Discovery and biological evaluation of 6-aryl-4-(3,4,5-trimethoxyphenyl) quinoline derivatives with promising antitumor activities as novel colchicine-binding site inhibitors

Tubulin, as the fundamental unit of microtubules, is a crucial target in the investigation of anticarcinogens. The synthesis and assessment of small-molecule tubulin polymerization inhibitors remains a promising avenue for the development of novel cancer therapeutics. Through an analysis of reported colchicine-binding site inhibitors (CBSIs) and tubulin binding models, a set of 6-aryl-4-(3,4,5-trimethoxyphenyl)quinoline derivatives were meticulously crafted as potential CBSIs. Notably, compound 14u exhibited potent anti-proliferative efficacy, displaying IC50 values ranging from 0.03 to 0.18 mu M against three human cancer cell lines (Huh7, MCF-7, and SGC-7901). Mechanistic investigations revealed that compound 14u could disrupt tubulin polymerization, dismantle the microtubule architecture, arrest the cell cycle at G2/M phase, and induce apoptosis in cancer cells. Furthermore, compound 14u demonstrated significant inhibition of tumor proliferation in vivo with no discernible toxicity in the Huh7 orthotopic tumor model mice. Additionally, physicochemical property predictions indicated that compound 14u adhered well to Lipinski's rule of five. These findings collectively suggest that compound 14u holds promise as an antitumor agent targeting the colchicine-binding site on tubulin and warrants further investigation.