Design, synthesis and biological evaluation of novel macrocyclic bisbibenzyl analogues as tubulin polymerization inhibitors

作者：Sun, Bin; Li, Lin; Hu, Qing-wen; Xie, Fei; Zheng, Hong-bo; Niu, Huan-min; Yuan, Hui-qing; Lou, Hong-xiang^*

来源：European Journal of Medicinal Chemistry, 2016, 121: 484-499.

DOI：10.1016/j.ejmech.2016.06.007

• Marchantin C
• Bisbibenzyls
• Analogues
• Tubulin polymerization inhibitors
• Anticancer

A series of novel macrocyclic bisbibenzyl analogues was designed, synthesized, and evaluated for their antiproliferative activity in vitro. All of the compounds were tested in five anthropic cancer cell lines, including a multidrug-resistant phenotype. Among these novel molecules, compounds 88, 92 and 94 displayed excellent anticancer activity against Hela, k562, HCC1428, HT29, and PC-3/Doc cell lines, with average IC50 values ranging from 2.23 M to 3.86 mu M, and were more potent than the parental compound marchantin C and much more potent than the positive control Adriamycin. In addition, the mechanism of action of compound 88 was investigated by cell cycle analysis and a tubulin polymerization assay in HCC1482 cells. The binding mode of compound 88 to tubulin was also investigated utilizing a molecular docking study. In conclusion, the present study improves our understanding of the action of bisbibenzyl-based tubulin polymerization inhibitors and provides a new molecular scaffold for the further development of antitumor agents that target tubulin.

• 出版日期2016-10-4
• 单位山东大学