Identification of novel non-toxic and anti-angiogenic α-fluorinated chalcones as potent colchicine binding site inhibitors

Abstract

α-Fluorinated chalcones were prepared and evaluated for their cell growth inhibitory properties against six human cancer cell lines. The most potent chalcone <b>4c</b> demonstrated excellent selective toxicity against cancer cells versus normal human cells, with IC₅₀ values at nanomolar concentration ranges against 5 cancer cell lines. A further study revealed that <b>4c</b> could bind to the colchicine site of tubulin, disrupt the cell microtubule networks, and effectively inhibit tubulin polymerisation. Cellular-based mechanism studies elucidated that <b>4c</b> arrested MGC-803 cell cycle at G2/M phase. In addition, <b>4c</b> dose-dependently caused Caspase-induced apoptosis of MGC-803 cells through mitochondrial dysfunction. Notably, compound <b>4c</b> was found to inhibit the HUVECs tube formation, migration, and invasion <i>in vitro</i>. Furthermore, our data suggested that treatment with <b>4c</b> significantly reduced MGC-803 cells metastasis and proliferation <i>in vitro</i>. Overall, this work showed that chalcone hybrid <b>4c</b> is a potent inhibitor of tubulin assembly with prominent anti-angiogenesis and anti-cancer properties.