Discovery of novel coumarin-sulfonates as tubulin polymerization inhibitors targeting the colchicine-binding site with potent anticancer activities

Abstract

A series of novel coumarin-sulfonate derivatives as potent microtubule-targeting inhibitors was constructed utilizing a molecular hybridization strategy, and their antiproliferative activities were evaluated against MGC-803, KYSE450 and HCT-116 cancer cell lines. Among them, compound C20 exhibited potent antiproliferative effects on KYSE450 cells (IC₅₀ = 0.36 μM) and EC-109 cells (IC₅₀ = 0.63 μM). Mechanistic studies revealed that C20 could occupied the colchicine-binding site to suppress tubulin polymerization, thereby disrupting the microtubule network integrity in KYSE450 and EC-109 cells. Notably, C20 activated the Hippo signaling pathway and downregulated the expression of the oncogenic protein YAP in KYSE450 and EC-109 cells. In addition, C20 effectively suppressed colony formation, induced G2/M phase cell cycle arrest, and promoted apoptosis in KYSE450 and EC-109 cells. These effects of cell apoptosis were correlated with the modulation of apoptosis related proteins cleaved PARP and cleaved Caspase3/7 level. Collectively, these findings elucidated that C20, as a tubulin polymerization inhibitor, could destroy microtubule dynamics and activate the Hippo signaling pathway, thereby exhibiting strong anti-esophageal cancer activities.

Keywords: Antiproliferative activities; Colchicine-binding site; Coumarin; Sulfonate; Tubulin.