Flavonoid glycosides

This presentation is one topic of a course given to pharmacy students (Pharmacognosy II). It gives a general information about flavonoids, definition, classification, pharmacological activity, identification and examples of drugs containing flavonoids

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

2. Flavonoid glycosides (Part 4) Ramzi A. Mothana, PhD 2 PHG322, Flavonoids, Feb 2013

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

4. Ramzi A. Mothana, PhD 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. 4 PHG322, Flavonoids, Feb 2013

5. Ramzi A. Mothana, PhD 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 . 5 PHG322, Flavonoids, Feb 2013

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

7. Ramzi A. Mothana, PhD 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 . 7 PHG322, Flavonoids, Feb 2013

8. Ramzi A. Mothana, PhD 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 . 8 PHG322, Flavonoids, Feb 2013

9. Ramzi A. Mothana, PhD 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. 9 PHG322, Flavonoids, Feb 2013

10. Ramzi A. Mothana, PhD 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 . 10 PHG322, Flavonoids, Feb 2013

11. Ramzi A. Mothana, PhD 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 . 11 PHG322, Flavonoids, Feb 2013

12. Ramzi A. Mothana, PhD 12 PHG322, Flavonoids, Feb 2013

13. Ramzi A. Mothana, PhD 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 . 13 PHG322, Flavonoids, Feb 2013

14. Ramzi A. Mothana, PhD Types of C-glycosides Mono-C- glycosylflavonoids Di-C- glycosylflavonoids C- glycosyl -O- glycosylflavonoids Acyl -C- glycosyl - flavonoids 14 PHG322, Flavonoids, Feb 2013

15. Ramzi A. Mothana, PhD Identification and Characterization with 5% AlCl 3 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 FeCl 3 , 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. 15 PHG322, Flavonoids, Feb 2013

16. Ramzi A. Mothana, PhD 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 . 16 PHG322, Flavonoids, Feb 2013

17. Ramzi A. Mothana, PhD 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. 17 PHG322, Flavonoids, Feb 2013

18. Ramzi A. Mothana, PhD 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. 18 PHG322, Flavonoids, Feb 2013

19. Ramzi A. Mothana, PhD 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 . 19 PHG322, Flavonoids, Feb 2013 Ruta graveolens Fagopyrum Sp.

20. Ramzi A. Mothana, PhD 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. 20 PHG322, Flavonoids, Feb 2013

21. Ramzi A. Mothana, PhD 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. 21 PHG322, Flavonoids, Feb 2013 Barosma betulina

22. Ramzi A. Mothana, PhD 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. 22 PHG322, Flavonoids, Feb 2013 C. monogyna

23. Ramzi A. Mothana, PhD 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 ) 23 PHG322, Flavonoids, Feb 2013

24. Ramzi A. Mothana, PhD 24 PHG322, Flavonoids, Feb 2013 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.

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26. Ramzi A. Mothana, PhD 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. 26 PHG322, Flavonoids, Feb 2013

27. Ramzi A. Mothana, PhD P. incarnata 27 PHG322, Flavonoids, Feb 2013

28. Ramzi A. Mothana, PhD 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 . 28 PHG322, Flavonoids, Feb 2013

29. Ramzi A. Mothana, PhD 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). 29 PHG322, Flavonoids, Feb 2013 Tilia cordata

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31. Ramzi A. Mothana, PhD 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). 31 PHG322, Flavonoids, Feb 2013

32. Ramzi A. Mothana, PhD Chemical test: 1- with FeCl 3 , 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 %. 32 PHG322, Flavonoids, Feb 2013

33. Ramzi A. Mothana, PhD 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 . 33 PHG322, Flavonoids, Feb 2013

34. Ramzi A. Mothana, PhD 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 . 34 PHG322, Flavonoids, Feb 2013 Classification

35. Ramzi A. Mothana, PhD 2- Isoflavanones , isoflavenes and isoflavanes - are much rarer than isoflavones . 3- Rotenoids Rotenoids are a chromanochromanones . They are insecticidal. (representative of the group is rotenone.) 35 PHG322, Flavonoids, Feb 2013

36. Ramzi A. Mothana, PhD 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. 36 PHG322, Flavonoids, Feb 2013

37. Ramzi A. Mothana, PhD 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 37 PHG322, Flavonoids, Feb 2013