3-Phenolic glycosides - part 2 Anthracene glycosides .pptx

content
Anthracene glycosides
mechanism of Action
Chemistry
Tests for Identification of anthracene glycosides
I- Anthraquinones (alizarin, aloe-emodin and rhein)
Metabolism of Diacerein (1-8 Diacetyl Rhein)
II- Anthranols and anthrones (Chrysarobin and Barbaloin)
III- Dianthrones (Sennosides A-D and Hypericin)

1. Phytochemistry Anthracene glycosides Assoc. Prof. Dr. Mostafa Mahmoud Hegazy

2. content Anthracene glycosides mechanism of Action Chemistry Tests for Identification of anthracene glycosides I- Anthraquinones (alizarin, aloe- emodin and rhein ) Metabolism of Diacerein (1-8 Diacetyl Rhein ) II- Anthranols and anthrones ( Chrysarobin and Barbaloin ) III- Dianthrones ( Sennosides A-D and Hypericin )

3. Glycosides Dr . Mostafa Hegazy Anthracene glycosides ( anthraquinone glycosides ) Def.: they are oxygenated derivatives of pharmacological importance that are used as laxatives or cathartics , anti-inflammatory , antibacterial , antifungal and also as natural dyes . alizarin

4. Glycosides Dr . Mostafa Hegazy M echanism of Action as stimulating hydragogue laxative By increasing the tone of the smooth muscle in the wall of the colon ( peristalsis ) and stimulating the secretion of water and electrolytes into the large intestine.

5. Glycosides Dr . Mostafa Hegazy Chemistry Anthracene derivatives occur as( O - or C -glycosides) and at different oxidation levels viz ., anthraquinone , anthranol , anthrone , and oxanthrone derivatives. Glycosides of anthranols and anthrones have a more drastic action than the corresponding anthraquinone glycosides.

6. Glycosides Dr . Mostafa Hegazy Tests for Identification of anthracene glycosides 1- Microsublimation test for free anthraquinones 2- Bornträger's test for anthraquinone glycosides 3- Modified Bornträger's test 4- Schontenten's test for anthranols 1- Microsublimation test for free anthraquinones Drugs containing free anthraquinones give on microsublimation needle-like crystals which give a characteristic red color with alkali .

7. Glycosides Dr . Mostafa Hegazy 2- Bornträger's test for anthraquinone The powdered drug (0.1g) is boiled for 10 minutes with about 5 ml of dilute acid (hydrolysis of glycosides), filter and cool ( aglycones are soluble in hot but not in cold water). Shake the filtrate with an immiscible organic solvent (benzene, ether or chloroform). Separate the organic layer ( anthraquinone aglycones ) and shake vigorously with ammonium hydroxide (10 %); the aqueous layer becomes rose pink or cherry red immediately .

8. Glycosides Dr . Mostafa Hegazy 3- Modified Bornträger's test I- Anthranols By addition of oxidizing agents such as a drop of H 2 O 2 (c.f. FeCl 3 not used) will speed the oxidation process . Anthranols give an initial yellow-orange colour in alkali , however they are air-oxidized to yield the corresponding anthraquinone and thus produce a red color only on standing for longtime (c.f. anthraquinones ). Anthranol glycosides should, therefore, be subjected to a process of oxidative hydrolysis to give a positive response.

9. Glycosides Dr . Mostafa Hegazy II- D ianthrones In case of dianthrones (such as sennosides ) , the powdered drug is boiled with alcoholic KOH (hydrolysis, formation of K salts of aglycones and cleavage of the C-C linkage) and filtered. The filtrate is treated with dilute HCl (acidification), extracted with ether and the ethereal layer treated with ammonia ; a rose-red to intense red color is produced in the aqueous layer . 4- Schontenten's test for anthranols : When a solution of borax is added to an aqueous extract of the crude drug ( Aloe ), a green fluorescence is produced.

