Open AccessDevelopment of N-Hydroxycinnamamide-Based Histone Deacetylase Inhibitors with an Indole-Containing Cap Group
Author(s) -
Yingjie Zhang,
Penghui Yang,
C. James Chou,
Chunxi Liu,
Xuejian Wang,
Wenfang Xu
Publication year - 2013
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml300366t
Subject(s) - histone deacetylase , acetylation , western blot , in vivo , gene isoform , histone deacetylase inhibitor , chemistry , histone , histone deacetylase 2 , indole test , pharmacology , histone h4 , in vitro , hdac1 , biochemistry , biology , gene , genetics
A novel series of histone deacetylase inhibitors combining N -hydroxycinnamamide bioactive fragment and indole bioactive fragment was designed and synthesized. Several compounds ( 17c , 17g , 17h , 17j and 17k ) exhibited comparable even superior total HDACs inhibitory activity and in vitro antiproliferative activities relative to the approved drug SAHA. A representative compound 17a with moderate HDACs inhibition was progressed to isoform selectivity profile, western blot analysis and in vivo antitumor assay. Although HDACs isoform selectivity of 17a was similar to that of SAHA, our western blot results indicated that intracellular effects of 17a at 1 μM were class I selective. It was noteworthy that the effect on histone H4 acetylation of SAHA decreased with time while the effect on histone H4 acetylation of 17a maintained even increased. Most importantly, compound 17a exhibited promising in vivo antitumor activity in a U937 xenograft model.