期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 5, 页码 1984-1995出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm301652t
关键词
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资金
- Natural Science Foundation of Jiangsu Province [BK2011626]
- Research and Innovation Project for College Graduates of Simcere Pharmaceutical Group [SPG02705164]
- Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University
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-alpha, IL-6, and IL-1 beta 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 kappa B-alpha, 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.
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