10. Glycosides Dr . Mostafa Hegazy Quantitative determination of anthracene glycosides The most commonly used methods are the colorimetric and biological methods , gravimetric determination is sometimes carried out. 1- Colorimetric method for determination of total anthraquinones   After hydrolysis with acid, the aglycone is extracted with ethyl acetate and is allowed to react with KOH to give red or violet color. The intensity of this color is directly proportional to the concentration of anthraquinone , and can be measured colorimetrically . Anthranol content can, similarly, be determined but after oxidation with H 2 O 2 .

11. Glycosides Dr . Mostafa Hegazy 2- Fluorimetric method Schontenten’s test for anthranols can be used for Fluorimetric estimation of the anthranol and anthrone contents in crude drugs. 3- Biological method Since anthraquinones induce laxation after oral administration to experimental animals, the concentration of these compounds can be determined by measuring the water content in feces of animals given certain doses of anthraquinones as compared to that obtained after administration of a standard laxative compound.

12. Glycosides Dr . Mostafa Hegazy I: Anthraquinones Anthraquinones are the most widely distributed anthracene derivatives in plant kingdom. They give a positive Bornträger's test. The most common examples of this group are: alizarin , aloe - emodin and rhein . Most naturally occurring anthraquinones are present together with their 8- O -glucoside derivatives (e.g. aloe- emodin 8- O -glucoside and rhein 8- O -glucoside).

13. Glycosides Dr . Mostafa Hegazy Metabolism of anthraquinone glycosides   Anthraquinones and their glycosides are reduced to the more active anthranols and anthrones by the action of specific bacterial enzymes in the large intestine .  Glycosides are first hydrolyzed then their aglycone reduced to yield the laxative principle e.g. the metabolism of Rhein and its derivatives:   Metabolism of Rhein –8-O-glucoside   Rhein –8-O-glucoside is hydrolyzed to rhein (by the effect of intestinal bacterial b -glucosidase enzyme) and then transformed to rhein anthrone that is the final laxative principle of both rhein and its glucoside .

14. Glycosides Dr . Mostafa Hegazy Metabolism of anthraquinone glycosides Rhein or rhein glucoside by themselves are not effective as laxative , but must be transformed first to rhein anthrone (i.e. after hydrolysis and/or reduction by intestinal bacteria). Rhein anthrone could be prepared from rhein by the treatment with SnCl 2 in acid medium . Yet, the synthetic rhein anthrone is unstable and readily oxidized to rhein or polymerized by the effect of light and oxygen.

15. Glycosides Dr . Mostafa Hegazy Metabolism of Diacerein (1-8 Diacetyl Rhein ) Diacerein (1,8-Diacetylrhein) is a synthetic diacetyl derivative of rhein . Diacerein exerts both analgesic and anti-inflammatory activities, and is clinically used for the treatment of osteoarthritis .   Diacerein is deacetylated by intestinal bacteria to yield rhein , which is the active compound and produces two different effects according to the site of absorption : When absorbed from the upper intestine to the blood stream it exerts an anti-inflammatory activity. The non-absorbed part of rhein undergoes reduction to rhein anthrone in the large intestine by the effect of intestinal bacteria and acts as laxative (this pathway leads to diarrhea in some of the patients taking diacerein ).

16. Glycosides Dr . Mostafa Hegazy Metabolism of Diacerein (1-8 Diacetyl Rhein ) except for moderate and transient digestive disturbances (soft stools, diarrhoea )

17. Glycosides Dr . Mostafa Hegazy Preparation of rhein from rhubarb Extract the powder with water (to remove water-soluble impurities such as tannins, sugars etc...). Extract the marc with methyl isobutyl ketone (to extract rhein ). Shake the extract with NaHCO 3 ( rhein as water-soluble sodium salt). Accordingly, any anthraquinone containing a free COOH group, e.g. Rhein can be separated from an organic solution by adding NaHCO 3 . Acidify with acetic acid (to precipitate rhein ). Wash with water followed by acetone (to remove pigments), Crystallize rhein from acetone.

