5)PLANT STEROIDS BY BILAL MALIK

PLANTS STEROIDS:
Contents:
• What are steroids?
• Sources
• Nomenclature
• Biosynthesis
• Plant steroids and their uses
 Plant sterols
 Cardiac glycosides
 Steroidal sapogenins
 Ecdysones
 Withanolides
• Animal steroids and their uses
 Steroid hormones (Sex hormones and adrenocortical
hormones)
 Bile acids
 Ecdysones

INTRODUCTION:
• Steroids comprise a natural product class of compounds widely
distributed throughout nature.
• A steroid is an organic compound with four rings arranged in a specific
configuration.
• Steroids have two principal biological functions: certain steroids (such as
cholesterol) are important components of cell membranes which alter
membrane fluidity, and many steroids are signaling molecules which
activate steroid hormone receptors.

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• Hundreds of steroids are found in plants, animals and fungi. All steroids
are manufactured in cells from the sterols:
• lanosterol (animals and fungi) or
• cycloartenol (plants).
• Plant steroids (aka Phytosteroids) are naturally occuring steroids that are
found in plants.
• Examples include digoxin, digitoxin, diosgenin, and guggulsterone, as
well as phytosterols like β-sitosterol and other phytoestrogens like
isoflavones.
• Guggulsterone-E and guggulsterone-Z, are the potent hypolipidemic and
hypocholesterolemic bioactive molecules present in the gum resin of
Commiphora wightii.
• In plants, cholesterol is widely distributed but often present in minute
quantities; other steroids not found in animals (the Phytosterols) tend to
predominate.
NOMENCLATURE:
• A steroid is any compound that contains a cyclo-penta-noper-hydro-
phenanthrene nucleus.
• Each parent tetracyclic hydrocarbon bears a specific stem name. Steroids
are numbered and rings are lettered as indicated in the structural formula
for cholesterol.
• When the rings of a steroid are denoted as projections onto the plane of
the paper, an atom or group attached to a ring is termed α if it lies below
the plane and β if it lies above the plane.
• The use of a stem name implies that atoms or groups attached at the ring
junction positions 8,9,10,13 & 14 are oriented as shown (8α ,9α , 10β,
13β, 14α) and a carbon chain attached to position 17 is assumed to be β
oriented.
• The configuration of hydrogen or a subsyituent at the ring-junction
position 5 is always designated by adding α or β after the numeral 5. This
numeral and letter are placed immediately before the stem name.
• For example, the chemical name of cholic acid is 3α, 7α, 12α-
trihydroxy-5β-cholan-24-oic acid.

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Some naturally occuring steroids..

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BIOSYNTHESIS:
• The hundreds of steroids found in animals, fungi, and plants are made
from lanosterol (in animals and fungi) or cycloartenol (in plants).
• Lanosterol and cycloartenol derive from cyclization of the triterpenoid
squalene.
• In animals the biosynthesis of steroids follows the mevalonate pathway,
which uses acetyl-CoA as building blocks for dimethylallyl
pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP). In
subsequent steps DMAPP and IPP join to form geranyl pyrophosphate
(GPP), which synthesizes the steroid lanosterol.
• In plants, the non-mevalonate pathway uses pyruvate and glyceraldehyde
3-phosphate as substrates.
• Squalene  Squalene oxide   Protosteryl cation  
Cycloartenol   Sitosterol  Stigmasterol
• Steroids are formed biosynthetically from isopentenyl pyrophosphate
(active isoprene).
• Steroid biosynthesis in plants proceeds via mevalonate and FPP in the
cytosol but differs from the pathway in mammals and fungi because of
the intermediary of the unusual cyclopropane ring-containing sterol
cycloartenol. A series of intricately co-ordinated Wagner-Meerwein
rearrangements accompanies the cascade of cyclization events which
produce the cycloartenol skeleton.
• Formation of cholesterol may be considered as a general mechanism of
steroid biosynthesis:

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• Acetate –>–> mevalonate–>–> isopentenyl –>–> pyrophosphate –>–>

squalene –>–> cholesterol

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Pyruvate +
Acetyl-CoA
Glyceraldehyde
phosphate

Acetoacetyl-CoA
Deoxy xylose phosphate

HMG-CoA
2-C-methyl-D-erthritol
4-phosphate
Mevalonate
Various erythitol
phosphate
Mevalonate intermediates
pyrophosphate

2-methylbutane-1,4-diol
IsoPentenyl
diphosphate
pyrophosphate (IPP)
+ Dimethylallyl
pyrophosphate Isopentenyl
pyrophosphate+
Dimethylallyl
Squalene pyrophosphate

Lanosterol Squalene

Cholesterol Cycloartenol

Steroid hormones Campesterol

Bile Acids Sitosterol

1) PLANT STEROLS:
• The first steroid isolated from nature were a series of C27-C29 alcohols
that were found in the lipid fractions of many tissues. These compounds
were solids and therefore named sterols from the greek stereos- meaning
solid.
• The most widely occuring sterol is cholesterol. It has been identified in
animals, algae, fungi, actinomycetes, bacteria, ferns and higher plants.

