A novel series of benzothiazepine derivatives as tubulin polymerization inhibitors with anti-tumor potency.

Abstract In this work, a series of diaryl benzo[b][1,4]thiazepine derivatives D1-D36 were synthesized and screened as tubulin polymerization inhibitors with anti-tumor potency. They were designed by introducing the seven-member ring benzothiazepine as the linker for CA-4 modification for the first time. Among them, the hit compound D8 showed potential on inhibiting the growth of several cancer cell lines (IC50 values: 1.48 μM for HeLa, 1.47 μM for MCF-7, 1.52 μM for HT29 and 1.94 μM for A549), being comparable with the positive controls Colchicine and CA-4P. The calculated IC50 value of D8 as an tubulin polymerization inhibitor was 1.20 μM. The results of the flow cytometry assay revealed that D8 could induce the mitotic catastrophe and the death of living cancer cells. D8 also indicated the anti-vascular activity. The possible binding pattern was implied by docking simulation, inferring the possibility of introducing interactions with the nearby tubulin chain. Since the novel structural trial has been conducted with preliminary discussion, this work might stimulate new ideas in further modification of tubulin-related anti-cancer agents and therapeutic approaches.