18. Why the drug is diacerin not rhein ?

19. Glycosides Dr . Mostafa Hegazy Chrysophanic acid ( Chrysophanol ) It occurs in the barks of Cassia , Rumex spp , cascara, frangula and rhubarb. Uses It is also used as antimicrobial and cathartic agent. It is used for commercial production of Chrysarobin by reacting chrysophanol with Zn dust/acetic acid.

20. Glycosides Dr . Mostafa Hegazy Carminic acid Red pigment present in scale insect ( Cocchineal ), Coccus cacti . Carminic acid is an anthraquinone C-glucoside. It is soluble in water and alcohol. Uses: In color photography and painting. As a natural color for foods and drugs. As a stain for bacteria.

21. Glycosides Dr . Mostafa Hegazy II- Anthranols and anthrones These are reduced anthraquinones and occur either free or combined. Oxidation of these compounds may take place during storage of specially powdered crude drugs. Examples are Chrysarobin and Barbaloin .

22. Glycosides Dr . Mostafa Hegazy Chrysarobin ( chrysophanic acid anthranol ) It is obtained from the roots of Cassia spp and Rumex spp. Uses  Chrysarobin is used as antipsoriatic for the treatment of skin diseases, but may cause renal damage .  It has antifungal and keratolytic properties

23. Glycosides Dr . Mostafa Hegazy Barbaloin It is a mild laxative C-glucoside isolated from Aloes . Barbaloin by itself is not laxative but must be transformed first to aloe- emodin anthrone that is the intestinal bacterial metabolite responsible for the laxative effect of barbaloin .

24. Glycosides Dr . Mostafa Hegazy III- Dianthrones These are derived from two molecules of anthrone The molecules may be identical or different. They occur in Senna, Rhubarb and Hypericum (in the free state and in glycosidal combination). Examples are: Sennosides A-D and Hypericin .

25. Glycosides Dr . Mostafa Hegazy Sennosides A-D are glucosides isolated from Senna leaves and pods ( Cassia angustifolia , Leguminosae ). The aglycones of these compounds are called sennidins A-D , respectively.

26. Glycosides Dr . Mostafa Hegazy Sennosides A and C are optically active (levorotatory, trans isomers), while sennoside B is the meso isomer (being intramolecularly compensated). All are soluble in NaHCO 3 (that is used for extracting sennosides from plant) as they all contain free carboxylic groups). Sennoside A is insoluble in water, while sennoside B is water-soluble (this can be used for separating a mixture of A & B). Uses Sennosides are used as irritant laxative .

27. Glycosides Dr . Mostafa Hegazy Rhein anthrone , the ultimate laxative principle of sennosides A and B, is liberated by the effect of intestinal bacteria after oral administration of sennosides . Sennosides A and B can be used for semi-synthesis of Rhein anthrone as follows: Hydrolysis with dilute HCl or H 2 SO 4 (to liberate the aglycones , sennidins ). Adjustment of the pH of the medium to 7-8 with NaHCO 3 (to help reductive cleavage of sennidins to rhein anthrone ), and finally addition of FeCl 3 /H 2 O 2 (to help in oxidation of rhein anthrone to rhein ).

28. Glycosides Dr . Mostafa Hegazy Structure-Activity Relationship: Glycosylation is essential for activity . Hydroxylation at C-1 and C-8 is essential for activity . Oxidation level at C-9 and C-10 is important: Highest level of oxidation ( anthraquinones ) have the lowest activity. Oxanthrones are less active than anthrones . Complete reduction of C-9 and C-10 eliminates the activity . Substitution at C-3 have great impact on activity : CH 2 OH > CH 3 > COOH

29. Glycosides Dr . Mostafa Hegazy Hypericin It is isolated from the dried flowering tops of Hypericum perforatum . It is an example of aromatic polycyclic dianthrones .

30. Glycosides Dr . Mostafa Hegazy Uses Hypericin is used as tranquilizer , antidepressant (MAO inhibitor), and antiviral (anti-HIV). Caution : Hypericin is a photosensitizing agent, so avoid sunray (UV) and solarium treatment, especially in people with fair skin.