nepetalactol 855, 239 (1R, 4aR, 7S, 7aS)-Nepetalactol 856, 239 (4aa, 7a, 7aa)-Nepetalactone 814, 239 (4aa, 7a, 7ab)-Nepetalactone 815, 204 6-O-Nerol-8-oyl-antirrhinoside 109a, 30 Ningpogenin 837, 212 Nishindaside 668, 36 Nordostachin 738, 155 Norviburtinal 193, 21 Nudifloside 768, 192 Nuzhenide 82, 28, 185, 215 Nyctanthic acid 463, 28 Nyctanthoside 454, 28 O 6-O-Octadienoylcatalpol 211, 21 Oleacein 754, 175 Oleonuzhenide 446, 28 Oleopolyanthoside A 94, 12 Oleoside aglycone 741, 173 Oleoside dimethyl ester 440, 27, 185, 207, 215 13 C-NMR data, 104 Oleoside 11-methyl ester 439, 27, 175 Oleuropein 80, 27, 90, 162, 173, 175, 176, 180, 184, 190, 192, 201, 203, 207, 214, 221, 225, 229, 260, 266 Oleuropeinic acid 449, 28 Oleuroside 464, 28 OPLC of iridoids, 84

293 1-Oxoeucommiol 412, 57 8-Oxogeranial 724, 134 Oreosolenoside 372a, 34 Oruwacin 63, 115 Owariensisone 108, 19 Oxysporone 52, 8 P Paederoside 594, 33, 90, 163 1 H-, 13C-NMR data, 95, 102 Paederoside B 603, 33 Paederosidic acid 604, 33, 163 6-epi-Paederosidic acid 604a, 33 Paederosidic acid dimer I 600, 33 Paederosidic acid dimer II 601, 33 Paederosidic acid dimer III 602, 33 Pagoside 503, 29, 158 Pakiside A 428, 27 Pakiside B 429, 27 Patrinalloside 30, 6 Patrinoside 29, 198, 222 Patrinovalerosidate 229, 21 Patriridoside G 775, 192 Patriridoside H 776, 192 Patriscabioin A 758, 178, 192 Patriscabioin C 759, 178, 192 Patriscabioin E 777, 192 Patriscadoid I 59, 8 Paulownioside 494, 29 PEC of iridoids, 84 Pedicularislactone 411, 26 Penstemonoside 475, 28 Penstemoside 379, 26 12-epi-PGF2a methyl esteranalogue 708, 124 Pharmacological activities of iridoids antiageing, 224 antiallergic, 145 antiamoebic, 208 antiangiogenic, 226 antiarthritis, 145 antibacterial and antifungal, 202–204 anticolitis, 194 anticonvulsant, 220 antidepressant, 217 antiglycation, 186 anti-inflammatory and antinociceptive, 146 antileishmanial, 210, 211 antimalarial, 145, 209 antimutagenic, 226 antiosteoporotic, 214–216 antioxidant, 145, 167, 172, 200–202, 267 antispasmodic, 222 antitrypanosomal, 212, 213

294 Pharmacological activities of iridoids (cont.) antitumor and anticancer, 187 antiviral, 145, 205–207, 267 anxiolytic, 217, 219 cardioprotective, 145, 175, 177 choleretic, 197, 198 diabetic-renal protective, 185 estrogenic, 226 gastroprotective, 195 hepatoprotective, 150, 162, 164 hypoglycemic and hypolipidemic, 180, 272 immunomodulating, 225 melanogenesis inhibitory, 224, 271 miscellaneous, 229 molluscicidal, 213, 214 nematocidal and insecticidal, 228 neuroprotective, 145, 164 ocular hypotensive, 198 pancreas protective, 186 purgative, 227 repellant and antifeedant, 228, 229 spermicidal, 227 wound healing, 196, 197 Phlomiol 377b, 26, 190, 203 13 C-NMR data, 103 Phlomiside 386, 26 Phloyoside I 804, 203 Phloyoside II 688, 89 Picconioside II 460a, 31 Picroside I 532, 30, 160, 161, 179, 191, 212 Picroside II 192, 206, 262 Picroside III 401, 26 Pikuroside 531, 30 Piscroside C 535, 30, 179 Plagiodial 728, 134, 238 Plagiolactone 851, 238 Plantarenaloside 176, 21, 70 Plantarenalosigenin 1-O-b-gentiobioside 177, 20 Plumericin 60, 20, 22, 32, 120, 156, 191, 202, 214 1 H-,13C- NMR data, 95, 96 Plumieride 34, 20, 85, 193, 227 1 H-,13C- NMR data, 95, 96, 103 Plumeridoid C 739, 156 Plumiepoxide 35, 6 Plumieride pentaacetate 34a, 193 Pondraneoside 206, 21 Prismatomerin 611, 33, 191 Procumbide 497, 30, 98 Procumboside 502, 29 10-O-Protocatechuylcatalpol 767, 192 Pseudocalymmoside 208, 21

