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Development of Bisindole-Substituted Aminopyrazoles as Novel GSK-3 beta Inhibitors with Suppressive Effects against Microglial Inflammation and Oxidative Neurotoxicity

文献类型：期刊论文

作者Liu, Jian-Guo1,2; Zhao, Danfeng3; Gong, Qi3; Bao, Fengxia3; Chen, Wen-Wen1; Zhang, Haiyan3; Xu, Ming-Hua1,2
刊名ACS CHEMICAL NEUROSCIENCE
出版日期2020-10-21
卷号11期号:20页码:3398-3408
ISSN号1948-7193
关键词Glycogen synthase kinase-3 bisindole-substituted aminopyrazoles Alzheimer's disease oxidative neurotoxicity microglial inflammation
DOI10.1021/acschemneuro.0c00520
通讯作者Chen, Wen-Wen(wenwen@shnu.edu.cn) ; Zhang, Haiyan(hzhang@simm.ac.cn) ; Xu, Ming-Hua(xumh@sustech.edu.cn)
英文摘要Development of glycogen synthase kinase-3 beta (GSK-3 beta) inactivation-centric agents with polypharmacological profiles is increasingly recognized as a promising therapeutic strategy against the multifactorial etiopathology of Alzheimer's disease (AD). In this respect, a series of disubstituted aminopyrazole derivatives were designed and synthesized as a new class of GSK-3 beta inhibitors. Most of these derivatives possess GSK-3 beta inhibitory activities with IC50 values in the micromolar ranges, among which bisindole-substituted aminopyrazole derivative 6h displayed moderate GSK-3 beta inhibition (IC50 = 1.76 +/- 0.19 mu M), and alleviative effects against lipopolysaccharide (LPS)-induced glial inflammation in BV-2 cells and glutamate-induced oxidative neurotoxicity in HT-22 cells. Further in vivo studies indicated that compound 6h had potent anti-inflammatory effect, by showing markedly reduced microglial activation and astrocyte proliferation in the brain of LPS-injected mice. Overall, the simultaneous modulation of 6h on multiple dysfunctions of disease network highlights this structural distinctively bisindole-substituted aminopyrazole could be a useful prototype for the discovery of novel therapeutic agents to tackle AD and other GSK-3 beta associated complex neurological syndromes.
WOS关键词GLYCOGEN-SYNTHASE KINASE-3-BETA ; ALZHEIMERS-DISEASE ; BIOLOGICAL EVALUATION ; POTENT INHIBITORS ; DESIGN ; IDENTIFICATION ; DERIVATIVES ; KINASES ; STRESS ; GSK3
资助项目National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002-006] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002-018] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA 12040106] ; National Natural Science Foundation of China[81402798] ; National Natural Science Foundation of China[81521005] ; Shenzhen Science and Technology Innovation Committee[ZDSYS20190902093215877]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Neurosciences & Neurology
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000584491300025
源URL[http://119.78.100.183/handle/2S10ELR8/296234]  
专题新药研究国家重点实验室
通讯作者Chen, Wen-Wen; Zhang, Haiyan; Xu, Ming-Hua
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Southern Univ Sci & Technol, Dept Chem, Shenzhen Key Lab Small Mol Drug Discovery & Synth, Shenzhen 518055, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Jian-Guo,Zhao, Danfeng,Gong, Qi,et al. Development of Bisindole-Substituted Aminopyrazoles as Novel GSK-3 beta Inhibitors with Suppressive Effects against Microglial Inflammation and Oxidative Neurotoxicity[J]. ACS CHEMICAL NEUROSCIENCE,2020,11(20):3398-3408.
APA Liu, Jian-Guo.,Zhao, Danfeng.,Gong, Qi.,Bao, Fengxia.,Chen, Wen-Wen.,...&Xu, Ming-Hua.(2020).Development of Bisindole-Substituted Aminopyrazoles as Novel GSK-3 beta Inhibitors with Suppressive Effects against Microglial Inflammation and Oxidative Neurotoxicity.ACS CHEMICAL NEUROSCIENCE,11(20),3398-3408.
MLA Liu, Jian-Guo,et al."Development of Bisindole-Substituted Aminopyrazoles as Novel GSK-3 beta Inhibitors with Suppressive Effects against Microglial Inflammation and Oxidative Neurotoxicity".ACS CHEMICAL NEUROSCIENCE 11.20(2020):3398-3408.

入库方式： OAI收割

来源：上海药物研究所

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