Bioactive heterocycles containing a 3,4,5-trimethoxyphenyl fragment exerting potent antiproliferative activity through microtubule destabilization

• DOI: 10.1016/j.ejmech.2018.07.060
• Publication Date: 2018-07-29T04:17:19Z
• Authors: Dong-Jun Fu; Jia-Jia Yang; Ping Li; Yu-Hui Hou; Sheng-Nan Huang; Matthew Alexander...; Victor Pham; Liankun Song; Xiaolin Zi; Wei-Li Xue; Li-Rong Zhang; Sai-Yang Zhang
• Keywords: Colchicine; Microtubule polymerization; IC50; Acetamide; Structure–activity relationship

Novel bioactive heterocycles containing a 3,4,5-trimethoxyphenyl fragment as antiproliferative agents by targeting tubulin were synthesized and their preliminary structure activity relationships (SARs) were explored. Among all these chemical agents, 2-(Benzo[d]oxazol-2-ylthio)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)acetamide (4d) exhibited the potent antiproliferative activity against MGC-803 cells with an IC50 value of 0.45 μM by induction of G2/M pahse arrest and cell apoptosis. In addition, 4d could change the membrane potential (ΔΨ) of the mitochondria against MGC-803 cells. Importantly, 4d acted as a novel tubulin polymerization inhibitor binding to colchicine site with an IC50 value of 3.35 μM.