期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 85, 期 -, 页码 468-479出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2014.08.020
关键词
Anti-inflammatory activity; Histone deacetylase inhibitors; Indole
资金
- Ministry of Science and Technology, Taiwan [MOST 103-2113-M-038-001-MY3, MOST 103-2320-B-002-008-MY3]
A series of 2-methyl-1H-indol-3-ethylsulfamoylphenylacrylamides based on LBH589-PXD101 core have been synthesized and evaluated for their histone deacetylase (HDAC) inhibitory and anti-inflammatory activity. In vitro, compounds 9-12 show 2.6-fold better HDAC inhibition and 3-fold better IL-6 suppression compared to LBH589.HCl (1.HCl). Furthermore, these compounds did not show apparent cell viability suppression on macrophages while in contrast, treatment with 1.HCl resulted in significant reduction in cell viability as demonstrated by an MTT assay. Repressed expression of iNOS, COX-2 and reduced phosphorylation of p65 revealed the inhibitory effect of these analogues on inflammatory mediator release which is related to inhibited NF-kappa B signals. (N-Hydroxy-3-{3-[2-(2-methyl-1H-indol-3-yl)-ethylsulfamoyl]-phenyl}-acrylamide) (9), exhibited ability superior to that of 1.HCl, was able to reduce carrageenan-induced acute inflammation in an animal model. Compounds 9-12 have potential anti-inflammatory activity and compound 9 can serve as lead compound for further development. (C) 2014 Elsevier Masson SAS. All rights reserved.
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