Discovery of Potent, Isoform-Selective Inhibitors of Histone Deacetylase Containing Chiral Heterocyclic Capping Groups and aN-(2-Aminophenyl)benzamide Binding Unit

Abstract

The synthesis of a novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contain a heterocyclic capping group and a N-(2-aminophenyl)benzamide unit that binds in the active site. In vitro assays for the inhibition of HDAC1, HDAC2, HDAC3-NCoR1, and HDAC8 by the N-(2-aminophenyl)benzamide 24a gave respective IC50 values of 930, 85, 12, and 4100 nM, exhibiting class I selectivity and potent inhibition of HDAC3-NCoR1. Both imidazolinone and thiazoline rings are shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)benzamides previously reported, an example of each ring system at 1 μM causing an increase in histone H3K9 acetylation in the human cell lines Jurkat and HeLa and an increase in cell death consistent with induction of apoptosis. Inhibition of the growth of MCF-7, A549, DU145, and HCT116 cell lines by 24a was observed, with respective IC50 values of 5.4, 5.8, 6.4, and 2.2 mM.

Efficient one-pot synthesis of ethyl 2-substitued-4-methylthiazole-5-carboxylates

“…Infrared (IR) spectra were recorded on a Nicolet FI-IR 360 Spectrophotometer. 1 H nuclear magnetic resonance (NMR) and 13 C NMR spectra were determined on a Bruker AM-400 (400 MHz) spectrometer with tetramethylsilane (TMS) as an internal standard. Chemical shifts are reported in δ.…”

“…Among the heterocyclic compounds, sulfur-and nitrogen-containing 1,3-thiazoles are very important class of heterocyclic compounds (1,2), which are well known for their biological properties (3-6). 2-Amino-1,3-thiazoles ring system (7) has found application in drug development for the treatment of allergies (8), hypertension (9), inflammation (10,11), schizophrenia (12), and bacterial (13) and HIV (14) infections.…”

“…The conventional synthesis of 4a usually starts from ethyl acetoacetate (1) and N-bromosuccinimide (NBS) (20)(21)(22) in dichloromethane to give the intermediate ethyl 2-bromo-3-oxobutanoate (2), which was then reacted with thiourea (3a) to give the target molecule (4a) (Scheme 1; 23). This two-step synthesis of 4a was limited by the tedious work-ups and low overall yield (11%; 24).…”

Comparative Modeling and Benchmarking Data Sets for Human Histone Deacetylases and Sirtuin Families

“…First, HDACs have been validated extensively as druggable targets for the treatment of various cancers. 1,6 On one hand, the upregulation of HDACs activity or overexpression induces the aberrant transcriptional repression of key genes that regulate important cellular functions, 2,17,18 which is linked to tumorigenesis. 19,20 On the other hand, it has been proved that HDAC inhibitors (HDACIs) could increase acetylation level thus to inhibit aberrant cellular proliferation by interfering with cell cycle regulation.…”

“…19,20 On the other hand, it has been proved that HDAC inhibitors (HDACIs) could increase acetylation level thus to inhibit aberrant cellular proliferation by interfering with cell cycle regulation. 6,12,21 Many HDACIs had been approved for clinical use to treat cancers such as vorinostat, 22 mocetinosat (MGCD0103), 23,24 entinostat (MS-275), 25,26 and romindepsin (cyclodepsipeptide or FK228). 27,1,6 Second, HDACs also serve as promising targets for modern drug discovery for the treatment of AD.…”