Glycosides & TanninsGlycosides & Tannins

GlycosidesGlycosides Glycosides consist of a sugar residue covalently Glycosides consist of a sugar residue covalently

bound to a different structure called the bound to a different structure called the aglycone.aglycone. The sugar residue is in its cyclic form and the The sugar residue is in its cyclic form and the

point of attachment is the hydroxyl group of the point of attachment is the hydroxyl group of the hemiacetal function. hemiacetal function.

The sugar moiety can be joined to the aglycone in The sugar moiety can be joined to the aglycone in various ways: various ways:

1.1. Oxygen Oxygen (O-glycoside)(O-glycoside)2.2. Sulphur Sulphur (S-glycoside)(S-glycoside) 3.3. Nitrogen Nitrogen (N-glycoside)(N-glycoside)4.4. Carbon (Carbon (CC­­glycoside)glycoside)

-Glycosides -Glycosides and and -glycosides -glycosides are distinguished are distinguished by the configuration of the hemiacetal hydroxyl by the configuration of the hemiacetal hydroxyl group. group.

The majority of naturally-occurring glycosides The majority of naturally-occurring glycosides are are -glycosides.-glycosides.

O-GlycosidesO-Glycosides can easily be cleaved into sugar can easily be cleaved into sugar and aglycone by hydrolysis with acids or and aglycone by hydrolysis with acids or enzymes.enzymes.

Almost all plants that contain glycosides also Almost all plants that contain glycosides also contain enzymes that bring about their hydrolysis contain enzymes that bring about their hydrolysis ((glycosidasesglycosidases). ).

Glycosides are usually soluble in water and in Glycosides are usually soluble in water and in polar organic solvents, whereas aglycones are polar organic solvents, whereas aglycones are normally insoluble or only slightly soluble in normally insoluble or only slightly soluble in water. water.

It is often very difficult to isolate intact It is often very difficult to isolate intact glycosides because of their polar character.glycosides because of their polar character.

Many important drugs are glycosides and their Many important drugs are glycosides and their pharmacological effects are largely determined pharmacological effects are largely determined by the structure of the aglycone.by the structure of the aglycone.

The term 'glycoside' is a very general one which The term 'glycoside' is a very general one which embraces all the many and varied combinations embraces all the many and varied combinations of sugars and aglycones.of sugars and aglycones.

More precise terms are available to describe More precise terms are available to describe

particular classes. Some of these terms refer to: particular classes. Some of these terms refer to:

1.1. the sugar partthe sugar part of the molecule (e.g. of the molecule (e.g. glucosideglucoside).).

2.2. the aglyconethe aglycone (e.g. anthraquinone). (e.g. anthraquinone).

3.3. the physical or pharmacological propertythe physical or pharmacological property (e.g. (e.g. saponin saponin ““soap-likesoap-like””, cardiac , cardiac ““having an action on having an action on the heartthe heart””).).

Modern system of naming glycosides using the Modern system of naming glycosides using the termination '-oside' (e.g. sennoside).termination '-oside' (e.g. sennoside).

Although glycosides form a natural group in that Although glycosides form a natural group in that they all contain a sugar unit, the aglycones are of they all contain a sugar unit, the aglycones are of such varied nature and complexity that glycosides such varied nature and complexity that glycosides vary very much in their physical and chemical vary very much in their physical and chemical properties and in their pharmacological action. properties and in their pharmacological action.

1. Anthracene glycosides1. Anthracene glycosides

Anthracene

A number of glycosides in which the aglycones are A number of glycosides in which the aglycones are anthracene derivatives occur as the pharmacologically anthracene derivatives occur as the pharmacologically active constituents of several cathartics of plant origin; active constituents of several cathartics of plant origin; e.g. cascara, rhubarb, aloe and senna.e.g. cascara, rhubarb, aloe and senna.

These anthracene glycosides are sometimes referred to as These anthracene glycosides are sometimes referred to as the anthraquinone glycosides or the anthraglycosides. the anthraquinone glycosides or the anthraglycosides.

These anthraquinone derivatives are glycosides, These anthraquinone derivatives are glycosides, often glucosides or rhamnosides.often glucosides or rhamnosides.

The presence of the sugar residue is a prerequisite The presence of the sugar residue is a prerequisite for the pharmacological effects.for the pharmacological effects.

Anthraquinones are colored substances and many Anthraquinones are colored substances and many of them are used technically as dyes e.g. alizarin.of them are used technically as dyes e.g. alizarin.

Reduced forms of anthraquinones, which exhibit Reduced forms of anthraquinones, which exhibit keto-enol tautomerism, are often encountered.keto-enol tautomerism, are often encountered.

The anthracene derivatives occur in vegetable The anthracene derivatives occur in vegetable drugs in different forms at different oxidation drugs in different forms at different oxidation levels; like anthraquinones, anthrones, levels; like anthraquinones, anthrones, anthranols, or oxanthrones.anthranols, or oxanthrones.

Interrelationship of anthraquinone derivativesInterrelationship of anthraquinone derivatives

O

O

O

OH

Anthrone­(keto­form)

Anthranol­(enol­form)

Anthraquinone

O

ODianthrone

O

H OH

Oxanthrone

A B C

1

2

3

45

6

7

8

9

10

4­H

2­H

2­H

Taut.

These anthracene compounds occur in these drugs or plant These anthracene compounds occur in these drugs or plant materials in some cases as the aglycones of materials in some cases as the aglycones of OO-glycosides-glycosides (e.g. (e.g. frangulin), and in other cases as the aglycones of frangulin), and in other cases as the aglycones of CC-glycosides-glycosides (e.g. aloin). (e.g. aloin).

BiosynthesisBiosynthesis; natural anthraquinones are synthesized either via ; natural anthraquinones are synthesized either via the acetate-malonate pathway (like the medicinally important the acetate-malonate pathway (like the medicinally important purgative anthraquinones), or they are derived from shikimate purgative anthraquinones), or they are derived from shikimate and mevalonate (like alizarin).and mevalonate (like alizarin).

