Glycosides

Definition:

Glycosides are (usually) non-reducing compounds, on hydrolysis by

reagents or enzymes yield one or more reducing sugars among the

products of hydrolysis.

1- Alcoholic or phenolic (aglycone): e.g., O-Glycoside

2- Sulphur containing compounds: e.g., S-Glycoside

3- Nitrogen containing compounds: e.g., N-Glycoside

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4- C-Glycoside

1- Sugars exist in isomeric α and β forms. Both α and β Glycosides

are theoretically possible.

2- All natural glycosides are of the β Type.

3- Some α linkage exists in sucrose, glycogen and starch . Also the

glycoside K-strophanthoside (strophanthidin-linke to

strophanthotriose (Cymarose + β-glucose + α- glucose).

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1- According to the type of glycosidic linkage: α- glycoside (α-sugar)

and β-glycosides (β-sugar).

2- According to the chemical group of the aglycone involved into

the acetal union:

a. O-glycoside (OH group)

b. S-glycoside (SH group).

c. N-glycoside (NH group).

d. C-glycoside (C group).

3- According to the nature of the simple sugar component of the

glycoside:

a. Glucosides (the glycone is glucose).

b. Galacosides (the glycone is galacose).

c. Mannosides (the glycone is mannose).

d. Arabinosides (the glycone is arabinose).

4- According to the number of the monosaccharides in the sugar

moiety:

a. Monoside (one monosaccharide) e.g., salicin.

b. Biosides (two monosaccharide) e.g., gentobioside.

c. Triosides (three monosaccharide) e.g., strophanthotriose.

5- According to the physiological or pharmacological activity

‘therapeutic classification)

a. Laxative glsycosides.

b. Cardiotonic glycosides.

6- according to the correlation to the parent natural glycoside:

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a. primary glycosides e.g., amygdalin, purpurea glycoside A,

b. Secondary glycosides e.g., prunasin, digitoxin.

7- According to the plant families.

8- According to the chemical nature of the aglycone:

a. Alcoholic and phenolic glycosides (aglycones are alcohols

or phenols)

b. Aldehydic G (aglycones are aldehydes).

c. Cyanogenic G (aglycones are nitriles or derivatives of

hydrocyanic acid).

d. Anthracene or anthraquinone G (aglycones are anthracene

der.).

e. Steroidal G (aglycones are steroidal in nature, derived from

cyclopentanoperhydrophenanthrene) .

f. Coumarin G (aglycones are derivative of benzo α-pyrone).

g. Chromone glycosides (aglycones are derivatives of benzo-

δ-pyrone)

h. Flavonoidal G (aglycones are 2-phenyl chromone

structure).

i. Sulphur containing or thioglycosides (aglycones are

contain sulphur).

j. Alkaloidal glycosides (aglycone is alkaloidal in nature) e.g.,

glucoalkaloids of solanum species.

Sugars in glycosides:

1- Monosaccharide (glucose in salicin, rhamnose in ouabain)

2- Disaccharides (gentiobiose in amygdalin).

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3- Trisaccharides (strophanthotriose).

4- Tetrasaccharides (purpurea glycosides)

5- Rare sugers (deoxy sugers)

6- Sugar linked in one position to the aglycone rarely in 2 positions as

sennosides.

A- 6-deoxy sugars

e.g., 1- methylpentoses

2- α-L-rhamnose.

B- 2,6-deoxy sugars (called rare sugars)

e.g.,

1- D.digitoxose 2- D.cymarose 3- diginose

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C- 2-deoxy sugars

e.g.,

2-deoxy-D-ribose

Characteristic of 2-deoxy sugers:

1- Give positive Schiff’s test for aldehydes.

2- Positive Keller-Kelliani test.

Diversity in structure makes it difficult to find general physical and

chemical properties:

1- A- Most glycosides are water soluble and soluble in alcohols.

B- Either insoluble or less soluble in non polar organic solvents.

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C- More sugar units in a glycoside lead to more soluble in polar

solvents.

2- Glycosides do not reduce Fehling’s solution, but when are

susceptible to hydrolysis give reducing sugars (C-glycosides are

exceptions).

1- Acid hydrolysis:

a- Acetal linkage between the aglycon and glycone more unstable than

that between two individual sugars within the molecule.

b- all glycosides are hydrolysable by acids non specific (except C-

glycosides).

c- Glycosides containing 2-deoxy sugars are more unstable towards acid

hydrolysis even at room temperature.

d- C-glycosides are very stable (need oxidative hydrolysis).

2- Alkali hydrolysis:

1- mild alkali

2- strong alkali

3- Enzyme hydrolysis:

1- Enzymatic hydrolysis is specific for each glycoside there is a specific

enzyme that exerts a hydrolytic action on it.

2- The same enzyme is capable to hydrolyze different glycosides, but α

and β sterio-isomers of the same glycoside are usually not hydrolysed by

the same enzyme.

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3- Emulsin is found to hydrolysed most β-glycoside linkages, those

glycoside are attacked by emulsin are regarded as β-glycosides.

