方汉林衍生物的合成及作为炎症小体失活的抗炎剂的生物学评价。

Synthesis and Biological Evaluation of Fangchinoline Derivatives as Anti-Inflammatory Agents through Inactivation of Inflammasome.

机构信息

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

Institute for Food and Cosmetics Control, National Institutes for Food and Drug Control, Beijing 100050, China.

出版信息

Molecules. 2019 Mar 23;24(6):1154. doi: 10.3390/molecules24061154.

Twenty eight 7-substitued fangchinoline analogues, of which twenty two were novel, were synthesized and evaluated for their effect to inhibit lipopolysaccharide/nigericin (LPS/NIG)-induced IL-1β release at both cell and protein levels at the concentration of 5 μM. Among them, compound exhibited promising inhibitory potency against IL-β activation with an IC value of 3.7 μM. Preliminary mechanism study revealed that might target NLRP3 protein, and then block ASC pyroptosome formation with-NLRP3, rather than acting on the activation of the NLRP3 inflammasome (NF-κB and MAPK pathways) or caspase-1 protein. Our current study supported the potential role of compound against IL-β activation, and provided powerful information for developing fangchinoline derivatives into a novel class of anti-inflammatory agents.

合成了 28 个 7-取代的防己诺林碱类似物，其中 22 个为新化合物，并用它们在 5 μM 的浓度下，通过细胞水平和蛋白水平来评估其抑制脂多糖/ Nigericin（LPS/NIG）诱导的白细胞介素-1β（IL-1β）释放的效果。其中，化合物对 IL-β 的激活表现出有希望的抑制作用，IC 值为 3.7 μM。初步的机制研究表明，化合物可能靶向 NLRP3 蛋白，然后阻止 ASC 焦亡小体的形成，而不是作用于 NLRP3 炎性体（NF-κB 和 MAPK 途径）或半胱天冬酶-1 蛋白的激活。我们目前的研究支持化合物对 IL-β 激活的潜在作用，并为将防己诺林碱衍生物开发成一类新型抗炎药物提供了有力的信息。