O

O

OH

OH

Alizarin

OHOOH

HO

O

CH3

Frangula emodin

A. AnthraquinonesA. Anthraquinones

Although anthraquinone is not used extensively in Although anthraquinone is not used extensively in medical practice, it is the starting material for the medical practice, it is the starting material for the preparation of several synthetic laxatives and preparation of several synthetic laxatives and represent the basic structure of a number of represent the basic structure of a number of important laxatives and dyestuffs.important laxatives and dyestuffs.

BorntragerBorntrager’’s tests test is often used for their detection. is often used for their detection. The derivatives of anthraquinone present in The derivatives of anthraquinone present in

purgative drugs may be dihydroxy phenols such as purgative drugs may be dihydroxy phenols such as chrysophanol, trihydroxy phenols such as emodin chrysophanol, trihydroxy phenols such as emodin or tetrahydroxy phenols such as carminic acid.or tetrahydroxy phenols such as carminic acid.

O

O

­Anthraquinone

OH O OH

O

CH3

Chrysophanol

OHOOH

HO

O

CH3

Emodin

HO

OH

OH

O

O

CH3

OH

COOH

O

HO

HO

OH

OH

Carminic­Acid

B. Anthrones & AnthranolsB. Anthrones & Anthranols These reduced anthraquinone derivatives occur These reduced anthraquinone derivatives occur

either free or combined as glycosides.either free or combined as glycosides. They are isomeric and one may be partially They are isomeric and one may be partially

converted to the other in solution.converted to the other in solution. Anthranols are converted upon oxidation into Anthranols are converted upon oxidation into

anthraquinones. Oxidation takes place in the crude anthraquinones. Oxidation takes place in the crude drug during storage especially if powdered.drug during storage especially if powdered.

SchontetenSchonteten’’s tests test is often used for anthranols is often used for anthranols (green fluorescence). (green fluorescence).

Anthranols and anthrones are the main constituents Anthranols and anthrones are the main constituents of chrysarobin, a mixture of substances.of chrysarobin, a mixture of substances.

OH OH OH

CH3

OH O OH

CH3

Chrysarobin

(1,8-dihydroxy-3-methyl-9-anthrone;­3-methyl-1,8,9-anthracenetriol)

C. OxanthronesC. Oxanthrones OH O OH

H OH

These are intermediate products between These are intermediate products between anthraquinones and anthranols.anthraquinones and anthranols.

They give anthraquinones on oxidation with They give anthraquinones on oxidation with hydrogen peroxide.hydrogen peroxide.

An oxanthrone has been reported as a constituent An oxanthrone has been reported as a constituent of of cascaracascara bark. bark.

D. DianthronesD. Dianthrones O OH

COOH

COOH

O

-D-glucose–O

-D-glucose–O OH

Sennosides

These are compounds derived from These are compounds derived from two anthrone molecules, which may two anthrone molecules, which may be identical or different.be identical or different.

They are important aglycones in They are important aglycones in species of species of CassiaCassia, , RheumRheum and and RhamnusRhamnus..

One of the best known is sennoside One of the best known is sennoside derived from two molecules of derived from two molecules of glucose and two molecules of rhein-glucose and two molecules of rhein-anthrone.anthrone.

On hydrolysis, sennoside yields the On hydrolysis, sennoside yields the aglycone sennidin.aglycone sennidin.

E. Aloin-type or E. Aloin-type or CC-glycosides-glycosides

Aloin (Barbaloin) was obtained Aloin (Barbaloin) was obtained from species of from species of AloeAloe..

It is strongly resistant to normal It is strongly resistant to normal acid hydrolysis.acid hydrolysis.

In aloin, the sugar is joined to In aloin, the sugar is joined to aglycone with a direct C-C linkage aglycone with a direct C-C linkage (a (a CC-glycoside).-glycoside).

Two aloins (A and B) are known Two aloins (A and B) are known and arise from the chiral centre at and arise from the chiral centre at C-10. C-10.

OH O OH

OH

O

HO

OH

OH

HO

Aloin

22 . .Saponin glycosidesSaponin glycosides

A group of plant glycosides known as saponins A group of plant glycosides known as saponins

share in varying degrees, two common share in varying degrees, two common

characteristics:characteristics:

(a)(a) They foam in aqueous solution.They foam in aqueous solution.

(b)(b) They cause haemolysis of red blood cells.They cause haemolysis of red blood cells.

The aglycones of the saponins are collectively The aglycones of the saponins are collectively

referred to as referred to as SapogeninsSapogenins. . The more poisonous The more poisonous

saponins are often called saponins are often called SapotoxinsSapotoxins..

Plant materials containing saponins have long Plant materials containing saponins have long

been used in many parts of the world for their been used in many parts of the world for their

detergent properties for example, in Europe, the detergent properties for example, in Europe, the

root of root of Saponaria officinalis Saponaria officinalis (Fam. (Fam.

CaryophyllaceaeCaryophyllaceae)) andand in South America, the bark in South America, the bark

of of Quillaia saponaria Quillaia saponaria (Fam. (Fam. Rosaceae). Rosaceae). Such Such

plants contain a high percentage of the glycosides plants contain a high percentage of the glycosides

known as saponins (Latin known as saponins (Latin SapoSapo, means Soap) , means Soap)

which are characterized by their property of which are characterized by their property of

producing a frothing aqueous solution.producing a frothing aqueous solution.

PropertiesProperties:: Saponins form colloidal solution in water Saponins form colloidal solution in water

(hydrophilic colloids) which froths upon shaking. (hydrophilic colloids) which froths upon shaking. These substances modify and lower the surface These substances modify and lower the surface tension and therefore foam when shaken. This has tension and therefore foam when shaken. This has led to their use to increase the foaming of beer.led to their use to increase the foaming of beer.

Practical industrial applications of saponins Practical industrial applications of saponins include their use in cleaning industrial equipment include their use in cleaning industrial equipment and fine fabrics and as powerful emulsifiers of and fine fabrics and as powerful emulsifiers of certain resins, fats and fixed oils. certain resins, fats and fixed oils.

