Discovery of a novel inhibitor of nitric oxide production with potential therapeutic effect on acute inflammation. (15th July 2021)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 44(2021)
• Publication Date: 2021-07-15
• Subjects: Anti-inflammatory activity -- Nitric oxide -- Structure-activity relationship -- Chrysamide B; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.128106
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: We have synthesized and evaluated the anti-inflammatory activity of Chrysamide B and its derivatives by targeting nitric oxide signaling pathway. Highlights: Design and synthesis of Chrysamide B and a series of derivatives. The SARs of Chrysamide B and its derivatives inhibiting NO production was summarized. The most active Chrysamide B can obviously inhibit the activation of iNOS. The mechanism of Chrysamide B may be that it interfered with the dimerization of iNOS. The good anti-inflammatory effect in vitro and in vivo of Chrysamide B was observed. Abstract: 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 (IC50 = 0.010 μM) and the activity of iNOS (IC50 = 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.