Saponins, cardioactive drugs and other steriods

SAPONINS, CARDIOACTIVE DRUGS &
OTHER STERIODS
ENOCH MUSUDO

Characteristics of saponins
• Produce a frothing aqueous solution.
• Have hemolytic properties
• Highly toxic when injected into the blood
• Comparatively harmless when taken orally for example
Sarsaparilla
• Have a high molecular weight
• Highly polar
• Occur as complex mixtures; the components differ slightly
from one another in the nature of the glycone and aglycone
• Hydrolyzed by acids to give an aglycone (sapogenin) and
various sugars and related uronic acids
• 50% of the plants containing a hemolytic substance contain
saponins

Classification of saponins
By the structure of the sapogenin
• The steroidal (tetracyclic triterpenoids)
• The pentacyclic triterpenoids
Both have a glycosidal linkage at C-3 and have a common biogenetic origin
via mevalonic acid and isoprenoid units.

Steroidal saponins
Less widely distributed in nature than the pentacyclic triterpenoids.
Present in many monocotyledonous families, particularly the
Dioscoreaceae e.g. Dioscorea spp, Agavaceae e.g. Agave and Yucca
spp.) and Smilacaceae (Smilax spp.)
In dicotyledons they occur 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.
They are used as starting materials for the synthesis of sex hormones,
cortisone, diuretic steroids, vitamin D and the cardiac glycosides.
Diosgenin is the principal sapogenin used by industry but most yams,
from which it is isolated, contain a mixture of sapogenins in the
glycosidic form.

Examples of steroidal saponins

Biogenesis of steroidal saponins
• Steroidal saponins arise via the
mevalonic acid pathway
• Cholesterol is not the obligatory
precursor
• Open-chain saponins are obtained
from cholesterol

Natural steroids for production of pharmaceuticals
• Natural steroids are involved in the partial synthesis of
pharmaceuticals
• Hecogenin with C-ring substitution provides a practical
starting material for the synthesis of the corticosteroids
• Diosgenin is suitable for the manufacture of oral
contraceptives and the sex hormones.
• Diosgenin is also used in corticosteroid synthesis
during microbial fermentation

Therapeutically occurring active steroids

Natural steroids and their sources

Soya bean sterols
They are also referred to as phytosterols.These include (1)
stigmasterol (2) sitosterol
They are not sapogenins but are widely used in steroid synthesis.
Actually stigmasterol is taking the place of diosgenin in sterol
synthesis.
Processed by microorgamisms. Phytosterols are obtained as by
products of soap making as they are components of unsaponified
mater of fixed oils

Solanum species steroids
• Many species of solanum are known for producing steroidal
alkaloids.
• The alkaloids are nitrogenous analogs of C27 sapogenins for
example solasodine and diosgenin
• Solanidine contains a tertiary nitrogen in a condensed ring
system
• These saponins can be employed in partial synthesis of
steroidal drugs. And are commonly found in species like
Solanm laciniatum, Solanum khasianum
• Other steroids from tigogenin and soladulcidine can be
extracted from Solanum dulcamara

Ginseng
Panax ginseng, contain dammarane type saponins known as
Ginsenosides or panaxosides
Acid hdrolysis of these saponins involves ring closure of the
aglycone giving either panaxadiol or panaxatriol.
Glucose is the principal sugar involved. Other sugars include
rhamnose and arabinose.
Steroids from ginseng

Pentacyclic triterpenoid saponins
Rare in monocotyledonous; however, widely distributed in
dicotyledonous plants. This trend of occurrence is opposite to that of
stroidal saponins.
Common dicotyledonous families include Caryophyllaceae,
Sapindaceae, Polygalaceae and Sapotaceae.
Other dicotyledonous families where they can be obtained include
Phytolaccaceae, Chenopodiaceae, Ranunculaceae, Berberidaceae,
Papaveraceae, Linaceae, Zygophyllaceae, Rutaceae, Myrtaceae,
Cucurbitaceae, Araliaceae, Umbelliferae, Primulaceae, Oleaceae,
Lobeliaceae, Campanulaceae, Rubiaceae and Compositae.
In these saponins the sapogenin is attached to a chain of sugar or uronic
acid units, or both, often in the 3-position

Pentacyclic triterpenoid saponins [2]
Triterpenoid saponins may be classified into three groups
represented by α-amyrin, β-amyrin and lupeol.