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• The plant sterols are similar to cholesterol and vary only in carbon side
chains and/or presence or absence of a double bond. More than 200
sterols and related compounds have been identified.
• The most common sterol in plants is β-sitosterol, a C29 compound.
• Closely related to β-sitosterol is stigmasterol, first isolated from calabar
beans but is also found in soybean oil.
• Stanols are saturated sterols, having no double bonds in the sterol ring
structure.
• Free phytosterols extracted from oils are insoluble in water, relatively
insoluble in oil, and soluble in alcohols.
• The richest naturally occurring sources of phytosterols are vegetable oils
and products made from them.
• Phytosterols are currently approved by the U.S FDA for use as a food
additive; however, there is some concern that they may block absorption
not only of cholesterol (thus helping to reduce cholesterol), but of other
important nutrients as well.
• At present, the American Heart Association has recommended that
supplemental plant sterols be taken only by those diagnosed with elevated
cholesterol, and has particularly recommended that they not be taken by
pregnant women or nursing mothers.

Sitosterols:
• Composition: The drug sitosterols is a mixture of β-sitosterols and
certain saturated sterols.
• It contains no less than 95% of total sterols and not less than 85% of
unsaturated sterols.
• Characteristics: It is a white, odourless, tasteless powder that is
practically insoluble in water.
• Source: They are widely distributed throughout the plant kingdom and
may be obtained from wheat germ oil, rye germ oil, cottonseed oil, corn
oil and other seed oils.

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• Uses: Sitosterols is a hypocholesterolemic agent used in the treatment of

atherosclerosis. The sitosterols are poorly absorbed and compete with
cholesterol for absorption sites in the intestine.
• Dose: 3g, 3 times a day before meals.
• Cytellin® a sitosterols suspensions is hydroalcoholic suspension of β-
sitosterol and a small amount of dihydro- β -sitosterol.

2) STEROIDAL SAPOGENINS:
• Sapogenins are the aglycones, or non-saccharide, portions of the family
of natural products known as saponins. Steroidal sapogenins contain
steroid framework as their key organic feature. Some steroidal sapogenins
can serve as a practical starting point for the semisynthesis of particular
steroid hormones.
• Occurrence:
• They are found in many monocotyledonous families. particularly the
Dioscoreacea (e.g. Dioscorea spp.) Agavaceae (e.g. Agave and Yucca
spp.) and Smilacacea (smilax spp.).
• In the dicotyledons the occurrence of diosgenin in Fenugreek
(Leguminosae) and of steroidal alkaloids in Solanum (Solanaceae) is of
potential importance. Some species of Strophanthus and Digitalis contain
both steroidal saponins and cardiac glycosides.

Saponin (not steroidal)

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Some steroidal sapogenins and their sources:

Uses:
• Steroidal saponins are of great pharmaceutical importance because of
their relationship to compounds such as the sex hormones, cortisone,
diuretic steroids, vitamin D and the cardiac glycosides.
• Some plant saponins can weakly mimic the human hormones that they
resemble. For example, yam (Dioscorea spp.) contains variable amounts
of a saponin called diosgenin, which can be converted into hormones
such as progesterone and estrogen. In fact, Mexican yam (D. composita)
has been used to make oral contraceptives
• Hecogenin (steroid isolated from Agave sisalana) with C-ring
substitution provides a practical starting material for the synthesis of
corticosteroids.
• Solanum species are noted for the production of C27 steroidal alkaloids.
Some of these alkaloids are the nitrogen analogues of Solasodine &
diosgenin etc. They are employed in the partial synthesis of steroidal
drugs.

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• Diosgenin, obtained from fenugreek (Trigonella foenum graecum), has

been found to exert anti-carcinogenic properties (cancer
chemopreventive), such as inhibiting proliferation and inducing apoptosis
in a variety of tumor cells.

