Design,Synthesis And Biological Evaluation Of A Novel Series Of STAT3/Tubulin Small Molecule Inhibitors

Overexpression and constitutional activation of STAT3 may lead to abnormal cell division and promote the carcinogenesis in normal cells.Currently,development of antineoplastic drug target STAT3 protein was a major research effort.Stattic,as a small molecule STAT3 inhibitor,was discovered through high-throughput screening in view of the SH2 domain of STAT3,further research effort based on the Stattic scarfold led to the discovery of compound E28 with improved activity in our group.Considering the broad cytotoxicity of E28,this research reported further structural optimiztion of E28 by removing the,?-unsaturated Michael acceptor in this molecule,which led to a number of N-substituted benzenesulfonyl-1H-indole compounds.Among them,compound 4a demonstrated the highest activity to inhibit the proliferation of several cancer cell lines,systemetic biological study confirmed 4a could inhibit STAT3 phorysporylation at Tyr 705,induce cell apoptosis,as well as arrest the cell as G2/M phase.Meanwhile,it was also found that these compounds exhibit inhibitory effect on tubulin polymerization.