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Pharma Cog Nosy I (Part 6)
Pharma Cog Nosy I (Part 6)
Pharma Cog Nosy I (Part 6)
Glycosides
Glycosides consist of a sugar residue covalently
bound to a different structure called the aglycone.
The sugar residue is in its cyclic form and the
point of attachment is the hydroxyl group of the
hemiacetal function.
The sugar moiety can be joined to the aglycone in
various ways:
1. Oxygen (O-glycoside)
2. Sulphur (S-glycoside)
3. Nitrogen (N-glycoside)
4. glycoside)
Carbon (Cglycoside)
-Glycosides and -glycosides are distinguished
by the configuration of the hemiacetal hydroxyl
group.
The majority of naturally-occurring glycosides
are -glycosides.
O-Glycosides can easily be cleaved into sugar
and aglycone by hydrolysis with acids or
enzymes.
Almost all plants that contain glycosides also
contain enzymes that bring about their hydrolysis
(glycosidases).
Glycosides are usually soluble in water and in
polar organic solvents, whereas aglycones are
normally insoluble or only slightly soluble in
water.
Anthracene
Taut.
O O
8 1
7 9 2
4H
A B C
6 10 3
5 4
Anthrone (keto form)
O
Anthraquinone 2 H
2H O
H OH
Oxanthrone
O
Dianthrone
These anthracene compounds occur in these drugs or plant
materials in some cases as the aglycones of O-glycosides (e.g.
frangulin), and in other cases as the aglycones of C-glycosides
(e.g. aloin).
Biosynthesis; natural anthraquinones are synthesized either via
the acetate-malonate pathway (like the medicinally important
purgative anthraquinones), or they are derived from shikimate
and mevalonate (like alizarin).
OH O OH O OH
OH
HO CH3
O O
Frangula emodin Alizarin
A. Anthraquinones
Although anthraquinone is not used extensively in
medical practice, it is the starting material for the
preparation of several synthetic laxatives and
represent the basic structure of a number of
important laxatives and dyestuffs.
Borntrager’s test is often used for their detection.
The derivatives of anthraquinone present in
purgative drugs may be dihydroxy phenols such as
chrysophanol, trihydroxy phenols such as emodin
or tetrahydroxy phenols such as carminic acid.
O
O
Anthraquinone
OH O OH OH O OH
CH3 HO CH3
O O
Chrysophanol Emodin
HO
O
OH O CH3
OH
COOH
HO
OH
HO OH
OH O
Carminic Acid
B. Anthrones & Anthranols
These reduced anthraquinone derivatives occur
either free or combined as glycosides.
They are isomeric and one may be partially
converted to the other in solution.
Anthranols are converted upon oxidation into
anthraquinones. Oxidation takes place in the crude
drug during storage especially if powdered.
Schonteten’s test is often used for anthranols
(green fluorescence).
Anthranols and anthrones are the main constituents
of chrysarobin, a mixture of substances.
OH OH OH OH O OH
CH3 CH3
Chrysarobin
(1,8-dihydroxy-3-methyl-9-anthrone; 3-methyl-1,8,9-anthracenetriol)
C. Oxanthrones OH O OH
H OH
be identical or different.
They are important aglycones in
- -glucose–O
D O OH
species of Cassia, Rheum and
Sennosides
Rhamnus.
One of the best known is sennoside
derived from two molecules of
glucose and two molecules of rhein-
anthrone.
On hydrolysis, sennoside yields the
aglycone sennidin.
E. Aloin-type or C-glycosides
OH O OH
acid hydrolysis. O
Aloin
In aloin, the sugar is joined to OH
HO
aglycone with a direct C-C linkage OH
(a C-glycoside).
Two aloins (A and B) are known
and arise from the chiral centre at
C-10.
Saponin glycosides .2
A group of plant glycosides known as saponins
share in varying degrees, two common
characteristics:
(a) They foam in aqueous solution.
(b) They cause haemolysis of red blood cells.