In general, they have a bitter, acrid taste and In general, they have a bitter, acrid taste and drugs containing them are usually sternutatory drugs containing them are usually sternutatory ((causing or producing sneezingcausing or producing sneezing) and irritating to the ) and irritating to the mucous membranes of eyes and nose.mucous membranes of eyes and nose.

Characteristic for all saponins is their ability to Characteristic for all saponins is their ability to cause haemolysis of red blood corpuscles and to cause haemolysis of red blood corpuscles and to destroy them. When injected into the blood destroy them. When injected into the blood stream, they are highly toxic.stream, they are highly toxic.

When taken by mouth, Saponins are When taken by mouth, Saponins are comparatively harmless, being not absorbed from comparatively harmless, being not absorbed from the intestinal tract. the intestinal tract. SarsaparillaSarsaparilla, for example, is , for example, is rich in saponins but is widely used in the rich in saponins but is widely used in the preparation of nonpreparation of non­­alcoholic beverages. alcoholic beverages.

Saponins are toxic especially to cold-blooded Saponins are toxic especially to cold-blooded animals e.g. frogs. Many are used as fish-poisons.animals e.g. frogs. Many are used as fish-poisons.

The actual cause of the haemolysisThe actual cause of the haemolysis: : The red blood cells carry sterols in their The red blood cells carry sterols in their membranes, and when brought into contact with membranes, and when brought into contact with saponins, the sterols of the RBCs are precipitated saponins, the sterols of the RBCs are precipitated and the colloidal chemical properties of the and the colloidal chemical properties of the membrane are so altered as to give hemoglobin membrane are so altered as to give hemoglobin passage to the surrounding medium. passage to the surrounding medium.

Saponins have a high molecular weight and their Saponins have a high molecular weight and their isolation in a state of purity presents some isolation in a state of purity presents some difficulties. difficulties.

Structure of SaponinsStructure of Saponins::According to the structure of the aglycone or According to the structure of the aglycone or sapogenin, two kinds of saponin are recognized:sapogenin, two kinds of saponin are recognized:

1.1. The steroidal type (commonly tetracyclic The steroidal type (commonly tetracyclic triterpenoids, C-27).triterpenoids, C-27).

2.2. The triterpenoid type (pentacyclic triterpenoids, The triterpenoid type (pentacyclic triterpenoids, C-30).C-30).

Both of these have a glycosidal linkage at C-3 Both of these have a glycosidal linkage at C-3 and have a common biosynthetic origin via and have a common biosynthetic origin via mevalonic acid and isoprene units.mevalonic acid and isoprene units.

Steroid skeleton3

25

26

27

1

18

19

21

17

Pentacyclic triterpenoid skeleton

23 24

25 26

27

28

29 30

3

1

A. Steroidal saponinsA. Steroidal saponins

The steroidal saponins are less widely distributed The steroidal saponins are less widely distributed in nature than the pentacyclic triterpenoid type. in nature than the pentacyclic triterpenoid type.

Steroidal saponins are of great pharmaceutical Steroidal saponins are of great pharmaceutical importance because of their relationship to importance because of their relationship to compounds such as the sex hormones, cortisone, compounds such as the sex hormones, cortisone, diuretic steroids, vitamin D and the cardiac diuretic steroids, vitamin D and the cardiac glycosides. glycosides.

Examples: Diosgenin (Examples: Diosgenin (Dioscorea sylvaticaDioscorea sylvatica), ), Sarsapogenin (Sarsapogenin (SmilaxSmilax sp.). sp.).

B. Pentacyclic triterpenoid saponinsB. Pentacyclic triterpenoid saponins Triterpenoid saponins my be classified into three Triterpenoid saponins my be classified into three

groups represented by groups represented by -amyrin, -amyrin, -amyrin and lupeol.-amyrin and lupeol. Examples: Primulagenin (Examples: Primulagenin (PrimulaPrimula sp.), Quillaiac acid sp.), Quillaiac acid

((Quillaia saponariaQuillaia saponaria) and Glycyrrhetinic acid ) and Glycyrrhetinic acid ((GlycyrrhizaGlycyrrhiza sp.). sp.).

E

D

Amyrin Amyrin Lupeol

2019

1713

14

3. Coumarin glycosides3. Coumarin glycosides

O O1

2

3

45

6

7

8

Coumarin

(Benzo--pyrone)

The coumarins are shikimate-derived metabolites.The coumarins are shikimate-derived metabolites. The majority of the coumarins are oxygenated at position The majority of the coumarins are oxygenated at position

C7.C7. Coumarins have a limited distribution in the plant Coumarins have a limited distribution in the plant

kingdom and have been used to classify plants according kingdom and have been used to classify plants according to their presence (chemotaxonomy). to their presence (chemotaxonomy).

Coumarins are commonly found in the plant Coumarins are commonly found in the plant families families ApiaceaeApiaceae, , RutaceaeRutaceae, , AsteraceaeAsteraceae and and Fabaceae.Fabaceae.

Some coumarins are Some coumarins are phytoalexinsphytoalexins and are and are synthesized synthesized de novode novo by the plant following by the plant following infection by a bacterium or fungus. infection by a bacterium or fungus.

PhytoalexinsPhytoalexins:: any of a group of compounds any of a group of compounds formed in plants in response to fungal infection, formed in plants in response to fungal infection, physical damage, chemical injury, or a physical damage, chemical injury, or a pathogenic process. Phytoalexins inhibit or pathogenic process. Phytoalexins inhibit or destroy the invading agent.destroy the invading agent.

These phytoalexins are These phytoalexins are broadly antimicrobial; for broadly antimicrobial; for example, example, scopoletin scopoletin is is synthesized by the potato synthesized by the potato (Solanum tuberosum) (Solanum tuberosum) following fungal infection.following fungal infection.

Khellin Khellin is an is an isocoumarin isocoumarin (chromone) (chromone) natural product natural product from from Ammi Visnaga Ammi Visnaga (Apiaceae) and has activity as (Apiaceae) and has activity as a spasmolytic and vasodilator. a spasmolytic and vasodilator.

