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
复制标题
DOI：
10.1021/acs.jmedchem.1c01007
复制
发表时间：
2021-09-10
影响因子：
7.3
通讯作者：
Liu, Xin Hua
中科院分区：
文献类型：
--
作者：
Chen, Liu Zeng;Zhang, Xing Xing;Liu, Xin Hua
研究表明，NLRP 3炎性体的异常激活参与了多种炎症性疾病。本研究首次建立了以炎性小体激活为靶点的高内涵筛选模型，发现了紫檀芪作为活性支架。在此基础上，设计并合成了50个紫檀芪衍生物。其中，发现化合物47是抑制细胞凋亡的最佳化合物[在10 μ M时抑制率（IR）= 73.09%]，显示出低毒性和高效率[对白细胞介素-1 β（IL-1 β）：半数最大抑制浓度（IC 50）= 0.56 μ M]。进一步的研究表明，化合物47通过靶向NLRP 3影响NLRP 3炎性体的组装。体内生物学活性表明，该化合物显着减轻葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎。总之，我们的研究提供了一种新的直接靶向NLRP 3蛋白的先导化合物，值得进一步研究和结构优化。
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 mu M], showing low toxicity and high efficiency [against interleukin-1 beta (IL-1 beta): half-maximal inhibitory concentration (IC50) = 0.56 mu M]. 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.