18 26
25
17
19
27
1
3
Steroid skeleton 29 30
25 26
28
3 27
Pentacyclic triterpenoid skeleton
23 24
A. Steroidal saponins
20
19
E
13 17
D
14
2
7
O O
8
1
Coumarin
(Benzo--pyrone)
Khellin is an isocoumarin
(chromone) natural product
from Ammi Visnaga
O
(Apiaceae) and has activity as O CH3
Khellin
It has long been known that
animals fed sweet clover OH OH
(Melilotus officinalis,
Fabaceae) die from
haemorrhaging. The O O O O
poisonous compound Dicoumarol
responsible for this adverse
effect was identified as
dicoumarol.
A number of compounds have OH O
been synthesized based on the
dicoumarol structure, e.g. CH3
Biosynthesis:
flavonoids are products from a cinnamoyl-CoA
(C6C3, precursor from the shikimate pathway)
starter unit, with chain extension using three
molecules of malonyl-CoA.
Flavonoids are therefore of mixed biosynthesis,
consisting of units derived from both shikimate
and acetate pathways.
The triketide starter unit undergoes cyclization by
the enzyme chalcone synthase to generate the
chalcone group of flavonoids. Cyclization can
then occur to give a pyranone ring containing
flavanone nucleus, which can either have the C2-
C3 bond oxidized (unsaturated) to give the
flavones or be hydroxylated at position C3 of the
pyranone ring to give the flavanonol group of
flavonoids. The flavanonols may then be further
oxidized to yield the anthocyanins, which
contribute to the brilliant blues of flowers and the
dark colour of red wine.
The flavonoids contribute to many other colors
found in nature, particularly the yellow and
less flavonoids
orange of petals; even the colourless
absorb light in the UV spectrum (due to their
extensive chromophores) and are visible to many
insects. [A chromophore is the part (or moiety)
of a molecule responsible for its color ].
It is likely that these compounds have high
ecological importance in nature as colour
attractants to insects and birds as an aid to plant
pollination.
Certain flavonoids also markedly affect the taste
of foods: for example, some are very bitter and
astringent such as the flavanone glycoside
naringin, which occurs in the peel of grapefruit
(Citrus paradisi). Interestingly. the closely
related compound naringin dihydrochalcone,
which lacks the pyranone ring of naringin, is
exceptionally sweet, being some 1000 times
sweeter than table sugar (sucrose).
the flavonoids have important dietary
significance because, being phenolic compounds,
they are strongly antioxidant.
OH O
OH
HO O HO O OCH3
OH O
OH OH OH
OH O OH O Silybin
Quercetin
Some action and therapeutic uses of
flavonoids
R2
OSugar
They are derivatives of -hydroxynitrile or 2-
hydroxynitrile (cyanohydrins).
In all cases the first sugar attached to the aglycone is
-D-glucose.
R1 and R2 are often different residues resulting in
pairs of C-2 epimers.
(Epimers are diastereomers that differ in configuration at only one
of their stereogenic centers).
Most cyanogenetic glycosides are biosynthetically
derived from the amino acids: valine, leucine, isoleucine,
tyrosine or phenylalanine.
Cyanogenetic glycosides are easy to detect with a strip
of filter paper impregnated with reagents able to give a
color reaction with the hydrocyanic acid released upon
crushing the plant material (e.g., picric acid/sodium
carbonate or benzidine/cupric acetate).
Although hydrocyanic acid is a violent poison, it is
important to remember that oral intake of cyanogenetic
drugs does not necessarily cause severe intoxication, this
is because the range of dangerous concentrations (0.5-
3.5 mg/kg) can only be achieved by rapid and massive
ingestion of plant parts rich in cyanogenetic glycosides.
Examples:
1. Amygdalin in bitter almonds (Prunus amygdalus). It is
biosynthetically derived from phenylalanine.
2. Linamarin in linseed (Linum usitatissimum). It is
biosynthetically derived from valine.
HO
CN O
HO
HO HO O
CH3
O OH O
O HO
CH3 HO O CN
OH
OH
HO H
OH Amygdalin
Linamarin
6. Steroidal cardioactive glycosides
Cardiac glycosides are a group of natural products
characterized by their specific effect on myocardial
contraction and atrioventricular conduction.
