title: Indole-3-ethylsulfamoylphenylacrylamides: potent histone deacetylase inhibitors with anti-inflammatory activity.
abstract: 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-ĸB 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.
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Samir
authors.initials: S
authors.lastname: Mehndiratta
authors.affiliation: School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Hsieh
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Yi-Min
authors.initials: YM
authors.lastname: Liu
authors.affiliation: School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Amber Weiching
authors.initials: AW
authors.lastname: Wang
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Hsueh-Yun
authors.initials: HY
authors.lastname: Lee
authors.affiliation: School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Lung-Yu
authors.initials: LY
authors.lastname: Liang
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Sunil
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
authors.affiliation: School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: cryang@ntu.edu.tw.
authors.forename: Chia-Ron
authors.initials: CR
authors.lastname: Yang
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan. Electronic address: jpl@tmu.edu.tw.
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Liou
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D004487:Edema / Q000188:drug therapy; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats
chemical_list: D000893:Anti-Inflammatory Agents; D056572:Histone Deacetylase Inhibitors; D007211:Indoles
keywords: Anti-inflammatory activity; Histone deacetylase inhibitors; Indole