2. Academic Validation
  3. Indole-3-ethylsulfamoylphenylacrylamides: potent histone deacetylase inhibitors with anti-inflammatory activity

Indole-3-ethylsulfamoylphenylacrylamides: potent histone deacetylase inhibitors with anti-inflammatory activity

  • Eur J Med Chem. 2014 Oct 6:85:468-79. doi: 10.1016/j.ejmech.2014.08.020.
Samir Mehndiratta 1,  Yi-Ling Hsieh 2,  Yi-Min Liu 1,  Amber Weiching Wang 2,  Hsueh-Yun Lee 1,  Lung-Yu Liang 2,  Sunil Kumar 1,  Che-Ming Teng 3,  Chia-Ron Yang 4,  Jing-Ping Liou 5
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
  • 2 School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 3 Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 4 School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: cryang@ntu.edu.tw.
  • 5 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan. Electronic address: jpl@tmu.edu.tw.
PMID: 25113875 DOI: 10.1016/j.ejmech.2014.08.020
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.

Keywords

Anti-inflammatory activity; Histone deacetylase inhibitors; Indole.

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