Synthesis and Pharmacological Evaluation of Tetrahydro-gamma-carboline Derivatives as Potent Anti-inflammatory Agents Targeting Cyclic GMP-AMP Synthase

doi:10.1021/acs.jmedchem.1c00398

	Synthesis and Pharmacological Evaluation of Tetrahydro-gamma-carboline Derivatives as Potent Anti-inflammatory Agents Targeting Cyclic GMP-AMP Synthase
	Tan, Jing 1,2,3; Wu, Bing 1,3; Chen, Tingting 2; Fan, Chen 1,3; Zhao, Jiannan1,2,3,4 ; Xiong, Chaodong 1,2,3; Feng, Chunlan 1,3; Xiao, Ruoxuan 2; Ding, Chunyong 2; Tang, Wei 1,3; Zhang, Ao1,2,3,4
	2021-06-10
发表期刊	JOURNAL OF MEDICINAL CHEMISTRY (IF:6.8[JCR-2023],7.1[5-Year])
ISSN	0022-2623
EISSN	1520-4804
卷号	64 期号:11 页码:7667-7690
DOI	10.1021/acs.jmedchem.1c00398
摘要	The activation of cyclic GMP-AMP synthase (cGAS) by double-stranded DNA is implicated in the pathogenesis of many hyperinflammatory and autoimmune diseases, and the cGAS-targeting small molecule has emerged as a novel therapeutic strategy for treating these diseases. However, the currently reported cGAS inhibitors are far beyond maturity, barely demonstrating in vivo efficacy. Inspired by the structural novelty of compound 5 (G140), we conducted a structural optimization on both its side chain and the central tricyclic core, leading to several subseries of compounds, including those unexpectedly cyclized complex ones. Compound 25 bearing an N-glycylglycinoyl side chain was identified as the most potent one with cellular IC50 values of 1.38 and 11.4 mu M for h- and m-cGAS, respectively. Mechanistic studies confirmed its direct targeting of cGAS. Further, compound 25 showed superior in vivo anti-inflammatory effects in the lipopolysaccharide-induced mouse model. The encouraging result of compound 25 provides solid evidence for further pursuit of cGAS-targeting inhibitors as a new anti-inflammatory treatment.
收录类别	SCIE
语种	英语
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Chemistry, Medicinal
WOS记录号	WOS:000662187100036
出版者	AMER CHEMICAL SOC
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/127610
专题	生命科学与技术学院_博士生生命科学与技术学院_特聘教授组_张翱组
通讯作者	Ding, Chunyong; Tang, Wei; Zhang, Ao
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, Shanghai 201203, Peoples R China; 2.Shanghai Jiao Tong Univ, Sch Pharm, Pharm Ctr 10, Shanghai 200240, Peoples R China; 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Tan, Jing,Wu, Bing,Chen, Tingting,et al. Synthesis and Pharmacological Evaluation of Tetrahydro-gamma-carboline Derivatives as Potent Anti-inflammatory Agents Targeting Cyclic GMP-AMP Synthase[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(11):7667-7690.
APA	Tan, Jing.,Wu, Bing.,Chen, Tingting.,Fan, Chen.,Zhao, Jiannan.,...&Zhang, Ao.(2021).Synthesis and Pharmacological Evaluation of Tetrahydro-gamma-carboline Derivatives as Potent Anti-inflammatory Agents Targeting Cyclic GMP-AMP Synthase.JOURNAL OF MEDICINAL CHEMISTRY,64(11),7667-7690.
MLA	Tan, Jing,et al."Synthesis and Pharmacological Evaluation of Tetrahydro-gamma-carboline Derivatives as Potent Anti-inflammatory Agents Targeting Cyclic GMP-AMP Synthase".JOURNAL OF MEDICINAL CHEMISTRY 64.11(2021):7667-7690.