Study On The Synthesis And Biological Activities Of Emodin Derivatives

Emodin is an important active component of Rheum Rhaponticum which exhibits many pharmacological activities, such as cathartic, anti-microbial, anti-inflammatory, attenuate metabolic, the inhibitor of a-glucoamylase, and anti-cancer properties.With Emodin as lead compound, Emodin derivatives with seriate different lipophilic property were synthesized by introducing different length alkyl at C8 position, meanwhile four different series emodin derivatives are synthesized by rhein and other compounds. Some biological effect of emodin derivates were evaluated including the antimicrobial activity, antihyperglycemic effect, anti-inflammatory and cell toxicity. The methods and results are as follows:1. The synthesis and molecular structure identification of emodin derivativesDue to the intramolecular hydrogen bond of two phenolic groups, the readily available material emodin was alkylated with RBr by microwave assist method selectively to obtain high yield A1～A11. The obtained A1～A5 was protected by acetylation to obtain D1-D5, which were oxidized by KMnO4-PyH-TBAB to generate the product E1～E5. The target compounds F1-F5 were finally obtained by de-protects of diacetate. B1-B4 and C1-C4 were synthesized by rhein and different amides. In order to study the infectors of synthesis of emodin derivatives, orthogonal design was used; Effects of microwave and conventional synthetic yield on the reaction synthesis were studied; Effects of oxidant were studied. The resulting compounds were purified by chromatography and their identities were confirmed by IR, 1H NMR, and MS spectroscopy.2. The antimicrobial activity of emodin derivatives in vitroFlat-panel drawing lines method, agar dilution method and microplate method were used to detect antibacterial activity of emodin derivatives to five different bacteria (including G+ bacteria, G- bacteria and fungi) and the MIC values.The results showed that emodin was the most sensitive to all bacteria. 6-alkoxy rhein derivatives (F1～F5) was less sensitive than emodin.1,8-diacetyl-3-emodin alkoxy ether (D1～D5) has the least sensitive to Antibacterial activity. The antimicrobial activity increased as the length of aliphatic chain elongated and then decreased gradually when the alkyl chain exceeded certain carbon atoms.3. The antihyperglycemic effect of emodin derivatives in vivo and vitroa-glucosidase and alloxan induced diabetic rats were used to observe the hypoglycemic activity of rhein derivatives(F1～F5). Accelrys Discovery Studio was carried out to dock emodin derivatives and a-glucosidase molecular.The new rhein derivatives exhibited good hypoglycemic activity through inhibition a-glucoamylase. Their hypoglycemic activity depends on aliphatic chain length, at first their activity increased with the aliphatic chain length and then gradually decreased when the number of carbon atoms was higher than eight. Compound F3 showed significant hypoglycemic activity in vitro and vivo.The results of molecular modeling and docking show that the Libscore increase with the length of alkyl chain and then gradually decreased when the number of carbon atoms was higher than eight, which accorded to the result of experiments.4. The anti-inflammatory effect of emodin derivatives in vivoWith Xylene and dextran as allergen, the anti-inflammatory activity of emodin derivatives was evaluated by mouse ear edema and rat paw edema.Anti-inflammatory activity of emodin derivatives results differs with different inflammation models. But in general the compounds E2, E3 showed certain anti-inflammatory activity to acute inflammation of mice and rats. The results of inflammation showed that the swelling is the most obvious in 60min after the injection of allergens. There are no significant difference between the control group and the experimental group afte 200min.5. Preliminary study on toxicity of emodin derivatives in vivoThe cytotoxicity of all compounds to human hepatic cell (HL-7702) and human Epithelial cells (9HTE) was evaluated by MTT assay to estimate the safety of emodin derivatives (F1～F5). The difference between treatment and concentration effects was determined. Cytotoxicity significantly varied between all compounds and between dosages. There was a significant interaction effect within compounds and dosages. There was a trend in which the cytotoxicity of each compound was lower than that of emodin alone at the same concentration, except at the highest dosage of 320μM. In general, the longer the aliphatic chain of F1～F5.This could be attributed to the reciprocity between the aliphatic chain and the cell.