1. Phenolic Glycosides 6-Flavonoids

2. Flavonoids-Distribution
Important constituents of human diet: fruits, vegetables, nuts, seeds, stems, flowers & common drinks (tea).
Common in higher plants: Polygonaceae, Rutaceae, Leguminosae, Umbelliferae & Compositae.
Seeds of Leguminosae: rich in isoflavonoids.
Plants of Polygonaceae: rich in flavan-3-ols & anthocyanins.

3. Flavonoids-Physiological role in plants
Role in plant defense mechanism: limited due to low toxicity (≠ alkaloids).
Pigments of flowers attracting birds & insects (Pollinators)
Plant growth regulators.

4. Flavonoids-Therapeutic uses
Flavonoid-containing plants are used as antioxidant, antibacterial & anti-inflammatory.
Flavonoids possess antiviral, anticancer, spasmolytic, estrogenic, cardiotonic & hepatoprotective activities.

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

6. Flavonoids-Chemistry
Variety of structural forms
Free aglycones or glycosides
Skeleton contains 15 carbon atoms:
C6-C3-C6 [2 phenyl rings linked by a three-carbon chain = diphenyl propane derivatives]
The three-carbon chain (-C3-) may be included through an oxygen bond

7. Flavonoids - Classification
According to type of oxygen bond:
Flavonoids with oxygen bond present in a 6-membered (pyran) ring including compounds:
with ring B attached to C-2: e.g. flavones, flavonols, flavanones, flavanonols, flavan-3-ols, anthocyanins etc…..
with ring B attached to C-3: e.g. isoflavonoids.
with oxygen atom of pyran ring carrying a +ve charge e.g. anthocyanins or anthocyanidins.
Flavonoids within each group are differentiated according to:
Oxidation state of C-3.
Unsaturation between C-2 & C-3.
Hydroxylation at C-3`& C-4`.

8. Flavonoids-Chemistry
Diphenyl propane skeleton
C6-C3-C6
Flavonoid skeleton

10. Flavonoids with oxygen bond present in a 5-membered (furan) ring: e. g
Flavonoids with oxygen bond present in a 5-membered (furan) ring: e.g. aurones & dihydroaurones.
Flavonoids with aliphatic oxygen bond: e.g. chalcones & dihydrochalcones.
Aurones

11. Flavonoids - Effect of hydroxylation pattern on physico - chemical properties
Increase of hydrophylic character & acidic nature.
Enhancement of U.V. & visible light absorption  pigments with different colors (ivory-yellow, red or blue).
Increase of chemical reactivity especially H-bonding capacity.
Ortho-dihydroxyls  oxidation  quinones & polymeric melanins.
Ortho-dihydroxyls + metals  modification of action.

12. Flavonoids-Isolation
Extraction
Glycosides: polar (due to sugar moiety) , extracted with alcohol, water or hydroalcoholic solutions.
Aglycones: less polar, extracted with ether, chloroform & ethyl acetate
Purification of crude extract:
Several methods:
Shaking with Na2CO3 or NaHCO3.
Precipitation with Pb acetate.
Chromatography (PC, TLC or CC).

13. Flavonoids -Tests for identification
All flavonoids + AlCl3  yellow color + UV light  different fluorescences
Aurones
Chalcones
Flavanones
Flavonols
Flavones
+ AlCl3
Pale-brown
Brownish- pink
Yellow to
Yellowish-green
Green
Fluorescence in UV
All flavonoids + Pb sub acetate  yellowish ppt
Flavanones & flavonols (Alcoholic solution) + Mg
metal / HCl  orange, red or violet (Shinoda's
test).
Chalcones (Alcoholic solution) + SbCl5/ CCl4 
red or violet.
Chromatography (PC & / or TLC)

14. Flavonoids- Structural Elucidation
Aglycones: by spectral analysis (UV, NMR & MS).
Glycosides: by spectral analysis before & / or after hydrolysis.
Acid hydrolysis: + 1 N HCl for min at 100oC & extract aglycones with organic solvent. C-glycosides need more drastic acid conditions.

