title: Development ofN-Hydroxycinnamamide-Based Histone Deacetylase Inhibitors with Indole-Containing Cap Group.
abstract: A novel series of histone deacetylase inhibitors combiningN-hydroxycinnamamide bioactive fragment and indole bioactive fragment was designed and synthesized. Several compounds (17c,17g,17h,17jand17k) exhibited comparable even superior total HDACs inhibitory activity andin vitroantiproliferative activities relative to the approved drug SAHA. A representative compound17awith moderate HDACs inhibition was progressed to isoform selectivity profile, western blot analysis andin vivoantitumor assay. Although HDACs isoform selectivity of17awas similar to that of SAHA, our western blot results indicated that intracellular effects of17aat 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 of17amaintained even increased. Most importantly, compound17aexhibited promisingin vivoantitumor activity in a U937 xenograft model.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong, 250012, P.R. China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Zhang
authors.forename: Penghui
authors.initials: P
authors.lastname: Yang
authors.forename: C James
authors.initials: CJ
authors.lastname: Chou
authors.forename: Chunxi
authors.initials: C
authors.lastname: Liu
authors.forename: Xuejian
authors.initials: X
authors.lastname: Wang
authors.forename: Wenfang
authors.initials: W
authors.lastname: Xu
keywords: Histone deacetylases; N-hydroxycinnamamide; indole; inhibitor