Design, synthesis and biological evaluation of novel macrocyclic bisbibenzyl analogues as tubulin polymerization inhibitors.
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.
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.
Bin
B
Sun
Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, Shandong University, Jinan, 250012, PR China.
Lin
L
Li
Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, Shandong University, Jinan, 250012, PR China.
Qing-Wen
QW
Hu
Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, Shandong University, Jinan, 250012, PR China.
Fei
F
Xie
Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, Shandong University, Jinan, 250012, PR China.
Hong-Bo
HB
Zheng
School of Medicine, Shandong University, Jinan 250012, PR China.
Huan-Min
HM
Niu
School of Medicine, Shandong University, Jinan 250012, PR China.
Hui-Qing
HQ
Yuan
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.
Hong-Xiang
HX
Lou
D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D047028:Macrocyclic Compounds; D050257:Tubulin Modulators
Analogues; Anticancer; Bisbibenzyls; Marchantin C; Tubulin polymerization inhibitors