2. Academic Validation
  3. Design, synthesis and biological evaluation of novel macrocyclic bisbibenzyl analogues as tubulin polymerization inhibitors

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

  • Eur J Med Chem. 2016 Oct 4:121:484-499. doi: 10.1016/j.ejmech.2016.06.007.
Bin Sun 1,  Lin Li 2,  Qing-Wen Hu 2,  Fei Xie 2,  Hong-Bo Zheng 2,  Huan-Min Niu 3,  Hui-Qing Yuan 3,  Hong-Xiang Lou 4
Affiliations

Affiliations

  • 1 National Glycoengineering Research Center, Shandong University, Jinan 250012, PR China; Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, Shandong University, Jinan, 250012, PR China.
  • 2 Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, Shandong University, Jinan, 250012, PR China.
  • 3 School of Medicine, Shandong University, Jinan 250012, PR China.
  • 4 National Glycoengineering Research Center, Shandong University, Jinan 250012, PR China; Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, Shandong University, Jinan, 250012, PR China. Electronic address: louhongxiang@sdu.edu.cn.
PMID: 27318123 DOI: 10.1016/j.ejmech.2016.06.007
Abstract

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 μM to 3.86 μM, 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.

Keywords

Analogues; Anticancer; Bisbibenzyls; Marchantin C; Tubulin polymerization inhibitors.

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