Flavonoid glycosides

Pharmacognosy II
(PHG322)
Ramzi A. Mothana, PhD 1PHG322, Flavonoids, Feb 2013

Flavonoid glycosides
(Part 4)

Ramzi A. Mothana, PhD
What are Flavonoids??
3PHG322, Flavonoids, Feb 2013

Flavane-derivatives
Chemically, they are 2-phenylchroman derivatives.
Flavonoids are virtually universal plant pigments.
They are responsible for the color of flowers, fruits
and sometimes leaves.
They ensure tissue protection against the
damaging effects of UV radiation.

Classification
They fall into many classes depending on the degree of oxidation
of the central pyran ring:
1- Flavanones (4-Oxo-flavane) such as naringenin.
2- Flavones (4-Oxo-flav-2-ene) such as apigenin.
3- Flavonols (3-Hydroxy-4-Oxo-flav-2-ene) such as quercetin.
4- Flavanols (3-Hydroxyflavane, Catechine) such as (+)-catechine.
5- Flavandiols (3,4-Hydroxyflavane) Leukoanthocyanidine).
6- Flavylium-salts (Anthocyanidine) such as cyanidine.

HO
OH O
OH
O
Flavone
HO
OH O
OH
O
OH
Falvonol
O
OH
OOH
HO
2
3
Flavanone
HO
OH
OH
O
OH
Flavanol
(Catechine)
HO
OH O
OH
O
OH
Flavylium-salt
(Anthocyanidine)
X
HO
OH OH
OH
O
OH
Flavandiol
(Proanthocyanidine)

Distribution
Flavonoids are common in the plant kingdom, Bryophytes
(mosses and hepaticas), and in Pteridophytes.
No flavonoids have been found in algae.
More than 3000 of these compounds are now known, with
nearly 500 aglycones.
They are abundant in the Polygonaceae, Rutaceae,
Rosaceae, Leguminosae, Umbelliferae, Lamiaceae and
Compositae.

Chemical structure
Many authors apply the term flavonoids to flavon-, flavanon-,
and flavonol-derivatives.
They occur in free state and as glycosides, most are O-glycosides.
But a considerable number of flavonoid C-glycosides are known.
In all the classes of flavonoids mentioned so far, biosynthesis
frequently places at least 3 phenolic OH-groups in the 5-, 7-, and
4´-positions of the aglycone.
O
OH
OOH
HO
2
3
Flavanone

Flavones and Flavonols
The essential difference between flavones and flavonols is the
presence of OH-group at C-3 in the flavonols.
Flavones and flavonols) represent about 80 % of the flavonoids.
Ring A is substituted by two phenolic OH-groups at C-5 and C-7.
These OH-groups are either free or etherified.
OHO
OH O
OH
5
7 2
3
3´
4´
R
A C
B
Apigenin: R = H
Luteolin: R = OH
B
CA
R
4´
3´
3
27
5
OH
OOH
HO O
OH
Quercetin: R = OH
Kaemferol: R = H
Flavons Flavonols

Flavanones and Dihydroflavonols
These molecules are characterized by the absence of a 2,3-double
bond and by the presence of at least one asymmetric center.
Two isomeric forms of each flavanone structure are possible, thus
the B ring can be in the (2S)- or in (2R)-configuration.
DihydroflavonolsFlavanons
Taxifolin: OH OH
Pinobanksin: H H
OH
OHO
OH O
R2
5
7 2
3
3´
4´
R1
A C
B
Hesperitin: OH OCH 3
Naringenin: H OH
B
CA
R1
4´
3´
3
27
5
R2
OOH
HO O
H
HH
H
H
R1 R2 R1 R2