Index Pulchelloside I 687, 203 Pulosarioside 145, 20 Pulverulentoside I 370b, 34 R Radiatoside 170, 20 Randinoside 612, 33 Rapulaside A 651, 35 Rapulaside B 652, 35 6-O-a-L-Rhamnopyranosylcatalpol 211d, 26 Rehmachingiioside F 767, 164 Rehmaglutin A 486, 29 Rehmaglutin B 487, 29, 30, 156 Rehmaglutin C 46, 29 Rehmaglutin D 488, 29, 156, 204 Rehmannioside A 482, 29 Rehmannioside B 483, 29 Rehmannioside C 484, 29 Rehmannioside D 485, 29 Reptoside 342, 25, 149 Retzioside 644, 35 6-O-a-L-Rhamnopyranosylcatalpol 211d, 34 Rotunduside A 669, 36 Rotunduside B 670, 36 Rotunduside C 671, 36 Rotunduside G 672, 36 Rotunduside H 673, 36 S Salvialoside A 391, 26 Salvialoside B 392, 26 Salvialoside C 393, 26 Salvialoside D 394, 26 Salvialoside E 395, 26 Sambacin 77, 10 Sambacoside A 93, 12 Sangunoside 158, 20 Sarracenin 147, 21, 32, 34, 127, 204 a/b-Scabrogenin 338, 24 Scabroside 337, 24 Scabrosidol 10, 24 Scaevoloside 333, 24 Scandoside 282a, 33, 90, 98, 140, 176, 228 1 H-, 13C-NMR data, 94, 95, 102 Scandoside methyl ester 282, 23, 27, 31, 33, 90, 189, 201, 224 Schismoside 285, 23, 27 Scholarein A 138, 19 Scholarein B 139, 19 Scholarein C 140, 19 Scholarein D 141, 19 Scorodioside 372b, 34, 150, 205 Scrolepidoside 835, 211

Index Scrophularianoid A 857, 176 Scrophularianoid B 858, 176 Scrophularioside 540, 31 Scrophuloside A4 372h, 197 Scropolioside A 372c, 149, 150, 197 Scropolioside B 372f, 150 Scropolioside D 372g, 181 Scrovalentinoside 372e, 149, 197 Scutelloside 397, 26 Scyphiphin C 618, 33 Scyphiphorin A 589, 33 Scyphiphorin B 589a, 33 Secogalioside 73, 141 Secologanin 64, 19, 21, 22, 27, 31, 35, 90, 130, 132, 137, 203 (±)-Secologanin aglucone-O-methyl ether 712, synthesis from sweroside aglucone-Omethyl ether, 128, 129 Secologanic acid 66, 27, 115, 268 Secologanol 320, 24, 27 Secologanoside 330, 24, 27, 28, 32, 34 1 H-, 13C-NMR data, 96, 104 Secoxyloganin 65, 20, 21, 22, 25, 28, 31, 34, 213, 267, 268 Semperoside A 310, 122 Serratoside B 664, 35 Sesamoside 686, 89 Sesinoside 507, 29 Shanzhilactone 43, 33 Shanzhiside 21, 92, 225, 267, 268 Shanzhiside methyl ester 103, 26, 28–31, 35, 147, 156, 203, 206 Siphonostegiol 493, 29 Specionin 181, 20, 122, 229 Specioside 180, 20, 30, 181, 200, 208 Splendoside 304, 23 Splendoside 10-acetate 304a, 23 Stachysoside E 405, 26 Stachysoside G 406, 26 Stanside 690, 98 Stansioside 178, 20, 98 Stansiosigenin 1-O-b-gentiobioside 179, 20 Stegioside I 388, 26 Stegioside II 389, 26, 30 Stegioside III 390, 26 Stereospermoside 212, 21 Stilbericoside 8, 19, 35 6-epi-Stilbericoside 115, 19 Strictoloside 154, 20 Strictosidine 674, 69 10-O-Succinoylgeniposide 577, 87 Suspensolide A 32, 6

