%0 Journal Article
%T Structure-activity relationship study of new carbazole sulfonamide derivatives as anticancer agents with dual-target mechanism.
%A Liu Y
%A Zhang J
%A Tian J
%A Wang C
%A Wang T
%A Gong J
%A Hu L
%J Eur J Med Chem
%V 273
%N 0
%D 2024 Jul 5
%M 38781920
%F 7.088
%R 10.1016/j.ejmech.2024.116509
%X A series of novel carbazole sulfonamide derivatives were synthesized and evaluated for antiproliferative activity. Among them, compounds 7 and 15 showed strong potency (IC50 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 (IC50(L02)/average IC50: 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.