Discovery of a Potential Anti-Inflammatory Agent: 3-Oxo-29-noroleana-1,9(11),12-trien-2,20-dicarbonitrile

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• 作者：Ran You ; Wenyan Long ; Zhonghui Lai ; Lei Sha ; Kai Wu ; Xing Yu ; Yisheng Lai ; Hui Ji ; Zhangjian Huang ; Yihua Zhang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 14, 2013
• 年：2013
• 卷：56
• 期：5
• 页码：1984-1995
• 全文大小：550K
• 年卷期：v.56,no.5(March 14, 2013)
• ISSN：1520-4804

文摘

Fifteen novel derivatives of glycyrrhetinic acid (GA) were synthesized and evaluated for anti-inflammatory activities. It was found that the introduction of 1-en-3-one and 9(11),12-diene and 2,20-dinitrile functionalities into the scaffold of GA led to the discovery of potent compound 19 for inhibition of LPS-induced NO production. Furthermore, 19 effectively inhibited the protein and mRNA expression of inducible NO synthase (iNOS) and the mRNA expression of TNF-伪, IL-6, and IL-1尾 in LPS-stimulated RAW 264.7 macrophages. Mechanistically, 19 exerted inhibitory effects on the activation of the three main MAPKs and phosphorylation and degradation of I魏B-伪, as well as the ratio of nuclear/cytosolic content of p65. Importantly, 19 significantly decreased the mortality rate in the mouse model of LPS-induced sepsis shock. It is noteworthy that inhibitory effect of 19 on NO production was not blocked by the glucocorticoid receptor antagonist mifepristone, indicating that it does not act through the glucocorticoid receptor.