O OHO

H3CO

Scopoletin

O

O

CH3

OCH3

OCH3

O

Khellin

It has long been known that It has long been known that animals fed sweet clover animals fed sweet clover (Melilotus officinalis, (Melilotus officinalis, Fabaceae) die from Fabaceae) die from haemorrhaging. The haemorrhaging. The poisonous compound poisonous compound responsible for this adverse responsible for this adverse effect was identified as effect was identified as dicoumaroldicoumarol..

A number of compounds have A number of compounds have been synthesized based on the been synthesized based on the dicoumarol structure, e.g. dicoumarol structure, e.g. warfarinwarfarin, which is widely , which is widely used as anticoagulant.used as anticoagulant.

O O

OH

CH3

O

Warfarin

O O

OH OH

O O

Dicoumarol

The psoralens are coumarins The psoralens are coumarins that possess a furan ring and that possess a furan ring and are sometimes known as are sometimes known as furanocoumarinsfuranocoumarins. e.g. . e.g. psoralen and bergapten.psoralen and bergapten.

These compounds may be These compounds may be produced by the plant as a produced by the plant as a protection mechanism against protection mechanism against high doses of sunlight and high doses of sunlight and some coumarins are some coumarins are formulated into sunscreens formulated into sunscreens and cosmetics for this and cosmetics for this purpose.purpose.

OO O

Bergapten

OCH3

OO O

Psoralen

4. Flavonoid glycosides4. Flavonoid glycosides

Biosynthesis:Biosynthesis:flavonoids are products from a cinnamoyl-CoA flavonoids are products from a cinnamoyl-CoA (C(C66CC33, precursor from the shikimate pathway) , precursor from the shikimate pathway)

starter unit, with chain extension using three starter unit, with chain extension using three molecules of malonyl-CoA.molecules of malonyl-CoA.

Flavonoids are therefore of mixed biosynthesis, Flavonoids are therefore of mixed biosynthesis, consisting of units derived from both shikimate consisting of units derived from both shikimate and acetate pathways. and acetate pathways.

The triketide starter unit undergoes cyclization by The triketide starter unit undergoes cyclization by the enzyme chalcone synthase to generate the the enzyme chalcone synthase to generate the chalconechalcone group of flavonoids. Cyclization can group of flavonoids. Cyclization can then occur to give a pyranone ring containing then occur to give a pyranone ring containing flavanoneflavanone nucleus, which can either have the C2-nucleus, which can either have the C2-C3 bond oxidized (unsaturated) to give the C3 bond oxidized (unsaturated) to give the flavonesflavones or be hydroxylated at position C3 of the or be hydroxylated at position C3 of the pyranone ring to give the pyranone ring to give the flavanonolflavanonol group of group of flavonoids. The flavanonols may then be further flavonoids. The flavanonols may then be further oxidized to yield the oxidized to yield the anthocyaninsanthocyanins, , which which contribute to the brilliant blues of flowers and the contribute to the brilliant blues of flowers and the dark colour of red wine. dark colour of red wine.

The flavonoids contribute to many other colors The flavonoids contribute to many other colors found in nature, particularly the yellow and found in nature, particularly the yellow and orange of petals; even the colourorange of petals; even the colour­­less flavonoids less flavonoids absorb light in the UV spectrum (due to their absorb light in the UV spectrum (due to their extensive chromophores) and are visible to many extensive chromophores) and are visible to many insects. [insects. [A A chromophorechromophore is the part (or moiety) is the part (or moiety) of a molecule responsible for its colorof a molecule responsible for its color]. ].

It is likely that these compounds have high It is likely that these compounds have high ecologicalecological importance in nature as colour importance in nature as colour attractants to insects and birds as an aid to plant attractants to insects and birds as an aid to plant pollination. pollination.

Certain flavonoids also markedly affect the taste Certain flavonoids also markedly affect the taste of foods: for example, some are very bitter and of foods: for example, some are very bitter and astringent such as the flavanone glycoside astringent such as the flavanone glycoside naringinnaringin, which occurs in the peel of grapefruit , which occurs in the peel of grapefruit (Citrus paradisi). (Citrus paradisi). Interestingly. the closely Interestingly. the closely related compound related compound naringin dihydrochalconenaringin dihydrochalcone, , which lacks the pyranone ring of naringin, is which lacks the pyranone ring of naringin, is exceptionally sweet, being some 1000 times exceptionally sweet, being some 1000 times sweeter than table sugar (sucrose).sweeter than table sugar (sucrose).

the flavonoids have important dietary the flavonoids have important dietary significance because, being phenolic compounds, significance because, being phenolic compounds, they are strongly antioxidant.they are strongly antioxidant.

Many disease states are known to be exacerbated Many disease states are known to be exacerbated

by the presence of by the presence of free radicalsfree radicals such as such as superoxide and hydroxyl, and flavonoids have the superoxide and hydroxyl, and flavonoids have the ability to scavenge and effectively ability to scavenge and effectively ‘‘mop upmop up’’ these these damaging oxidizing species. damaging oxidizing species.

Foods rich in this group have therefore been proposed to Foods rich in this group have therefore been proposed to be important in ameliorating diseases such as cancer and be important in ameliorating diseases such as cancer and heart disease (which can be worsened by oxidation of heart disease (which can be worsened by oxidation of low-density lipoprotein); low-density lipoprotein); quercetinquercetin, , a flavonoid present a flavonoid present in many foodin many food­­stuffs, is a strong antioxidant. Components stuffs, is a strong antioxidant. Components of milk thistle of milk thistle (Silybum marianum), (Silybum marianum), in particular in particular silybinsilybin,, are antihepatotoxins; extracts of milk thistle are are antihepatotoxins; extracts of milk thistle are generally known as generally known as silymarin.silymarin.