295 Swerilactone A 820, 207 Swerilactone C 821, 207 Swerilactone D 822, 207 Swerilactone H 824, 207 Swerilactone I 823, 207 Sweroside 67, 21, 22, 24, 27, 31, 34, 90, 153, 175, 189, 197, 205, 223, 228, 265, 267, 268 (±)-Sweroside aglucone-O-methyl ether 711, synthesis from 1,4-cyclohexadiene, 127 Swerosidic acid 220, 21 Swertiamarin 68, 10, 22, 24, 27, 31, 90, 154, 159, 161, 162, 175, 184, 197, 205, 209, 221, 223, 259, 265 1 H-, 13C-NMR data, 95, 104 Sylvestroside I 221, 21, 193 Sylvestroside III 222, 21, 193 Sylvestroside IV 785, 193 Syringolactone A 443, 28 Syringolactone B 442, 28 Syringopicroside 467, 28, 194 6-O-Syringyl barlerin 105a, 26 T Tarennin 621, 33 Tarenninoside A 622, 33 Tarenninoside B 623, 33 Tarenninoside C 624, 33 Tarenninoside D 625, 33 Tarenninoside E 626, 33 Tarenninoside F 627, 33 Tarenninoside G 628, 33 Tecoside 215, 51 Teucardoside 407, 26 Teuhircoside 95, 19 Theveside 164, 20, 35 Theviridoside 165, 20, 21, 35, 90 Thunbergioside 116, 19, 35 8-O-Tigloyldiderroside 566, 31 TLC of iridoids, 84, 237 Tomentoside 495, 29 Torricellate 650, 35, 115 Torrilliolide 649, 35 Tricoloroside methyl ester 417, 27 Triohimas A 86, 22 Triohimas B 235, 22 Triohimas C 236, 22 Tudoside 607, 33 U E-Uenfoside 609, 33 Z-Uenfoside 610, 33

296 Undulatin 216, 21 Unedide 213, 23 Unedoside 7, 35, 92 V Vaccinoside 279, 23 Valejatanin A 774, 192 Valerianoid A 744, 174 Valerianoid C 745, 174 Valeriotriate B 242, 22 Valerosidate 28, 21 8-epi-Valerosidate 28a, 103 13 C-NMR data, 103 Valtrate 54, 176, 192, 218, 219, 223 Valtrate acetoxyhydrin 839, 220 Valtrate chlorohydrine 840, 220 Valtrate isovaleroyloxyhydrin 840, 220 6-O-Vanilloylajugol 255, 22 10-O-Vanilloyltheviridoside 165a, 36 Velpetin 384, 26 6-O-Veratroylcatalpol 195d, 21 10-O-Veratroyleranthemoside110a, 34 Verbaspinoside 370a, 34 Verbenalin 647, 35, 90, 92, 147, 206, 227 Verbeofflin I 667, 35 Verminoside 195, 21, 30, 34, 149, 176, 181, 192, 200, 208 Veronicoside 195a, 30, 192 Verproside 195b, 30, 178, 193, 261 Viburnalloside 31, 19 Viburtinal 50, 8 Viteoid I 53, 26 Viteoid II 409, 26 Vogeloside 234, 22, 24, 31 13 C-NMR data, 104 epi-Vogeloside 234a, 24 Volvaltrate A 237, 22

Index Volvaltrate B 238, 22, 192 Volvaltrate C 239, 22 Volvaltrate D 240, 22 VR-I 408a, 26 W Williamsoside A 126, 19 Williamsoside B 127, 19 Williamsoside C 128, 19 Williamsoside D 129, 19 Wallichiiside A 357, 25 Wallichiiside B 358, 25 Wallichiiside C 359, 25 Wallichiiside D 360, 25 Wallichiiside E 361, 25 Wallichiiside F 362, 25 Wallichiiside G 363, 25 Wendoside 634, 34 Wolfenoside 544, 31 X Xylomollin 430, 27, 229 X-ray study of 5aH-6-epi-dihydrocornin, gibboside, 115 aucubin, 8-deoxyshanzhiside, 115 methylcatalpol, molucidin, negundoside, 114, 115 torricellate, 115 Y Yopaaoside A 37, 32 Yopaaoside B 595, 32 Yopaaoside C 596, 32 Z Zaluzioside 643, 34