Glycolysis

Lec. ( 3 )
Glycosides
Introduction
Glycosides: are compounds containing a carbohydrate and a non carbohydrate residue in the same molecule.
The carbohydrate residue is attached by an acetal linkage at carbon atom 1 to a non carbohydrate residue or AGLYCONE.
The non sugar component is known as the AGLYCONE. The sugar component is called the GLYCONE.
If the carbohydrate portion is glucose, the resulting compound is a GLUCOSIDE.
An example is the methyl glucoside formed when a solution of glucose in boiling methyl alcohol is treated with 0.5% HCl as a catalyst.


The aglycone may be methyl alcohol, glycerol, a sterol, a phenol, etc. An acetal has two ether functions at a single carbon atom.




PROPERTIES, FUNCTIONS, HYDROLYSIS, THERAPEUTIC EFFICIENCY OF GLYCOSIDES

Properties: -

Chemically glycosides are considered as sugar-ether. In pure state glycosides is mostly levo-rotatory, crystalline, colourless, bitter, soluble in alcoholic, chloroform.

Functions: -

From biological point of view glycosides play an important role in the life of plants involving its regulatory, transperatory and protective functions.
R OH+HO XUR O X+H2O
SugarAglyconeGlycoside
C6H11O5OH+HOC6H4CH2OHUC6H12O5.O.C6H4+H2O

Hydrolysis: -

Glycosides are hydrolysed by acid or alkali and by enzymes resulting in cleavage of glycosidic linkage. However certain glycosides are broken down or modified.
For example some cardioactive steroidal glycosides which can be broken by strong alkali result in loss of pharmacological activity. The enzymes frequently occur along with glycosides in the same plant.
Therefore the compound may be hydrolysed when two come in contact during extraction and isolation procedure.
The glycosides exert their potent effect in mg. Doses in human being.

Therapeutic Efficiency: -

The therapeutic efficiency of glycosides is due to their aglycone. The sugar part of glycoside when administered orally helps to carry the aglycone to the site of particular organ or tissue when physiological or pharmacological actions are required.

CLASSIFICATION OF GLYCOSIDES

When the chemical nature of the aglycone group is used as the basis of systematization, the classification is as follows:



1- SAPONIN GLYCOSIDES
Saponin glycosides are divided into 2 types based on the chemical structure of their aglycones (sapogenins). Saponins on hydrolysis yield an aglycone known as "sapogenin".


The so-called NEUTRAL saponins are derivatives of STEROIDS with spiroketal side chains. The ACID saponins possess triterpenoid structures.

The main pathway leading to both types of sapogenins is similar and involves the head-to-tail coupling of acetate units. However, a branch occurs, after the formation of the triterpenoid hydrocarbon, squalene, that leads to steroids in one direction and to cyclic triterpenoids in the other.









Glycyrrhiza is the dried rhizome and roots of Glycyrrhiza glabra. Glycyrrhiza contains:
1. A saponin glycoside called Glycyrrhizin (glycyrrhizinic acid).

Glycyrrhizin is the Ca2+ and K+ salts of glycyrrhizinic acid.


Glycyrrhizinic acid is 50 times sweeter than sugar (sucrose). Upon hydrolysis, the glycoside loses its sweet taste and is converted to the aglycone glycyrrhetinic acid plus two molecules of glucuronic acid.
Glycyrrhetinic acid is a pentacyclic triterpenoid derivative of the beta-amyrin type. It has expectorant and antitussive properties (Chandler,1985). Expectorants are used to decrease the viscosity of tenacious mucus, or to increase the secretion of mucus in dry irritant unproductive cough, thereby, lubricating the air passages and making coughing more productive. It is used considerably as a flavoring agent and is frequently employed to mask the taste of bitter drugs such as aloe, quinine etc.
Glycyrrhetinic acid inhibits the enzymes (15-hydroxyprostaglandin dehydrogenase & delta 13-prostaglandin) that metabolise the prostaglandins, PGE2 and PGF2alpha to their respective 15 keto-13,14-dihydro metabolites which are INACTIVE. This causes an increased level of prostaglandins in the digestive system. Prostaglandins inhibit gastric secretion but stimulate pancreatic secretion and mucous secretion in the intestines and markedly increase intestinal motility. They also cause cell proliferation in the stomach. The effect on gastric acid secretion, promotion of mucous secretion and cell proliferation shows why licorice has potential in treating peptic ulcer.
PGF2alpha stimulates activity of the uterus during pregnancy and can cause abortion, therefore, licorice should not be taken during pregnancy.
The structure of glycyrrhetinic acid is similar to that of cortisone. Both molecules are flat and similar at position 3 and 11.

This might be the basis for licorice s anti-inflammatory action.
3-Beta-D-(monoglucuronyl)18-beta-glycyrrhetinic acid, a metabolite of glycyrrhetinic acid inhibits 11-beta-hydroxysteroid dehydrogenase which converts ACTIVE cortisol to INACTIVE cortisone in the kidneys. The increased amounts of cortisol binds to the unprotected, unspecific mineralocorticoid receptors and induce sodium and fluid retention, hypokalaemia, hypertension and inhibition of the RENIN-ANGIOTENSIN-ALDOSTERONE system. Licorice should not be given to patients with a known history of high blood pressure. A prolonged usage of licorice can also cause the formation of cataracts.
Glycyrrhizin inhibits liver cell injury caused by many chemicals and is used in the treatment of chronic hepatitis and cirrhosis in Japan. It also inhibits the growth of several DNA and RNA viruses, inactivating herpes simplex virus particles irreversibly.









