Novel trifluoromethylquinoline derivatives as potent tubulin polymerization inhibitors with antitumor activity.

Herein, two series of N-aryl-2-trifluoromethyl-quinoline-4-amine derivatives as tubulin polymerization inhibitors were designed and synthesized. Compounds 14b exhibited potency inhibitory activity against LNCaP cells (IC50 = 0.0027 μM and Selectivity Index = 4.07) which was more effective than the positive control colchicine, while compounds 12, 16a, and 14e exhibited moderate activity against LNCaP cells with IC50 values of 0.28, 0.0413, and 0.43 μM, respectively. Moreover, mechanism studies showed that 14b could disrupt tubulin polymerization effectively, block cell cycle in G2/M phase, and induced cellular apoptosis. 14b significantly inhibited LNCaP cell migration and invasion. Meanwhile, SwissADME predictions showed that 14b has good pharmacokinetic properties and molecular docking confirmed that it may bind to the colchicine binding site. In brief, these data suggested that 14b was a promising lead compound with antitumor activity for discovering novel tubulin polymerization inhibitors.