Biflavonoids
They are flavonoids, which bond to one another, particularly
through their very reactive C-6 or C-8.
The interflavanic linkage can be of:
Carbon-carbon-type (3´,8, e.g. in amentoflavone, or 6,8, e.g. in
agathisflavone, or 8,8, e.g. in cupressiflavone).
Carbon-oxygen-carbon-type (6-O-4´, e.g. in hinokiflavone).
Biflavonoids are characteristic of the Gymnosperms.
OR1O
OH O
OR2
5
7 2
3
4´
4´
3
27
5
OR4
OOH
R3O O
3´
R1=R2=R3=R4= H, Amentoflavone
R2=Me, R1=R3=R4= H, Bilobetin
R1=R2=Me, R3=R4= H, Ginkgetin
R2=R4=Me, R1=R3= H, Isoginkgetin

4´
7
5
OH
OOH
HO
4´
3
27
5
OH
OOH
HO O
O
Agathisflavone
HO
OH O
OH
4´
HO
OH O
OH
5
7
4´
O
O
Cupressuflavone
OHO
OH O
OH
5
7 2
3
4´
HO
OH O
O
5
7 2
3
4´
O
Hinokiflavone

Flavonoid glycosides
The sugar moiety may be a mono-, di-, or trisaccharide, linear or
branched.
Monosaccharides include D-glucose, D-glalctose or D-allose, L-
rhamnose, or D-glucuronic or D-galacturonic acid.
The glycosidic bond may be established through any of the phenolic
OH-group on the aglycone (O-glycosides).
C-glycosides are not rare, more than 300 are known.
The bond is established between the asymmetric carbon on the
sugar and the C-6 or C-8 of the aglycone.

Types of C-glycosides
Mono-C-glycosylflavonoids
Di-C-glycosylflavonoids
C-glycosyl-O-glycosylflavonoids
Acyl-C-glycosyl-flavonoids
R4
OH
OOH
R2O O
R3
R1
Vitexin H H Glu H
Isovitexin Glu H H H
Schaftoside Glu H Ara H
Vicenin 2 Glu H Glu H
R1 R2 R3 R4

Identification and Characterization
with 5% AlCl3 in methanol (yellow-green fluorescent spots in UV
light)
with 1 % solution of diphenylboric acid-2-aminoethyl ester
(Naturstoff Reagenz A) (red-brown color is formed).
with FeCl3, anisaldehyde-reagent phenols.
Pacheco´s test for dihydroflavonols (with sodium acetate/acetic
anhydrid/HCl) (Red color).
Pew´s test for dihydroflavonols (with Zinc/HCl)
a deep purple-red with dihydroflavonols and brownish color
Flavanones and other flavonoids.
Shinoda test for flavanones and dihydroflavonols (with Mg/HCl)
Deep-red or magenta color is produced.

Pharmacological and biological properties
They decrease capillary permeability and fragility
They are enzyme inhibitors such as lipooxygenase,
cyclooxygenase, histidine decarboxylase, hyaluronidase,
cAMP phosphodiesterase.
Many flavonoids are antioxidants, because they react with
free radicals.
Therefore, they show anti-inflammatory, antiallergic,
hepatoprotective and antispasmodic.
They can decrease blood cholestrol, be diuretic,
antibacterial and antiviral.

Therapeutic uses
Treatment of the symptoms of venous and
lymphatic vessel insufficiency (tiredness or
fullness in the legs, cramps, pains and other
dysfunctions, edemas)
Treatment of circulatory disturbances.
Treatment of capillary fragility disorders of the
skin (ecchymosis, petechiae) and of mucosas
(gingival hemorrhage, epistaxis).
Treatment of dysfunctions linked to the acute
attack of piles.
Metrorrhagias linked to intra-uterine
contraceptive devices.