Pentacyclic triterpenoid saponins [3]
Plant materials often contain these saponins in considerable
amounts.
Thus, primula root contains about 5–10%; root about 2–12%
of glycyrrhizic acid (and a correspondingly larger amount of
glycyrrhizin, the potassium calcium salt); quillaia bark up to
about 10% of the mixture known as ‘commercial saponin’; the
seeds of the horsechestnut up to 13% of aescin.
As some plants contain more than one saponin and purification
is often difficult, the structures of even some of the well-
known saponins given in have only recently been established.
Oleanolic acid also occurs as a saponin in sugar beet, thyme,
Guaiacum spp., and in the free state in olive leaves and clove
buds.

Biosynthetic pathway of triterpenoids

Liquorice root
By pharmacopeial standards, the drug is defined as the dried
unpeeled or peeled, whole or cut root and stolons of Glyrrhiza
glabra L. and/or of G. inflata Bat. and/or G. uralensis Fisch.
The following are varieties of Glyrrhiza glabra that are
commercial sources of liquorice root extract;
1) Glycyrrhiza glabra var. typica
2) G. glabra L. var. glandulifera
3) G. glabra L. var. glandulifera

Pentacyclic triterpenoid saponins

Constituents of Liquorice [1]
Glycyrrhizin
• It’s the major constituent of liquorice
• The potassium and calcium salts of glycyrrhizinic acid
• Glycyrrhizinic acid is the diglucopyranosiduronic
• acid of glycyrrhetic (glycyrrhetinic) acid
• Responsible for the sweet taste of liquorice
• Used as an emulsifier and gel forming agent in food and cosmetic
industry
• Can alleviate bronchitis, gastritis, and jaundice
Flavonoids
• These include liquiritin, isoliquiritin (a chalcone, which occurs as a
glycoside), liquiritigenin, isoliquiritigenin (chalcone form).
• They account for the yellow color of liquorice
• Others are pyranoisoflavan, glabridin, isoflavones - glabriso flavone
A and B, and glabrocoumarone

Constituents of Liquorice [2]
Polysaccharides
These include glycyrrhizan GA (posses immunologic activity)
Other constituents include
• Glucose and sucrose (5-15%)
• Asparagine (1–2%)
• Volatile compounds (0.04–0.06% )
• β-sitosterol
• Starch
• Protein
• Bitter principles (glycyramarin) – highly present in the
outer root tissue

Pharmaceutical uses of liquorice
• Flavouring agent
• Demulcent
• Mild expectorant
• Treatment of Rheumatoid arthritis & Addison’s disease
• Exhibit Spasmolytic and anti-ulcerogenic activity
• Symptomatic relief from peptic ulcer pain
• Glycyrrhizin enhances skin penetration
Excessive consumption of liquorice leads to
hypertension and hypokalaemic alkalosis

Primula Root
Primula root BP/EP consists of the dried rhizome and root of
Primulaveris (L.) (cowslip) or P. elatior Hill. (oxlip), family
Primulaceae.
P. elatior is differentiated by the possession of groups of pitted
sclereids.
Constituents include a mixture of triterpenoid saponins of the oleane
type (5–10%) and phenolic glycosides such as primulaverin
(primulaveroside).
The latter, by enzyme hydrolysis during the drying process, forms the
disaccharide primeverose and methyl 5-methoxysalicylate, the latter
being responsible for the odour of the drug.
Primula root, like senega, is used as an expectorant for the treatment of
bronchial conditions.

Quillaia Bark
Quillaia bark (Soap Bark, Panama Wood, Quillaia)
is the dried inner bark of Quillaja saponaria Molina
and of other species of Quillaja (Rosaceae).
The generic name is derived from the Chilean word
quillean, to wash, from the use made of the bark.
The powdered drug is very sternutatory and
produces an abundant froth when shaken with water.
Taste, acrid and astringent.

Constituents of Quillaia Bark
A mixture of saponins on hydrolysis yield the principal
sapogenin quillaic acid (hydroxygypsogenin) and gypsogenin
together with sugars, uronic acids and acyl moieties.
Di- and tri-saccharides are attached at C-3 and various
complex oligosaccharides at C-28, the fucosyl moiety of
which may be substituted with C9-aliphatic acids or an O-
acetyl group
Quillaia contains about 10% of saponins, BP ethanol (45%)-
soluble extractive not less than 22.0%, and also sugars, starch
and calcium oxalate.

Quillaia is used as an emulsifying agent,
particularly for tars and volatile oils

CARDIOACTIVE DRUGS
These drugs contain C23 or C24 steroidal glycosides which
exert on the failing heart a slowing and strengthening effect.
They are commonly glycosides of various Digitalis species.
Plants cardiac glycosides appear to be confined to the
Angiosperms.
The heart-arresting properties of these glycosides also render
them most effective as arrow poisons and a number of tropical
plants are better-known in this respect than for their medicinal
use.

