Design, synthesis, and evaluation of anti-breast cancer activity of colchicine - combretastatin A-4 analogues containing quinoline as microtubule-targeting agents

Research on compounds derived from, or inspired by, natural compounds as novel anticancer agents has been a significantly focus in recent years. In this study, we reported the design, synthesis, in vitro, and in silico evaluation of novel colchicine - combretastatin A-4 analogues fused with the quinoline moiety for their potential anti-breast cancer activities. A series of 21 desired analogues (2a-4g) was synthesized from quinoline-3-carbaldehydes (2-4) and anilines (a-g) via reductive amination. In vitro cytotoxicity evaluations of these analogues on breast cancer MDA-MB-231 cells revealed significant cell growth inhibition in 13 out of 21 compounds. Among them, compounds 2b (IC50 30.40 mu M), 2e (IC50 18.98 mu M), 4b (IC50 34.97 mu M), and 4e (IC50 14.54 mu M) demonstrated remarkable anti-breast cancer activities compared to colchicine (IC50 9.08 mu M). Furthermore, these potential analogues were further characterized via several ligand-based computational models including SwissADME, ADMETlab2.0, and SEA Search Server, thereby suggesting their favorable physicochemical and pharmacokinetictoxicological properties, as well as their abilities to target the beta-tubulin chain. A structure-based computational approach such as molecular docking was also applied to investigate their binding characteristics with the colchicine-binding site inside alpha,beta-tubulin, indicating that these compounds could exhibit a binding mode similar to that of colchicine or combretastatin A-4. These findings suggested the potential of these analogues as antibreast cancer agents that could inhibit microtubule assembly. In conclusion, our study has provided a comprehensive understanding of the anticancer activities of the desired analogues, serving as the basis for future research on novel anti-breast cancer agents that target microtubules.