Glycosides

are compounds containing a carbohydrate and a noncarbohydrate residue in the same

molecule.
The carbohydrate residue is attached by an acetal linkage at carbon atom 1 to a
noncarbohydrate residue or AGLYCONE.
The nonsugar 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.

CLASSIFICATION OF GLYCOSIDES
When the chemical nature of the aglycone group is used as the basis of systematization,
the classification is:

Squalene, a triterpene, is a precursor of steroids

Steroids
Many hormones are steroids

The B, C, and D rings are trans fused

Methyl groups at C-10 and C-13 are called angular

methyl groups

The A and B rings are also trans fused in most naturally

occurring steroids

Substituents on the same side of the steroid ring system

as the angular methyl groups are -substituents
Thoseon the opposite side of the plane of the ring
system are -substituents

Biosynthesis of Cholesterol

Synthetic Steroids

STEROIDS
Steroids form an important group of compounds based on the fundamental
saturated tetracyclic hydrocarbon : 1,2-cyclopentano-perhydro-phenanthrene.

This nucleus, partially or completely hydrogenated, is generally substituted by

methyl groups at C10 and C13. A chemical group (ketone, hydroxyl...) or an alkyl
side-chain may also be present at C17. Steroids may possess a nucleus derived
from sterane by one or more C-C bond scissions or ring expansions or
contractions.
As natural steroids are derived from squalene by cyclization, unsaturation and
substitution, they may be considered as modified triterpenes.

FREE STEROLS
Sterols form an important group among the steroids. Unsaturated steroids with most of the
skeleton of cholestane containing a 3-hydroxyl group and an aliphatic side chain of 8 or
more carbon atoms attached to position 17 form the group of sterols.

In animals, another sterol, lanosterol (C30 compound) is found as a major

constituent of the unsaponifiable portion of wool fat (lanoline) and was shown to be
an intermediate in the biosynthesis of cholesterol. Animal tissues contain in addition
to cholesterol small amounts of 7-dehydrocholesterol.

In the tissues of vertebrates, the main sterol is the C27 alcohol cholesterol
(Greek, chole, bile), particularly abundant in adrenals (10%, w/w), nervous tissues
(2%,w/w), liver (0.2%,w/w) and gall stones, its fundamental carbon structure
being a cyclopentano-perhydro-phenanthrene ring (also called sterane). It was
the first isolated sterol around 1770 by Poulletier de La Salle from gall stones. In
1815, it was isolated from the unsaponifiable fraction of animal fats and named
cholesterine (Greek, khole, bile and stereos, solid). The correct formula
(C27H46O) was proposed in 1888 by F. Reinitzer but structural studies from 1900
to 1932, mainly by H.O. Wieland "on the constitution of the bile acids and related
substances" (Nobel Prize Chemistry 1927) and by A.O.R. Windaus on "the
constitution of sterols and their connection with the vitamins" (Nobel Prize
Chemistry 1928), led to the exact steric representation of cholesterol.
In 1936, Callow and Young designated as steroids all compounds chemically
related to cholesterol.

In higher plants, the first sterols were isolated by Hesse (1878) from the Calabar beans
(Phytostigma venenosum) which coined the term "phytosterine".
This substance was later named stigmasterol (Windaus and Hault, 1906) from the plant
genus.
The denomination "phytosterol" was proposed in 1897 for all sterols of vegetal origin.
Chemically, these sterols have the same basic structure as cholesterol but differences
arise from the lateral chain on carbon 17. Most phytosterols are compounds having 28 to
30 carbon atoms and one or two carbon-carbon double bonds, typically one in the sterol
nucleus and sometimes a second in the alkyl side chain.
All phytosterols were shown to derive from cycloartenol, direct product of the cyclization
of squalene in plants.

More than 200 different types of phytosterols have been reported in plant species.
Representatives of these sterols are campesterol, stigmasterol and -sitosterol
which is present in all plant lipids and is used for steroid synthesis. An important
C28 sterol from the fungus Claviceps purpurea (ergot) is ergosterol (mycosterol).
As ergosterol is a cell membrane component largely restricted to fungi, its amount
in environmental matrices may be used as an index molecule for these microorganisms in a living biomass.

STEROL ESTERS
In animal tissues, especially in the liver, adrenals and plasma lipids, cholesterol is esterified by
a variety of fatty acids and most frequently by essential fatty acids, thus forming cholesterol
esters.
Thus, the esterification of cholesterol with arachidonic acid gives cholesteryl arachidonate.
Sterol esters are important but highly variable components of the yeast cell with values ranging
from traces to 50% of the total lipids.
The esterification of free cholesterol within intestinal cells allows the cholesterol to be stored as
a neutral lipid in cytosolic droplets and in the packing of cholesterol into lipoprotein particles for
export via the plasma to liver cells.

STERYL GLYCOSIDES

This family consists of one carbohydrate unit linked to the hydroxyl group of one sterol molecule.
The sterol moiety was determined to be composed of various sterols: campesterol, stigmasterol,
sitosterol, brassicasterol and dihydrositosterol. The sugar moiety is composed of glucose, xylose
and even arabinose.
In bacteria, Helicobacter was shown to be particularly rich in cholesterol glucosides (up to 33% of
total lipids), thus suggesting that these molecules may be important chemotaxonomic markers for
these species.
It was shown that sterol glucosides participate in the synthesis of cellulose.

