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Design, Synthesis, and Biological Evaluation of a Series of Benzo[de][1,7]naphthyridin-7(8H)-ones Bearing a Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors

文献类型：期刊论文

作者Ye, Na2,3; Chen, Chuan-Huizi4; Chen, TianTian1,2; Song, Zilan2,3; He, Jin-Xue4; Huan, Xia-Juan4; Song, Shan-Shan4; Liu, Qiufeng1,2; Chen, Yi4; Ding, Jian4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2013-04-11
卷号56期号:7页码:2885-2903
ISSN号0022-2623
DOI10.1021/jm301825t
文献子类Article
英文摘要A series of benzo[de][1,7]naphthyridin-7(8H)-ones possessing a functionalized long-chain appendage have been designed and evaluated as novel PARP1 inhibitors. The initial effort led to the first-generation PARP1 inhibitor 26 bearing a terminal phthalazin-1(2H)-one framework and showing remarkably high PARP1 inhibitory activity (0.31 nM) but only moderate potency in the cell. Further effort generated the second-generation lead 41, showing high potency against both the PARP1 enzyme and BRCA-deficient cells, especially for the BRCA1-deficient MDA-MB-436 cells (CC50 < 0.26 nM). Mechanistic studies revealed that the new PARP1 inhibitors significantly inhibited H2O2-triggered PARylation in SKOV3 cells, induced cellular accumulation of DNA double-strand breaks, and impaired cell-cycle progression in BRCA2-deficient cells. Significant potentiation on the cytotoxicity of Temozolomide was also observed. The unique structural character and exceptionally high potency of 41 made it stand out as a promising drug candidate worthy for further evaluation.
WOS关键词POLY(ADP-RIBOSE) POLYMERASE INHIBITORS ; DNA-DAMAGE RESPONSE ; CANCER-THERAPY ; HIGHLY POTENT ; BREAST-CANCER ; PHASE-I ; IDENTIFICATION ; DISCOVERY ; CELLS ; OLAPARIB
资助项目Distinguished Young Scholars of Chinese NSF[81125021] ; Distinguished Young Scholars of Chinese NSF[81025020] ; Chinese National Science Foundation[81072528] ; Chinese National Science Foundation[81021062] ; National Science & Technology Major Project of China[2012ZX09103-101-035] ; National Science & Technology Major Project of China[2012ZX09301001-001] ; National Science & Technology Major Project of China[2012ZX09301-001-002] ; National Science & Technology Major Project of China[2010ZX09401-401] ; National Basic Research Program of China[2012CB932502] ; CAS[00000000] ; State Key Laboratory of Medical Neurobiology and Collaborative Innovation Center for Brain Function and Remodeling[00000000]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000317551700015
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/277656]  
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
作者单位1.Chinese Acad Sci, SIMM, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, SIMM, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China;
3.Chinese Acad Sci, SIMM, Synthet Organ & Med Chem Lab, Shanghai 201203, Peoples R China;
4.Chinese Acad Sci, SIMM, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
推荐引用方式
GB/T 7714		 Ye, Na,Chen, Chuan-Huizi,Chen, TianTian,et al. Design, Synthesis, and Biological Evaluation of a Series of Benzo[de][1,7]naphthyridin-7(8H)-ones Bearing a Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2013,56(7):2885-2903.
APA Ye, Na.,Chen, Chuan-Huizi.,Chen, TianTian.,Song, Zilan.,He, Jin-Xue.,...&Zhang, Ao.(2013).Design, Synthesis, and Biological Evaluation of a Series of Benzo[de][1,7]naphthyridin-7(8H)-ones Bearing a Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,56(7),2885-2903.
MLA Ye, Na,et al."Design, Synthesis, and Biological Evaluation of a Series of Benzo[de][1,7]naphthyridin-7(8H)-ones Bearing a Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY 56.7(2013):2885-2903.

入库方式： OAI收割

来源：上海药物研究所

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