3-Difluoroalkyl Quaternary Oxindoles Inhibit Macrophage Pyroptosis by Blocking Inflammasome Recruitment of Caspase-1.,ACS Medicinal Chemistry Letters

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3-Difluoroalkyl Quaternary Oxindoles Inhibit Macrophage Pyroptosis by Blocking Inflammasome Recruitment of Caspase-1.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-06-12 , DOI: 10.1021/acsmedchemlett.0c00070
Qi Xiao ₁ , Jin-Sheng Yu ₂ , Yufang Wang ₁ , Danjun Ma _{3,

4} , Jian Zhou _{2,

5} , Xin Lou ₁

Affiliation

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.

中文翻译：

3-二氟烷基季氧基吲哚通过阻断Caspase-1的炎症小体募集抑制巨噬细胞的凋亡。

炎症反应失调是许多使人衰弱和代价高昂的疾病（包括免疫疾病，癌症和感染）的关键驱动因素。细胞凋亡是程序性细胞死亡的高度炎性形式，其由各种刺激触发并由炎性胱天蛋白酶激活而被冥想。提供用于调节研究和临床实践的调节细胞凋亡的策略的药物仍然非常有限。在当前的研究中，我们确定3-二氟烷基季吲哚是caspase-1的化学抑制剂。我们的结果表明，化合物6可以直接结合caspase-1的CARD结构域，以抑制它的消炎体募集和化合物6抑制焦细胞凋亡的药理作用在败血症模型中部分有效。因此，化合物6是炎症性疾病的潜在治疗剂，并且是进一步研究人类健康和疾病中炎症的工具。

更新日期：2020-07-09

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