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

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, exhibited the most potent inhibitory activity against different cancer cell lines (MCF-7, HL-60, HCT-116 and HeLa) with IC ranging from 0.010 to 0.042 µM, and with selectivity profile against MCF-10A non-cancer cells. Further mechanistic studies suggest that can inhibit tubulin polymerisation and cell migration, leading to G/M phase arrest. Besides, induces apoptosis 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 showed significant antiproliferative activities against different cancer cell lines.Compound effectively inhibited tubulin polymerisation and competed with [H] colchicine in binding to tubulin.Compound arrested the cell cycle at G/M phase, effectively inducing apoptosis and inhibition of cell migration.