In large doses they are toxic and bring about cardiac
arrest in systole, but in lower doses they are
important drugs in the treatment of congestive heart
failure.
They have a diuretic activity. Since, the improved
circulation tends to improve renal secretion, which
relieves the edema often associated with heart failure.
Distribution in nature
Cardiac glycosides occur in small amounts in
11 13 17
19
C D 16
1 14
9
2 15
10 8
A B
3
5 7
O
4 6
Sugar moiety
24
O O
O 23
23
21 21
22 22
20 20
17 17
16 16
14 14
15 15
C D
A B OH
HO
O
CH3
O
CH3 H
OH H
H
H
HO Digitoxigenin
A/B cis - B/C trans - C/D cis
H
Biosynthetic origin
CH3
O
CH H
H OH
O
OH
Cymarose-D-glucose -D-glucose
Cymarin
K-strophanthin-
K-strophanthoside
Squill glycosides
Urginea maritima (L.)
0.1% 2.4% total bufadienolides,
15 glycosides
White variety: average 0.2%-0.4%
proscillaridin A, scillaren A,
glucoscillaren A (aglycone:
scillarenin)
scilliphaeoside, scilliglaucoside
Red variety: < 0.1%
scilliroside and glucoscilliroside
(aglycone: scillirosidin);
proscillaridin A and scillaren A as
in the white variety
Pharmacological properties of squill
White squill:
it is an expectorant, but it also possesses emetic,
cardiotonic (proscillaridin
( A), and diuretic
properties.
Red squill:
it is used as a rat poison (scilliroside
( ), because
rodents lack the vomiting reflex, which makes
red squill particularly lethal to these animals.
O
CH3
CH3 OH
H OH
-D-glucose–O Scilliroside
O CH3
O
(3,6)-6-(Acetyloxy)-3-(-D-glucopyranosyloxy)-8,14-dihydroxybufa-4,20,22-trienolide
Digitalis glycosides
Several species of Digitalis yield pharmacologically
active principles. The most important of these species
are Digitalis purpurea and Digitalis lanata.
1. Digitalis purpurea folium (Red foxglove leaves)
0.15% 0.4% total cardenolides, 30 glycosides
Purpurea glycosides A and B (60%), digitoxin (12%),
gitoxin (10%) and gitaloxin (10%).
2. Digitalis lanata folium (White foxglove leaves)
0.5% 1.5% total cardenolides, 60 glycosides
Lanatosides A and C (50%), lanatosides B, D, E as
well as digoxin and digitoxin.
Digitoxin is a cardiotonic Digoxin is the most widely
glycoside obtained from D. used of the cardiotonic
purpurea, D. lanata. glycosides, and it is
It is the most lipid-soluble of obtained from the leaves of
the cardiac glycosides used in D. lanata.
therapeutics. It is a highly potent drug and
The major pharmacokinetic should be handled with
parameters for digitoxin exceptional care.
include complete oral Digoxin tablets are 60 to
absorption, which 80% absorbed.
distinguishes it from other Digoxin is indicated when the
cardiac glycosides. risk of digitalis intoxication is
Digitoxin may be indicated in great, since it is relatively short-
patients with impaired renal acting and rapidly eliminated
when compared with digitoxin.
function.
Digitalis purpurea
7. Tannins
Historically, the importance of tannin-containing
drugs is linked to their tanning properties, in
other words their ability to transform fresh hides
into an imputrescible material: leather.
HO O
OH
HO OH OH
OH OH
Gallic acid Catechin
HOOC OH
OH
O
HO O OH
OH
Chlorogenic acid
Function of tannins in plants
Hydrolysable tannins
Hydrolysable tannins are esters of a sugar (or
related polyol) and of a variable number of
phenolic acid molecules.
The sugar is most generally glucose.
The phenolic acid is either gallic acid, in the case
of gallitannins, or Ellagic acid, in the case of the
tannins conventionally referred to as
ellagitannins.
Ellagic acid can arise by lactonization of
hexahydroxydiphenic acid (= HHDP) during
chemical hydrolysis of the tannin.
Hydrolysable tannins were formerly known as
pyrogallol tannins, because on dry distillation
gallic acid and similar components are converted
into pyrogallol.
