Medicinal Plant Glycosides 9781487584771

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MEDICINAL PLANT GLYCOSIDES An Introduction for Pharmacy Students

STEPHEN K. SIM Associate Professor of Pharmacognosy Faculty of Pharmacy University of Toronto

UNIVERSITY OF TORONTO PRESS

©

Universit7 ot Toronto Press

1967

The use of oortions of the text of the United States Pharmacopeia Seventeenth Revision, official September 1, 1965, is by permission received from the Board of Trustees of the United States Pharmacopeial Convention. The said Board is not responsible for any inaccuracies of the text thus used. Permission to use portions of the text of the National Formulary, Twelfth Edition, official September 1, 1965, has been granted by the American Pharmaceutical Association. The American Pharmaceutical Association is not responsible for any inaccuracy of quotation, or for false implications that may arise by reason of the separation of excerpts from the original context.

Printed in Canada

Reprinted in 2018 ISBN 978-1-4875-7303-4 (paper)

PREFACE The plant gl.ycosides that are currently used in medicine, though not large in number, are important drugs.

A great many plant

glycosides which are not currently used as medicinal agents, are ot interest · to pharmacy and iredicine because ot their high toxicity or as possible potential sources of new drugs. All students of pharmacy learn somethi~ about the medicinally useful glycosides and the crude plant drugs containing them in a number of pharmaceutical subjects, for which the standard textbooks are, :in their relevant sections dealing with glycosides, usually oriented around individual. medicinal preparations.

The

descriptions and discussions given here tor the few selected groups of plant glycosides of medicinal significance are primarily intended to introduce the student to an appreciation ot (a) their structural variety and principal physico-chemical. propertiu, (b) the variety of plant sources, (c) the basic problems encountered in, and those properties important to, the extraction and separation of the individual. glycosides from plant materials, and (d) some aspects ot their biosynthesis.

These aspects, presented here at an introductory

level, are of ccurse available, at a more advanced level, in a number ot specialized reference books and in review articles and research reports in various scientific periodical publications, m,st, if not all of which are often not easily comprehensible or readily available to undergraduate students.

- iii -

The selection of the glycosides for presentation here has been confined to three groups, namely, the steroidal cardioactive glycosides, the anthracene glycosides having cathartic properties, and the biofiavonoids of medicinal :interest.

In addition, a brief

sumnary of the sapogenins is included on account of their usefulness as starting materials for the chemical synthesis of medicinal hormone substances and their structural relationship to the cardioactive glycosides.

The discussions on biosynthesis are limited to

those of digitoxin and rutin, for which some significant and definitive experimental studies have appeared in the literature. No exhaustive coverage of the botanical or chemical. aspect is attempted. Pharoacological action and uses are only briefly indicated for each group of the glycosides.

Medicinal preparations, those

from the pharmacopoeial. compendia and the pharmaceutical. special.ties, are given only as ex!l!!lples for the purpose of relating them to each

group of the glycosides discussed. It is hoped that such an introductory study of the few selected groups of medicinal plant glycosides, especially as a supplement to the relevant sections in the standard pharmaceutical. text-books, may prepare the student to apply some of the principles and methods to further studies at a IOOre advanced level of these and other glycosides.

S.K.S. Toronto, June, 1966. - iv -

CONTENTS

Chapter

Page

l

1.

DiTROOUCTION

2.

STEROIDAL CARDIOACTM CX.YCOSIDES

10

3. SAPONINS AND SAPOGENlNS

49

4.

55

FLAVONOID GLYCCSIDES

5. ANTHRACENE GLYCCSIDES

63 73

INDEX

-T-

CHAPTER 1

INTRODUCTIOO A glycoside is an organic compound, usually of plant origin, and comprising a sugar-portion linked to a non-sugar :noiety in a particular manner.

The molecule from which the non-sugar DX>iety of

a glycoside is derived is called the aglycone or genin.

In the

great majority of the seve~al. hundred plant glycosides that have been isolated, the linkage between the sugar and the a.glycone is a hemiacetal linkage fonned by the reducing group (usually aldehyde or keto group) of the sugar and an alcoholic or phenolic hydroxyl group of the aglycone.

The term glycosidic linkage is often used

to mean this kind of linkage.

In the sugar molecule, usually, but

not always, the carbon atom that is linked to two oxygen atoms (e.g., C-1 in glucose) is the one forming this glycosidic linkage in which it is linked, through an oxygen bridge, to the carbon (in the aglycone molecule) carrying an alooholic or phenolic hydroxyl group. The glycosides with this type of glycosidic linkage are designated as the ~glycosides.

type.

Most of the plant glycosides known are of thjs

However, there are some S-glycosides and N-glyoosides, in

which, respectively, the sugar is linked to the thiol (sul.fhydryl) group (as in sinigrin) or an amino group (e.g., the streptidine moiety of streptomycin, glucose.mine, adenosine) of the aglycone. There are also C-glycosides (e.g., barbaloin) in which the sugar is linked to the aglycone by a carbon-to-carbon bond.

