2. Academic Validation
  3. Synthesis and pharmacological validation of fluorescent diarylsulfonylurea analogues as NLRP3 inhibitors and imaging probes

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

  • Eur J Med Chem. 2022 Jul 5;237:114338. doi: 10.1016/j.ejmech.2022.114338.
Jiannan Zhao 1,  Yongling Li 2,  Jing Ma 3,  Jingting Liu 3,  Ruoxuan Xiao 3,  Linlin Wang 4,  Peng Li 5,  Yinyan He 6,  Feng Qian 3,  Ao Zhang 1,  Zhen-Liang Sun 7,  Chunyong Ding 8
Affiliations

Affiliations

  • 1 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Pharm-X Center, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 2 Pharm-X Center, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; Affiliated Fengxian Hospital, School of Pharmaceutical Science, Southern Medical University, Shanghai, 201499, China.
  • 3 Pharm-X Center, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 4 School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China.
  • 5 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, China.
  • 6 Department of Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201204, China.
  • 7 Affiliated Fengxian Hospital, School of Pharmaceutical Science, Southern Medical University, Shanghai, 201499, China. Electronic address: [email protected].
  • 8 Pharm-X Center, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China. Electronic address: [email protected].
PMID: 35436667 DOI: 10.1016/j.ejmech.2022.114338
Abstract

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 IC50 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.

Keywords

Fluorescence imaging; Inflammasome; Inhibitor; NLRP3; Sulfonylurea.

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