Structure-activity relationship study of new carbazole sulfonamide derivatives as anticancer agents with dual-target mechanism.

A series of novel carbazole sulfonamide derivatives were synthesized and evaluated for antiproliferative activity. Among them, compounds 7 and 15 showed strong potency (IC 50 values of 0.81–31.19 nM) against five different cancer cells including multidrug-resistant MCF7/ADR cells. Compound 15 displayed a high cancer cell selectivity (IC 50 (L02)/average IC 50 : SI = 7.7). The l -valine prodrug 7a and the phosphate prodrug 15a exerted rohust in vivo antitumor efficacies and accepted safety prolifes. Further mechanism studies revealed that 7 and 15 directly bind to the colchicine site in tubulin to block tubulin polymerization, promote microtubule fragmentation at the cellular level, and induce apoptosis with G2/M cell cycle arrest. These compounds also inhibit HEMC-1 cells migration and vascular tube formation. Additionally, compound 7 displayed a selective inhibition of Topo I. Collectively, these studies suggest that 7 and 15 represents a promising new generation of tubulin inhibitors for cancer treatment. [Display omitted] • Compound 7 is a novel dual-mechanism antitumor agent with targeting tubulin and Topo I. • Compounds 7 and 15 showed an average IC 50 value of 17.99 and 6.94 nM against five cancer cells, respectively. • Compound 15 showed a high selective between cancer cells and L02 cells with SI of 7.7. • Compounds 7 and 15 possessed antitumor effect in MCF-7 xenograft model with IR 0f 66 % and 73 %, respectively. [ABSTRACT FROM AUTHOR]