Discovery of New Quinolines As Potent Colchicine Binding Site Inhibitors: Design, Synthesis, Docking Studies, and Anti-proliferative Evaluation

Discovering of new anticancer agents with potential activity against tubulin polymerisation is still a promising approach. Colchicine binding site inhibitors are the most relevant anti-tubulin polymerisation agents. Thus, new quinoline derivatives have been designed and synthesised to possess the same essential pharmacophoric features of colchicine binding site inhibitors. The synthesised compounds were tested against a panel of three human cancer cell lines (HepG-2, HCT-116, and MCF-7) using colchicine as a positive control. Comparing to colchicine (IC = 7.40, 9.32, and 10.41 µM against HepG-2, HCT-116, and MCF-7, respectively), compounds , , and exhibited superior cytotoxic activities with IC values ranging from 1.78 to 9.19 µM. In order to sightsee the proposed mechanism of anti-proliferative activity, the most active members were further evaluated for their inhibitory activities against tubulin polymerisation. Compounds and exhibited the highest tubulin polymerisation inhibitory effect with IC values of 9.11 and 10.5 nM, respectively. Such members showed activities higher than that of colchicine (IC = 10.6 nM) and CA-4 (IC = 13.2 nM). The impact of the most promising compound on cell cycle distribution was assessed. The results revealed that compound can arrest the cell cycle at G2/M phase. Annexin V and PI double staining assay was carried out to explore the apoptotic effect of the synthesised compounds. Compound induced apoptotic effect on HepG-2 thirteen times more than the control cells. To examine the binding pattern of the target compounds against the tubulin heterodimers active site, molecular docking studies were carried out.