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Synthesis and Target Identification of Benzoxepane Derivatives as Potential Anti-Neuroinflammatory Agents for Ischemic Stroke

文献类型：期刊论文

作者Gao, Cheng-Long1,2; Hou, Gui-Ge1,3; Liu, Jin1; Ru, Tong1; Xu, Ya-Zhou2; Zhao, Shun-Yi2; Ye, Hui2; Zhang, Lu-Yong2; Chen, Kai-Xian1,4; Guo, Yue-Wei1,4
刊名ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
出版日期2020-02-03
卷号59期号:6页码:2429-2439
ISSN号1433-7851
关键词anti-inflammatory drug discovery heterocycles photoaffinity labeling proteins
DOI10.1002/anie.201912489
通讯作者Guo, Yue-Wei(ywguo@simm.ac.cn) ; Pang, Tao(tpang@cpu.edu.cn) ; Li, Xu-Wen(xwli@simm.ac.cn)
英文摘要Benzoxepane derivatives were designed and synthesized, and one hit compound emerged as being effective in vitro with low toxicity. In vivo, this hit compound ameliorated both sickness behavior through anti-inflammation in LPS-induced neuroinflammatory mice model and cerebral ischemic injury through anti-neuroinflammation in rats subjected to transient middle cerebral artery occlusion. Target fishing for the hit compound using photoaffinity probes led to identification of PKM2 as the target protein responsible for anti-inflammatory effect of the hit compound. Furthermore, the hit exhibited an anti-neuroinflammatory effect in vitro and in vivo by inhibiting PKM2-mediated glycolysis and NLRP3 activation, indicating PKM2 as a novel target for neuroinflammation and its related brain disorders. This hit compound has a better safety profile compared to shikonin, a reported PKM2 inhibitor, identifying it as a lead compound in targeting PKM2 for the treatment of inflammation-related diseases.
WOS关键词PHOTO-CROSS-LINKERS ; INHIBITORS ; EXPANSION ; ASSAY ; CELL
资助项目National Natural Science Foundation of China (NSFC)[81991521] ; National Natural Science Foundation of China (NSFC)[41676073] ; National Natural Science Foundation of China (NSFC)[81973512] ; National Natural Science Foundation of China (NSFC)[81520108028] ; National Natural Science Foundation of China (NSFC)[21672230] ; NSFC/CNRS joint project[81811530284] ; Drug Innovation Major Project[2018ZX09711-001-001-009] ; Natural Science Foundation of Jiangsu Province[BK20160032] ; Double First-Class Project of China Pharmaceutical University[CPU2018GY06] ; Double First-Class Project of China Pharmaceutical University[CPU2018GY20] ; Six Talent Peaks Project of Jiangsu Province ; SKLDR/SIMM Project[SIMM1903ZZ-04] ; Youth Innovation Promotion Association from the Chinese Academy of Sciences[2016258] ; SA-SIBS Scholarship Program
WOS研究方向Chemistry
语种英语
出版者WILEY-V C H VERLAG GMBH
WOS记录号WOS:000504475800001
源URL[http://119.78.100.183/handle/2S10ELR8/282290]  
专题新药研究国家重点实验室
通讯作者Guo, Yue-Wei; Pang, Tao; Li, Xu-Wen
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zu Chong Zhi Rd,Zhangjiang Hitech Pk, Shanghai 201203, Peoples R China
2.China Pharmaceut Univ, Jiangsu Key Lab Drug Screening, State Key Lab Nat Med, 24 Tong Jia Xiang St, Nanjing 210009, Jiangsu, Peoples R China
3.Binzhou Med Univ, Sch Pharm, State Adm Tradit Chinese Med China, Key Lab Prescript Effect & Clin Evaluat, Yantai 264003, Peoples R China
4.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Druggabil Res Marine Nat Prod, 1 Wenhai Rd, Qingdao 266237, Shandong, Peoples R China
推荐引用方式
GB/T 7714		 Gao, Cheng-Long,Hou, Gui-Ge,Liu, Jin,et al. Synthesis and Target Identification of Benzoxepane Derivatives as Potential Anti-Neuroinflammatory Agents for Ischemic Stroke[J]. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,2020,59(6):2429-2439.
APA Gao, Cheng-Long.,Hou, Gui-Ge.,Liu, Jin.,Ru, Tong.,Xu, Ya-Zhou.,...&Li, Xu-Wen.(2020).Synthesis and Target Identification of Benzoxepane Derivatives as Potential Anti-Neuroinflammatory Agents for Ischemic Stroke.ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,59(6),2429-2439.
MLA Gao, Cheng-Long,et al."Synthesis and Target Identification of Benzoxepane Derivatives as Potential Anti-Neuroinflammatory Agents for Ischemic Stroke".ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 59.6(2020):2429-2439.

入库方式： OAI收割

来源：上海药物研究所

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