Medicinal Chemistry

Design, Synthesis and Anti-tubulin Activity of Novel Dinitro Diphenyl Ether Derivatives as Potent Anticancer Agent

Abstract

Li-Fei Bai, Hui-Hong Qian, Da-Wei Jiang, Xiao-Ming Wang and Ren-Lei Wang

In this study, a series of Dinitrodiphenyl Ether derivatives (1b-5b) were synthesized and their biological activities were also evaluated as potential tubulin inhibitors. Among them, compound 3b (IC50=1.26 ± 0.84 μM) exhibited the most potent anti-proliferative activity of MCF-7 cancer cell line in vitro, which was comparable to that of colchicine (IC50=0.93 ± 0.46 μM) as reference. And it also showed the most potent growth inhibitory activity against tubulin (IC50=5.10 ± 0.81 μM), which was also compared with colchicine (IC50=3.42 ± 0.63 μM). Molecular docking simulation results demonstrated that 3b could bind to the colchicine binding site of tubulin and effectively inhibit tubulin polymerization. Moreover, the subsequent cell cycle arrest and apoptosis assay further confirmed that 3b could cause MCF-7 cell cycle arrest in the middle and later stages of mitosis and thus leading to cell apoptosis. To sum up, we recommend 3b as the best candidate of potential anti-cancer agent among these new compounds. Based on the preliminary results, compound 3b with potent inhibitory activity in tumor growth may be a potential anti-cancer agent.