Design, synthesis, biological evaluation and molecular modeling study of novel macrocyclic bisbibenzyl analogues as antitubulin agents
| Autor: | Hui Tang, Qing-wen Hu, Huanmin Niu, Hongbo Zheng, Bin Sun, Huiqing Yuan, Hong-Xiang Lou, Lin Li |
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| Rok vydání: | 2017 |
| Předmět: |
Models
Molecular 0301 basic medicine Macrocyclic Compounds Molecular model Stereochemistry Antineoplastic Agents 01 natural sciences HeLa Structure-Activity Relationship 03 medical and health sciences Tubulin Cell Line Tumor Bibenzyls Drug Discovery Humans Mitosis Cell Proliferation Biological evaluation Pharmacology biology 010405 organic chemistry Chemistry Organic Chemistry General Medicine biology.organism_classification Combinatorial chemistry Tubulin Modulators 0104 chemical sciences Molecular Docking Simulation 030104 developmental biology Design synthesis Cell culture Drug Design biology.protein K562 cells |
| Zdroj: | European Journal of Medicinal Chemistry. 129:186-208 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2017.02.021 |
| Popis: | 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 IC 50 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. |
| Databáze: | OpenAIRE |
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