Chief flavonoids on the Market
1- Rutin
It is a flavonol glycoside. Chemically, it is quercetin-3-O-(6-O-
rhamnoside) glucoside.
It occurs as yellow crystals, soluble in boiling water and alcohol.
Rutin alone or in combination with other substances is used as
described previously, particulaly to treat hemorrhages linked to
diabetes and hypertension, and to treat the functional symptoms
of the acute attack of piles.
O
OHO
OH O
OH
5
7 2
3
3´
4´
OH
Rutin
Glu Rham

Sources of rutin
Ruta graveolens (Fam. Rutaceae)
Buckwheat-species: Herb of Fagopyrum esculentum (Fam.
Polygonaceae) (up 5%) and of Fagopyrum tataricum (up to 3%).
Japanese pagoda tree (Sophora japonica, Fam. Fabaceae).
The flower buds of which contain 15-23 % Rutin.
Ruta graveolens Fagopyrum Sp.

2- Citroflavonoids (especially Hesperidin)
They are extracted from Pericarps and pulbs of
Citrus-trees as Ca and Mg derivatives.
Hesperidin is hesperitin-7-O-(6-O-rhamnoside)
glucoside, it occurs up to 8 % in the pericarp.
Uses:
in the treatment of the leg symptoms of
chronic, functional and organic venous
insufficiency,
and as adjuvant or prophylactic with vitamin C
for the treatment of common cold and
infections.
OH
4´
3´
3
27
5
OCH3
OOH
O O
Glu
Rham
Hesperidin

3- Diosmin
It is a flavone glycoside found in
Buchu leaves (Barosma sp.)
It occurs in pale yellow needles or
powder.
Acid hydrolysis of diosmin yields
diosmetin (aglycone) besides one
molecule of rhamnose and glucose.
Uses:
diuretic and diaphoretic effect
also in the treatment of venous
disorders.
Diosmin
Rham
Glu
OO
OH O
OCH3
5
7
OH
Barosma betulina

Flavonoid containing drugs
1- Whitethorn herb
The drug consists of the herb and sometimes of
the fruits of Crataegus monogyna, C. laevigata
and of C. pentagyna (Fam. Rosaceae)
The drug contains:
2 % flavonoids (0.7 % as hyperoside), other chief
constituents are vitexin, rutoside, apigenin- and
luteolin-derivatives.
Up to 1 % oilgomeric procyanidines (4,8- or 4,6
dimeric, trimeric to hexameric flavan-3-ols).
It is used in the treatment of cardiac insufficiency
(grad I-II to NYHA), in treatment of brady
arrhythmia and to improve the circulation of the
coronary artery.
C. monogyna

2- Maidenhair tree
Leaves of Ginkgo biloba (Fam. Ginkgoaceae)
found in China and Japan, but also cultivated
in Europe.
The drug contains:
1- 0.4-2 % biflavonoids (amentoflavone,
bilobetin, and ginkgtin)
2- 0.5-2 % flavonol glycosides. (quercetin and
kaempferol-derivatives)
3- 4-12 % flavan-3-ols and proanthocyanidins
4- 0.02-0.2 % ginkgolides (comlexes of
diterpenlactones)

Uses:
In the treatment of the symptoms of senile
cerebral insufficiency (vertigo, tinnitus and
hearing loss, lack of concentration).
In the treatment of the intermittent
claudication and of Raynaud´s disease.

3- Passion flower
The drug consists of the herb of Passiflora incarnata (Fam.
Passifloraceae), found in south and North America (USA and Mexico).
The drug contains:
up to 2.5 % flavonoids (C-glycosylflavonoids) such as Vitexin,
isovetexin, schaftoside and vicenin-2.
Uses:
as sedative to treat the symptoms of nervousness in adults and
children and particularly minor sleeplessness.
also used to treat abnormities of the cardiac rhythm in the adult.
R4
OH
OOH
R2O O
R3
R1
Vitexin H H Glu H
Isovitexin Glu H H H
Schaftoside Glu H Ara H
Vicenin 2 Glu H Glu H
R1 R2 R3 R4

P. incarnata

4- Birch leaf
The drug consists of the leaves of Betula
pendula or Betula pubenscens (Fam.
Betulaceae), which is found in Europe
and in China.
The drug contains:
3 % flavonoids, paticularly
Hyperoside and quercitrin
used as diuretic (in the bacteriuria),
particularly in the urinary tract
infections such as pyelonephritis,
ureteritis, cystitis and urethritis.

