Synthesis And Biological Evaluation Of New Podophyllotoxin Derivates

Podophyllotoxin as well as its congeners and derivatives exhibit pronounced biological activity mainly as strong antiviral agents and as antineoplastic drugs. The podophyllotoxin derivatives etoposide, teniposide and Etopophos are thus successfully utilized in treatment of a variety of cancers, including small-cell lung cancer, testicular carcinoma, lymphoma, and Kaposi’s sarcoma. However, toxicity, poor water solubility, drug resistance and other shortcomings were found in clinical use. In order to discover new anticancer drugs based podophyllotoxin, the synthesis of two series of podophyllotoxin derivatives and their preliminary evaluation of anti-tumor activity have finished in this thesis.Firstly, according to the combination principle of drug design, a series of conjugates of deoxypodophyllotoxin and 5-FU were synthesized by different diamines as linkers. The cytotoxic activity of these compounds against human cancer cell lines (Hela, A-549, HCT-8 and HepG-2) were evaluated, and the results indicated that compound 13a showed the more potent cytotoxicity than VP-16. Moreover, we found that compound 13a induced cell cycle arrest in the G2/M phase carried out by apoptosis in A-549 cells.Secondly, to obtain the analogues of podophyllotoxin with water-soluble, we have got intermediates with Burgess reaction between podophyllotoxin and chlorine isocyanate. Subsequently, we have obtained podophyllotoxin compounds substituted by sulfonamido through reaction with some types of amine compounds. These compounds have good water solubility, their biological activity is being studied.