4- Maltase and invertase are α-glycosidases, capable of hydrolyzing α-

glycosides only.

1- Water mixed with different proportions of methanol or ethanol

(most suitable extracting solvent).

2- Non-polar organic solvents are generally used for de-fating

process.

3- Glycosides are not precipitate from aqueous solutions by lead

acetate.

1- Destruction of hydrolysing enzymes.

a. Drying for 15-30 min. at 100 C˚.

b. Place plant in boiling water or alcohol 10-20 min.

c. Boiling with acetone.

d. Cold acid pH treatment.

e. Extract at very low temperature.

2- De-fating or purification of the plant material (in case of seeds).

3- Extraction of the glycosidal constituents by alcohol, water or

dilute alcohols. Some times ether saturated with water for dry

material.

4- Concentrate the alcoholic extract (to get rid of the organic solvent).

Add water (or hot water)→ filter any precipitate.

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5- Purify aqueous extract:

a- Extract non glycosidal impurities by org solvent.

b- Water soluble impurities precipitate by lead acetate.

6- Precipitate excess lead salts.

7- Isolation of the glycosides from the purified aqueous solution, by

crystallization.

They do not themselves reduce Fehling’s. but reducing sugars upon

hydrolysis.

To test for the presence of glycosides

Estimate reducing sugars before and after hydrolysis. (by acids or

enzymes)

1- Steroidal or cardiac glycosides:

Give positive Liebermann’s test (steroidal structure).

2- Anthraquinone glycosides and/or aglycone:

Give positive Borntrager’s test, characteristic reddish coloration with

alkalies.

3- Flavonoidal glycosides and/or aglycones:

Characteristic color with, NH4OH, AlCl3, FeCl3.

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4- Cyanogenetic glycosides give upon hydrolysis hydrocyanic acid

can be easily tested by change Na bikrate paper (yellow) to red

color.

5- Sulphur containing glycosides give black precipitate of silver

sulphate upon treatment with AgNO3 solution.

1- Keller Killiani’s test for 2-deoxy sugers:

Specificity of action of the hydrolyzing enzymes is often applied for the

identification of the sugar moieties of glycosides or even the glycoside as

alcohol.

1- Scillarin A [acid hydrolysis] →→→ Scillaridine A + Scillabiose

Scillabiose [Scillabiase] →→→ Rhamnose + glucose.

2- Prunasin [Prunase] →→→ glucose + HCN +

3- Amygdalin [amygdalase] → Prunasin + glucose

4- Myrosin enzyme is specific for thio D- glucosides e.g., Sinigrin and

sinalbin.

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Determination of the glycosidic linkages:

1- By the use of α and β glycosidases.

2- By acid hydrolysis of glycosides, immediate optical activity

measurement of the resulting solution.

Color reactions based on the sugar moiety [2-deoxy sugars]:

1- Keller Killiani:

glacialacetic acid containing + FeCl3 + H2SO4 → brown ring free from

red (acetic acid a quire blue).

2- Xanthydrol:

xanthydrol in glacial acetic containing 1% HCl + glycoside [heat]→

red color.

N.B. Stability indicating after extraction. U.S.P.

Medicinal importance of glycosides:

1- Cardiac drugs: cardiotonic glycosides e.g., digitalis glycosides,

strophanthus, squill.

2- Laxatives e.g., anthraquinone glycosides of senna, aloes, rhubarb,

cascara, frangula.

3- Counter irritants e.g., thioglycosides and their hydrolytic

products ‘allylisothiocyanate’

4- Analgesics e.g., methylsalicylate ‘a hydrolytic product of

gaultherin.

5- Anti rheumatic e.g., salicin.

6- Some glycosides are claimed to reduce the capillary fragility e.g.,

flavonoidal glycosides, rutin, hisperidin.

7- Anti-inflamatory: e.g., the glycoside glycyrrhizin has a

demulcent, expectorant and antispasmodic action.

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8- More recently as an anticancer agent e.g., amygdalin known in

the U.S. as Laetrile.

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1-The genins of all cardiac glycosides are

steroidal in nature, that act as cardiotonic

agents.

2-They are characterized by their highly

specific action cardiac muscle, increasing

tone, excitability and contractility of this

muscle, thus allowing the weakened heart

to function more efficiently.

All cardio active glycosides are characterized by the

following structural features:

1- The presence of β-OH at position C-3, which is always involved in

a glycosidic linkage to a mono, di, tri, OR tetra saccharide.

2- The presence of another β-OH group at C-14.

3- The presence of unsaturated 5 or 6- membered lactone ring at

position C-17, also in the β configuration.

4- The A/B ring junction is usually (cis), while the B/C ring junction

is always (trans) and the C/D ring junction is in all cases (cis).

5- Additional OH groups may be present at C-5, C-11 and C-16.

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1- Cardiac glycosides that α-β unsaturated 5-membered

lactose ring in position C-17 are known as cardenolides. These

are represented by the digitalis and straphanthus group.