5- Lime tree flowers or Linden flowers
The drug consists of the flowers of Tilia
cordata or Tilia platyphyllos (Fam.
Tiliaceae), which is found in Europe and
in Asia (China).
The drug contains 1% flavonoids, specially
glycosides of quercetine such as rutin,
hyperoside and quercitrine and glycosides
of kaemferol such as tiliroside.
The drug is used as expectorant for the
treatment of cough and as diaphoretic
(common cold and fever).
Tilia cordata

Catechines
They are flavan-3-ol derivatives.
They are the mother substances of condensed tannins.
The representative substances of this group are the diastereomeric
pairs (+)-catechine and (-)-epicatechine as well as (+)-gallocatechine
and (-)-epigallocatechine (2R: 3S or 2R: 3R).
OH
H
R
4´
3´
3
27
5
OH
OH
HO O
H
OH
H
R
4´
3´
3
27
5
OH
OH
HO O
H
OH OH
(+)-Catechine (R = H)
(+)-Gallocatechine (R = OH)
(-)-Epicatechine (R = H)
(-)-Epigallocatechine (R = OH)

Chemical test:
1- with FeCl3, it gives green color.
2- on heating with acids, it forms phloroglucinol (lignin-test)
Uses:
• Immunostimulant.
• Adjuvant in the treatment of infections with chemotherapy,
also in the treatment of liver-diseases especially hepatitis.
Sources:
1- Gambir (extract of Uricaria gambir) 20-50%.
2- Black Catechu (extract of Acacia Catechu) 4-12%.

Isoflavonoids
• Isoflavonoids are distinct from other flavonoid classes in that they
contain a rearranged C15 skeleton based on 3-phenylchroman.
• They are about 700 known structures.
Distribution:
• Isoflavonoids are very limited in the plant kingdom, they occur in the
Leguminosae.
OH
O

Isoflavonoides may be classified into a dozen structural types
according to their oxidation level and variation in the complexity
of the skeleton (by the existence of added heterocycles):
1- Isoflavones
• They form the largest group (with 234 known structure).
• They occur in the free state or more rarely as glycosides.
• e.g. daidzein, formononetin and genistein.
O
7
OOR1
HO
OR2
Daidzein: H H
Formononetin: H CH3
Genistein: OH H
R1 R2
Classification

2- Isoflavanones, isoflavenes and isoflavanes
- are much rarer than isoflavones.
OH
O
O
O
OH
O
OH
3- Rotenoids
 Rotenoids are a chromanochromanones.
 They are insecticidal. (representative of the group is rotenone.)
O
O
1
2
4
5
6
6 a
8
9
11
12 12 a
Rotenoid skeleton
9
O
OO
O
OCH3
OCH3
Rotenone
O

4- The pterocarpans
They are the second largest class of isoflavonoids after the
isoflavones.
They all have a tetracyclic ring system.
5- The Coumestans
They represent the highest possible level of oxidation for the
isoflavonoid skeleton.
Coumestrol is the best-known member of this group.
11
9
8
6 a
6
5
4
2
O
O
1
10
7
11 a
O
OHO
OCH3
Pterocarpan skeleton Medicarpin
CoumestrolCoumestan skeleton
OH
HO O
O
11 a
7
10
1
O
O
2
4
5
6
6 a
8
9
11
O O

Isoflavonoids show three important activities, these are:
1- Oestrogenic activities (simple isoflavones and coumestans)
2- Antibacterial properties (the isoflavonoid phytoalexins)
3- Insecticidal properties (rotenoids)
Pharmacological and biological properties

Flavonoid glycosides

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Notes de l'éditeur