Design, Synthesis And Anticancer Study Of Diarylmethenecycloalkane Derivatives As Tubulin Inhibitors

Tubulin inhibitors are very effective anticancer drugs and two of them, paclitaxel and vincristine, are widely used in clinic. But both of them have obvious shortcomings, a typical one is their contribution to multi-drug resistance in clinic. These shortcomings are serious challenges to their effectiveness of treatment. Therefore, it is very necessary to develop novel small-molecular tubulin inhibitors. Due to the small volume of the colchicine binding site and the simplicity of the structures of its inhibitors, drugs that bind to this site are undergoing intensive investigation and some of them are making good progress. Many studies are focusing on synthesizing and studying the derivatives of lead compound CA-4and some of them are very promising.In this thesis, in order to solve the problem of double bond’s transformation from "cis" configuration to "trans" configuration and maitain the structure features of A ring and B ring in CA-4, we designed some compounds which has four, five or six-ring-methene as rigid structural fragments. The designed compounds were screened by Sybyl7.3software. Then we tried to synthesize the chosen11active target compounds and study their antitumor activities. All of these work were aimed at finding new and active tubulin inhibitors and thus layed the foundation for developing new anticancer drugs.In this thesis,33compounds (22compounds are novel) were synthesized, among which9compounds (9compounds are novel) were taget compounds. The structures of all target compounds were confirmed by both’H NMR and HRMS spectrum. The results of antitumor activity in vitro showed that compound20a presented potent activity against human liver cancer cells Bel-7402(IC50:0.02μg/ml) and was even more potent than CA-4(IC50:0.3μg/ml). The inhibition rate (20a) of the growth of solid tumor in nude mice heterotransplanted human liver cancer cells Bel-7402was53.3%, which means20a was more potent than CA-4under the same dose. The cute toxicity of20a was150mg/kg (LD50), which was70times as much as vincristine (LD50:2.13mg/kg), and it showed no significant toxicity. Thus, compound20a deserved further research and development.The inhibitory activity of all target compounds in vitro against human cervical carcinoma cells (HELA) were equal to or better than positive control CA-4, which means these compounds were active and worthy of further research.