-1-

ro 0

N·O-SC2.-CK

Ck ' ~ H1

OH

;~V, _ --< f,

S

I

C Hi

II

-cI CH2·

C

' CH

CH

Gitorin (an 0-glycoside)

Barbaloin ( a C-glycoside)

CH ::CH~

H

Sinigrin (an S-glycoside)

Adenosine (an N-glycoside)

COOH Rhein-8-glucoside (an 0-g~coside)

- 2 -

Sugars in Glzcosides When the sugar-portion of a glycoside is glucose, the glycoside is known as a glucoside.

Similarly, rhamnosides, galacto-

sides, ribosides, et.c., contain, respectively, rhamnose, galactose, ribose, etc., as the suga~portion. In the sugar molecule in a glycoside, the configuration at the carbon fo:rming the glycosidic linkage may be in the

:(.-form or

f3 -torm (one or the other of two diastereoisomers), giving rise to an

°" -glycoside or a

/3-glycoside respectively.

the plant glycosides lax,wn to date are sugars being of the D series. oi,

The majority o!

(3-glycosides with the

There are some medicinally important

-glycosides containing sugars o! the L series, especially L-

rhamnose. A glycoside molecule may contain, in some cases, one molecule of a monosaccharide (be it glucose or some other sugar), or, in other cases, two or more molecules of monosaccharides.

Also, a

glycoside 1110lecule may contain two or 1110re 1110lecules of the same monosaccharide.

For example, the glycoside, digitoxin, contains

three digitoxose units.

In some cases, the glycoside molecule may

contain two or more different kinds of monosaccharides.

Thus, the

glycoside, digital.inum verum, contains one digitalose and one glucose;

the glycoside, k-strophanthoside, contains one cymarose-wu.t

and two glucose-units;

the glycoside, rutin, contains one rhamnose

and one glucose. When there are two or more monosaccharide-units (either of the same kind or of different kinds) in a glycoside molecule, the

- .3 -

sugars are, in most cases, linked together in disaccharide, trisaccharide, or polysaccharide fashion (in a chain), and the saccharide-chain is then linked to the aglycone at one position, rather than having two or three sugars linked to two or three different positions or the aglycone.

However, there are some exceptions:

a

few glycosides are kno"m in which two monosaccharide-units are linked to two dirterent positions of the aglycone (e.g., the sennosides ), but these are exceptions rather than the rule. The sugar most comnonly encountered in the glycosides known so far is

(3-D-glucose.

But there are glycosides (including some

medicinally important ones) in which the sugar-portion contains hexoses other than glucose, or pentoses (e.g. xylose, arabinose, ribose, etc.), or 5-methylpentoses (which are also referred to as 6-desoxyhe:xoses) such as digitoxose, digitalose, cymarose, rhamnose, etc. (2).

Some of the sugars occurring in the cardioactive, ster-

oidal glycosides are 2-desoxy sugars (e.g., digitoxose, cymarose, sarmentose).

In a few cases, the sugar-portion in a glycoside may

not be a true sugar but a sugar-derivative such as the uronic acids of the sugars.

Thus, in the glycoside, glycyrrhizin, the sugar-

portion is a diglucuronide. The nature and number ot saccharide-units in the sugarportion of a glycoside naturally affect the degree of polarity of the glycoside and consequently its solubility in and partition between different solvents.

Also, the nature ot the sugar adjacent

to a glycosidic linkage to a considerable extent governs the degree of susceptibility ot that linkage to cleavage by' di!terent methods

-4-

ot acidic or enz,matic bydrol7sis. 'l'hia aspect will be turtber discussed later. Agl;v:cones The aglycones or the glycosides cal ccnstitutions.

varr

widely in their chemi-

They include alcoholic an::!. i:nenollc compounds,

isothiocyanates, cyanogeneti c nitriles, anthracene derivatives, rlavonoid and steroidal molecules.

The plant glycosides which are

currently or the greatest medicinal significance are ID)Stly among those with steroidal, navonoid or antbracene aglyoones.

These will

be the only ones to be discussed in thia book, although, it should be noted, a number or glycosides with other types ot aglycones and the plant materials containing them al.so have some medicinal usefulness. Solubility The medicinally useful glycosides are generally only very slightly soluble in water, but are more soluble in ethanol, methanol, or mixture of water with ethanol or methanol.

A number of

the steroidal glycosides a.re also soluble in chloroform, ether, or acetone.

