Discovery of novel quinoline-based analogues of combretastatin A-4 as tubulin polymerisation inhibitors with apoptosis inducing activity and potent anticancer effect

Abstract

A new series of quinoline derivatives of combretastatin A-4 have been designed, synthesised and demonstrated as tubulin polymerisation inhibitors. These novel compounds showed significant antiproliferative activities, among them, <b>12c</b> exhibited the most potent inhibitory activity against different cancer cell lines (MCF-7, HL-60, HCT-116 and HeLa) with IC₅₀ ranging from 0.010 to 0.042 µM, and with selectivity profile against MCF-10A non-cancer cells. Further mechanistic studies suggest that <b>12c</b> can inhibit tubulin polymerisation and cell migration, leading to G₂/M phase arrest. Besides, <b>12c</b> induces apoptosis <i>via</i> a mitochondrial-dependant apoptosis pathway and caused reactive oxygen stress generation in MCF-7 cells. These results provide guidance for further rational development of potent tubulin polymerisation inhibitors for the treatment of cancer.HighlightsA novel series of quinoline derivatives of combretastatin A-4 have been designed and synthesised.Compound <b>12c</b> showed significant antiproliferative activities against different cancer cell lines.Compound <b>12c</b> effectively inhibited tubulin polymerisation and competed with [³H] colchicine in binding to tubulin.Compound <b>12c</b> arrested the cell cycle at G₂/M phase, effectively inducing apoptosis and inhibition of cell migration.