O

OH

OOH

HO

OH

OH

Quercetin

OO

O

HO

OH O

OH

OCH3

OH

OH

Silybin

Some action and therapeutic uses of Some action and therapeutic uses of flavonoidsflavonoids

Many flavonoid containing plants areMany flavonoid containing plants are::

1.1. Diuretic.Diuretic.

2.2. Antispasmodic.Antispasmodic.

3.3. Diaphoretic.Diaphoretic.

4.4. Increase tensile strength of capillary walls.Increase tensile strength of capillary walls.

5.5. Free radical scavengers.Free radical scavengers.

5. Cyanogenetic glycosides5. Cyanogenetic glycosides(Cyanide glycosides)(Cyanide glycosides)

Cyanogenesis is the ability of certain living Cyanogenesis is the ability of certain living organisms, plants in particular, to produce organisms, plants in particular, to produce hydrocyanic acid (HCN, prussic acid).hydrocyanic acid (HCN, prussic acid).

Cyanogenesis in plants is a chemical defense Cyanogenesis in plants is a chemical defense mechanism against organism damaging or feeding mechanism against organism damaging or feeding on plant tissues and lead to release of HCN gas, on plant tissues and lead to release of HCN gas, which is toxic.which is toxic.

They are distributed in over 2000 plant species They are distributed in over 2000 plant species belonging to 110 families. belonging to 110 families.

These compounds, in presence of enzymes such These compounds, in presence of enzymes such as as -glucosidase-glucosidase, lose their sugar portion to , lose their sugar portion to form a form a cyanohydrincyanohydrin which, in the presence of which, in the presence of water and water and hydroxynitrile lyasehydroxynitrile lyase, can undergo , can undergo hydrolysis to give hydrolysis to give benzaldehydebenzaldehyde and the highly and the highly toxic toxic hydrogen cyanidehydrogen cyanide (HCN). (HCN).

The sugar portion of the molecule may be a The sugar portion of the molecule may be a monosaccharide or a disaccharide such as monosaccharide or a disaccharide such as gentiobiose or vicianose. If a disaccharide, gentiobiose or vicianose. If a disaccharide, enzymes present in the plant may bring about enzymes present in the plant may bring about hydrolysis in two stages, as in the case of hydrolysis in two stages, as in the case of amygdalinamygdalin. .

They are derivatives of They are derivatives of -hydroxynitrile or 2--hydroxynitrile or 2-hydroxynitrile (cyanohydrins).hydroxynitrile (cyanohydrins).

In all cases the first sugar attached to the aglycone is In all cases the first sugar attached to the aglycone is -D-glucose.-D-glucose.

RR11 and R and R22 are often different residues resulting in are often different residues resulting in pairs of C-2 epimers.pairs of C-2 epimers.((EpimersEpimers are diastereomers that differ in configuration at only one are diastereomers that differ in configuration at only one of their stereogenic centers). of their stereogenic centers).

R1

R2

CN

O Sugar

Most cyanogenetic glycosides are biosynthetically Most cyanogenetic glycosides are biosynthetically derived from the amino acids: valine, leucine, isoleucine, derived from the amino acids: valine, leucine, isoleucine, tyrosine or phenylalanine.tyrosine or phenylalanine.

Cyanogenetic glycosides are easy to detect with a strip Cyanogenetic glycosides are easy to detect with a strip of filter paper impregnated with reagents able to give a of filter paper impregnated with reagents able to give a color reaction with the hydrocyanic acid released upon color reaction with the hydrocyanic acid released upon crushing the plant material (e.g., picric acid/sodium crushing the plant material (e.g., picric acid/sodium carbonate or benzidine/cupric acetate).carbonate or benzidine/cupric acetate).

Although hydrocyanic acid is a violent poison, it is Although hydrocyanic acid is a violent poison, it is important to remember that oral intake of cyanogenetic important to remember that oral intake of cyanogenetic drugs does not necessarily cause severe intoxication, this drugs does not necessarily cause severe intoxication, this is because the range of dangerous concentrations (0.5-is because the range of dangerous concentrations (0.5-3.5 mg/kg) can only be achieved by rapid and massive 3.5 mg/kg) can only be achieved by rapid and massive ingestion of plant parts rich in cyanogenetic glycosides. ingestion of plant parts rich in cyanogenetic glycosides.

Examples:Examples:1.1. AmygdalinAmygdalin in bitter almonds ( in bitter almonds (Prunus amygdalusPrunus amygdalus). It is ). It is

biosynthetically derived from phenylalanine.biosynthetically derived from phenylalanine.

2.2. LinamarinLinamarin in linseed ( in linseed (Linum usitatissimumLinum usitatissimum). It is ). It is biosynthetically derived from valine. biosynthetically derived from valine.

OHO

HO O

O

HO O

OH

HO

HOOH

CN

Amygdalin

CN

OO

HO

OH

HOOH

Linamarin

CH3

CH3

H

6. Steroidal cardioactive glycosides6. Steroidal cardioactive glycosides

Cardiac glycosides are a group of natural products Cardiac glycosides are a group of natural products characterized by their specific effect on myocardial characterized by their specific effect on myocardial contraction and atrioventricular conduction.contraction and atrioventricular conduction.

In large doses they are toxic and bring about cardiac In large doses they are toxic and bring about cardiac arrest in systole, but in lower doses they are arrest in systole, but in lower doses they are important drugs in the treatment of important drugs in the treatment of congestive heart congestive heart failurefailure..

They have a diuretic activity. Since, the improved They have a diuretic activity. Since, the improved circulation tends to improve renal secretion, which circulation tends to improve renal secretion, which relieves the edema often associated with heart relieves the edema often associated with heart failure.failure.

Distribution in natureDistribution in nature Cardiac glycosides occur in small amounts in

the seeds, leaves, stems, roots or barks of plants of wide geographical distribution, particularly of the Fam. Apocyanaceae (e.g. seeds of Strophanthus, roots of Apocynum and fruits of Acokanthera); others are found in the Scrophulariaceae (e.g. leaves of Digitalis sp.), Liliaceae (e.g. scales of the bulbs of Urginea and Convallaria), and Ranunculaceae (Adonis).

Cardiac glycosides are also found in animals only in exceptional cases: Bufadienolides occur in toads (Bufo).

Structure of glycosidesStructure of glycosides

The structure comprise a steroidal aglycone of The structure comprise a steroidal aglycone of the (Cthe (C2323) ) cardenolidecardenolide type or of the (C type or of the (C2424) )

bufadienolidebufadienolide type, and a sugar moiety, most type, and a sugar moiety, most often an oligosaccharide.often an oligosaccharide.