'lhe solubility in and the partition between these solvents

vary considerably among the different glycosides. The presence or absence ot various polarity-contributing functional groups :in the structure ot the aglycone portion of a glycoside would, of course, contribute to the degree of solubility in a given solvent.

ilso, the nuaber and kind ot monosaccharide

units present in the sugar-portion of a glycoside w~d ccntribute

- 5-

a varying -number of free hydroxyl groups in proportion to the molecular weight of the whole glycoside molecule, and would therefore be an important factor influencing the degree of solubility in polar solvents. Stability and hydrolytic cleavage Generally speaking, rost of the glycosides are subject to hydrolysis in acidic mediu:n, resulting in the cleavage of the glycosidic linkages.

Glycosidic linkages involving different kinds of

sugars are hydrol~ed (cleaved) with different degrees of ease by a given method of acid hydrolysis.

In other words, different methods

of acid hydrolysis utilizing varying degrees of mildness are required for hydrolyzing glycosidic linkages involving different sugars. Certain glycosides are ~dified or broken down, either in the aglycone portion or in the sugar portion, by alkali.

Different

degrees of alkalinity may affect a given glycoside molecule

differently.

Thus, the lactone ring of the aglycone portion of the

cardioactive, steroidal glycosides is opened (with loss of cardiotonic activity) by strong alkali.

The acetyl group attached by

ester linkage to one of the sugar units in a glycoside (e.g., in lanatosides A, B, c, D, and E) may be removed under controlled conditions of mild alkaline hydrolysis. '!he glycosides are also subject to hydrolysis (cleavage of the glycosidic linkage) by the appropriate enzymes (the glycosidases).

Some of these enzymes are often present in the same plant

- 6 -

materials in which the susceptible gl.yeosides occur.

The glyeosid.ic

linkage involving (3 -D-glucose is particularly susceptible to hydrolysis by the widely-occurring materials.

{3-glucosidases in plant

Failure to take appropriate precautions about them in

extraction and isolation procedures may result in the loss

ot gly-

cosides or in creating artifacts 'Which are hydrolytic products and which may be mistaken for what are truly present in the original plant materials used. Extraction and isolation From the brief discussion, earlier, or the solubilitr of the plant glycosides in general, it is not surprising to find that water mixed with ditrerent proportions or methanol (or ethanol) is the most comnonly used medi\Dll for the initial extraction or a wide range of glycosides from plant materials.

ait it should be noted

that, for the initial extraction or a particular glycoside or a particular group or glrcosides, a particular proportion of water to alcohol may be required for the most efficient extraction.

Examples

of such procedures will be discussed in the subsequent chapters. Also, in the initial extraction procedure, in many cases, inactivation of enzymes (the glycosidases) is necessary before or during the extraction of the glycosides particularly- when fresh plant materials are used.

Sometimes it mq be necessary to apply

special drying procedures such as a short heat-treatment (15 - 30 minutes at 100°

c.)

of the treshl.7 collected plant material to be

followed by slow drying at a lower temperature.

- 7-

Inactivation

ot

these enzymes may also be carried out by one o! the following methods (1,

J,

4, 5,

6):

(a) placing the fresh or dry plant

material into boiling water or boiling alcohol for 10 - 20 minutes (thus simultaneously inactivating the enzymes and extracting the glycosides);

(b) boiling with acetone;

(c) treating the plant

material with acid at pH l - 2 at cold temperature ( the cold temperature would prevent excessive loss of the glycosides by hydrolysis by the acid);

(d) by carrying out the initial extraction at a

very low temperature

(4,

6).

Pharmacological. activity Many glycosides in milligram doses exert potent pharmacological actions.

Among the medicinally useful glycosides, some digitoxin with l - l. 5

examples o! therapeutic dosage levels are:

mg. as initial dose or O.l - 0.2 mg. as maintenance dose;

20 mg.;

sennosides A and B, 20 - 21+ mg.

rutm,

The LD50 (in the cat) for

most of the Digitalis glycosides is in the range of 0.2 - 0.4 mg. per Kg. Generally the pharmacological action of a glycoside is due

to its aglycone.

But for administration, especially by oral route,

as a medicinal agent, the sugar-portion of the glycoside is in most cases necessary to carry the aglycone to the site of action at a particular organ or tissue where the pharmacological. action is intended.

REFERmCES l.

Gisvold,

o. -

J. Am.. Phar.n. Assoc., Sci. - 8 -

F.d.,

liJ.:594-602 (1958).

2. Reichstein, T., (1962). 3. Stoll, A., 4.

&

&

Weiss, E. - Adv. Carbohydr. Chem., ll:65-120

Kreis, ·t1. - !ielv. :him. Acta, ll:120-141 (1935).

Stoll, A., Kreis, ·.v., & von ··r artburg, A. - !ielv. Chim. Acta, ,rz:1134-1148 (1954).

c. - in L. Zechmeister (ed. ) : Progress in the Che:11.stry o! Organic Natural Products, 'Tol. 13, pp. 137-231, Sprir.gerVerlag, Vienna, 1956.

