Zhu Long-Qing, Fan Xiao-Hong, Li Jun-Fang, Chen Jin-Hong, Liang Yan, Hu Xiao-Ling, Ma Shu-Meng, Hao Xiang-Yong, Shi Tao, Wang Zhen
School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, China.
Bioorg Med Chem Lett. 2021 Jul 15;44:128106. doi: 10.1016/j.bmcl.2021.128106. Epub 2021 May 13.
Inflammation as a host's excessive immune response to stimulation, is involved in the development of numerous diseases. To discover novel anti-inflammatory agents and based on our previous synthetic work on marine natural product Chrysamide B, it and a series of derivatives were synthesized and evaluated for their anti-inflammatory activity on inhibition of LPS-induced NO production. Then the preliminary structure-activity relationships were conducted. Among them, Chrysamide B is the most potent anti-inflammatory agent with low cytotoxicity and strong inhibition on the production of NO (IC = 0.010 μM) and the activity of iNOS (IC = 0.082 μM) in LPS-stimulated RAW 264.7 cells. Primary studies suggested that the mechanism of action may be that it interfered the formation of active dimeric iNOS but not affected transcription and translation. Furthermore, its good performance of anti-inflammatory effect on LPS-induced multiple inflammatory cytokines production, carrageenan-induced paw edema, and endotoxin-induced septic mice, was observed. We believe that these findings would provide an idea for the further modification and research of these analogs in the future.
炎症作为宿主对刺激的过度免疫反应，参与了多种疾病的发生发展。为了发现新型抗炎剂，基于我们之前对海洋天然产物Chrysamide B的合成工作，合成了它及其一系列衍生物，并评估了它们对脂多糖诱导的一氧化氮（NO）产生的抑制作用的抗炎活性。然后进行了初步的构效关系研究。其中，Chrysamide B是最有效的抗炎剂，对脂多糖刺激的RAW 264.7细胞中NO的产生（IC = 0.010 μM）和诱导型一氧化氮合酶（iNOS）的活性（IC = 0.082 μM）具有低细胞毒性和强烈抑制作用。初步研究表明，其作用机制可能是干扰了活性二聚体iNOS的形成，但不影响转录和翻译。此外，还观察到它对脂多糖诱导的多种炎性细胞因子产生、角叉菜胶诱导的爪肿胀以及内毒素诱导的脓毒症小鼠具有良好的抗炎作用。我们相信这些发现将为未来这些类似物的进一步修饰和研究提供思路。