Structure of glycosides
Two types of genin may be distinguished according to whether
there is a five-or six-membered lactone ring.

Biogenesis od cardiac glycosides
Aglycones of the cardiac glycosides are derived from acetate-
mevalonic acid pathway
The final molecules arise from a condensation of a C21 steroid with C2
unit (the source of C-22 and C-23)
Bufadienolides are condensation products of a C21 steroid and a C3
unit
Progesterone, which is formed with cardiac glycosides, in Digitalis
lanata as a result of feeding pregnenolone, is itself a precursor of the
cardiac glycosides.
A key enzyme in the biosynthesis of cardiac glycosides is progesterone
5β-reductase. This enzyme is also involved in the production of animal
steroids

Common sugars in cardiac glycosides
Glucose is the most effective precursor of digitoxose and of the sugar
side-chain of the Nerium oleander glycosides.

Cardenolides
Cardenolides are the more common and are particularly
abundant in the Apocynaceae and Asclepiadaceae family.
Some can be found in Liliaceae (e.g. Convallaria), and in the
Ranunculaceae, Moraceae, Cruciferae, Sterculiaceae,
Euphorbiaceae, Tiliaceae, Celastraceae, Leguminosae and
Scrophulariaceae family.
Most important cardio-active glycosides medicinally.
All the medicinal preparations are derived from natural
sources.

Digitalis leaf (Purple Foxglove leaf)
Consists of the dried leaves of Digitalis purpurea L. (fam. Scrophulariaceae).
It is required to contain not less than 0.3% of total cardenolides calculated as
digitoxin.
Digitalis grows readily from seed. In the wild state it is usually found in semi-
shady positions.
It grows well in sandy soil, provided that a certain amount of manganese is
present, this element being apparently essential and is always to be found in
the ash.
Either first- or second-year leaves are permitted by the pharmacopoeias.
Pharmacological activity of leaves increases during the course of a day to
reach a maximum in the early afternoon.
Leaves should be dried as rapidly as possible at a temperature of about 60°C
and subsequently stored in airtight containers protected from light. Their
moisture content should not be more than about 6%.

Constituents of digitalis
Primary glycosides
• Purpurea glycoside A
• Purpurea glycoside B
• Glucogitaloxin
Purpurea glycoside A is formed last and eventually becomes the major
component at 50% of the total glycoside mixture.
All possess at C-3 of the genin a linear chain of three digitoxose sugar
moieties terminated by glucose.
On drying , purpurea glycoside A, purpurea glycoside B and
glucogitaloxin undergo enzyme degradation by loss of the terminal
glucose to yield digitoxin, gitoxin and gitaloxin, respectively.
Main active component of dried drug = …………………………
Principal components of fresh
leaves.

Constituents of digitalis [2]
Other glycosides include verodoxin, involving the same genins
contain digitalose and glucose; they exist as mono- and
diglycosides.
Verodoxin is claimed to have a toxicity of three times that of
gitaloxin.
Digitalis purpurea leaves also contain anthraquinone derivatives,
which include: 1-methoxy-2-methylanthraquinone, 3-methoxy-2
methylanthraquinone, digitolutein (3-methylalizarin-1-
methylether), 3-methylalizarin, 1,4,8-trihydroxy-2-methyl-
anthraquinone.

The seeds of D. purpurea contain different glycosides from those
of the leaves.
When extracted and standardized, they are known as ‘Digitalin’
(Digitalinum Purum Germanicum or amorphous Digitalin).
This consists of the physiologically active ‘digitalinum verum’,
with other water-soluble glycosides, including the
saponins digitonin and gitonin.