15. Flavonoids-Quantitative determination
Spectrophotometric method: depends on measuring the absorbance of the aluminum chloride complex.
Chromatographic methods: e.g. HPLC analysis of aglycones obtained after extraction & acid hydrolysis of the glycosides

16. Flavone glycosides - Apiin
Source
Leaves & seeds of parsley (Petroselinum sativum) & celery (Apium graveolens) & flowers of Roman chamomile
(Anthemis nobilis)
Hydrolysis
% H2SO4  partial hydrolysis  apiose + glucoapigenin.
+ Mineral acid + reflux  complete hydrolysis  apiose + glucose + apigenin.
Tests for identification
+ FeCl3  reddish brown color
+ alkali  yellow color
+ lead acetate  yellow precipitate

17. Flavone glycosides-Diosmin (Barosmin)
Source
Buchu leaves, Conium &
Dahlia.
Hydrolysis
Acid hydrolysis rhamnose +
glucose + diosmetin
Uses
Reduces capillary fragility:
used as prophylactic & in
treatment of varicose veins &
acute hemorrhoids.

18. Flavonol glycosides-Rutin (Quercetin-3-rutinoside)
Source
Ruta graveolens, Nicotiana tabacum & Sophora
japonicum.
Isolation
Extract with 80% ethanol, concentrate & filter.
Shake filtrate with ether (remove lipoid impurities).
Concentrate alcoholic layer  crystals of rutin
Hydrolysis
+ 1 N H2SO4 + reflux  quercetin + glucose +
rhamnose
Tests for identification
+ FeCl3  green color.
+ PbAc  yellow precipitate.
+ Ammoniacal AgNO3  reduction.
Uses
Reduces capillary fragility, permeability & bleeding.
Ruta graveolens

19. Acylated flavonol Glycosides from Gingko biloba

20. Acylated flavonol Glycosides from Gingko biloba
Standardized extract of Gingko biloba leaf is used in treatment of cerebrovascular insufficiency & poor arterial circulation.
Main active constituents: acylated flavonol glycosides of kaempferol, quercetin, & isorhamnetin.
Ginko biloba glycosides are acylated with p-coumaric acid at C-6 of the glucose moiety.

21. Flavanone glycosides General characters
Flavanones have a reactive C=O: with hydroxylamine  oximes (c.f. from flavones).
On treatment with alkalis: flavanones  chalcones  flavones.
In presence of acid: chalcones  flavanones.
On treatment with strong alkalis: flavanones  benzaldehyde + HAC + phenol , while flavones produce cinnamic acid + phenol

22. Flavanone glycosides-Hesperidin- Hesperitin-7-rutinoside
Source
Peel of unripe Citrus fruits e.g. bitter orange &
orange.
Hydrolysis
+ acid + heat  hesperitin + rhamnose +
glucose
Isolation from orange peel
Extract powder with ether (to remove volatile oil).
Dry the marc & reflux with methanol for 3 hours.
Concentrate  crude hesperidin is precipitated.
Bitter orange

23. Flavanone glycosides-Hesperidin
Properties
Sparingly soluble in cold water, more soluble in hot water & alcohol.
On treatment with alkali hesperidin chalcone.
On acid hydrolysis  hesperitin + rhamnose +glucose
Tests for identification
+ FeCl3 solution  wine-red color.
Alcoholic solution + Mg metal + conc. HCl  violet color.
Uses:
Hesperidin is necessary for the absorption of vitamin C &
it reduces capillary fragility

24. Flavanone glycosides-Naringin (naringenin-7-neohesperidoside)
Source
Peels of grape fruit [mainly immature] (Citrus paradisi, Fam. Rutaceae)
Main bitter constituent of grape fruit juice.
Hydrolysis
Naringin (intensely bitter glycoside) Naringenase enzyme (hydrolysis)  naringenin (non-bitter aglycone)
Peel of grape fruit

25. Flavanone glycosides-Naringin (naringenin-7-neohesperidoside)
Properties
Very bitter in taste.
Sparingly soluble in cold H2O, soluble in hot H2O
Naringin (intensely bitter glycoside) + alkali (e.g. NaOH) + reduction  naringin dihydrochalcone (intensely sweet derivative).
Uses
Bitter stomachic & antiinflammatory.
Starting material for semisynthesis of naringin dihydrochalcone (used as substitute for sucrose in diabetes,1000 times sweeter than sucrose).

