Synthesis and pharmacological validation of fluorescent diarylsulfonylurea analogues as NLRP3 inhibitors and imaging probes

doi:10.1016/j.ejmech.2022.114338

	Synthesis and pharmacological validation of fluorescent diarylsulfonylurea analogues as NLRP3 inhibitors and imaging probes
	Zhao, Jiannan1,2,4,5 ; Li, Yongling 2,3; Ma, Jing 2; Liu, Jingting 2; Xiao, Ruoxuan 2; Wang, Linlin 8; Li, Peng 7; He, Yinyan 6; Qian, Feng 2; Zhang, Ao1,2,4,5 ; Sun, Zhen-Liang 3; Ding, Chunyong 2
	2022-07-05
发表期刊	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (IF:6.0[JCR-2023],6.1[5-Year])
ISSN	0223-5234
EISSN	1768-3254
卷号	237
发表状态	已发表
DOI	10.1016/j.ejmech.2022.114338
摘要	The NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) is a key cytosolic pattern recognition receptor that senses diverse pathogen- and host-originated threat signals. Aberrant activation of NLRP3 inflammasomes is closely associated with the pathogenesis of various complex inflammatory diseases. Nevertheless, the detailed regulation mechanism of NLRP3 inflammasome and its pathogenic roles in the inflammation progression remain to be fully elucidated. Fluorescent imaging with small molecule probe can provide valuable visualization information on the expression, occupancy and bio-distribution of target protein. Herein, we reported a series of diarylsulfonylurea NLRP3 fluorescent inhibitors bearing an amino benzodiazole fluorophore. Compared to the previously reported NLRP3 fluorescent probes, these inhibitors are more structurally concise and membrane permeable due to no additionally appended fluorophore via a linker. Among this series, compound 13a exhibited the most potent cellular NLRP3 inhibitory effect with an IC value of 49 nM, and significantly suppressed LPS/Nigericin-induced secretion of active caspase-1 and mature IL-1β in a dose-dependent manner to block the activation of NLRP3 inflammasome. Meanwhile, this new probe exhibited promising fluorescent properties for specifically detecting and imaging the LPS-induced or constitutively expressed NLRP3 proteins in RAW264.7 cells. Collectively, probe 13a is a potent NLRP3 fluorescent inhibitor with cellular NLRP3 imaging ability, which is useful for NLRP3 inhibitor screening and related mechanism study.
关键词	Fluorescence imaging Inflammasome Inhibitor NLRP3 Sulfonylurea
URL	查看原文
收录类别	SCIE ; SCI ; IC
语种	英语
资助项目	National Natural Science Foundation of China[21877120,22177068,81872418] ; Science and Technology Commission of Shanghai Municipality["21ZR1429100","21S11902000",21142203500] ; Shanghai Jiao Tong University["AF1700037","WF220217002","WH101117001","WF540162618"]
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Chemistry, Medicinal
WOS记录号	WOS:000793638500008
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Scopus 记录号	2-s2.0-85128198698
来源库	Scopus
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/176063
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	Sun, Zhen-Liang; Ding, Chunyong
作者单位	1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 2.Shanghai Jiao Tong Univ, Pharm X Ctr, Sch Pharmaceut Sci, Shanghai 200240, Peoples R China 3.Southern Med Univ, Affiliated Fengxian Hosp, Sch Pharmaceut Sci, Shanghai 201499, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, Shanghai 201203, Peoples R China 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 6.Tongji Univ, Shanghai Matern & Infant Hosp 1, Dept Gynecol Oncol, Sch Med, Shanghai 201204, Peoples R China 7.Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Macau 999078, Peoples R China 8.Univ Shanghai Sci & Technol, Sch Hlth Sci & Engn, Shanghai 200093, Peoples R China
第一作者单位	生命科学与技术学院
第一作者的第一单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Zhao, Jiannan,Li, Yongling,Ma, Jing,et al. Synthesis and pharmacological validation of fluorescent diarylsulfonylurea analogues as NLRP3 inhibitors and imaging probes[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2022,237.
APA	Zhao, Jiannan.,Li, Yongling.,Ma, Jing.,Liu, Jingting.,Xiao, Ruoxuan.,...&Ding, Chunyong.(2022).Synthesis and pharmacological validation of fluorescent diarylsulfonylurea analogues as NLRP3 inhibitors and imaging probes.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,237.
MLA	Zhao, Jiannan,et al."Synthesis and pharmacological validation of fluorescent diarylsulfonylurea analogues as NLRP3 inhibitors and imaging probes".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 237(2022).