5. Tamm, 6.

in K. Paech & ~-: . 7. :'racey (eds.): :,:oder:i '.·fethods of Plant Analysis, Vol. II, pp. 301-303, Springer, :erl.1.~, 1955.

Trim, A. R. -

- 9 -

CHAPTER 2

STEROIDAL CARDIOACTIVE GLYCO.SIDES Plant sources A number of ca.rdioactive glycosides with steroidal aglycones occur in a wide variety of plant species in several plant families.

Eany of these steroidal gzycosides are of phazinacologi-

cal significance, and some are important therapeutic agents.

In

Table 1 are listed some of the better known plant species and the principal glycosides occuITing in them.

In crude drug form, as dry

plant material, Digitalis purpurea, Digitalis lanata, Urginea maritwa and Urginea indica constitute the plant sources for certain crude drug substances of the B.P .c. and of the u.s.P.

But a number

of the individual glycosides which are drug substances of the B.P. and the u.s.P. occur in these as well as other Digitalis species. Also, a number of cardioactive steroidal glycosides occurring in various species of genera other than the Genus Digitalis are of pharmacological significance. Among the plant species listed in Table 1, it may be noted that the glycosides occur principally in the seed in the Strophanthus species, in the root in the Apocynum species, in the scales ot the bulb in the Urginea species, in the leaf in the Digi tails species.

Certain glycosides (e.g., digitalinum verum) also occur

principally in the seed in certain Digitalis species. A number of additional glycosides, other than those listed here, have also been found to occur in a number of the plant species shown in Table l.

- 10 -

Table l.

Some Plant Sources ot Cardioactive Glycosides

Glycosidesa

Plant species

Pl~t part and content

References

(%)

Fam. Apocyoaceae Acokanthera friesiorum Markgr.

*Ouabain

Sd 0.016

BO

Apoc;ynum cannabinum L.

Apocanno side -cyma.rin

R R

13 13

Strophanthus gratus Wall. et Hook.

*Ouabain

Sd J.6

Cymarol *Cymarin *k-Strophanthin- ;3 *k-Strophanthoside

Sd Sd Sd Sd

Stropha.~thus

~

Oliv.

2,5,24,80

0.085 4,5,80 O.l-0.J 4,9,25,80 0.6-0.8 25,26,80 4.2 · 78,80

Fam. Liliaceae

Convallaria !!!2,j alis L.

Con val.latoxin Convallamarin Convalloside

L 0.09

R R

Sd 0.04 L O.l

Gl.ucoconvalloside R Ornithogalum. umbell.atum L.

Convallatoxin

B, R

40,80,85 80,91 63,85 61,80 40,80,85 63,85 42

Urginea burkei Baker

*Scillaren A

B 0.045

80,84, 94

Urginea indica Kunth.

*Scillaren A

B

77,84,94

Urginea maritima (L) Baker *Scillaren A B 0.6 White var. Proscillaridin A B 0.05 Urginea maritima (L) Baker *Scillaren A Red var. Scilliroside Scillirubroside - 11-

;s

B B

71,79,80 79,80 63 77 90

Table l (Continued) Plant species

Glycosidesa

Plant partb and content

(%)

References

Fam. Ranunculaceae Adonis araurensis L.

*Cymarin

R 0.014

Adonis vernalis L.

-1:·Cymarin

L, St

Fam. Scrophulariaceaec Digitalis cariensis Boiss.

*Acetyldigitoxin *Lanatoside A

L L

80 80

Digitalis ferrue:inea L. *Acetyldigitoxin- f L *Lanatoside A L *Lanatoside 9 L *Lanatoside C L Lanatoside E L ii-Total cardioactive glycosides L 0.4,-0.7 Digitalis e:randiflora *Digitoxin L Hill. *Digoxin L (• D, ambigua Hurr.) Digitalis lanata Ehrh.

Digitalis lutea L.

*Acetyldigitoxin-cJ.. *Acetyldigitoxin-/3 Diginatin Digitalinum verum *Digitoxin Digitoxigenin-allomethyloside *Digoxin Gitorin Gi toside il-Gito.xin Glucodigifucoside *Lanatoside A *Lanatoside B *Lanatoside C Neoglucodigi!ucoside Strospeside *Acetyldigi toxin-cdinoxanthrone, and isoeirodin as aglycones.

Cascara has also been shown

to contain Cascaros~des A, B, C, and D.

Cascaroside

A is (+)-bar-

baloin with an additional m::,lecule of glucose attached by an 0-glycosidic linkage and with an additional unidentified. fragt:ient (smaller than glucose) attached.

Cascaroside B is related to (-)-barba-

loin in the sa.11e manner as cascaroside A is related to ( + )-barbaloin. These optical isomers of barbaloin differ from each other in the configuration around C-10.

Cascarosides C and D are related to (+ )-

chrysaloin and (-)-chrysaloin respectively in a similar manner (2,

3).

