Design, synthesis, biological evaluation and cocrystal structures with tubulin of chiral beta-lactam bridged combretastatin A-4 analogues as potent antitumor agents
文献类型：期刊论文
| 作者 | Zhou, Pengfei2,4; Liang, Yuru2; Zhang, Hao3; Jiang, Hao3; Feng, Kechang2; Xu, Pan3; Wang, Jie2; Wang, Xiaoming4; Ding, Kuiling4; Luo, Cheng1,3
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2018-01-20 |
| 卷号 | 144页码:817-842 |
| 关键词 | 1,4-Diaryl-2-azetidinone Combretastatin A-4 Tubulin polymerization Antitumor |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2017.12.004 |
| 文献子类 | Article |
| 英文摘要 | A diverse of chiral beta-lactam bridged analogues of combretastatin A-4 (CA-4), 3-substituted 1,4-diaryl-2-azetidinones, were asymmetrically synthesized and biologically evaluated, leading to identify a number of potent anti-proliferative compounds represented by 14b and 14c with IC50 values of 0.001-0.021 mu M, against four human cancer cell lines (A2780, Hela, SKOV-3 and MDA-MB-231). Structure-activity relationship (SAR) studies on all stereoisomers of 14b and 14c revealed that the absolute configurations of the chiral centers at 3- and 4-position were critically important for the activity and generally a trans configuration between the "A" and "B" rings is optimal. In addition, 14b and 14c displayed less cytotoxicity on normal human oviduct epithelial cells than malignant cells indicating good selectivity in vitro. Further biochemical evaluation and cocrystal structures with tubulin demonstrated that both compounds disrupted tubulin polymerization through interacting at the colchicine-binding site, suppressed angiogenesis in vitro and in vivo, blocked cell cycle progression at mitotic phase and induced cellular apoptosis. The in vivo assays verified that both compounds inhibited xenograft tumor growth in nude mice with acceptable therapeutic window, showing promising potentials for further clinical development. (C) 2017 Elsevier Masson SAS. All rights reserved. |
| WOS关键词 | ASYMMETRIC ALLYLIC AMINATION ; BAYLIS-HILLMAN ADDUCTS ; ANTICANCER AGENTS ; POLYMERIZATION INHIBITOR ; DERIVATIVES ; CELLS ; MECHANISMS ; PHOSPHATE ; DISCOVERY ; MOLECULE |
| 资助项目 | National Natural Science Foundation of China[21472025] ; NSFC[21472208] ; NSFC[81625022] ; NSFC[81430084] ; NSFC[21232009] ; CAS[QYZDY-SSW-SLH012] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000425198100062 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272278]  |
| 专题 | 药物发现与设计中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Ding, Kuiling; Luo, Cheng; Liu, Mingming; Wang, Yang |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 2.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Organometall Chem, Shanghai 200032, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhou, Pengfei,Liang, Yuru,Zhang, Hao,et al. Design, synthesis, biological evaluation and cocrystal structures with tubulin of chiral beta-lactam bridged combretastatin A-4 analogues as potent antitumor agents[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,144:817-842. |
| APA | Zhou, Pengfei.,Liang, Yuru.,Zhang, Hao.,Jiang, Hao.,Feng, Kechang.,...&Wang, Yang.(2018).Design, synthesis, biological evaluation and cocrystal structures with tubulin of chiral beta-lactam bridged combretastatin A-4 analogues as potent antitumor agents.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,144,817-842. |
| MLA | Zhou, Pengfei,et al."Design, synthesis, biological evaluation and cocrystal structures with tubulin of chiral beta-lactam bridged combretastatin A-4 analogues as potent antitumor agents".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 144(2018):817-842. |
入库方式： OAI收割
来源：上海药物研究所
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