3-Difluoroalkyl Quaternary Oxindoles Inhibit Macrophage Pyroptosis by Blocking Inflammasome Recruitment of Caspase-1

Qi Xiao; Jin-Sheng Yu; Yufang Wang; Danjun Ma; Jian Zhou; Xin Lou

doi:10.1021/acsmedchemlett.0c00070

3-Difluoroalkyl Quaternary Oxindoles Inhibit Macrophage Pyroptosis by Blocking Inflammasome Recruitment of Caspase-1

ACS Med Chem Lett. 2020 Jun 12;11(7):1392-1401. doi: 10.1021/acsmedchemlett.0c00070. eCollection 2020 Jul 9.

Authors

Qi Xiao¹, Jin-Sheng Yu², Yufang Wang¹, Danjun Ma^{3

4}, Jian Zhou^{2

5}, Xin Lou¹

Affiliations

¹ Model Animal Research Centre, Nanjing University, Nanjing, 210061, China.
² Shanghai Engineering Research Centre of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China.
³ College of Mechanical Engineering, Dongguan University of Technology, Dongguan 523000, China.
⁴ Qingzi Biotechnology (Shenzhen) Co., Ltd., Shenzhen 518116, China.
⁵ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201204, China.

Abstract

Dysregulation of the inflammatory response is a key driver of many debilitating and costly diseases including immune disorders, cancer, and infection. Pyroptosis is a highly inflammatory form of programmed cell death, triggered by various stimuli and meditated by the activation of inflammatory caspases. Pharmacologic agents that provide strategies to modulate pyroptosis for research and clinical practice are still very limited. In current study, we identify 3-difluoroalkyl quaternary oxindoles as chemical inhibitors of caspase-1, the pyroptosis driving caspase. Our results demonstrated compound 6 could directly bind to the CARD domain of pro-caspase-1 to inhibit its infammasome recruitment and pharmacologic inhibition of pyroptotic cell death by compound 6 is partially efficacious in sepsis models. Compound 6 is thus a potential therapeutic for inflammatory disorders and a tool for further study of the inflammation in human health and disease.