26. Flavanone glycosides-Liquiritin- (Liquiritigenin-4`-glucoside)
Source
Licorice roots & rhizome
Main constituents of DGL (Deglycyrrhizinated Licorice extract) almost free from Glycyrrhizin (triterpenoid saponin of licorice)
Uses
Liquiritin & its aglycone are used in gastric & duodenal ulcers, & as antiinflammatory.

27. Flavanonol glycosides-Astilbin & Neoastilbin
Source
Roots of Smilax glabra (Sarsaparilla), Vitis vinifera & Astilbe spp.
Hydrolysis: Taxfiolin from Astilbin, Neotaxifiolin from Neoastilbin
Action & Uses
Antioxidants, hepatoprotectives & prevention
of cataract in diabetics

28. Chalcone glycosides - C-glucosyl quinochalcones-Tinctormine & Carthamin

29. Chalcone glycosides - C-glucosyl quinochalcones- Tinctormine & Carthamin
Source
Both are isolated from the petals of Carthamus tinctorius.
Tinctormine is a yellow pigment while Carthamin is a red pigment.
Pharmacological action & uses
Tinctormine: calcium antagonist used in treatment of heart diseases.
Carthamin: natural red dye.

30. Isoflavonoid glycosides- Daidzin & Genistin
Source
Daidzin in soya beans
Genistin in Lupinus & Prunus spp.
Pharmacological action & uses
Isoflavones are considered as dietary phytoestrogens.
They are cancer-protective, effective in preventing breast & prostate cancer.
They also aid in the treatment of osteoporosis.
Daidzin is used as antioxidant.

31. Anthocyanidins & their glycosides-General characters
Structurally related to flavones
Hydroxylated cations.
Keto group at C-4 is absent.
Glycosides are known as anthocyanins.
Colored compounds named after the Greek words antho = flower & kyanos = blue.

32. Anthocyanidins & their glycosides-General characters
Color is pH dependent.
Example: cyanidin 3, 5-diglucoside:
blue in corn flower [pH of cell sap alkaline]
red in roses [pH of cell sap acidic]
Soluble in water, insoluble in ether, acetone & chloroform.
Stable in acidic medium.

33. Flavan-3-ols - General characters
Do not possess a keto group at C-4.
Source
Green tea
(fresh leaves of Camelia sinensis),
rhubarb & black tea.
Pharmacological action & uses
Mainly used as antioxidant,
anticancer, antiviral &
antibacterial.

34. Biflavones - Amentoflavone
Source
Chrozophora spp. (black haw) bark & Amentotaxus spp.
Pharmacological action & uses
Uterine antispasmodic.
Delay diabetic cataract (astilbin) & diabetic neuropathies.
Cardiotonic.
Chrozophora
Amentotaxus

35. Flavonoid-containing compounds Flavonolignans - Silymarin
Silydianin

36. Flavonoid-containing compounds Flavonolignans-Silymarin
Source
Silybum marianum fruits
Structure
Silymarin is a mixture of various flavanonol & flavonol derivatives
Main components of silymarin are: silybin, silychristin & silydianin
Uses
Hepatoprotective prophylactic in:
Liver damage caused by metabolic toxins.
Liver dysfunction after hepatitis.
Chronic degenerative liver conditions, e.g. liver cirrhosis & fatty liver.
The oxeran ring is responsible for the antihepatotoxic effect of silybin, opening of this ring results in loss of activity.