2. Academic Validation
  3. Discovery of Novel Pterostilbene-Based Derivatives as Potent and Orally Active NLRP3 Inflammasome Inhibitors with Inflammatory Activity for Colitis

Discovery of Novel Pterostilbene-Based Derivatives as Potent and Orally Active NLRP3 Inflammasome Inhibitors with Inflammatory Activity for Colitis

  • J Med Chem. 2021 Sep 23;64(18):13633-13657. doi: 10.1021/acs.jmedchem.1c01007.
Liu Zeng Chen 1 2,  Xing Xing Zhang 1,  Ming Ming Liu 1,  Jing Wu 1,  Duo Ma 1,  Liang Zhuo Diao 1,  Qingshan Li 3,  Yan Shuang Huang 1,  Rui Zhang 1,  Ban Feng Ruan 2,  Xin Hua Liu 1
Affiliations

Affiliations

  • 1 School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, P.R. China.
  • 2 Key Lab of Biofabrication of Anhui Higher Education, Hefei University, Hefei 230601, P.R. China.
  • 3 School of Food and Biological Engineering, Hefei University of Technology, Hefei 230059, P.R. China.
PMID: 34506712 DOI: 10.1021/acs.jmedchem.1c01007
Abstract

Studies have shown that the abnormal activation of the NLRP3 inflammasome is involved in a variety of inflammatory-based diseases. In this study, a high content screening model targeting the activation of inflammasome was first established and pterostilbene was discovered as the active scaffold. Based on this finding, total of 50 pterostilbene derivatives were then designed and synthesized. Among them, compound 47 was found to be the best one for inhibiting cell Pyroptosis [inhibitory rate (IR) = 73.09% at 10 μM], showing low toxicity and high efficiency [against interleukin-1β (IL-1β): half-maximal inhibitory concentration (IC50) = 0.56 μM]. Further studies showed that compound 47 affected the assembly of the NLRP3 inflammasomes by targeting NLRP3. The in vivo biological activity showed that this compound significantly alleviated dextran sodium sulfate (DSS)-induced colitis in mice. In general, our study provided a novel lead compound directly targeting the NLRP3 protein, which is worthy of further research and structural optimization.

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