Since barbaloin and chrysaloin are C-glycosides and the casca-

rosides contain additional glucose attached to these C-glycosides by 0-glycosidic linkage, therefore these cascarosides a:~ both Cglycosides and 0-glycosides. The bark of Rhamnus Frangula L. ( Buckthom Bark), and the fruit of Rh~nus Cathartica L. (Buckthorn Berry) also contain anthracene glycosides, mainly rhamnosides and rnamno-glucosides or ernodin and other anthraquinone derivatives. has been m:,stly replaced. by Cascara.

- 64 -

Their medicinal use

Senna Toe leaves and fruits (pods) of Cassia acutifolia Delile (Alexandria Senna), and Cassia angustifolia 7ahl. (Tinnevelly Senna) constitute the botanical sources of the various medicinal preparations of Senna. posae.

These plants are shrubs of the plant fa;:tlly Leg-..w.:i-

It has been shown (2) that aloe-emodin glucoside constitutes

12 - 20% of the total antbracene glycosides of the leaves but constitutes only about 2.5% of the total anthracene glycosides of the fruits.

Senno sides A and B constitute about 2. 5,'b of the dry leaves

and about 2. 9 - 3% of the dry fruits.

It may be noted here t..'1at in

the sennosides, the anthracene derivative constituting the aglycone is in the dianthrone form (dimeric form of rhein anthrone) a.-ii the two glucose molecules are attached to two different points of the aglycone (8).

Rhein and rhein-8-glucoside (2, 5) and glycoside of

chrysophanol (5) also occur in Senna fruits.

Recently sennosides

C md D have been isolated from Senna leaf (6, 7). Aloe (Aloes) The dried, hardened mass resulting fro:n evaporation of the juice exuding from cut ends of the thick and succulent leaves of various Aloe sµ!cies and their hybrids constitutes the drug substance Aloe.

Aloe ferox Eiller (giving rise to Cape Aloe), Aloe

Perryi Baker (yielding Socotrine Aloe), and Aloe barbaiensis V,iller ( yielding Cura9ao Aloe or Barb ado es Aloe) are the mo st com:J.on botanical sources of various medicinal Aloes.

These Aloe species

are perennial herbs of the plant family Liliaceae.

An important

anthracene-glyco side in Aloe is barbaloin which is a C-glucoside

- 65 -

of aloe-er.iodin.

The presence in Aloe of other anthracene glycosides

related to barbaloin has been reported in the literature but their exact identities have not been well established..

Aloe also contains

a considerable aioount of resinous material. Rhub11rb Various anthracene cocnpounds, both in the free fonn and as glycosides, occur in several kinds of rhubarb which are derived from the root and rhizome of ~ oalmatu.'ll L. (Ghinese Rhubarb), ~

officinale Bai.lion,~ anodi ·.iallich (Indian Rhubarb),

~

·.iebbianum Royle (India1 Rhubarb),

~

rhaoonticum L.

(?.hapontic '=lhubarb;

COJre\On garden rhubarb), and other Rheu.'11 species

a.."ld their hybrids.

The Rheum species are members of the plant fami-

ly Polygonaceae. The B.P. 1963 and K.F. XI specifically exclude R. rhaoonti~

as a source for the official Rhubarb.

?.hapontic Rhubarb contains

chrysophanol as its principal anthracene derivative but little or no e:nodin, aloe-emodin, or rhein. Rhein anthrone gl_vcosides are said to be the principal pharr.1acologically active constituents in Chinese Rhubarb (5).

Several

other anthracene compounds, in their free forms or as glycosides, have also been shown to be present, and they include rhein, emodin, chrysophanol, emodin monomethyl ether, and aloe-emodin (2).

Indian

Rhubarb is said to resemble Chinese Rhubarb in its anthracene caistituents.

- 66 -

Structures and Properties As noted earlier, the anthracene derivatives occur in these plant materials in the different forms at different oxidationlevels.

That is, they may occur as derivatives of anthraquinone, or

of al'lthrone, or of oxanthrcne, or of anthranol.

The structural re-

lationship between aloe-emodin and aloe-emodin &ithrone is shown on the next page.

The structures of emodin and emodin anthrcne, rhein

and rhein anthrone, emodin and emodin oxanthrone, etc., are related in a similar manner (see page 68). These anthracene compounds occur in these plant materials in some cases as the aglycones of 0-glycosides, and in other cases, as the aglycones of C-glycosides.

Among the known 0-glycosides from

these plant materials are rhein-8-glucoside (in semia), aloe-er:iod.in glucoside (in rhubarb) with the glucose attached to either C-1 or C-8 by 0-glycosidic linkage, chrysophal'lol glucoside (in rhubarb) with the sugar attached at C-1 or C-8, eJIDdin-o.xanthrone-10-glucoside (in cascara), and the sennosides (in senna) which are 0-glucosides of rhein d.ianthrone.

