Synthesis Of Betulin-ester Derivatives

Many clinical anticancer drugs have insignificant toxicity and side effects, so hunting for high-efficiency and low-toxic new antitumor agents is one of hot topics in the research of new drugs. It found that betulin and its derivatives as a pentacyclic triterpene with a lupane skeleton exhibited a lot of biological activities such as antitumor, anti-HIV, low toxicity, different mechanisms of action and so on. However, lower water-solubility of betulin and its derivatives resulted in worse bioavailability and clinical using. In order to improve the biological activities and water-solubility of betulin and its derivatives, based on the structural features of betulin, we modified the raw material betulin on C-3and C-28to synthize some betulin derivativess:3,28-di-O-itaconic-betulin, tert-butyl ester of3,28-di-o-succinyl-alanylamino-betulin, tert-butyl ester of3,28-di-o-succinyl-glycylamino-betulin. The structures of the products were identified by FT-IR,1HNMR and MS spectras. All the results were as follows:(1)3,28-di-O-itaconic-betulin was successfully obtained by itaconic anhydride and betulin as raw materials. The solubility data of betulin and3,28-di-O-itaconic-betulin was determined by equilibrium method with HPLC. The results showed that at37℃the solubility datas of the first3,28-di-O-itaconic-betulin were separately52.2653and57.9743of betulin in actone> anhydrous alcohol. The solubility datas of the second3,28-di-O-itaconic-betulin were separately51.9072and55.9304of betulin. Bioactivities of3,28-di-O-itaconic-betulin to the cell lines such as HepG-2、pc-3、7721、MCF-7、SK、 A549of the products were examined by MTT. The conclusion showed that IC50of the product were more lower than betulin to the six cell lines. IC50of the product was4.07μmol/L against SK,1/11of betulin. IC50of the product was5.18μmol/L against A549, lower than1/20of betulin. It showed that the product had strong activity.(2) In order to improve the targeting and biological activities,3,28-di-O-succinyl-betulin which synthized by betulin and butanedioic anhydride as raw material, tert-butyl ester of3,28-di-o-succinyl-alanylamino-betulin was successfully obtained by3,28-di-O-succinyl-betulin and tert-butyl ester of glycine hydrochloride under HOBt, DCC and HOBt, EDC1as condersing agents separately. The solubility data of betulin and the product was determined by equilibrium method with HPLC.The results showed that at37℃the solubility of tert-butyl ester of3,28-di-o-succinyl-alanylamino-betulin was49.4379and51.7508of betulin in actone、anhydrous alcohol. IC50of the product was15.33μmol/L against HepG-2at72h. It was about1/6of betulin by MTT.(3) Tert-butyl ester of3,28-di-o-succinyl-glycylamino-betulin was successfully obtained by the same way to (2).The solubility data of betulin and the product was determined by equilibrium method with HPLC.The results showed that at37℃the solubility of tert-butyl ester of3,28-di-o-succinyl-glycylamino-betulin was41.6274and40.5442of betulin in actone^anhydrous alcohol.IC50of the product was15.33μmol/L against HepG-2at72h. It was about1/6of betulin by MTT.