1

2

3

4

56

7

89

10

11

12

13

14

15

16

17

18

19

Lactone ring

O

Sugar moiety

A B

C D

A. Structure of the aglyconesA. Structure of the aglycones

All of the aglycones have in common the classic, All of the aglycones have in common the classic, tetracyclic, steroidal nucleus.tetracyclic, steroidal nucleus.

The A, B, C and D rings normally have a The A, B, C and D rings normally have a cis-cis-trans-cistrans-cis configuration or less often, a configuration or less often, a trans-trans-trans-cistrans-cis configuration. configuration.

Also common to all the aglycones is the presence Also common to all the aglycones is the presence of two hydroxyl groups: one is a 3of two hydroxyl groups: one is a 3 secondary secondary alcohol, the other is a 14alcohol, the other is a 14 tertiary alcohol. tertiary alcohol.

All of the aglycones have a All of the aglycones have a constituent at C-17: constituent at C-17: an an ,,-unsaturated lactone. -unsaturated lactone.

The size of the lactone ring distinguishes two groups of The size of the lactone ring distinguishes two groups of aglycones: the aglycones: the C23C23 cardenolides with an cardenolides with an ,,-unsaturated -unsaturated -lactone (= butenolide) and the -lactone (= butenolide) and the C24C24 bufadienolides bufadienolides with a di-unsaturated with a di-unsaturated -lactone (= pentadienolide). -lactone (= pentadienolide).

O

O

OO

1415

16

17

20

21

22

23

1415

16

17

20

21

22

23

24

Lactone ring ofCardenolide

Lactone ring ofBufadienolide

B. Structure of the sugar moietyB. Structure of the sugar moiety The sugar moiety is generally linked to the aglycone The sugar moiety is generally linked to the aglycone

through the hydroxyl group at C-3.through the hydroxyl group at C-3. The majority of the saccharides found in cardiac The majority of the saccharides found in cardiac

glycosides are highly specific:glycosides are highly specific:1.1. 2,6-dideoxyhexoses, e.g. D-digitoxose2,6-dideoxyhexoses, e.g. D-digitoxose2.2. 2,6-dideoxy-3-methylhexoses, e.g. D-diginose2,6-dideoxy-3-methylhexoses, e.g. D-diginose3.3. 6-deoxyhexoses, e.g. L-rhamnose6-deoxyhexoses, e.g. L-rhamnose4.4. 6-deoxy-3-methylhexoses, e.g. D-digitalose6-deoxy-3-methylhexoses, e.g. D-digitalose5.5. Hexose, e.g. glucose (Hexose, e.g. glucose (when these is a glucose unit, it is always when these is a glucose unit, it is always

terminalterminal). ). The sugars can modify The sugars can modify the activitythe activity (potency, toxicity), (potency, toxicity),

the solubilitythe solubility, , the diffusionthe diffusion through membranes, the rate through membranes, the rate of of absorptionabsorption and and transportationtransportation of the glycosides. of the glycosides.

C. Structure-Activity Relationships (SAR)C. Structure-Activity Relationships (SAR)

The cardiac activity is linked to the aglycone.The cardiac activity is linked to the aglycone. The sugar moiety does not participate directly in the The sugar moiety does not participate directly in the

activity, but its presence enhances the activity and activity, but its presence enhances the activity and modulates it by modifying the polarity of the compound.modulates it by modifying the polarity of the compound.

The presence of a certain number of structural elements is The presence of a certain number of structural elements is required for, or at least favorable, to the activity:required for, or at least favorable, to the activity:

1.1. The lactone at C-17, and it must be in the The lactone at C-17, and it must be in the configuration. configuration.2.2. The configuration of the rings. The activity is maximized The configuration of the rings. The activity is maximized

when the A, B, C and D rings are in the when the A, B, C and D rings are in the ciscis, , transtrans, , ciscis configuration. The C and D rings must be configuration. The C and D rings must be ciscis fused. fused.

3.3. The substituents. The inversion of the configuration at C-The substituents. The inversion of the configuration at C-3 diminishes the activity, but 3-deoxy compounds are not 3 diminishes the activity, but 3-deoxy compounds are not completely inactive. completely inactive.

HO

H

H

CH3

H

H

CH3

O

O

HOH

Digitoxigenin

A/B cis - B/C trans - C/D cis

O

OH

HO

A B

C D

O

Biosynthetic originBiosynthetic origin

Aglycone of the cardiac glycosides are derived Aglycone of the cardiac glycosides are derived from mevalonic acid but the final molecules arise from mevalonic acid but the final molecules arise from a condensation of a Cfrom a condensation of a C2121 steroid with a C steroid with a C22

unit (the source of C-22 and C-23). unit (the source of C-22 and C-23). Bufadienolides are condensation products of a Bufadienolides are condensation products of a CC2121 steroid and a C steroid and a C33 unit. unit.

Color reactionsColor reactions

They can be due to the sugars or to the aglycone:They can be due to the sugars or to the aglycone:

A.A. Color reactions of the sugarsColor reactions of the sugars. The only color reactions of . The only color reactions of the sugars that are of interest are those specific to 2-the sugars that are of interest are those specific to 2-deoxyhexoses. e.g. deoxyhexoses. e.g. Keller-Kiliani testKeller-Kiliani test..

B.B. Color reactions of the aglyconesColor reactions of the aglycones (steroidal nucleus). (steroidal nucleus). These are positive with any compound containing a These are positive with any compound containing a steroidal nucleus including cardenolides or bufadienolide:steroidal nucleus including cardenolides or bufadienolide:

1)1) Antimony trichloride (SbClAntimony trichloride (SbCl33))

2)2) Liebermann's test (for bufadienolides)Liebermann's test (for bufadienolides)

C.C. Color reactions of the aglyconesColor reactions of the aglycones (lactone ring). (lactone ring).