3) CARDIAC GLYCOSIDES:
• Occurrence:
• These glycosides are found in the plant genera Digitalis, Scilla, and
Strophanthus. They are used in the treatment of heart diseases, e.g.,
congestive heart failure and arrhythmia.
• A considerable number of plants throughout the plant kingdom contain
steroidal glycosides which exert on the failing heart a slowing and
strengthening effect. These steroids occur as glycosides with sugars
attached at the 3-position of the steroid nucleus.
• Structure of glycosides
• Two types of genin may be distinguished: cardenolides (C23 steroids)
and bufanolides (C24 steroids).
• The sugar moieties, attached to the aglycone by a C-3, B-linkage are
composed of upto four sugar units.
• Bufalin, ouabain and digoxin are a few toxic cardiac glycosides. Digoxin
from the foxglove plant is used clinically, whereas bufalin and ouabain
are used only experimentally due to their extremely high potency.

Genins of some cardiac glycosides and their sources:

• CARDENOLIDES
• Digitoxigenin (Digitalis purpurae) (Digitalis lanata)
• Gitoxigenin (Digitalis purpurae) (Digitalis lanata)
• Gitaloxigenin (Digitalis purpurae) (Digitalis lanata)
• Digoxigenin (Digitalis lanata)
• Diginatigenin (Digitalis lanata)
• Strophanthidin (Strophanthus combes)
• Oubagenin (Strophanthus gratus)

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• Sarmentogenin (Strophanthus sarmentosus)

• Oleaderigenin (Nerium oleader)
• BUFADIENOLIDES
• Scillarenin (Urignea maritima)
• Scilliphaeosidin (Squill)
• Hellebrigenin (Helleborus niger)

4) STEROID HORMONES:
• The steroid hormones can be divided into two classes:
• The sex hormones and the adrenocortical hormones.
• Sex hormones are produced in the gonads and fall into 3 chemically and
physiologically distinct categories:
• The estrogens & progestins (regulates various functions of female
reproductive tract) and androgens (stimulates development of the male
reproductive organs)
• The adrenocortical hormones are produced by the outer cortical portion of
the adrenal glands and they are divided into 2 classes, depending on their
biologic activity:
• Mineralocorticoids (affects the excretion of fluid and electrolytes) and
glucocorticoids (affects intermediary metabolism)
Commercial Production of Steroids:
• At the present time, the principal source of the steroid chemical nucleus
used in the drug industry is the plant kingdom.
• Initially, the source of steroid hormones was from gonads and adrenal
glands of animals but the amount of hormones present in these glands
was extremely small and large quantities of glands were required to
isolate mg quantities of hormones.
• A vast amount of research has resulted in extension and improvement of
the basic procedure of isolation.

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• Inexpensive starting materials like stigmasterol from soybeans, hecoenin

from the sisal industry or diosgenin from dioscorea species are now
employed to produce compounds of potential therapeutic importance.
Examples:
• Stigmasterol may be converted chemically to progesterone, which in
turn, incubated in large fermentors with suitable conditions to yield 11-a-
hydroxyprogesterone, which may then be converted chemically to
cortisone.
• Diosgenin is used to prepare cortexolone and is then converted by
streptomyces fradiae to corticol (hydrocortisone)
• Cortisone or cortisol is dehydrogenated by Corynebacterium simplex to
yield prednisolone.
Therapeutic uses:
• Sex steroids are used to treat low levels of these hormones in the body,
for diseases that destroy muscles, anemia, delayed puberty, hormone
sensitive cancers (breast, prostate cancer) etc.
• Testosterone -> Breast cancer that has spread to other parts of the body.
• Dehydroepiandrosterone (DHEA)/ Prosterone -> in post-menopausal
women for pain.
• Estrogens -> Oral contraceptives, Hormone replacement therapy in
hypogonadal, transgender or menopausal women.
• Non-medicinal use of anabolic steroids: in Body building as
‘performance enhancing drug’
• Glucocorticoids may be used in low doses in adrenal insufficiency.
• In much higher doses, oral or inhaled glucocorticoids are used to suppress
various allergic, inflammatory, and autoimmune disorders. Inhaled
glucocorticoids are the second-line treatment for asthma.
• They are also administered as post-transplantory immunosuppressants
to prevent the acute transplant rejection and the graft-versus-host disease.
• Glucocorticoids are potent anti-inflammatories.

