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Discovery of chiral N-2 '-aryletheryl-1 '-alkoxy-ethyl substituted arylisoquinolones with anti-inflammatory activity from the nucleophilic addition reactions of the thiophenols and oxazolinium

文献类型：期刊论文

作者Li, Bo1,2,3; Li, Heng3,4; Zhu, Zhengdan1,2,3; Xiang, Caigui3,4; Xu, Zhijian1,2,3; Fan, Chen4; Zhao, Yitian1; Feng, Chunlan4; Sun, Haiguo1,2,3; Zhang, Yong1,2,3
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021-10-15
卷号222页码:11
ISSN号0223-5234
关键词Anti-inflammatory activity TNF alpha ER beta IBD Arylisoquinolones
DOI10.1016/j.ejmech.2021.113583
通讯作者Tang, Wei(tangwei@simm.ac.cn) ; Zhu, Weiliang(wlzhu@simm.ac.cn)
英文摘要Herein we disclosed the novel nucleophilic addition reactions of the thiophenols and oxazolinium (DCZ0358) to produce N-2'-aryletheryl-1'-alkoxy-ethyl substituted arylisoquinolones. After evaluating the anti-inflammatory activity in vitro, 2d was found having significant anti-TNF alpha activity. Through the amplified synthesis of 2d, four monomers (3a-b and 4a-d) were obtained by chiral separation of the product. The reaction mechanism was proposed and explored by the control experiments. However, only the R-stereoisomers 3b and 4b have significant anti-TNF alpha activity in vitro (IC50 = 56 and 14 nM, respectively). Moreover, 4b exerts potent therapeutic effects on ulcerative colitis in vivo (30 mg/kg bw, qd, i. g.). The subsequent bio-target exploration of compound 4b via molecular docking and the experimental validation disclosed that 4b has 3-fold selectivity of binding activity on estrogen receptor (ER) beta (beta) (Ki = 760.86 nM) vs. alpha (alpha) (Ki = 2320.58 nM). Thus, it provides a novel type of non-steroidal leads for developing anti-inflammatory drugs. (C) 2021 Elsevier Masson SAS. All rights reserved.
资助项目Natural Science Foundation of China[22077131] ; Natural Science Foundation of China[81872797] ; National Key Research and Development Program of China[2016YFA0502301] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002] ; Natural Science Foundation of Shanghai, China[19ZR1467800]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号WOS:000685593800024
源URL[http://119.78.100.183/handle/2S10ELR8/297961]  
专题中国科学院上海药物研究所
通讯作者Tang, Wei; Zhu, Weiliang
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Sch Pharm, 19A Yuquan Rd, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Lab Antiinflammat & Immunopharmacol, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Li, Bo,Li, Heng,Zhu, Zhengdan,et al. Discovery of chiral N-2 '-aryletheryl-1 '-alkoxy-ethyl substituted arylisoquinolones with anti-inflammatory activity from the nucleophilic addition reactions of the thiophenols and oxazolinium[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2021,222:11.
APA Li, Bo.,Li, Heng.,Zhu, Zhengdan.,Xiang, Caigui.,Xu, Zhijian.,...&Zhu, Weiliang.(2021).Discovery of chiral N-2 '-aryletheryl-1 '-alkoxy-ethyl substituted arylisoquinolones with anti-inflammatory activity from the nucleophilic addition reactions of the thiophenols and oxazolinium.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,222,11.
MLA Li, Bo,et al."Discovery of chiral N-2 '-aryletheryl-1 '-alkoxy-ethyl substituted arylisoquinolones with anti-inflammatory activity from the nucleophilic addition reactions of the thiophenols and oxazolinium".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 222(2021):11.

入库方式： OAI收割

来源：上海药物研究所

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