Biosynthetically, gallic acid (= 3,4,5-
trihydroxybenzoic acid) arises from the
metabolism of shikimic acid.
Examples of drugs containing Hydrolysable
tannins:
Gallitannins:
Gallitannins rhubarb, cloves, Chinese galls,
Turkish galls, hamamelis, chestnut and maple.
Ellagitannins:
Ellagitannins pomegranate rind, pomegranate
bark, eucalyptus leaves, and oak bark.
OH OH
HO HO
COOH
O
HO COOH O
HOOC OH O
HO OH O
OH
OH OH
Gallic acid
OH OH
HO OH
OH
Pyrogallol
Condensed tannins (proanthocyanidins)
Condensed tannins or proanthocyanidins are
polymeric flavans. They consist of flavan-3-ol
units linked together by carbon-carbon bonds,
most often 48 or 46, which result from
coupling between the electrophilic C4 of a
flavanyl unit from a flavan-4-ol or flavan-3,4-diol
and a nucleophilic position (C-8, less commonly
C-6) of another unit, generally a flavan-3-ol.
Unlike hydrolysable tannins, these are not
readily hydrolyzed to simpler molecules and they
do not contain a sugar moiety.
OH OH
HO O HO O
OH OH
OH OH
OH OH OH
OH
HO O
OH
OH OH
OH
HO O
OH
OH
OH
A dimeric structure
Biosynthetically, flavonoids are derived from
acetate and shikimate pathways.
Condensed tannins occur due to polymerization
(condensation) reactions between flavonoids.
The polymers may include up to 50 monomer
units.
On treatment with acids or enzymes condensed
tannins are converted into red insoluble
compounds known as phlobaphenes.
Phlobaphenes give the characteristic red colour to
many drugs such as red cinnamon bark.
Examples of drugs containing Condensed
tannins:
Some drugs (e.g. tea, hamamelis leaves and hamamelis
bark) contain both hydrolysable and condensed tannins.
The following are rich in condensed tannins.
(1) Barks: cinnamon, wild cherry, cinchona, willow, acacia,
oak and hamamelis
(2) Roots and rhizomes: krameria (rhatany) and male fern
(3) Flowers: lime and hawthorn
(4) Seeds: cocoa, guarana, and kola
(5) Leaves: hamamelis, hawthorn and tea, especially green tea
(6) Extracts and dried juices: catechu, acacia and mangrove
cutches
Properties and tests of tannins
Tannins are soluble in water, dilute alkalis, alcohol,
glycerol and acetone, but generally only sparingly
soluble in other organic solvents.
Solutions precipitate heavy metals, alkaloids, glycosides
and gelatin.
With ferric salts, gallitannins and ellagitannins give blue-
black precipitates and condensed tannins brownish-green
ones. If a very dilute ferric chloride solution is gradually
added to an aqueous extract of hamamelis leaves (which
contains both types of tannin), a blue colour is produced
which changes to olive-green as more ferric chloride is
added. Other useful tests are the following:
1. Goldbeater's skin test
Soak a small piece of goldbeater's skin in 2%
hydrochloric acid; rinse with distilled water and
place in the solution to be tested for 5 min.
Wash with distilled water and transfer to a 1%
solution of ferrous sulphate. A brown or black
colour on the skin denotes the presence of
tannins. Goldbeater's skin is a membrane
prepared from the intestine of the ox and
behaves similarly to an untanned hide.
2. Gelatin test
Solutions of tannins (about 0.5-1 %) precipitate a
1% solution of gelatin containing 10% sodium
chloride. Gallic acid and other pseudotannins
also precipitate gelatin if the solutions are
sufficiently concentrated.
3. Phenazone test
4. Test for catechin
5. Test for chlorogenic acid
Medicinal and biological properties
The applications of tannin-containing drugs are
limited, and result from their affinity for proteins.
Tannin-containing drugs will precipitate protein
and have been used traditionally as styptics and
internally for the protection of inflamed surfaces
of mouth and throat.
They act as antidiarrhoeals and have been
employed as antidotes in poisoning by heavy
metals, alkaloids and glycosides.
sumac