5) BILE ACIDS:
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• In the liver of man and other animals the side chain of cholesterol is
degraded to C24 steroids, which possess a C-24 carboxyl. These steroids
are collected as the bile, therefore they are referred to as bile acids.
• Primary bile acids formed in the liver of man are: Cholic acid and
chenodesoxycholic acid.
• Des-oxycholic acid and lithocholic acid are produced in the intestinal
tract by the action of microorganisms.
• Generally, bile acids are conjugated to glycine or taurine through a
peptide bond. The conjugated bile aids are discharged into the duodenum
to where they act as emulsifying agents to aid in the absorption of fats.
Functions of Bile Acids:
• Eliminates cholesterol from the body,
• Drives the flow of bile to eliminate certain catabolites (including
bilirubin)
• Emulsifies fat-soluble vitamins to enable their absorption,
• Aids in motility and the reduction of the bacteria flora found in the small
intestine and biliary tract.
• Bile acids also act as steroid hormones having various direct metabolic
actions in the body through the nuclear receptor Farnesoid X receptor
(FXR)
Ox bile extract:
• Bile salts are the sodium salts of the conjugated acids and are the
principal constituent of ox bile extract.
• Preparation:
1. Partial evaporation of fresh ox bile
2. Precipitation of the mucus and albuminous matter with alcohol
3. Filteration
4. Washing
5. Evaporating the combined filtrates to dryness at a temperature not
exceeding 80 C.

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• It contains an amount of the sodium salts of glycocholic acid and

taurocholic acid equivalent to not less than 45% of cholic acid.
• Use:
• Choleretic (substances that increase the volume of secretion of bile from
the liver as well as the amount of solids secreted).
• Helps in digestion of food
• People, who have had their gallbladder removed, use ox bile to
supplement their bile production with meals.
• Dose: 300 mg
• Non-prescription product: Bilron Pulvules®

6) WITHANOLIDES:
• Withanolides are a group of at least 300 naturally occurring steroids built
on an ergostane skeleton
• In 1968, the structure of a constituent lactone (withaferin A) of Withania
somnifera was determined, since then many more compounds have been
characterized.
• Other genera of the family in which they occur include: Aenistus, Datura,
Hyoscyamus, Iochroma, Jaborosa, Lycium, Nicandra, Physalis and
Solandra.
• The first report of a withanolide from the Labiatae concerns the
characterization of a new compound, ajugin, from ajuga parviflora whole
plants.
Examples and Uses:
• They have potential pharmacological value as sedatives, hypnotics,
antiseptics and anti-mitotics.
• Some withanolides are cell differentiation inducers- compounds of a new
type of anti tumour agent.
• Withaferin A acts as an anti angiogenic compound by inhibiting
Transcription Factors Sp1 and NF-κB. Withaferin A also inhibits
angiogenesis on chick chorioallantoic membrane. Withanalides inhibit
COX-2 and exhibit anti-inflammatory activity.

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• Salpichrolides A, B and G (isolated from Salpichroa origanifolia)

exhibit an inhibitory effect on the growth of larva of the Mediterranean
Fruit Fly
• The nicandrenones of Nicandra physalodes are another group of
withanolides with insecticidal effects.

7) ECDYSONES:
• The ecdysis of insects relates to the moults which larvae undergo during
their transformation into an adult, a process controlled by complex
hormonal mechanisms.
• Ecdysones, insect-moulding hormones, are substances which stimulates
these changes and one example is ecdysone itself, first isolated from silk-
worm pupae.
• Ecdysone is a steroidal prohormone of the major insect molting hormone
20-hydroxyecdysone, which is secreted from the prothoracic glands
• In plants they occur in much greater variety and abundance, where they
appear mostly as protective agents against herbivorous insects.
• Insects do not themselves biosynthesize steroids de novo and rely on
plant materials for suitable precursors.
• Ecdysterone is also an example of one which has been obtained from
both plant and insect sources.
• In the plant, cholesterol is a precursor of insect-moulding hormones and
in one morphological group of helleborus, it has been shown that they are
formed together with bufadienolides and saponins.

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• Ecdysterone (20-Hydroxyecdysone) is also an example of one which

has been obtained from both plant and insect sources.
• In the plant, cholesterol is a precursor of insect-moulding hormones and
in one morphological group of helleborus, it has been shown that they are
formed together with bufadienolides and saponins.
• In arthropods, it acts through the ecdysone receptor. Although mammals
lack this receptor, it may affect mammalian (including human) biological
systems in vitro, but there is uncertainty whether any in vivo or
physiological effects occur.
• 20-Hydroxyecdysone is an ingredient of some supplements that aim to
enhance physical performance and increase muscle mass, but there is no
clinical evidence for this effect.

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