That is, in the sennosides, one l:k:>le-

cule of rhein-anthrone-8-glucoside (an 0-glycoside) is linked, backterback, to another molecule of rhein-8-glucoside by a carbon-tocarbon bond at C-10.

Sennoside A is the dextrorotatory isomer, and

Sennoside 3 is the meso isomer (8).

In the isomeric sennosides C

and D, sennoside C (of which the aglycone has been given the name sennidin C) is the (-)-iscmer, and sennoside D, the (+ )-iscmer (6,

7). Among the C-glycosides occurring in these plant materials - 67 -

0

CO)

0

0

HC

Anthracene

Anthraquinone

0

OH

Oxanthrone

Anthranol

0

0

Emod in 0xa."l throne

OH

0

Aloe-emodin 0

OH

0

Rhein anthrone

- 68 -

OH

Aloe-emodin anthrooe

OH

Rhein

H

Anthrone

Eloodin

OH

CH

H

Glucose - 0

Glucose - 0

0

O

OH

OH

Sennosides A and B: R • COOH

Barbaloin

Sennosides C and D: R • CH2 0H

are barbaloin (in cascara and aloes) and chrysaloin (in cascara).

Chrysaloin is also lmown as deoxybarbaloin, and its aglycone is cbrysophanol.

The aglycme or barbaloin is aloe-emodin anthrone.

These and other C-glycosides or cascara and aloes are collectively referred to by some authors as the aloin glycosides.

The term

aloin is also sometimes used in the literature to mean an extract ot Aloes containing a mixture of such anthracene glycosides, e.g.,

in N.F. XI and in B.P.c. 1963. As has been pointed out earlier, cascarosides A and B are,

respectively, (+ )~arbaloin and (-)~arbaloin, in each case with an additional 110lecule of glucose attached thrcugh an 0-glycosidic linkage and an additional unidentified fragment.

Cascarosia.es

\J

and D are related to chrysaloin presumably in a similar manner. These cascarosides are, therefore, both C-glycosides and (}..glycosides.

- 69 -

These anthracene derivatives give a red colour with alkali.

en

the basis of this reaction and under standardized conditions,

colorimetric assay methods for estimating the anthracene constituents of the plant drugs have been devised.

But cootents of anthra-

cene compounds in these plant materials as estimated by such colorimetric methods do not correlate with their cathartic action (2) as the different forms of the anthracene derivatives differ in their cathartic activity.

It should be pointed out al.so that the C-glyco-

sides resist the usual acid hydrolysis which cleaves the normal~ glycosidic linkage. The generic or trivial names of these anthracene derivatives a.,d their structures shown on page 68 may also be descr:ibed by their relationship to anthraquinone as follows: Aloe-emodin - 1,8-dihydroJcy-J-hydroxymet.hyl-anthraquinone Chrysophanol (also known as chrysophanic acid) - l,8-dihydroxy-3-:nethyl-anthraquinone :&oodin - 4,5,7-trihydroJcy-2-methyl-anthraquinone Iso-emodin - 2,5,8-trihydroxy-J-met.hyl-anthraquinone Rhein - 1,8-dihydroxy-anthraquinone-J-carboxylic acid Action and Uses The plant drugs Cascara, Senna, Aloes, and Rhubarb have been used as effective cathartic agents for a long time.

Their action is

due to their anthracene constituents acting on the large intestine. When these constituents are present in the plant material as glycosides, the sugar helps to transport the anthracene aglycone intact to the large intestine where the aglycone is liberated by enzymes.

- 70 -

These anthracene derivatives without the sugar are mostly broken

down and only a small proportion is able to reach the large intestine to exert the cathartic action.

Further:nore, when these anthra-

cene derivatives exert their action at the large intestine, their different fonns possess different degrees of activity (2).

The

anthraquinone forras are relatively poor in their cathartic action. Those, forms with partial reduction of the C-9 and C-10 carbonyl groups (the anthrone end anthranol fo?'t:lS) are cuch :n:>re active.

Of

course, in each case, by oral ad!!li.nistration, the aglycones by them.selves are less effective than the corresponding glycosides.

There

appears to be also some evidence (1, 2) indicating that those with two phenolic hydroxyl groups are active while those with one phenolic hydroxyl group are not active, and that reooval or acetylation of the phenolic hydroxyl grcups in these anthracene derivatives leads to loss of cathartic action. Eedi cinal Preparations Principal preparations of the u.s.P. XVII, N.F. XII, B.P. 1963 and B.P.c. 1963 are the following: Aloes U.S.P., B.P. Aloin B.P.C. Cascara Sagrada u.s.P. (Cascara B.P.) Cascara Extract N.F. Cascara Fluid extract N.F. Rhubarb B.P. Senna N.F. (Senna Leaf B.P.) Senna Fluid extract N.F. Senna Fruit B.P. Some examples of pharmaceutical specialties are:

AlophenR,

Cas-EvacR, Casakol R, Cosanyl R, DicasanR, GlysennidR, Peristal tin R,

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R

R

R

Peristini, Senokot , Senokap. References 1.

