4-_Phenolic_glycosides_-_part__3_flavo_and_misc_.pptx

FLAVONOID GLYCOSIDES & MISC.
ASSOC. PROF. DR. MOSTAFA MAHMOUD HEGAZY

 content
 Flavonoids (importance, Physiological role and Therapeutic uses).
 Flavonoids biosynthesis, General Properties and Tests for identity.
 Flavone Glycosides (Diosmin and Apiin)
 Flavonol Glycosides (rutin and Quercetrin)
 Flavanone Glycosides (Hesperidin)
 Silymarin (flavonolignans)
 Isoflavonoids (Genistein)
 Coumarin Glycosides

Glycosides Dr. Mostafa Hegazy
Flavonoids
 They are one of the most diverse and
widespread group of phenolic natural products.
 They are amongst the dye stuffs and water-
soluble pigments of plant origin.
1- They are often yellow pigments.
2- Red and blue pigments e.g. anthocyanin
derivatives.
 They are one of the most important
constituents of the human diet (Nutraceutical).
They are found in fruits, vegetables, nuts, seeds,
stems, flowers and common drinks e.g. tea.

 Nutraceutical is a comprehensive
term which includes substances that
are considered as foods, parts of
foods or dietary supplements that
may claim to provide medical or
health benefits – this includes the
treatment of or prevention of disease.
 Flavonoids bind to a range of cellular
receptor sites and show a wide range
of biological activities.

 Physiological role for the plant
1- They are the pigments of flowers and
attract pollinating birds and insects.
2- They play a role in plant growth control
by inhibiting and activating enzymes.
 Therapeutic activities and uses
Most flavonoid-containing plants are used as
antioxidant, antibacterial, and anti-
inflammatory. Several members of the
group are known to possess antiviral,
anticancer spasmolytic, estrogenic,
cardiotonic and hepatoprotective
activities.

 Mechanisms of antioxidant
activity
1- Complexing of heavy metal ions.
2- Electron transferring in enzyme
systems, e.g. oxido-reductases.
3- Free radical scavenging.

Therapeutic use Constituents Natural source
Cardiotonic Procyanidins Crateagus spp
Antioxidant Catechins Thea sinensis (green tea
leaves)
Antiviral Flavonoids Licorice
Anticancer Isoflavonoids (Daidzin and
Genistin)
Soya bean
Reduction of capillary fragility Flavonols e.g.Rutin
Flavones e.g. Diosmin
Ruta spp
Buchu leaves
Diuretic Flavonoids Buchu leaves
Broom tops
Calcium antagonist Quinochalcones e.g.
Tinctormine
Saflower
Antihepatotoxic Flavanonols e.g. Astilbin
Flavolignans e.g.Silybin
Smilax spp
Silybium marianum
Therapeutic uses of flavonoids and related compounds

Flavonoids biosynthesis
They can be looked at as a C-15 skeleton
(1,3-diphenylpropane) formed of two
benzene rings linked together by a pyran ring
as bridge i.e. C6- C3-C6. One of the benzene
rings is derived from the shikemic acid
pathway (ring B) while the other (ring A) is
derived from the acetate and is formed by
ring closure of a polyketide.

Classification:
Based on the structure and the oxidation
level of the central pyran ring, they can be
classified into:
Flavones; Isoflavones; Flavonols;
Flavanones; Flavanols; Chalcones; Aurones,
and Anthocyanins (flavylium salts).

General Properties:
1- Flavonoid glycosides are generally soluble in water and alcohol but insoluble
in chloroform and ether. The aglycones are slightly soluble in water (especially
hydroxylated ones), but soluble in ether.
2- Flavonoids are usually soluble in alcohol with a yellow color which can be
intensified by addition of alkalis. They can be precipitated from their alcoholic
solution by addition of lead salts.
3- Flavonoids are phenolic and hence change in color when treated with base or
ammonia, thus they are easily detected on chromatograms or in solution.
4- Flavonoids contain conjugated aromatic systems and thus show intense
absorption bands in UV and visible regions of the spectrum.

Isolation:
Two general procedures used for the extraction and isolation of flavonoids:
I- The powdered plant is first defatted, then extracted with alcohol, the alcohol is
evaporated and the remaining aqueous solution is extracted with ether (to take
the aglycones if any), then with ethyl acetate (to take glycosides). The individual
aglycones or glycosides are separated by chromatographic methods.
II- The powdered plant material is defatted, and then extracted with alcohol as
before, the alcoholic extract is freed from the solvent and the obtained residue was
dissolved in water. Lead acetate is added to precipitate the flavonoid. The
obtained precipitate was collected by filtration and then suspended in water and
H2S gas is passed through to precipitate, to liberate the flavonoids which then
can be separated by chromatography.

