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

被引：57

作者：

You, Ran ^{[1
,2
]}

Long, Wenyan ^{[1
,3
]}

Lai, Zhonghui ^{[4
]}

Sha, Lei ^{[1
,3
]}

Wu, Kai ^{[1
,3
]}

Yu, Xing ^{[1
,2
]}

Lai, Yisheng ^{[1
,3
]}

Ji, Hui ^{[1
,2
]}

Huang, Zhangjian ^{[1
,3
]}

Zhang, Yihua ^{[1
,3
]}

机构：

[1] China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Peoples R China

[2] China Pharmaceut Univ, Dept Pharmacol, Nanjing 210009, Peoples R China

[3] China Pharmaceut Univ, Ctr Drug Discovery, Nanjing 210009, Peoples R China

[4] China Pharmaceut Univ, Sch Pharm, Nanjing 210009, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 05期

关键词：

NF-KAPPA-B; GLYCYRRHETINIC-ACID-DERIVATIVES; NITRIC-OXIDE PRODUCTION; MAP KINASES; INFLAMMATION; INHIBITION; MACROPHAGES; CYTOKINES; PROTEIN; TARGET;

D O I：

10.1021/jm301652t

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

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.

引用

页码：1984 / 1995

页数：12

共 48 条

[1]

AFFINITY OF LIQUORICE DERIVATIVES FOR MINERALOCORTICOID AND GLUCOCORTICOID RECEPTORS [J].