Fairbairn, J. :v. - in J. w. Fairbairn (ed.): Pharmaco"logy of Plant Phenolics, Academic Press, New York, pp. 39-49.

2.

Fairbairn, J.

3.

Fairbairn, J. 'd., Friedman, c. A., & Simic, Pha.macol., 12_:292T-294T (1963).

4.

Fairbairn~ J. (1951).

5.

Khorana, H. L., & Sanghavi, H. l•:. - J. Phann. Sci., .U:ll0-111 (1964).

6.

Lrolli, J., & Cuveele, J. - Pharm. Acta Helv., M!_:667-670 (1965).

7.

Schmid, :l., & Ang liker, E. - Helv. Chim. Acta, ,l& :l 9ll-l 921 (1965).

8.

Stoll, A., Pecker, B., & Helfenstein, A. - Helv. Chim. Acta, 33:313-336 (1950).

·.1. w.,

Lloydia, '?:1,:79-87 (1964).

& Lou, T.

c. -

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s. -

J. Pharm.

J. Phann. Pharmacol., ,i:93-104

Bufotoxins, 23

Acetyldigitoxin, 12, 15, 38 Acetyl purpurea glycoside A, see Lanatoside A Acetyl purpurea glycoside B, see Lanatoside a Acokanthera friesiorum, ll Adonis amurensis, 12 A, vernalis, 12 Agave atrovirens. 51 A, aurea, 51 A, cerulata, 51. A, deserti, 51 A, gracilipes, 51 A, mapisaga, 51 A. mirabilis, 51 A, nelsonii, 51 A, promontori, 51 A, rosea.'la, 51 A, sisala.na, 52 A, sobria, 52 A, sulli v anii, 52 A, toumeyana, 52 A, vilrnoriniana, 52 Aglycone, 1, 5 Aloe barbadensis, 65 Aloe-emodin, 66-68, 70 Aloe-emodin anthrone, 66-68 ~~,65 ~ Perryi, 65 Aloes, 63, 65, 69, 71 Aloin, 69, 71 A.~thracene glycosides, 63-62 action and us es, 70 medicinal preparations, 71 Anthranol, 63, 67-68 Anthraquinone, 63-64, 67-68 Anthrone, 63, 68 Apocynamarin, 16 ApocyntDD cannabinum, 11

Cardenolides, 18, 22 Cardioactive glJcosides, 10 acid hydrolysis, 31-33 action and uses, 36-37 aglycone types, 1.4-17 biosynthesis, 39-43 colour tests, 22, 25-27 enzyme hydrolysis, 34-35 extraction and isolation,

28-31

medicinal preparations,

38-39 paper chromatograpny, 30-Jl plant sources, ll-13 structures, 1.4-25 thin-layer chromatography,

31

Cascara, 63-64, 69, 71 Cascarosides, 64, 69 Cassia acutifolia, 65 C, angustifolia, 65 Chrysaloin, 64, 69 Chrysophanic acid, see Chrysophanol Chrysophanol, 66, 70 Colour tests for cardioactive glycosides, 25-27 Convallaria. majalis, 11 Convallato.xin, 11, 17 Convalloside, 11, 17 Cornilla glauca, 35 Correllogenin, 50 see al.so Neobotogenin Cymarin, 11, 12, 16, 20 Cymarol, ll, 16 Cymarose, 3, 4, 24, 25

Barbaloin, 1, 63, 69 Bioflavonoids, 55-60 Botogenin, 50-52 Bu!adienolides, 18, 22 also see Scilladienolides Bu!agins, 23

Deoxybarbaloin, 64, 69 Desacetyl lanatoside A, see Purpurea glycoside A

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Desacetyl lanatoside B, see Purpurea glycoside B Desacetyl lanatoside c, see Deslanoside Dianthrone, 63, 65 Digilanid A, see Lanatoside A Digilanid B, see Lanatoside B Digilanid C, see Lanatoside C Diginatigenin, 16, 21 Diginatin; 12, 16 Digitalinum verwn, 3, 12, 13, 15, 20 Digitalis cariensis, 12 D, rerruginea, 12 D. grandirlora, l2 0 1 lanata, 10, 12, 36, 38, 49 D, lutea, l2 D, obscura, 13 D, orientalls, 13 D, purpurea, 10, JJ, 36, 49 D, tha-,si, 13 Digitalose, 15, 20, 23, 24 Digitogenin, 49 Digitonin, 49-50 Digitoxigenin, 15, 19, 21 biosynthesis, 39-43 Digitoxin, 3, 8, 12, 13, 15, 35, 38 Digitoxose, 3, 4, 15, 16, 19, 23, 24 Digoxigenin, 16, 21 Digoxin. 12, 16, 38 Dioscorea 00:nposita, 51 D. rloribunda, 51 D. mexicana, 51 D, spiculiflora, 51 D1 tepinaoensis, 51 D, tokora, 51 Diosgenin, 50-53