Tests for identity:
The flavonoids can be characterized by some color tests, which may also
differentiate between some members of the flavonoids:
1-Alkaline reagents such as KOH, NaOH or NH4OH give yellow color when
added to an aqueous solution of flavonoids.
2-Aluminum chloride flavonoids produce a yellow or green complex with ALCl3.
3- Lead acetate flavonoids with ortho dihydroxy group give a precipitate with
lead acetate.
4- Conc. sulfuric acid produce intense yellow color with flavones and flavonols
may be due to formation of flavylium salts. A deep red to crimson color is
produced with chalcones and aurones may be due to isomerization.

5- Boric acid flavonoids which contain free OH group at C-5 react with
boric acid in the presence of organic or mineral acids giving bright yellow
complex with green fluorescence.
6- Mg/HCl reduction This is one of the most useful qualitative and
quantitative tests for study of flavonoids. This test differentiates between
the aglycones and glycosides:
Extract + Mg+ + HCl ------ red to violet + isoamyl alcohol ------- if the
colour is removed from the aqueous ------ it is aglycone. ---- if the red
colour is remained in the aqueous ----- it is glycoside.

Flavone Glycosides
Diosmin:
Diosmin presents in Buchu leaves (Barosma betulina f.
Rutaceae). Diosmin is 5,7,3'-trihydroxy,4‘ methoxyflavone-
7-rhamnoglucoside.
Properties: Diosmin occurs in pale yellow needles or
powder. It is sparingly soluble in pyridine and DMSO. It
dissolves in aqueous KOH solution and in H2SO4
producing a slight fluorescence.

 Uses:
 The diuretic action of Buchu leaves is due to
diosmin and also to the volatile oil dioshpenol.
 Diosmin has found also wide application in the
Egyptian pharmaceutical market and used for the
treatment of venous disorders

Apiin:
It is a flavone glycoside present in the fruits and leaves of celery (Apium
graveolens fam. Umbelliferae) and in parsley. It is 5,7,4'-trihydroxy-7-
glucoapioside.
Properties:
Apiin is a colorless flavonoid which dissolves in hot water and hot alcohol but
sparingly soluble in cold water or alcohol. It can not be hydrolyzed by emulsin
or yeast, but upon acid hydrolysis ----- aglycone apigenin + apiose + glucose.
Apiin develops a reddish brown color with FeCl3 and yellow precipitate with
basic lead acetate.

Flavonol Glycosides
Rutin: It was isolated from Ruta graveolens. The
commercial supply is made from tobacco residues,
sophora and eucalyptus. Rutin is 5,7,3', 4'-
tetrahydroxyflavonol-3-rhamnoglucoside.
Uses and Pharmaceutical Products:
Rutin is used mainly in cases of increased capillary
fragility. Common pharmaceutical products containing
rutin as the major medicine include: Rutin C® Ruta C
60® , Rutin with Vit. C.

 Properties:
 Rutin occurs as yellow crystals.
 It is slightly soluble in boiling water and alcohol,
 insoluble in chloroform, ether and ethyl acetate.
 It is also soluble in pyridine and alkalis solutions.
 It gives a yellow color when treated with AlCl3.
 Rutin reduces ammoniacal silver nitrate but not Fehling's solution.

Hydrolysis
 Acid hydrolysis of rutin ------- glucose +
rhamnose + aglycone called quercetin.
 Careful hydrolysis may split one glucose unit
leaving a secondary glycoside called quercetrin.
 On the other hand enzymatic hydrolysis splits
the intact disaccharide rutinose (rhamnose +
glucose) and the aglycone quercetin.

Quercetrin
It is quercetin-3-rhamnoside. This flavonol glycoside is
found in the bark of Quercus tinctoria and Q. trifida.
It was also isolated from many other plant sources.
Properties: Quercetrin is a pale yellow flavonol
glycoside, which is sparingly soluble in water but
shows better solubility, in alcohol. It reduces
ammoniacal silver nitrate but not Feliling 's solution.
On hydrolysis quercitrin ------ rhamnose + quercetin.

Flavanone Glycosides
Flavanone glycosides are distributed in
some plant families including: Rutaceae,
Rosaceae and Compositae. The
dihydropyrone ring imparts some
unstability to the flavanone and may be
converted to the corresponding chalcons
in alkaline solutions.

