Flavonoid glycosides

PHG322, Flavonoids, Feb 2013 1

Pharmacognosy II(PHG322)

Ramzi A. Mothana, PhD

PHG322, Flavonoids, Feb 2013 2

Flavonoid glycosides (Part 4)

Ramzi A. Mothana, PhD

PHG322, Flavonoids, Feb 2013 3Ramzi A. Mothana, PhD

What are Flavonoids??


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.

6PHG322, Flavonoids, Feb 2013Ramzi A. Mothana, PhD

HO

OH O

OH

O

Flavone

HO

OH O

OH

O

OH

Falvonol

O

OH

OOH

HO2

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 structureMany 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

HO2

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 = HLuteolin: R = OH

B

CA

R

4´

3´

3

27

5

OH

OOH

HO O

OH

Quercetin: R = OHKaemferol: 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 OHPinobanksin: 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 OH

HHH

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, AmentoflavoneR2=Me, R1=R3=R4= H, BilobetinR1=R2=Me, R3=R4= H, GinkgetinR2=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

OH4´

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-glycosylflavonoidsDi-C-glycosylflavonoidsC-glycosyl-O-glycosylflavonoidsAcyl-C-glycosyl-flavonoids

R4

OH

OOH

R2O OR3

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 Characterizationwith 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 rutinRuta 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 effectalso in the treatment of venous disorders.

Diosmin

Rham

Glu

O O

OH O

OCH3

5

7

OH

Barosma betulina


Flavonoid containing drugs1- 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 proanthocyanidins4- 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 flowerThe 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 OR3

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 leafThe 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 quercitrinused 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


CatechinesThey 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

HOH

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.

O7

OOR1

HO

OR2

Daidzein: H HFormononetin: 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.)

OO

1

2

4

5

6

6 a8

9

11 12 12 a

Rotenoid skeleton

9 OOO

O

OCH3

OCH3Rotenone

O


4- The pterocarpansThey are the second largest class of isoflavonoids after the isoflavones. They all have a tetracyclic ring system.

5- The CoumestansThey 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

54

2

O

O1

10

7

11 a

O

OHO

OCH3

Pterocarpan skeleton MedicarpinCoumestrolCoumestan skeleton

OH

HO O

O11 a

7

10

1

O

O

2

45

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

Education

Transcript of Flavonoid glycosides