Acetylated side-chain glycosides of Digitalis purpurea
Aglycone and sugar components of digitalis leaves

Actions and uses of digitalis drugs
Digitalis preparations are mainly used for their action on cardiac
muscle.
Digitalis probably acts in competition with K+ ions for specific
receptor enzyme (ATPase) sites in the cell membranes of cardiac
muscle
The clinical effect in cases of congestive heart failure is to increase the
force of myocardial contraction (the positive inotropic effect) resulting
in a complete emptying of the ventricles.
As a result of depression of conduction in the bundle of His, the
atrioventricular conduction time is increased, resulting in an extended
P–R interval on the electrocardiogram.
Digitalis glycosides are also used to control supraventricular (atrial)
cardiac arrhythmias.
The diuretic action of digitalis, important in the treatment of dropsy,
arises from the improved circulatory effect

Other sources of cardenolide glycosides
Digitalis Lanata Leaf (Fam. Scrophulariaceae)

Strophanthus gratus seeds contain 4–8% of ouabain (G-
strophanthin), a rhamnose glycoside more stable than those
present in other species
Strophanthus sarmentosus seeds yield a number of glycosides
with sarmentogenin as the aglycone.
Other sources of cardenolide glycosides [2]

Nerium oleander (fam. Apocynaceae) and related species contain
glycosides having a similar action to that of digitalis. They are
commonly known as Oleander glycosides
The principal constituents of the leaves are oleandrin and digitalinum
verum. Oleandrin is the monoside, comprising oleandrigenin (16-
acetylgitoxigenin) and l-oleandrose.
Others areuzarigenin glycosides, Adynerigenin.
The leaves also contain gitoxigenin and digitoxigenin glycosides.
nerizoside, neritaloside and odoroside-H have also been isolated.
Nerium odorum contains oleandrigenin-β-d-glucosyl-β-d-diginoside
and gentiobiosyloleandrin.

Thevetia peruviana (T. neriifolia) fam.Apocynaceae
Also known as the yellow oleander, its seeds are a rich source
of the glycoside thevetin A.
On partial hydrolysis and the loss of two glucose units,
thevetin A yields peruvoside (cardioactive). Peruvoside
consists of L-thevetose linked to the aglycone cannogenin.
Thevetin is useful in cases of mild myocardial insufficiency
and where digitalis intolerance exists.
Oleander ingestion causes many cases of poisoning world-
wide

BUFADIENOLIDES
The bufadienolides are less widely distributed in
nature than are the cardenolides.
They are found in some Liliaceae and
Ranunculaceae, and in the toad venoms the genins
are partly free and partly combined with suberyl
arginine.
Therapeutically they find little use as cardioactive
drugs because of their low therapeutic index and
their production of side effects.

Squill
Squill BP consists of the dried sliced bulbs of Drimia maritima
(L.) Stearn [Urginea maritima (L.) Baker], Liliaceae collected
after the plant has flowered and from which the membranous
outer scales have been removed.
Red squill, which is also derived from a variety of U. maritima, is
collected in Algiers and Cyprus, and differs from the white in
containing red anthocyanin pigment and the glycoside
scilliroside.
Constituents are crystalline glycoside, scillaren A, and an
amorphous mixture of glycosides, scillaren B. Scillaren A, the
most important constituent of squill, is readily hydrolysed by an
enzyme scillarenase or by acids.

Hydrolysis of Scillaren A
Note
In small doses the drug promotes mild gastric irritation causing a reflex
secretion from the bronchioles.
It is for this expectorant action that it is widely used; in larger doses it causes
vomiting.

Chemical Tests for Steroid and Triterpenoid Glycosides
Antimony trichloride test
Alcoholic extract of drug was
evaporated to dryness and
extracted with CHCl3.
Add saturated solution of
SbCl3 in CHCl3 containing
20% acetic anhydride.
Formation of pink colour on
heating indicates presence of
steroids and triterpenoids.

Chemical Tests for Cardiac Glycosides
Keller-kiliani test
To the alcoholic extract of drug equal volume of water and 0.5 ml of strong lead acetate
solution was added, shaked and filtered.
Filtrate was extracted with equal volume of chloroform. Chloroform extract was
evaporated to dryness and residue was dissolved in 3 ml of glacial acetic acid followed
by addition of few drops of FeCl3 solution.
The resultant solution was transferred to a test tube containing 2 ml of conc. H2SO4.
Reddish brown layer is formed, which turns bluish green after standing due to presence
of digitoxose.
Legal test
To the alcoholic extract of drug equal volume of water and 0.5 ml of strong lead acetate
solution was added, shaked and filtered. Filtrate was extracted with equal volume of
chloroform and the chloroform extract was evaporated to dryness.
The residue was dissolved in 2 ml of pyridine and sodium nitropruside 2 ml was added
followed by addition of NaOH solution to make alkaline. Formation of pink color in
presence of glycosides or aglycon moiety.

Other steroids
• The phytosterols (e.g. stigmasterol and sitosterol)
• Steroidal alkaloids in which the nitrogen may be either cyclic
or noncyclic
• Read more about other steroids of pharmaceutical
importance

Saponins, cardioactive drugs and other steriods

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