Hesperidin: It is 5,7,3'-trihydroxy-4'-methoxy
flavanone-7-rhamnoglucosidc or it is the 7-
Orutinoside of the aglycone hesperitin, It is
found in rinds of many Citrus fruits. The
substance which was formerly known as
Citrin, was found to be a mixture of
rhamnoglucoside of eriodictyl
(tetrahydroxyflavone ) and methyl eriodictyl
(hesperetin).

Properties:
White to Faint Yellow color, sparingly soluble in
cold water and alcohol, more readily soluble in
hot water. It is insoluble in ether, benzene and
chloroform Hesperidin can be converted into
hesperidin chalcone by the action of alkali;
hesperidin can be regenerated in acid solution.

Uses:
Hesperidin increases capillary resistance that
decreases greatly with vitamin C deficiencies.
Hesperidin is necessary for absorption and
retention of vitamin C. So, it is usually used in
combination with vitamin C to reduce capillary
fragility. Hesperidin is
also reported to be of value in the treatment of
influenza (with ascorbic acid).

Silymarin ( class. as Flavanols or flavonolignans)
Silymarin was isolated from the fruits of the milk
thistle Silybum marianum L. family Compositae,
Silymarin consists mainly of a mixture of
flavonolignans e.g. silybin (the main) , silydianin
and silychristin (Silicristin). Silymarin is produced
through the oxidative combination of taxifolin with
coniferyl alcohol.

Uses:
generally used in liver dysfunction as it increase the bile
solubility, increase the activity of the antioxidant
enzymes and reduce the fat deposits in liver.
It is used in combination with penicillin in the treatment
of poisoning with the death cap (fungus Amanita
phalloides).
Pharmacological experiments have shown that silymarin
has a protective effect for the liver against the effects of
amatoxins produced by a group of highly toxic fungi of
the genus Amanita.

Isoflavonoids
Isoflavonoids have been found in many plant
families e.g. Leguminosae and Rosaceae.
The relationship of the structure of isoflavonoids
and diethylstilbosterol is quite evident. This
would explain the estrogenic activity of some
drags bearing isoflavonoids.
Genistein:
Genistein is the aglycone of genistin (7-D-
glucoside) which is obtained from Andira inermis
family Leguminosae. It occurs also in some
Prunus species (fam. Rosaceae).

Anthocyanins are very numerous and very widely
distributed in the plant kingdom. They are
responsible of the different colors of plant organs.
They occur in the cell sap of flowers, fruits and other
organs, and impart their attractive colors. The color
depends on the pH of the cell sap. Anthocyanidins,
which are the aglycones of anthocyanins, are all
derived from 2-phenyl benzopyrylium or flavylium
cation structure.

Coumarin Glycosides
This group of glycosides includes coumarin itself,
which has a basic structure of benzo-a-pyrone or
lactone of O-hydroxy cinnamic acid. It may have
additional functional groups (OH, OCH3 or CH3),
attached to the benzene ring. Coumarin and its
derivatives are distributed in several plant families
including: Umbelliferae, Leguminosae (Fabaceae),
Rutaceae, Solanaceae and Asteraceae.

 Uses:
 Coumarins and hydroxy coumarins are closely
related to cinnamic and hydroxycinnamic acids, so
it has a flavoring and taste improving properties in
pharmacy as in tobaccos, and food industry.
 It is now not used for this purpose as it has been
found to have liver-damaging and carcinogenic
properties. Also it has insecticidal effects.

 Umbelliferone:
 Umbelliferone, (7-hydroxy-coumarin), is found in
many plants.
 It can be obtained by distillation of the resins of
Umbelliferae (Apiaceae).
 It is freely soluble in alcohol, chloroform and
alkalis.
 Umbelliferone glucoside occurs in the bark and
wood of Skimmia japonica family Rutaceae.

Aesculin (6-b-D-glucosyloxy-7-hydroxy coumarin)
It is isolated from the bark and leaves of the horse-
chestnut, Aescullus hippocastanum family
Hippocatanaceae.
Uses:
1-Coumarin derivatives e.g. umbelliferone and aesculin are
employed for protection from sun-light, as they absorb
short-UV radiation (280-310 nm) which is harmful to skin,
and transmit the long-UV radiation (315-400 nm), which
give the brown suntan. So, coumarins are used in suntan
preparations.
2-Umbelliferone is used in brain intercellular pH
measurements and in fluorescent immunoassays.

Vanilloside (glucovanillin)
occurrence: vanilla pods.
Vanilla is the fully-grown but unripe fruit of Vanilla planfolia
fam. Orchidaceae, which has been subjected to a
fermentation process. Green vanilla contains vanilloside
and vanilloloside (vanillyl alcohol glucoside).
1- Glucovanillin is an odorless glucoside. During curing
(fermentation) these glycosides subjected to an oxidizing
and a hydrolyzing enzymes (which present in the plant
tissues) and vanillin with its characteristic odour is set free.
2- Glucovanillin is an aldehydic and a phenolic glucoside.

