Design, synthesis and biological evaluation of tetrahydroquinoxaline sulfonamide derivatives as colchicine binding site inhibitors

Colchicine binding site inhibitors (CBSIs) are potential microtubule targeting agents (MTAs), which can overcome multidrug resistance, improve aqueous solubility and reduce toxicity faced by most MTAs. Novel tetrahydroquinoxaline sulfonamide derivatives were designed, synthesized and evaluated for their antiproliferative activities. The MTT assay results demonstrated that some derivatives exhibited moderate to strong inhibitory activities against HT-29 cell line. Among them, compound I-7 was the most active compound. Moreover, I-7 inhibited tubulin polymerization, disturbed microtubule network, disrupted the formation of mitotic spindle and arrested cell cycle at G2/M phase. However, I-7 didn't induce cell apoptosis. Furthermore, the prediction of ADME demonstrated that I-7 showed favorable physiochemical and pharmacokinetic properties. And the detailed molecular docking confirmed I-7 targeted the site of colchicine through hydrogen and hydrophobic interactions. (1) 26 derivatives were synthesized and evaluated for their antiproliferative activities against HT-29 cells. (2) I-7 inhibited tubulin polymerization, arrested cell cycle at G2/M phase. (3) I-7 is located at the colchicine binding site.

Automated summary

Colchicine binding site inhibitors (CBSIs) are potential microtubule targeting agents (MTAs) that can overcome multidrug resistance and reduce toxicity. In this study, tetrahydroquinoxaline sulfonamide derivatives were synthesized and evaluated for their antiproliferative activities. Compound I-7 showed the most inhibitory activity against HT-29 cell line, inhibited tubulin polymerization, and arrested cell cycle at G2/M phase. Additionally, it was found that I-7 targeted the colchicine binding site through hydrogen and hydrophobic interactions.