These are characteristic for cardenolides having a These are characteristic for cardenolides having a five-membered lactone ring:five-membered lactone ring:

1.1. Legal's testLegal's test

2.2. Raymond's testRaymond's test

3.3. Kedde's testKedde's test

4.4. Baljet's testBaljet's test

Pharmacological propertiesPharmacological properties Cardiac glycosides increase the force and speed of

contraction of the heart. In patients with cardiac insufficiency, this positive inotropic effect translates into 1an increase in cardiac output, 2an increase in cardiac work capacity without any increase in oxygen consumption, 3a decrease in heart rate, and, indirectly, 4a decrease in arterial resistance. (MOA) The glycosides are thought to act at the membrane level, by inhibition of the Na-K ATPase, which would result in an increase of the intracellular calcium ion concentration.

Therapeutic indicationsTherapeutic indications

Cardiac glycosides are currently indicated forCardiac glycosides are currently indicated for::

1.1. Cardiac insufficiency with low output (generally Cardiac insufficiency with low output (generally in combination with diuretics), particularly when in combination with diuretics), particularly when there is atrial fibrillation.there is atrial fibrillation.

2.2. Supraventricular rhythm abnormalities: to slow Supraventricular rhythm abnormalities: to slow down or decrease atrial fibrillation or flutter.down or decrease atrial fibrillation or flutter.

ExamplesExamples Strophanthus glycosidesStrophanthus glycosides

The name Strophanthus is The name Strophanthus is derived from the Greek derived from the Greek strophos (a twisted cord or strophos (a twisted cord or rope) and anthos (a flower)rope) and anthos (a flower)..

e.g. e.g. Strophanthus kombeStrophanthus kombe

The principle glycosides are:The principle glycosides are:

1.1. K-strophanthosideK-strophanthoside

2.2. K-strophanthin-K-strophanthin-3.3. Cymarin Cymarin

CH

CH3

OH

O

OH

H

H

O

O

O

Cymarose -D-glucose­ -D-glucose

Cymarin

K-strophanthin-

K-strophanthoside

Squill glycosidesSquill glycosidesUrginea maritima (L.)

0.1% 2.4% total bufadienolides, 15 glycosides

White variety: average 0.2%-0.4%proscillaridin A, scillaren A, glucoscillaren A (aglycone: scillarenin)scilliphaeoside, scilliglaucoside

Red variety: < 0.1%scilliroside and glucoscilliroside (aglycone: scillirosidin); proscillaridin A and scillaren A as in the white variety

Pharmacological properties of squill Pharmacological properties of squill

White squill:White squill:

it is an expectorant, but it also possesses emetic, it is an expectorant, but it also possesses emetic, cardiotonic (cardiotonic (proscillaridin A), and diuretic ), and diuretic properties. properties.

Red squill:Red squill:

it is used as a rat poison (it is used as a rat poison (scilliroside), because ), because rodents lack the vomiting reflex, which makes rodents lack the vomiting reflex, which makes red squill particularly lethal to these animals.red squill particularly lethal to these animals.

CH3

-D-glucose–O

CH3

O CH3

O

O

O

H

OH

OH

Scilliroside

(3,6)-6-(Acetyloxy)-3-(-D-glucopyranosyloxy)-8,14-dihydroxybufa-4,20,22-trienolide

Digitalis glycosidesDigitalis glycosides

Several species of Several species of DigitalisDigitalis yield pharmacologically yield pharmacologically active principles. The most important of these species active principles. The most important of these species are are Digitalis purpureaDigitalis purpurea and and Digitalis lanataDigitalis lanata..

1. Digitalis purpurea folium (Red foxglove leaves)

0.15% 0.4% total cardenolides, 30 glycosides Purpurea glycosides A and B (60%), digitoxin (12%), gitoxin (10%) and gitaloxin (10%).

2. Digitalis lanata folium (White foxglove leaves)

0.5% 1.5% total cardenolides, 60 glycosides Lanatosides A and C (50%), lanatosides B, D, E as well as digoxin and digitoxin.

DigitoxinDigitoxin is a cardiotonic glycoside obtained from D. purpurea, D. lanata.

It is the most lipid-soluble of the cardiac glycosides used in therapeutics.

The major pharmacokinetic parameters for digitoxin include complete oral absorption, which distinguishes it from other cardiac glycosides.

Digitoxin may be indicated in patients with impaired renal function.

DigoxinDigoxin is the most widely used of the cardiotonic glycosides, and it is obtained from the leaves of D. lanata.

It is a highly potent drug and should be handled with exceptional care.

Digoxin tablets are 60 to 80% absorbed.

Digoxin is indicated when the risk of digitalis intoxication is great, since it is relatively short-acting and rapidly eliminated when compared with digitoxin.

Digitalis purpureaDigitalis purpurea

7. Tannins7. Tannins

Historically, the importance of tannin-containing drugs is linked to their tanning properties, in other words their ability to transform fresh hides into an imputrescible material: leather.

Tannins are "phenolic natural products that precipitate proteins from their aqueous solutions".

The consequence of tanning is the formation of bonds between the collagen fibers in the hide, which imparts resistance to water, heat, and abrasion. This capability of tannins to combine with macromolecules explains why they precipitate cellulose, pectins, and proteins; it also explains their characteristic astringency and tartness: by precipitating the glycoproteins contained in saliva, tannins make the latter lose its lubricating power.

Most true tannins have molecular weights from about 1000 5000.

PseudotanninsPseudotannins

They are compounds of lower molecular weight They are compounds of lower molecular weight than true tannins and they do not respond to the than true tannins and they do not respond to the goldbeater's skin testgoldbeater's skin test..

Examples of drugs containing Pseudotannins areExamples of drugs containing Pseudotannins are:: Gallic acidGallic acid: Rhubarb: Rhubarb CatechinsCatechins: Guarana, Cocoa: Guarana, Cocoa Chlorogenic acidChlorogenic acid: Mate, Coffee: Mate, Coffee Ipecacuanhic acidIpecacuanhic acid:: ipecacuanhaipecacuanha

Gallic acid

COOH

OH

OH

HO

Catechin

OHO

OH

OH

OH

OH

Chlorogenic acid

O

O

OH

HO

OHHOOC

OH

OH

Function of tannins in plantsFunction of tannins in plants

1.1. Tannins are considered the Tannins are considered the source of energysource of energy through their oxygen content.through their oxygen content.