Cardiac Glycosides
.
Structure
Cardiac glycosides are composed of two structural features : the sugar (glycoside) and the non-sugar (aglycone - steroid) moieties. (figure below)

The R group at the 17-position defines the class of cardiac glycoside. Two classes have been observed in Nature - the cardenolides and the bufadienolides (see figure below). The cardenolides have an unsaturated butyrolactone ring while the bufadienolides have an a-pyrone ring.

Nomenclature : The cardiac glycosides occur mainly in plants from which the names have been derived. Digitalis purpurea, Digitalis lanata, Strophanthus grtus, and Strophanthus kombe are the major sources of the cardiac glycosides. The term genin at the end refers to only the aglycone portion (without the sugar). Thus the word digitoxin refers to a agent consisting of digitoxigenin (aglycone) and sugar moieties (three). The aglycone portion (figure below) of cardiac glycosides is more important than the glycone portion.


The aglycone moiety: The steroid nucleus has a unique set of fused ring system that makes the aglycone moiety structurally distinct from the other more common steroid ring systems. Rings A/B and C/D are cis fused while rings B/C are trans fused. Such ring fusion give the aglycone nucleus of cardiac glycosides the characteristic U shape as shown below. To view the 3-dimensional structure of the aglycone moiety click on the figure.

The steroid nucleus has hydroxyls at 3- and 14- positions of which the sugar attachment uses the 3-OH group. 14-OH is normally unsubstituted. Many genins have OH groups at 12- and 16- positions. These additional hydroxyl groups influence the partitioning of the cardiac glycosides into the aqueous media and greatly affect the duration of action.
The lactone moiety at C-17 position is an important structural feature. The size and degree of unsaturation varies with the source of the glycoside. Normally plant sources provide a 5-membered unsaturated lactone while animal sources give a 6-membered unsaturated lactone.
Sugar moiety : One to 4 sugars are found to be present in most cardiac glycosides attached to the 3?-OH group. The sugars most commonly used include L-rhamnose, D-glucose, D-digitoxose, D-digitalose, D-digginose, D-sarmentose, L-vallarose, and D-fructose. These sugars predominantly exist in the cardiac glycosides in the ?-conformation. The presence of acetyl group on the sugar affects the lipophilic character and the kinetics of the entire glycoside. Because the order of sugars appears to have little to do with biological activity Nature has synthesized a repertoire of numerous cardiac glycosides with differing sugar skeleton but relatively few aglycone structures.


Structure - Activity Relationships
• The sugar moiety appears to be important only for the partitioning and kinetics of action. (see section on pharmacokinetics of cardiac glycosides) It possesses no biological activity. For example, elimination of the aglycone moiety eliminates the activity of alleviating symptoms associated with cardiac failure.
• The "backbone" U shape of the steroid nucleus appears to be very important. Structures with C/D trans fusion are inactive.
• Conversion to A/B trans system leads to a marked drop in activity. Thus although not mandatory A/B cis fusion is important.
• The 14?-OH groups is now believed to be dispensible. A skeleton without 14?-OH group but retaining the C/D cis ring fusion was found to retain activity.
• Lactones alone, when not attached to the steroid skeleton, are not active. Thus the activity rests in the steroid skeleton.

The unsaturated 17-lactone plays an important role in receptor binding. Saturation of the lactone ring dramatically reduced the biological activity.

The lactone ring is not absolutely required. For example, using ?,?-unsaturated nitrile (C=C-CN group) the lactone could be replaced with little or no loss in biological activity.






Examples of Glycosides
Importance Present in

Glycoside


High efficiency in several heart conditions.
Use under strict medical supervision Digitalis purpurea, onion, cactus

Cardiotonic
choleretic antibiotics and cholagogue balsamic rubefacients


Horseradish, mustard seed, garlic, watercress, onions, and cabbage

Sulphuretted
Antirheumatic
Antiseptic, anti-inflammatory, strengthen hair. Characterize the color of the flowers

Cornflower, Cranberry, mallow, purple loosestrife, violet and rose
Anthocyanins
By the enzymatic reaction with saliva are hydrolysed producing hydrocyanic acid.

Powerful Poison
Bitter almonds, black elderberry flower, blackthorn blossom, cherry leaves, sour cherry leaves, seeds of plums

Cyanogenic

Have laxative and purgative effects
Aloe, Rubia tinctorum, rhubarb rhizome and lycium bark

Anthrachinone

They are antispasmodics, antibiotics and venous tonics. They are also used in cosmetics, perfumes, inks
Burdock, horse chestnut, sweet clover, butcher s broom, hawkweed and biznaga



Coumarin

have properties of strengthening the blood capillaries
Hawthorn, horsetail, shepherd s purse, orange, rue, butcher s broom, elderberry and coltsfoot

Flavonoids

Relax the bowel and increase the secretions of the bronchial mucosa, diuretics and urinary tract disinfectants,

analgesic and tissue healing
Acacia leaf, birch leaf, horse chestnut, ginseng, mullein flower, licorice, ivy, primula,

saponaria root and sarsaparilla





Saponin


Professor Dr. Saad Ali Ihsan
Ph.D. in Pharmacognosy & Medicinal Plants