Jing Wu, Juanjuan Du, Ruinan Gu
Apr 1, 2015
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ChemMedChem
Abstract
Androstene derivatives incorporating amino acid methyl esters were prepared, and their anti‐inflammatory effects were evaluated in lipopolysaccharide (LPS)‐activated BV‐2 microglial cells. Several compounds exhibited dose‐dependent inhibition. The most active compound, methyl ((3S,10R,13S)‐3‐hydroxy‐10,13‐dimethyl‐2,3,4,7,8,9,10,11,12,13,14,15,16,17‐tetradecahydro‐1H‐cyclopenta[a]phenanthrene‐17‐carbonyl)‐L‐phenylalaninate (10) significantly suppressed LPS‐induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase‐2 (COX‐2), interleukin‐6 (IL‐6), and tumor necrosis factor‐α (TNF‐α). Mechanistic studies revealed that compound 10 markedly inhibits phosphorylation of p38 mitogen‐activated protein kinases (MAPKs) and subsequent transcription factor (NF‐κB) and activator protein‐1 (AP‐1) activation. Furthermore, compound 10 decreased LPS‐activated microglial neurotoxicity in a condition medium/HT‐22 neuroblastoma co‐culture model. Taken together, these results suggest 10 is a potential lead compound for the development of a novel therapeutic agent for neurodegenerative diseases.