2- Digitalis glycosides contain angular methyl group at C-10,

while strophanthus glycoside are characterized by presence of

either an aldehydic (CHO) or primary alcoholic (C`H2OH)

group at C-10.

Cardenolides

Digitalis glycosides R=CH3

Strophanthus glycosides R=CHO OR CH2OH

3- Cardiac agents that have doubly unsaturated 6-membered

lactone ring in position C-17 are referred to as Bufadienolides.

4- This group includes the squill glycosides and the toad

venom, Bufotoxin.

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Bufadienolides

Squill glycosides R1=OH, R2=H

Bufotoxin R1 & R2 = ester group

5- The glycone portion at position C-3 of cardiac glycosides

may contain four monosaccharide molecules linked in series.

Thus, from a single genin one may have a monoside, a bioside, a

trioside or a tetroside.

6- With the exception of D-glucose and L-rhamnose, all the

other sugars that are found in cardiac glycosides are uncommon

deoxy-sugars e.g., Digitoxose, Cymarose, Thevetose.

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Digitoxose Cyamarose Thevetose

Isolation difficulties:

1- Major difficulty in the isolation of 1ry glycosides from the

crude drug.. why? because 1ry glycosides are converted

into secondary glycosides by hydrolysable enzymes.

2- Other difficulty is the existence of several closely related

glycosides in the same drug, which are extremely difficult

to separate and purify.

Origin: D. purpurea, D. lanata, D. lutea and D. thapsi

The structures of the common aglycones of the digitalis

group are indicated below:

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Compounds R1 R2

Digitoxigenin H H

Gitoxigenin H OH

Digoxigenin OH H

DX = Digitoxose, DX (AC)=Acetyldigitoxose,G

= Glucose.

1- Glycosides derived from Digitoxigenin:

a- Lanatoside A = Digitoxigenin---DX---DX----DX(AC)---G.

b- Acetyl-digitoxin = Digitoxigenin---DX---DX----DX---(AC).

c- Digitoxin = Digitoxigenin------DX---DX----DX.

d- Purpurea gly A = Digitoxigenin---DX---DX----DX---G

2- Glycosides derived from Gitoxigenin:

a- Lanatoside B = Gitoxigenin---DX---DX----DX(AC)---G.

b- Acetyl-gitoxin = Gitoxigenin---DX---DX----DX---(AC).

c- Gitoxin = Gitoxigenin------DX---DX----DX.

d- Purpurea gly B = Gitoxigenin---DX---DX----DX---G

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3- Glycosides derived from Digoxigenin:

a- Lanatoside C = Digoxigenin---DX---DX----DX(AC)---G.

b- Acetyl-digoxin = Digoxigenin---DX---DX----DX---(AC).

c- Digoxin = Digoxigenin------DX---DX----DX.

d- Deslanoside = Digoxigenin---DX---DX----DX---G

1- The 1ry glycosides Lanatoside A, Lanatoside B,

Lanatoside C are acted by specific enzyme which split

the terminal glucose, give the 2ry glycosides

acetyldigitoxin, acetylgitoxin and acetyldigoxin

respectively.

2- The deacetyl-lanatosides A, B and C can be obtained by

the alkaline hydrolysis of the corresponding lanatosides.

3- Digitoxin, gitoxin and digoxin are obtained by the action

of alkali on their acetyl-derivatives.

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1- The glycoside K-strophanthoside (a trioside), K-

strophanthin B (bioside) and cymarin (a monoside) were

isolated from different strophanthus species.

2- The 1ry glycoside K-strophanthoside gives by hydrolysis one

molecule of glucose and the 2ry glycoside K-strophanthoside B

or K- strophanthin B.

3- The later gives by hydrolysis one molecule of glucose and the

tertiary glycoside cymarin, which on turn hydrolyze into the

genin K-strophanthidin and the deoxysugar cymarose.

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The seeds of Strophanthus gratus contains another glycoside

named Ouabain or (G-strophanthin), which yield on

hydrolysis rhamnose and the aglycone ouabagenin.

Ouabagenin differs from K-strophanthidin in having 2

additional (OH) groups at C-1 and C-11 and having a 1ry

alcoholic group at C-10 instead of the aldehydic group.

Ouabain (G-strophanthin)

This group of cardioactive agents includes the squill glycosides

(the scillarins) and the Toad poison (Bufotoxin).

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The genins of squill glycosides differ from those of

the cardenolides in two important aspects:

1- They have six membered doubly unsaturated lactone

ring in position C-17.

2- They have at least one double bond in the steroid nucleus.

The Bufadienolides of Squill

Name of glycosides Structure

Glucoscillarin Scillaridin A ---RH—G---G

Scillarin A Scillaridin A ---RH—G

Proscillaridin A Scillaridin A ---RH

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* The different cardiac glycosides show different solubilities in

aqueous and organic solvents. They are usually soluble in water

or aqueous alcohol and insoluble in the fat solvents with

exception of chloroform and ethylacetate.

* The higher number of sugar units in the molecule, the greater

solubility in water but lower soluble in chloroform.

* Alcohols are good solvents for both the glycosides and the

aglycones. Therefore, they are considered as the solvents of

choice for the extraction of all CG from drugs.

* pet.ether and ether are used for defatting process of drug, they

do not dissolve CG.

1- Acid hydrolysis cleavage of the glycosides into aglycones

and sugar residues.

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2- Specific enzyme usually coexist with CG in plants, which

may split the primary G into G with less sugar units. Thus,

CG deteriorate during drying and storage unless special

precautions are taken.

3- So it is required by many pharmacopoeias that CG

containing drugs must contain not more than specified moisture

content and that these drugs should be stored in sealed

containers over dehydrating agents.

4- It is recommended to heat stabilize these CG, by destroying

the enzymes at higher temperatures. At higher temperature, the

tertiary OH gp at C-14 may split off as water, leading to

formation of an inactive anhydro-form of CG.

5- The gitoxin has in addition to tertiary OH at C-14 another

secondary OH at C-16. Both OH gps split as water by the

action of H2SO4 with the formation of two additional double

bonds. These with the double bond of the lactone ring from a

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conjugated double bond system that makes the compound

fluorescent in UV light.

The detection of gitoxin in other digitalis G is based on the

above mentioned reaction.

1- CGs are steroidal in nature, give +Ve with Liebermann’s

and Salkoviski’s test.

2- CG that contain deoxy-sugars are distinguished by Keller

Kiliani’s test, e.g., digitoxose and cymarose.

3- Cardenolides are distinguished from the scillarins by a

group of color reagents, that are all alkaline solutions of

aromatic nitro compounds, namely,

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Kedde’s reagent, 3,5 dinitrobenzoic,

Raymond’s reagent, metadinitrobenzene,

Baljet’s reagent, picric acid,

Legal’s test, alkaline solution of sodium nitroprusside.

4- All these nitrocompounds react with the active

methylene of the five membered lactone ring (in alkaline

medium) to give characteristic colors.

1- Cardiotonics, CHF, rheumatic heart disease,

atherosclerosis, HTN.

2- Diuretics (capillary of the kidneys are dialated).

1- The glycone part displays a great influence on the

solubility and the rate of absorption and distribution of the

glycosides to the site of action.

2- Small change in the molecules such as a change of the

location of the OH gp, modify the cardiac activity or even

eliminate it completely.

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3- The saturation and/or cleavage of the lactone ring,

destroys the cardiac activity.

Therefore, the closely related CG, differ greatly in the rate

of absorption, duration of action and their cumulative effect.

1- digitalis leaf (digitalis tablets)

2- digitoxin tablets 200μg/tablet

3- digoxin injection contain 0.0025% digoxin

4- digoxin tablets contain 250μg/tablet

5- gitalin, lanatoside C, deslanoside, strophanthus,

strophanthin, ouabain and squill.

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1- O-glycosides where the aglycone moiety is 1,8

dihydroxyanthraquinone derivatives, e.g.,

2- O-glycoside where the aglycone moiety partially reduced 1,8

dihydroxy anthraquinone, e.g., Oxanthrone-type.

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Emodin-oxanthrone-9-glucoside

3- C-glycoside where the aglycone structure (anthrone der.)

Barbaloin

4- O-glycosides where the aglycone moiety is di-anthrone der.

(i.e., dimmer) e.g., Sennosides where there is C-C bridge

between the anthranol units. Sennoside A&B

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The most widely used drugs that contain anthracene

compounds are:

Consists of the dried leaflet of Alexandrian or Khartoum

senna, Cassia senna (C.acutifolia), Tinnevelly senna

(C.angustifolia).

Constituents:

Dimeric anthracene glycosides derived from two anthrones

moieties which may be:

1- Similar anthrone moiety (Homo-dianthrones) i.e., 2 rhein

anthrone moieties condensate through two C-10 atomes.

Thus it can be exist in two optical forms, Sennoside A (L-

form) & Sennoside B (meso form).

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Sennosides A &B

2- Or different (Hetero-dianthrones) i.e., one rhein-anthrone

& one emodin anthrone, Sennoside C (L- form) and

Sennoside D (meso form).

Sennoside C&D

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The dried bark of Rhamnus purshiana Family Rhamnaceae.

B. P. specified that the collection must be made at least one

year before the bark is used (fresh bark contains an emetic

principle).

Constituents:

A- Four primary glycosides:

1- cascarosides A&B (glycosides of barbaloin)

2- cascarosides C&D (glycosides of chrysaloin)

B-Two aloins (secondary glycosides):

Barbaloin derived from (C-10-C-glycoside) of aloe-emodin

anthrone and chrysaloin derived from (C-10-C-glycoside) of

chrysophanol anthrone.

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C- A number of O- glycosides:

e.g., derived from emodin, emodine oxanthrone, aloe emodin

and chrysophanol.

E- Free anthraquinones:

Aloe emodin, chysophanol and emodin.

1- Frangulin (frangula emodin rhamnoside).

2- Glucofrangulin (frangula emodin glucorhamnoside).

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3- hydrolysis of glucofrangulin yields frangulin and glucose.

4- Hydrolysis of frangulin gives frangula emodin and

rhamnose.

1- Consist of glycoside of rhein, rhein anthrone,

chrysophanol and aloe emodin.

2- Dianthrones of heteroanthrone types are palmidin A, B, C,

Rheidins, sennosides A&B and their oxalate esters

(sennosides E&F).

3- The presence of tannins in rhubarb makes the drug

constipating. So in small doses, rhubarb exerts no

purgative action but acts only as intestinal astringent, but

large doses cause purgation.

Cascara is a purgative, mainly in the form of liquid extract,

elixir or as tablets prepared from a dry extract.

The laxative action of the crude drugs is always higher

than from their content of anthracene der. The different

anthracene der. contained by the crude drug are said to

exert a synergistic action.

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Thus, the naturally occurring anthracene glycosides were

found superior to the synthesis of numerous hydroxyl

anthracene der.

Some of these synthetic compounds act too drastically and

also caused kidney damage.

The only compound which is used to some extent in

current medicine is danthrone. It is also used as a

standared in colorimetric assays of anthraquinone

glycosides.

Danthrone

Note:

1- The 1ry glycosides are more active than the aloins while

the free anthraquinon have little purgative activity.

2- C-C glycosides, aloins are very resistance to hydrolysis

and are not easily hydrolysed (like other anthrones and

anthranols) to corresponding anthraquinones.

3- Aloin type glycosides are present in aloes and other

anthracene bearing drugs of the family liliaceae.

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1- Glycosilation:

The purgative action of anthracene bearing drugs is owed to

their anthracene glycosidal content rather than their content

of free anthracene aglycones (i.e., glycosylation is the main

requirement for activity, as the sugar moiety serve to

transport the aglycone to the site of action in the large

intestine).

2- Hydroxylation:

Hydroxylation of C-1, C-8 is essential for activity. Increase

hydroxylation leading to increase solubility.

3- Oxidation level:

The degree of oxidation at positions C-9 & C-10 plays an

important role in the pharmacological activity. Higher

oxidation level at C-9 & C-10 caused lowering of activity.

i.e., anthrones and anthranols are more potent than their

corresponding oxanthrones, which in turn more active than

their corresponding anthraquinones. Complete reduction of

C-10 &C-9 lead to complete loss of activity.

4- The nature of substances at C-3:

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Derivative with CH2OH (as in aloe emodin) are more active

than those with CH3 substitution. The latter more active than

derivative with COOH substitution at C-3.

Anthraquinone glycosides containing adimer more active than

a monomer.

5- Effect of storage on the active of anthracene glycosides:

a- Prolonged storage of anthracene bearing drugs may bring

oxidation of anthranols and anthrones to give the less

active anthraquinones. Thus, the activity of drugs

decreases by time. However, anthraquinone glycosides

do not cause any griping action (like anthranol and

anthone), thus no antispasmodic such as belladonna is

prescribed with them.

b- Drugs as senna, Aloe and cascara preparations retain

their activity for a long time.

c- Cascara and frangula must be aged for one year before it

is used for medicinal preparation.WHY?

Stability is achieved as follows:

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1- In senna, there is dimeric glycoside in which a C-C bridge

between two anthrone units is formed (the C-10 position of

one anthrone is involved in a C-C-covalent bonding with C-

10 of the other anthrone). Thus, the C-10 position can not be

easily oxidized and the anthrone structure is stabilized.

2- In the aloe, the aloins (barbaloin & chrysaloin) contain C-

C glycosidic linkage (anhydroglycosides) stabilise the

anthrone structure.

4- In cascara, cascarosides have an additional O-glycosidic

linkage (beside the C-10-C glycosidic linkage. The

solubility of cascarosides is increased and thus, produce

higher pharmacological activity.

The glycosides are extracted and hydrolyzed by boiling the drug

with acids.

The aglycones are extracted from the acidic solution with ether

or benzene. Upon shaking the ether or benzene layer with

aqueous alkali or ammonia solution, the aqueous layer assumes

a deep red color, because of the formation of anthraquinone

salts.

Borntrager’s reaction can distinguish anthraquinones from

anthrones and anthranols which do not give the test unless they

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are converted to anthraquinone by oxidation with mild oxidants

such as hydrogen peroxide or ferric chloride.

Official anthraquinone drugs in B.P and U.S.P.:

1- Senna leaf & senna fruit (pod).

2- Aloes.

3- Cascara tablets, elixir, dry exract, liquid extract.

4- Rhubarb powdered, tincture.

5- Danthrone

6- Frangula bark

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- Flavonoidal compounds are considered as the largest

group of naturally occurring phenols.

- Flavonoidals constitute the majority of the yellow

colored plant pigments.

- Many flavonoidal compounds present as a glycosidic

or as a free forms.

- All derived from the same parent nucleus, 2-phenyl-

benzopyran (flavan), thus they have a basic C-15

skeleton.

Flavonoidal compounds are classified according to the

oxidation level of central pyran ring they are classified into

flavones, isoflavones, flavonols, flavanones, (true

flavanoids) anthocyanidins, chalcones and aurones.

True flavones, are 2-phenyl chromones (2-phenyl

benzopyrone), while isoflavones are 3-phenyl chromones

der.

Flavonols are 3-hydroxyflavones, while flavanones are 2,3-

dihydro der. of flavones (2,3-double bond is lacking).

(2-phenylbenzopyran) (2-phenylbenzopyrone)

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Anthocyanidines, chalcones and aurones are lack the typical

flavone structure. Anthocyanidins and its glycosides

(anthecyanins) are ionic oxonium salts. This is responsible

for the permanent blue, purple, violet, mauve, and red color

of flower, fruits and leaves of higher plants.

Anthocyanidins and anthecyanins are soluble in polar

solvents.

Cyanidin chloride is an example of anthocyanidines .

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Chalcones, have no central pyrone ring, so they are not true

flavonoidal compounds. The parent compound chalcone, is

chemically phenyl-styryl ketone, or benzylidene

acetophenone.

Aurones are oxidized forms that are obtained by enzymatic

oxidation. Instead of the central pyrone ring of the normal

flavonoidal structure, aurones have five membered ring.

Chalcon Aurone

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Flavonoids dissolve in alkalis give intense yellow color

solution, on the addition of acid become colorless.

Flavonoids exhibit strong fluorescence under UV light.

Flavonoidal glycosides are soluble in water and alcohol.

Ethylacetate is the solvent of choice for the extraction of

flavonoids from aqueous solution.

Flavonoids compounds may be characterized through the

investigation of their UV Spectra, that usually show two

main bands,

1- Band at higher wavelength (band I) which is attributed

to the cinnamoyl fraction of the flavonoidal structure Why?.

2- Band at lower wavelength (band II) which is due to the

benzoyl fraction of the flavonoidal structure.

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Band I >> 300 nm

If R= H R=OH R=O-substitution

Flavones flavonols 3-sub flavonol

Band I: 304-350 nm Band I: 352-385 Band I: 328-357

Band II << 300nm

(250-280 nm)

Note:

More OH in ring A: Bathochromic shift in band II.

More OH in ring B: Bathochromic shift in band I.

Shift reagents:

Back to lab.

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1- Diosmin: flavone glycoside

Occurance: buchu leaves, Barosma crenulata F. Rutaceae.

Uses: diuretic and diaphoretic action of the leaves is owed in

part to diosmin, and in part to diosphenol, the main

constituent of the volatile oil of the leaf.

Diosmin

Upon hydrolysis, diosmin yields rhamnose, glucose and

diosmetin.

2- Rutin and quercetrin: are examples of flavonol

glycosides

a- Rutin occurs in the leaves of buckwheat. It is the 3-

rhamnoglucoside (called rutinose) of the genin quercitin.

It gives on hydrolysis the aglycone (quercitin) beside one

molecule of glucose, and one molecule of rhamnose.

Rutin is used to

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1- Decrease capillary fragility.

2- It is a biflavonoids that plays a true vitamin function.

b- Quercitrin is quercitin 3-O-rhamnoside.

It occurs in the bark of Quercus tinctoria.

Quercitrin yield upon acid hydrolysis rhamnose and

quercetin.

The aglycone quercetin occurs in bearberry leaves (Uva

Ursi) and has a diuretic action of the leaves.

3- Hesperidin: it is an example of flavanones. It is the main

flavonoidal glycoside of citrus fruits.

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Upon hydrolysis by acid, hesperidin gives rhamnose,

glucose and hesperitin.

Uses:

1- Hesperidin appears to be identical to vitamin P (citrin).

2- It is necessary for absorption and retention of vit C that

lead to decrease capillary fragility.

3- Decrease CVD and HTN.

Uses of flavonoids:

1- Increase capillary resistance and decrease vitamins C & P

deficiency.

2- They are recommended in the treatment of thrombopenia

(blood coagulation).

3- They are reported of value in the treatment of influenza,

when given with ascorbic acid.

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Isoflavone:

1- Genistein show significant oestrogenic activity.

2- Rotenoids employed as insecticide.

Flavono-lignans

Coupling of a flavonoid moiety with hemi-lignan molecule

by oxidative coupling.

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The leaves and fruits of Silybum marianum family

Compositae contain silymarin (silybin).

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1- Silymarin is a very effective lipotropic and hepato protective therapy.2- It is a free radical scavenger.

3- Supportive treatment of acute and chronic alcoholic poisoning and toxin induce hepatitis.

4- It is used for treatment of liver cirrhosis caused by plant toxins (mushroom, amanita), silymarin is applied as intravenous injection.

5- Silymarin is available in the market in the form of tablets, effervescent granules. Trade name legalon, silyhexal, silirex…etc.

Synthetic flavonoids

Flavoxate:

Uses:To remove pain (anti-spasmodic) and anti-inflammatory of the genitor urinary tract.

Flavoxate tablets are available under several names: Urispas, Uronid, Spasurit, Genurin).

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* Saponins are a group of amorphous colloidal glycodides which is wiedly distributed in the higher plants.

* Have ability to form lasting foam when shaking in aqueous solution.

* They are excellent emulsifying agents (modify surface tension).

* Formerly used as detergents to replace soap (e.g., quillaia).

* Saponins are colorless and optical active. They form colloidal solution with water and are soluble in alcohol and dilute alcohols.

* Saponins have haemolytic properties, they precipitate the

cholesterol and lethisins that exist in the memberanes of the

red blood cells and thus haemoglobin is liberated. So,

saponins are extremely toxic when injected into the blood

stream. However, they are not harmful when taken orally.

* Saponins are difficult to purify. However, they

precipitated from solutions containing them by the addition

of a solution of the sterol, filtering off the insoluble sterol-

saponin compound and boiling it with toluene which resolves

the compound again into sterol (which is soluble in toluene)

and saponin (which is insoluble in toluene).

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Chemically:

Saponins are classified according to the genin part into:

1- Steroidal type C25.

2- Triterpinoidal type C30.

Both types of saponins have the glycosidic linkage at position 3.

Medicinal importance of saponins:

1- The steroidal saponins are structurally related to modern

synthetic compounds that have a therapeutic significance,

such as adrenocortecoids and the sex hormones. So, they

are a suitable precursors in the partial synthesis of these

hormones, e.g., Diosgenin (sapogenins) isolated from the

rhizome of Dioscoria species.

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2- Saponins increase the rate of absorption of many

pharmacological active substances (e.g., cardiac

glycosides).

3- Many saponin-containing drugs are used as expectorants

(e.g., Ipeca, Senaga and liquorice) as their contents of

saponins stimulate bronchial secretion and also activate

the ciliary epithelium of the bronchi.

a-The triterpenoidal saponin glycoside, glycyrrhizin, is the

main sweet principle of liquorice. It is calcium and

potassium salts of glycyrrhizic acid, which in tern is the

diglucuronic acid glycoside of glycyrrhitinic acid.

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b- Beside being a valuable flavouring and sweetening agent,

liquorice has demulcent, expectorant and antispasmodic

action. All these activities attributed to the saponin,

glycyrrhizin.

c- Recently, glycyrrhizin was shown to be effectively in

gastric ulcer treatment and have a cortisone like action in

rheumatic arthritis and other inflammatory diseases.

Saponins drugs officially in the B.P and U.S.P:

1- Quillaia bark: used as emulsifier.

2- Liquorice root: used as flavouring agent and expectorant.

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1- Tannins are widely distributed phenolic plant constituents.

It is characterized by being able to combine with proteins of

animal hides thus preventing their putrefaction and

converting them into leather (true tannins).

2- Tannins are detected qualitatively by Goldbeater’s skin

test (a tanning test), and can be quantitatively estimated by

absorption on standard hide powder. Only high

molecular weight tannins that are capable of tanning hide.

It is more acceptable to define true tannins as those high

molecular weight phenolic plant constituents that can be

detected by Glodbeater’s skin tanning test.

3- True tannin solutions have the ability of precipitating

soluble proteins (gelatine), heavy metals, alkaloids and

glycosides.

4- This will exclude simple molecular weight compounds

such as gallic acid, catechin, flavan-3,4-diol and

chlorogenic acid, that usually coexist with true tannins.

These simpler tannins like compounds are referred to as

pseudotannins.

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Hydrolysable tannins Condensed tannins

1- Hydrolysable tannins:

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a- These can be hydrolyzed by acids or enzymes to give

phenolic acids (gallic or ellagic) and glucose, so called

phenolic acid glycosides.

b- Tannins of gallic acid are called gallitannins and those of

ellagic acid is called ellagitannins.

c- Dry distillation of hydrolysable tannins gives pyrogallol.

This class is named pyrogallol tannins.

d- Gallitannins and ellagitannins react with ferric salts to give

bluish color precipitate.

2- Condensed tannins:

a- These are more resistant to hydrolysis upon prolonged

heating with acids.

b- They undergo decomposition (not hydrolysis) to give a

red soluble compound (phlobaphane).

c- Condensed tannins are derived from catechin and flavan,

3,4-diol.

d- Dry distillation of condensed tannins gives catechol. This

class is named catechol tannins.

e- Being phenolic, it reacts with ferric salts to give greenish

color precipitate.

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1- Salicin:

Salicin is classified as:

1- Alcoholic glycoside, as it contains free primary alcoholic

group.

2- A phenolic glycoside, as its aglycone is phenolic in

nature.

Salicin

1- Salicin is obtained from different species of Salix, the

principle commercial source is Salix fragilis.

2- Salicin is used for many years as a remedy in the

treatment of fever and rheumatism.

3- It is now used as an analgesic-antipyretic in case of

periodic fever. It is better tolerated in the stomach than

sodium salicylate, asprin and other antipyretics and anti-

inflammatory agents, which have largely displaced in

medical practice.

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4- Salicin is hydrolyzed by the enzyme emulsin into

saligenin (Salicyl alcohol) and glucose.

5- Acid hydrolysis of salicin gives glucose and a phenolic

ether called saliretin which is a condensation product of

two molecules of saligenin.

6- Oxidation of saligenin gives salicylic acid and this

accounts for the medicinal value of salicin.

1- Arbutin is a phenolic glycoside that occurs in bearberry

leaves Arectostaphyllos uva ursi.

2- When hydrolysed with acids or with emulsin it yields glucose

and hydroquinone.

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3- It is used as diuretic and also has bactericidal action. This

activity is due to the hydroquinone given by hydrolysis.

3- Uva ursi leaf contains also methylarbutin (the methyl ether

of arbutin), that also contributes to the diuretic and urinary

antiseptic action of the leave.

1- Glucovanillin is a glycosidal constituent of green vanilla

pods.

2- The fruits of the plant (pods) are collected and carefully

cured. To permit enzymatic action on the glycoside with

the liberation of vanillin (the aglycone) which is the

principal flavouring constituent of the pods.

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3- Vanillin is widely used as a flavouring agent. It may be

obtained from vanilla pod or prepared from the glycoside

coniferin, lignin or from the phenolic volatile oil

constituents eugenol.

1- From Coniferin and lignin

2- From Eugenol

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The bulk of vanillin which is produced commercially is

prepared from lignin, which gives upon hydrolysis coniferyl

alcohol.

Lignin is obtained in extremely large amounts as a by product

of timber industry.

1- These are glycosides that are yield hydrocyanic acid as one

of their hydrolytic products.

2- Plant containing these glycosides are toxic.

3- The aglycone part is cyanohydrin of a carbonyl compound

(condensation product of HCN with an aldehyde or keton).

4- The majority of cyanogenic glycosides are derived of

benzaldehyde cyanohydrin.

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D-Mandelonitrile gentiobioside

1- Amygdalin is the most widely distributed cyanophore

glycoside.

2- It occurs in several Prunus species, and is obtained from

bitter almonds (Prunus amygdalus Var. amara Family

Rosaceae).

3- Amygdalin is considered as gentiobioside of D-

mandelonitrile. Gentiobioside is a reducing disaccharide

consisting of two molecules of β-glucose linked by β-1,6

linkage.

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4- Acid hydrolysis of amygdalin split two molecules of

glucose and one molecule of mandelonitrile. The latter

decomposes spontaneously to form benzaldehyde and

HCN.

5- Different enzymes act upon amygdalin in different ways:

The plant material is cutted into small fragments and then a

filter paper moistened with sodium picrate is then suspended in

the neck of the flask, the flask is stoppered and incubated in a

warm place (40˚C) for about 30-60 min. By this time, the

coexisting enzymes act upon the glycosides with the liberation

of HCN which turns, the sodium picrate paper convert to brick

red color.

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Thioglycosides

1- A number of plants of the family Cruciferae yield glycosides

containing sulphur.

2- Hydrolysis of these, yield volatile genins of thiocyanate

structure e.g., mustard oils.

3- The best known compounds Sinigrin and Sinalbin, two

glycosides occurring in black mustard and white mustard seed

respectively.

4- The glycosides and their specific enzymes are found in

different cell in the seeds. They donot interact until they are

brought together by the distruction of the cell walls.

5- The general structure of thioglycosides is:

6- The anion is called the glucosinolate ion, R may be aliphatic

or aromatic. The cation (X) may be a simple metal ion or a

complex organic cation, e.g., sinapine ion of sinalbin.

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6- Sinigrin gives upon hydrolysis, glucose,

allylisothiocyanate (volatile oil of mustard) and

potassium acid sulphate.

7- Hydrolysis of the glycoside sinalbin gives a phenolic

isothiocyanate (Acrinyl isothiocyanate), glucose and the

acid sulphate of a quaternary alkaloid, sinapine.

8- Black and white mustard seeds are used as rubefacients

and counter irritants. These effects are attributed to their

contents of thioglycosides.

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Aglycone 1- coumarin (benzo-α-pyrane).

2-coumarin derivative (hydroxyl and methoxy coumarins).

3- Umbelliferone [7-hydroxy coumarin] is the lactone of

umbellic acid which occurs both in the free state and in the

form of glycosides in some resins of the Umbelliferae

(Asafetida and galbanum).

4- Coumarin and its derivatives give blue or violet

fluorescence in aqueous ammonical solutions (conjugated

double bond system). This is made use of in qualitative

testing for coumarin, coumarin derivatives and coumarin

glycosides and drugs containing them.

5- The oleo gum resin galbanum that contains

umbelliferone in a free state is distinguished from

asafoetida that contains only combind umbelliferone, by

the addition of ammonia to its aqueous alcoholic extract,

when the characteristic blue fluorescence is given.

Asafetida responds positive to the fluorescence test only

after acid hydrolysis.

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