TY - JOUR
T1 - Indole-3-ethylsulfamoylphenylacrylamides
T2 - Potent histone deacetylase inhibitors with anti-inflammatory activity
AU - Mehndiratta, Samir
AU - Hsieh, Yi Ling
AU - Liu, Yi Min
AU - Wang, Amber Weiching
AU - Lee, Hsueh Yun
AU - Liang, Lung Yu
AU - Kumar, Sunil
AU - Teng, Che Ming
AU - Yang, Chia Ron
AU - Liou, Jing Ping
PY - 2014/10/6
Y1 - 2014/10/6
N2 - 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-KB 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.
AB - 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-KB 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.
KW - Anti-inflammatory activity
KW - Histone deacetylase inhibitors
KW - Indole
UR - http://www.scopus.com/inward/record.url?scp=84905843046&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84905843046&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2014.08.020
DO - 10.1016/j.ejmech.2014.08.020
M3 - Article
C2 - 25113875
AN - SCOPUS:84905843046
SN - 0223-5234
VL - 85
SP - 468
EP - 479
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -