Design,Synthesis And Antitumor Activity Of Sulfonamide Tubulin Inhibitors

Microtubules are the major components of the cytoskeleton, with biological functions of maintaining cell shape, promoting cell division and so on. Inhibitors can stop cell mitosis with disturbing tubulin dynamics and induce tumor apoptosis or atrophy. Besides, inhibitors can destroy the cytoskeleton and make vascular endothelial cell lysis, which led to hemorrhagic necrosis of tumor tissue. Based on the core function of tumor cell proliferation and growth, microtubules have been one of the most important targets of anti-cancer drugs. Within three binding sites of tubulin, the colchicine site shows smaller binding pocket and can be more suitable for the study of small molecule inhibitors.We select E7010 and E7070 which have been in ?pre?clinical trials as leading compounds to construct a series of novel sulfonamide analogues guided by binding modes of reported tubulin together with the utilization of basic principles of drug design. 56 new sulfonamide derivatives ?series A and series B? were designed and synthesized by changing the two hydrophobic parts and subsituents of sulfonamide connecting chain. All compounds were tested for their in vitro cytotoxic activities against two human tumor cell lines. The results revealed that sulfonamide derivatives with amino-acid ester, amide or urea of series A showed excellent activities (IC₅₀ from 0.06 to 0.53 ?M) and four among them are more effective than E7070. Only two compounds of series B showed moderate activity close to E7070, the potency of others were not obvious. Further tubulin inhibitory activity of those compounds is to be tested. The above study provides a reliable basis for futher research of potent anticancer drugs.