title: Discovery of a potential anti-inflammatory agent: 3-oxo-29-noroleana-1,9(11),12-trien-2,20-dicarbonitrile.
abstract: 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-α, IL-6, and IL-1β 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 IκB-α, 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.
authors: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors: Ran
authors: R
authors: You
authors: Wenyan
authors: W
authors: Long
authors: Zhonghui
authors: Z
authors: Lai
authors: Lei
authors: L
authors: Sha
authors: Kai
authors: K
authors: Wu
authors: Xing
authors: X
authors: Yu
authors: Yisheng
authors: Y
authors: Lai
authors: Hui
authors: H
authors: Ji
authors: Zhangjian
authors: Z
authors: Huang
authors: Yihua
authors: Y
authors: Zhang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000502:physiology; D012772:Shock, Septic / Q000188:drug therapy / Q000401:mortality; D014315:Triterpenes / Q000138:chemical synthesis* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D000893:Anti-Inflammatory Agents; D048049:Extracellular Signal-Regulated MAP Kinases; D006034:Glycyrrhetinic Acid; D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D000072000:NF-KappaB Inhibitor alpha; D052247:Nitric Oxide Synthase Type II; D011965:Receptors, Glucocorticoid; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C581004:3-oxo-29-noroleana-1,9(11),12-trien-2,20-dicarbonitrile; C000606205:Nfkbia protein, mouse