Design and synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole carboxamides as novel orally efficacious Poly(ADP-ribose)polymerase (PARP) inhibitors
文献类型：期刊论文
| 作者 | Chen, Xuxing2,3; Huan, Xiajuan1; Liu, Qiufeng3,4; Wang, Yuqin2; He, Qian2 ; Tan, Cun2; Chen, Yi1; Ding, Jian1; Xu, Yechun4; Miao, Zehong1
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2018-02-10 |
| 卷号 | 145页码:389-403 |
| 关键词 | PARP1/2 inhibitor Benzimidazole 4,5,6,7-Tetrahydrothienopyridine Co-crystal structure Isothermal Titration Calorimetry |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2018.01.018 |
| 文献子类 | Article |
| 英文摘要 | The nuclear protein poly(ADP-ribose) polymerases-1/2 (PARP-1/2) are involved in DNA repair damaged by endogenous or exogenous process. And PARP-1/2 inhibitors have been proved to be clinically efficacious for DNA repair deficient tumors in the past decade. We have developed a series of 4,5,6,7-tetrahydrothienopyridin-2-yl benzimidazole carboxamides as novel and potent PARP-1/2 inhibitors. The best compound resulted from this series is compound 27 which displays excellent PARP-1 and PARP-2 inhibitory activity with IC50 of 18 nM and 42 nM, respectively. Furthermore, it can selectively kill BRCA2 deficient V-C8 cells with a CC50 of 920 nM. In the MDA-MB-436 (BRCA-1 mutant) xenograft model, this compound was well tolerated and showed single-agent activity. Based on the results above, compound 27 has been selected as a lead candidate targeting PARP-1/2 and its preclinical characterization is also underway. (C) 2018 Elsevier Masson SAS. All rights reserved. |
| WOS关键词 | CANCER-THERAPY ; POLYMERASE INHIBITORS ; BIOLOGICAL EVALUATION ; ANTICANCER ACTIVITY ; EXCISION-REPAIR ; CELLS ; TARGETS ; CYTOTOXICITY ; ACTIVATION ; BINDING |
| 资助项目 | National Natural Science Foundation of China[21072205] ; National Natural Science Foundation of China[81422047] ; Chinese Academy of Sciences[CASIMM0120152003] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000425198200032 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279907]  |
| 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 药物化学研究室 药理学第一研究室 |
| 通讯作者 | Xu, Yechun; Miao, Zehong; Yang, Chunhao |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Synthet Organ & Med Chem Lab, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Xuxing,Huan, Xiajuan,Liu, Qiufeng,et al. Design and synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole carboxamides as novel orally efficacious Poly(ADP-ribose)polymerase (PARP) inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,145:389-403. |
| APA | Chen, Xuxing.,Huan, Xiajuan.,Liu, Qiufeng.,Wang, Yuqin.,He, Qian.,...&Yang, Chunhao.(2018).Design and synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole carboxamides as novel orally efficacious Poly(ADP-ribose)polymerase (PARP) inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,145,389-403. |
| MLA | Chen, Xuxing,et al."Design and synthesis of 2-(4,5,6,7-tetrahydrothienopyridin-2-yl)-benzoimidazole carboxamides as novel orally efficacious Poly(ADP-ribose)polymerase (PARP) inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 145(2018):389-403. |
入库方式： OAI收割
来源：上海药物研究所
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