Er.lOdin, 63, 64, 66, 67, 68, 70 F.ir.odin anthrone, 67 F.nzyme hydrolysis or cardioacti ve glycosides, 34-35 Euhadra guaesi ta, 34

Fagopy1'Ul1 esculentum, 55 F. tataricum, 55, 60 Flavanone, 55, 56 Flavone, 55, 56 Flavonoid glycosides, 55~ Flavonol, 55, 56 Forsythia suspensa, 57

Genin, see Aglycone Gentrogenin, see Botogenin Gitalin. 17 Gitaloxigenin, 16, 21 Gitaloxin, 13, 16 Gitorin, 12, 13, 15 Gitoside, 12, JJ, 15 Gitostin, 13, 15 Gitoxigenin, 15, 20, 21 Gitoxin, 12, 13, 15, 17 Glucoconvalloside, 11, 17 Glucose, 3, 4, 7, 15, 16, 19, 20, 23, 24, 28, 34, 35, 49,

56, 69

Glycosides, 1 cardioactive, see Cardioactive glycosides extraction & isolation, 7 pharmacological activity, 8 solubility, 5 stability and hydrolytic cleavage, 6 steroidal, see Cardioactive types or, 1-5 Glycosidic linkage, 1-2 GosSYpium hirsutum, 57

Hecogenin, 50-53 E9matia, 34 Hesperetin, 57 Hesperidin, 55-57, 60 Hesperidin chalcone, 56-57 Hesperidin methyl chalcaie, ~

56-57

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Quercet in, 56-62

Iso-emodin, 64, 70

k-Strophanthin, see Cymarin k-Strophanthin, 11, 16, 20 k-Strophanthin, see k-Strophanthoside k-Strophanthoside, 3, ll, 16, 20, 34 Kedde reagent, 23, 25, 26 Keller-Kiliani test, 27

Lanatoside A, 6, 12, 15, Lanatoside B, 6, 12, 15, Lanatoside c, 6, 12, 16, Lanatoside D, 6, 16 Lanatoside E, 6, 12, 16 Legal test, 26 Liebermann test, 27 Lzcoeersicum esculentum,

19, 38 38 38

55

Neobotogenin, 50, 52 Nicotiana tabacum, 55

Ornithogalum umbellatum, 11 Ouabagenin, 16, 21, 33 Ouabain, 11, 16, 38 OXanthrone, 63, 67, 68

Proscillaridin A, 11, Purlanosides A and B, Purpurea glycoside A, Purpurea glycoside B,

17 13 13, 15, 28 13, 15, 28

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biosynthesis, 60-62 isolation, 58-59 Quercetrin, 57 Quercitin, see ~uercetin Quercitrin, see Quercetrin

Raymond test, 25, 26 Rhamnose, J, 4, 16, 17, 23, 24 Rha.mnus cathartica, 64 R, Frangul a,

64

R, purshiana, 63 Rhein, 65-68, 70 Rhein anthron e, 65, oo, 67, 68 Rhein-8-glucoside, 65, 67 Rhubarb, 63, 66, 67, 70, 71 ~ graveolens, 55 Rutin, 55-60 action and uses, 60 biosynth esi s, see Quercetin extraction and isolation, 58 plant scnrces, 55 properties, 57~58 structure, 56-57 Rutinose, 56-57

Sapogenins, 49-54 plant sources, 51-52 structures, 49, 52, 53 uses, 52, 54 Saponins, 4 9-50 Scilladienolides, 18, 22 see also Bufadienolides Scillaren A, 11, 17 Scillarenin, 17, 22 Scilliroside, ll, 17 Scillirosidin, 17, 22 Scillirubroside, 11, 17 Scillirobrosidin, 17, 22 Senna, 63, 65, 71 Sennosides A and B, 65, 67, 69 Sennosides C and D, 65, 67, 69 Sisalagenin, 50-53

Snail enzymes, 34 Sophora japonica, 55 Squill, 22, 37, 38, 39 also see Urginea species Steroidal g lyco sides, see Cardioactive glycosides Strophanthidin, 16, 20, 21 Strophanthidol, 16, 21 Strophanthin-G, see Ouabain Strophanthin-k, see· k-Strophanthin Stroohenthus courmonti, 34 s, gratus, 11 S1 kombe, 11 Strospeside, 12, 13, 15 Sugars in glycosides, 1, 3, 4

Tollens test, 26 Transvaalin, see Scillaren A

Urginea burkei, ll U. indica, 10, ll U, rnaritima, 10, ll

Xanthydrol test, 27

YaI!Ogenin, 50-52 Yucca elephantipes, 52 Y. p.minsularis, 52

Toad poisons, 23

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