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.
- 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: [email protected].
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.