Uses:
for the production of vanillin that is used in
confectionery and in perfume; it has been
replaced by vanillin obtained by
biotransformation or chemical synthesis.

Cyanogenetic, cyanogenic or cyanophore
glycosides
produce the toxic gas HCN (prussic acid or hydrogen
cyanide) as a result of enzymatic hydrolysis.
Amygdalin
found in bitter almond (Prunus amygdalus var.amara
family Rosaceae) , in the kernel of apricot, cherries,
peaches and plums.

Isolation:
The fixed oil is expresses from the bitter almond seeds, and
then cake is extracted with alcohol (95%). The alcoholic
extract is concentrated and a large volume of ether is
added, where Amygdaline is insoluble in ether, so it will
crystallize out.
Uses:
Bitter almond and bitter almond oil are used as spices, but
this use is not entirely safe because of the hydrogen cyanide
content.

Hydrolysis:
1- by acid hydrolysis to give two
molecules of glucose and
mandelonitrile.
2- Almond seeds contain emulsin
which is a mixture of enzymes, of
which amygdalase which hydrolyze
amygdalin into prunasin, which in turn
hydrolyzed by prunase into
mandelonitrile, which hydrolyzed by
hydroxynitrile lyase
(hydroxynitrilase) into benzaldehyde.

Prunasin: a cyanogenetic
glycoside obtained from
1- Wild cherry bark (Prunus
serotina, family Rosaceae).
2- By the partial hydrolysis of
amygdalin.

Linamarin
A cyanogenetic glycoside of the aliphatic type. It occurs
in linseed (Linum usitatissimum, family Linaceae).
Hydrolysis: On hydrolysis linamarin produces glucose
and acetone cyanhydrine. Further degradation gives
acetone and hydrocyanic acid.
Purification of linseed oil from HCN:
1- By boiling the fixed oil and 2- passing super-heated
steam through the oil to remove any traces of HCN.

Detection of Cyanogentic glycosides:
crushed pieces in a tube + H2O cover with
sodium picrate paper, put in water bath for 1h.
the yellow color of the sodium picrate paper color
will change into brick red color due to liberation
of HCN and reduction of sodium picrate to sodium
picramate.

Thio-Glycosides (glucosinolates, sulfur containing glycosides or
S-glycosides)
Thioqlycosides are a group of compounds that yield upon
hydrolysis sulphurated aglycones (often with acrid volatile
flavors).
The sugar part is always β-D-1-glucopyranosyl residue, which is
linked to the aglycone via a sulpher atom.
The appropriate hydrolytic enzyme, a thioglucosidase known as
myrosinase, always accompanies glucosinolates.

Sinigrin
Occurrence: seeds of black mustard (Brassica nigra family Cruciferae).
Black mustard seed contains myrosin enzyme and when macerated with water it
yields volatile oil (90% of which is allylisothiocyanate).
Preparation of sinigrin:
The crushed defatted seeds are treated with boiling alcohol …?. Most of the fixed
oil is removed by expressing the marc while hot and sinigrin is extracted by
maceration with cold water. The aqueous extract is then treated with mild alkali
(BaCO3) to neutralize
any free acidity and concentrated to a syrupy liquid. the aqueous extract is boiled
with alcohol 95%....? and the alcoholic extract is filtered from the precipitated
mucilage and cooled when
sinigrin crystallizes out.

Hydrolysis of sinigrin:
Sinigrin can be hydrolyzed by myrosin into allylisothiocyanate, glucose and
potassium hydrogen sulfate.

Sinalbin white mustard seed (Sinapis alba).
Hydrolysis: Upon hydrolysis of sinalbin with
myrosinase, it yields P. hydroxybenzyl
isothiocyanate, sinapine hydrogen sulfate and
glucose. The P-hydroxybenzyl isothiocyanate (acrinyl
isothiocyanate) is an oily liquid having a pungent
taste and rubefacient properties but, owing to its slight
volatility, it lacks the pungent odor of
allylisothiocyanate (c.f black mustard). Sinapine
hydrogen sulfate is the salt of an unstable quaternary
alkaloid and is hydrolyzed by KOH to yield sinapic
acid and choline.

Uses: as a plasters as rubefacients and counter irritants. condiments . In large
doses as emetic. It should be noted that many glucosinolates have an antithyroid
and goiter inducing effect in man.

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