Eur J Med Chem. 2017 Feb 10;129:186-208. doi: 10.1016/j.ejmech.2017.02.021. [Epub ahead of print]
Design, synthesis, biological evaluation and molecular modeling study of novel macrocyclic bisbibenzyl analogues as antitubulin agents.
Sun B1, Li L2, Hu QW2, Zheng HB2, Tang H2, Niu HM3, Yuan HQ3, Lou HX4.
Author information
1National 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.
2Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, Shandong University, Jinan, 250012, PR China.
3School of Medicine, Shandong University, Jinan 250012, PR China.
4National 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.
Abstract
A series of macrocyclic bisbibenzyls with novel skeletons was designed, synthesized, and evaluated for antiproliferative activity against five anthropic cancer cell lines. Among these novel molecules, compound 47 displayed excellent anticancer activity against HeLa, k562, HCC1428, HT29 and PC-3/Doc cell lines, with IC50 values ranging from of 1.51 μM-5.51 μM, which were more potent than the parent compound, marchantin C. Compounds 44 and 55 with novel bisbibenzyl skeletons also exhibited significantly improved antiproliferative potency. Structure-activity relationship (SAR) analyses of these synthesized compounds were also performed. In addition, compound 47 effectively inhibited tubulin polymerization in HCC1482 cells and induced HCC1482 cell cycle arrest at the G2/M phase in a concentration-dependent manner. The binding mode of compound 47 to tubulin was also investigated utilizing a molecular docking study. In conclusion, the present study discovered several potent antitubulin compounds with novel bisbibenzyl skeletons, and our systematic studies revealed new scaffolds that target tubulin and mitosis and provide progress towards the discovery of novel antitumor drugs discovery.
Copyright © 2017 Elsevier Masson SAS. All rights reserved.
KEYWORDS:
Anticancer; Bisbibenzyls; Molecular modeling; Tubulin polymerization inhibitors
PMID: 28222318 DOI: 10.1016/j.ejmech.2017.02.021
[PubMed - as supplied by publisher]
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Design, synthesis, biological evaluation and molecular modeling study of novel macrocyclic bisbibenzyl analogues as antitubulin agents.
Sun B1, Li L2, Hu QW2, Zheng HB2, Tang H2, Niu HM3, Yuan HQ3, Lou HX4.
Author information
1National 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.
2Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, Shandong University, Jinan, 250012, PR China.
3School of Medicine, Shandong University, Jinan 250012, PR China.
4National 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.
Abstract
A series of macrocyclic bisbibenzyls with novel skeletons was designed, synthesized, and evaluated for antiproliferative activity against five anthropic cancer cell lines. Among these novel molecules, compound 47 displayed excellent anticancer activity against HeLa, k562, HCC1428, HT29 and PC-3/Doc cell lines, with IC50 values ranging from of 1.51 μM-5.51 μM, which were more potent than the parent compound, marchantin C. Compounds 44 and 55 with novel bisbibenzyl skeletons also exhibited significantly improved antiproliferative potency. Structure-activity relationship (SAR) analyses of these synthesized compounds were also performed. In addition, compound 47 effectively inhibited tubulin polymerization in HCC1482 cells and induced HCC1482 cell cycle arrest at the G2/M phase in a concentration-dependent manner. The binding mode of compound 47 to tubulin was also investigated utilizing a molecular docking study. In conclusion, the present study discovered several potent antitubulin compounds with novel bisbibenzyl skeletons, and our systematic studies revealed new scaffolds that target tubulin and mitosis and provide progress towards the discovery of novel antitumor drugs discovery.
Copyright © 2017 Elsevier Masson SAS. All rights reserved.
KEYWORDS:
Anticancer; Bisbibenzyls; Molecular modeling; Tubulin polymerization inhibitors
PMID: 28222318 DOI: 10.1016/j.ejmech.2017.02.021
[PubMed - as supplied by publisher]
Similar articles
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