2.2. They serve as a They serve as a protectiveprotective to the plant (plant to the plant (plant antiseptics).antiseptics).

3.3. They may have They may have function in respiratory activityfunction in respiratory activity, i.e. , i.e. in the mechanisms of hydrogen transfer in plant in the mechanisms of hydrogen transfer in plant cells.cells.

4.4. Tannins play an important part in the Tannins play an important part in the acceptance acceptance of many foods and beveragesof many foods and beverages by consumers e.g. by consumers e.g. tea, cocoa.tea, cocoa.

Classification of tanninsClassification of tannins

In higher plants, two groups of tannins are generally distinguished, which differ by their structure, as well as their biosynthetic origin: hydrolysablehydrolysable tannins and condensedcondensed tannins.

Hydrolysable tannins

Hydrolysable tannins are esters of a sugar (or related polyol) and of a variable number of phenolic acid molecules.

The sugar is most generally glucose. The phenolic acid is either gallic acid, in the case

of gallitannins, or Ellagic acid, in the case of the tannins conventionally referred to as ellagitannins.

Ellagic acid can arise by lactonization of hexahydroxydiphenic acid (= HHDP) during chemical hydrolysis of the tannin.

Hydrolysable tanninsHydrolysable tannins were formerly known as were formerly known as pyrogallol tanninspyrogallol tannins, because on dry distillation , because on dry distillation gallic acid and similar components are converted gallic acid and similar components are converted into pyrogallolinto pyrogallol. .

Biosynthetically, gallic acid (= 3,4,5-trihydroxybenzoic acid) arises from the metabolism of shikimic acid.

Examples of drugs containing Hydrolysable tannins:

GallitanninsGallitannins: rhubarb, cloves, Chinese galls, Turkish galls, hamamelis, chestnut and maple. EllagitanninsEllagitannins: pomegranate rind, pomegranate bark, eucalyptus leaves, and oak bark.

Gallic acid

COOH

OH

OH

HO

OH

OH

HO

Pyrogallol

OH

OH

OH

HO

OH

COOHHO

HOOC

Hexahydroxydiphenic acid

O

OO

O

OH

OH

OH

HO

Ellagic Acid

Condensed tannins (proanthocyanidins)Condensed tannins (proanthocyanidins)Condensed tannins or proanthocyanidins are polymeric flavans. They consist of flavan-3-ol units linked together by carbon-carbon bonds, most often 48 or 46, which result from coupling between the electrophilic C4 of a flavanyl unit from a flavan-4-ol or flavan-3,4-diol and a nucleophilic position (C-8, less commonly C-6) of another unit, generally a flavan-3-ol.

Unlike hydrolysable tannins, these are not readily hydrolyzed to simpler molecules and they do not contain a sugar moiety.

OHO

OH

OH

OH

OH

(+) Catechin (catechol)

OHO

OH

OH

OH

OH

OH

Flavan-3,4-diol­structure

OHO

OH

OH

OH

OH

OHO

OH

OH

OH

OH

A dimeric structure

Biosynthetically, flavonoids are derived from acetate and shikimate pathways.

Condensed tannins occur due to polymerization (condensation) reactions between flavonoids.

The polymers may include up to 50 monomer units.

On treatment with acids or enzymes condensed tannins are converted into red insoluble compounds known as phlobaphenes. Phlobaphenes give the characteristic red colour to Phlobaphenes give the characteristic red colour to many drugs such as red cinnamon bark. many drugs such as red cinnamon bark.

Examples of drugs containing Condensed tannins:Some drugs (e.g. tea, hamamelis leaves and hamamelis bark) contain both hydrolysable and condensed tannins. The following are rich in condensed tannins.

(1) Barks: cinnamon, wild cherry, cinchona, willow, acacia, oak and hamamelis

(2) Roots and rhizomes: krameria (rhatany) and male fern

(3) Flowers: lime and hawthorn

(4) Seeds: cocoa, guarana, and kola

(5) Leaves: hamamelis, hawthorn and tea, especially green tea

(6) Extracts and dried juices: catechu, acacia and mangrove cutches

Properties and tests of tanninsProperties and tests of tannins Tannins are soluble in water, dilute alkalis, alcohol,

glycerol and acetone, but generally only sparingly soluble in other organic solvents.

Solutions precipitate heavy metals, alkaloids, glycosides and gelatin.

With ferric salts, gallitannins and ellagitannins give blue-black precipitates and condensed tannins brownish-green ones. If a very dilute ferric chloride solution is gradually added to an aqueous extract of hamamelis leaves (which contains both types of tannin), a blue colour is produced which changes to olive-green as more ferric chloride is added. Other useful tests are the following:

1.1. Goldbeater's skin testGoldbeater's skin test

Soak a small piece of goldbeater's skin in 2% hydrochloric acid; rinse with distilled water and place in the solution to be tested for 5 min. Wash with distilled water and transfer to a 1% solution of ferrous sulphate. A brown or black colour on the skin denotes the presence of tannins. Goldbeater's skin is a membrane prepared from the intestine of the ox and behaves similarly to an untanned hide.

2.2. Gelatin testGelatin test

Solutions of tannins (about 0.5-1 %) precipitate a 1% solution of gelatin containing 10% sodium chloride. Gallic acid and other pseudotannins also precipitate gelatin if the solutions are sufficiently concentrated.

3.3. Phenazone testPhenazone test

4.4. Test for catechinTest for catechin

5.5. Test for chlorogenic acidTest for chlorogenic acid

Medicinal and biological propertiesMedicinal and biological properties

The applications of tannin-containing drugs are limited, and result from their affinity for proteins.

Tannin-containing drugs will precipitate protein and have been used traditionally as styptics and internally for the protection of inflamed surfaces of mouth and throat.

They act as antidiarrhoeals and have been employed as antidotes in poisoning by heavy metals, alkaloids and glycosides.

sumac­