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Discovery of Novel Imidazo[4,5-c]quinoline Derivatives to Treat Inflammatory Bowel Disease (IBD) by Inhibiting Multiple Proinflammatory Signaling Pathways and Restoring Intestinal Homeostasis

文献类型：期刊论文

作者Liang, Xuewu2,3; Xie, Yongle2,3; Liu, Xuyi2,3; Xu, Hui2,3; Ren, Hairu1; Tang, Shuai2,3; Liu, Qi2,3; Huang, Min2,3; Shao, Xueqing2,3; Li, Chunpu2,3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-09-02
页码21
ISSN号0022-2623
DOI10.1021/acs.jmedchem.2c00390
通讯作者Xie, Zuoquan(zqxie@simm.ac.cn) ; Liu, Hong(hliu@simm.ac.cn)
英文摘要As a complex pathogenesis driven by immune inflammatory factors and intestinal microbiota, the treatment of inflammatory bowel disease (IBD) may rely on the comprehensive regulation of these important pathogenic factors to reach a favorable therapeutic effect. In the current study, we discovered a series of imidazo[4,5-c]quinoline derivatives that potently and simultaneously inhibited two primary proinflammatory signaling pathways JAK/STAT and NF-kappa B. Especially, lead compound 8l showed potent inhibitory activities against interferon-stimulated genes (IC50: 3.3 nM) and NF-kappa B pathways (IC50: 150.7 nM) and decreased the release of various proinflammatory factors at the nanomolar level, including IL-6, IL-8, IL-1 beta, TNF-alpha, IL-12, and IFN-gamma. In vivo, 8l produced a strong anti-inflammatory activity in both dextran sulfate sodium (DSS)-and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced acute enteritis models and restored the structural composition of gut microbiota. Collectively, this study provided valuable lead compounds for the treatment of IBD and revealed the great anti-inflammatory potential of the simultaneous suppression of JAK/STAT and NF-kappa B signals.
WOS关键词KAPPA-B ACTIVATION ; GUT MICROBIOTA ; COMPLEMENT-SYSTEM ; CYTOKINES ; COLITIS ; CELLS ; BARRIER ; INNATE ; MODELS ; IL-17A
资助项目National Natural Science Foundation of China[21907102] ; National Natural Science Foundation of China[21977106] ; National Natural Science Foundation of China[82103969] ; Lingang Laboratory[LG202103-02-07] ; Lingang Laboratory[LG202103-04-01] ; Lingang Laboratory[LG-QS-202205-09] ; Natural Science Foundation of China[81821005] ; Collaborative Innovation Cluster Project of the Shanghai Municipal Commission of Health and Family Planning[2020CXJQ02]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000860464200001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/302610]  
专题新药研究国家重点实验室
通讯作者Xie, Zuoquan; Liu, Hong
作者单位1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Liang, Xuewu,Xie, Yongle,Liu, Xuyi,et al. Discovery of Novel Imidazo[4,5-c]quinoline Derivatives to Treat Inflammatory Bowel Disease (IBD) by Inhibiting Multiple Proinflammatory Signaling Pathways and Restoring Intestinal Homeostasis[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022:21.
APA Liang, Xuewu.,Xie, Yongle.,Liu, Xuyi.,Xu, Hui.,Ren, Hairu.,...&Liu, Hong.(2022).Discovery of Novel Imidazo[4,5-c]quinoline Derivatives to Treat Inflammatory Bowel Disease (IBD) by Inhibiting Multiple Proinflammatory Signaling Pathways and Restoring Intestinal Homeostasis.JOURNAL OF MEDICINAL CHEMISTRY,21.
MLA Liang, Xuewu,et al."Discovery of Novel Imidazo[4,5-c]quinoline Derivatives to Treat Inflammatory Bowel Disease (IBD) by Inhibiting Multiple Proinflammatory Signaling Pathways and Restoring Intestinal Homeostasis".JOURNAL OF MEDICINAL CHEMISTRY (2022):21.

入库方式： OAI收割

来源：上海药物研究所

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