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.

Sapogenins
They form the aglycon part of saponins which have well known detergent
properties. They are oxygenated C27 steroids with an hydroxyl group in C-3. The
structure of diosgenin is given below as an example of these compounds.

These steroids can mimic or regulate steroid hormones. Thus, diosgenin can be
chemically converted into corticosteroids, estrogens and progesterone. They are
externally distributed in plants. They are extremely distributed in plants since they
occur in over 90 plant families. They are used in nutrition, as herbal medicine, and
in cosmetics.

Cardiac Glycosides
Heart diseases can be primarily grouped into three major disorders:
cardiac failure, ischemia and cardiac arrhythmia.
Cardiac failure can be described as the inability of the heart to pump blood effectively at
a rate that meets the needs of the metabolizing tissues. This occurs when the muscles
that perform contraction and force the blood out of heart are performing weakly. Thus
cardiac failures primarily arise from the reduced contractility of heart muscles, especially
the ventricles. Reduced contraction of heart leads to reduced heart output but new blood
keeps coming in resulting in the increase in heart blood volume. The heart feels
congested. Hence the term congestive heart failure.
Congested heart leads to lowered blood pressure and poor renal blood flow. This
results in the development of edema in the lower extremities and the lung (pulmonary
edema) as well as renal failure.

Cardiac Glycosides
Increasing the force of contraction of the heart (positive inotropic activity)
is very important for most heart failure patients. There are several mechanisms
by which this could be achieved. Cardiac steroids are perhaps the most useful.
The cardiac glycosides are an important class of naturally occurring drugs
whose actions include both beneficial and toxic effects on the heart.
Plants containing cardiac steroids have been used as poisons and heart drugs
at least since 1500 B.C. Throughout history these plants or their extracts have
been variously used as arrow poisons, emetics, diuretics, and heart tonics.
Cardiac steroids are widely used in the modern treatment of congestive heart
failure and for treatment of atrial fibrillation and flutter. Yet their toxicity remains
a serious problem.

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

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.
The cardenolides have an unsaturated butyrolactone ring while the bufadienolides
have an a-pyrone ring.

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 name digitoxin refers to a agent

consisting of digitoxigenin (aglycone) and
sugar moieties (three).
The aglycone portion 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.

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 12and 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 : 1 to 4 sugars are found to be present in most cardiac glycosides

attached to the 3-OH group. The sugars most commonly used include Lrhamnose, D-glucose, D-digitoxose, D-digitalose, D-digginose, D-sarmentose, Lvallarose, 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.

Cardenolides
Their structure is closely related to bufadienolides but these C23 steroids possess a
butenolide ring located at C-17. The structure of digitoxigenin is given below as a
typical example of cardenolides.

They are widely distributed in plants mainly as glycosides and are either toxic or
insect deterrents. As potent cardiotonics, these steroids were largely studied.
Monarch butterfly is well known to be highly toxic to birds because of cardenolides
which come from the milkweed leaves eaten by its caterpillar.

Cardenolides (most prevalent) are C23 steroids.

Cardenolides have a hormonal nature as substances. Their effects are on the heart and
kidney.
Strong, bitter and disagreeable taste.
Cardiotonic = affect contractions of the heart muscle.
Break down in fermentation by enzymatic action.
Symptoms of poisoning include dizziness, vomiting, irregular heart beat, and delerium or
halucinations.
Treatment: atropine and activated charcoal, lidocaine
Assumed mechanism of action: inhibition of the Na+, K+-ATPase resulting in increased
intracellular sodium and subsequent intracellular calcium leading to enhanced muscle
contraction in cardiac tissue.
Cardenolides are classified according to the chemical composition of their aglycones as
lanataglucosides A, B, C, D and E.
Only Digitalis lanata, the woolly foxglove contains all five forms. The entire foxglove plant is
toxic. Digitonin is probably the best known derivative of the Digitalis cardenolides. It is a drug
derived from D. purpurea. It is used in modern medicine to increase the force of the systolic
contractions and prolong duration of the diastolic phase in congestive heart failure.
Digitalis drugs lower venous pressure in hypersensetive heart ailments, elevate blood
pressure in a weak heart act as a diuretic, and reduce edema.
However, the therapeutic dose is dangerously close to the lethal dose

Bufadienolides
They are typically polyhydroxy C24 steroids with a pentadienolide ring at C-17. The
structure of hellebrigenin is given below as a typical example of bufadienolides.

They have been isolated from plants and animals. More than 250 compounds have
been identified. In plants, thay are mostly glycosides with one to three sugars in a
chain linked to the 3-hydroxyl group.
They are important for their cardiotonic activity. Furthermore, they possess
insecticidal and antimicrobial properties, those produced by the toad skin are
strongly poisonous.

Structure - Activity Relationships

The sugar moiety appears to be important only for the partitioning and
kinetics of action. 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 a,bunsaturated nitrile (C=C-CN group) the lactone could be replaced with little or
no loss in biological activity.

Monarch butterfly on milkweed

Danaus plexippus

The larvae feed on the plant leaves for about two weeks
and develop into caterpillars about 2 inches long.

Limenitis archippus