Discovery of new quinolines as potent colchicine binding site inhibitors: design, synthesis, docking studies, and anti-proliferative evaluation

Abstract

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 <i>in vitro</i> 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 (IC₅₀ = 7.40, 9.32, and 10.41 µM against HepG-2, HCT-116, and MCF-7, respectively), compounds <b>20</b>, <b>21</b>, <b>22, 23, 24, 25, 26,</b> and <b>28</b> exhibited superior cytotoxic activities with IC₅₀ 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 <i>in vitro</i> for their inhibitory activities against tubulin polymerisation. Compounds <b>21</b> and <b>32</b> exhibited the highest tubulin polymerisation inhibitory effect with IC₅₀ values of 9.11 and 10.5 nM, respectively. Such members showed activities higher than that of colchicine (IC₅₀ = 10.6 nM) and CA-4 (IC₅₀ = 13.2 nM). The impact of the most promising compound <b>25</b> on cell cycle distribution was assessed. The results revealed that compound <b>25</b> 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 <b>25</b> 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.