Structure-activity relationships and antiproliferative effects of 1,2,3,4-4H-quinoxaline derivatives as tubulin polymerization inhibitors.

[Display omitted] • A series of 1,2,3,4-4 H -quinoxaline derivatives were synthesized. • The antiproliferative activities of all target compounds were determined. • 11a and 11b showed the most antiproliferative activities up to nanomolar level. • 11a arrest cell cycle in G2/M and induce cell apoptosis in dose-dependent manner. • 11a acted on the colchicine binding site based on the molecular docking study. Colchicine binding site inhibitors (CBSIs) hold great potential for the treatment of various tumors and they can overcome multidrug resistance which the existing tubulin inhibitors such as paclitaxel and vinorelbine are faced with. Herein, we report the design, synthesis and biological evaluation of a series of tetrahydro-quinoxaline derivatives as colchicine binding site inhibitors. All the synthesized compounds were evaluated for their in vitro antiproliferative activities against HT-29 and Hela cancer cell lines, and most of the target compounds demonstrated moderate to strong activities towards two tumor cell lines. In addition, the structure-activity relationships of these derivatives were also discussed. Among them, compounds 11a and 11b showed the most potent activities. Moreover, compound 11a inhibited the tubulin polymerization in both cell-free and cellular assays. Further profiling of compound 11a revealed that it arrested cell cycle in G2/M and induced cell apoptosis in a dose-dependent manner. Furthermore, molecular docking study proved that compound 11a acted on the colchicine binding site. Therefore, 11a is a promising candidate for the discovery of colchicine binding site inhibitors. [ABSTRACT FROM AUTHOR]