2-trifluoroacetylthiophenes, a novel series of potent and selective class II histone deacetylase inhibitors

被引：57

作者：

Jones, Philip ^{[1
]}

Bottomley, Matthew J. ^{[1
]}

Carfi, Andrea ^{[1
]}

Cecchetti, Ottavia ^{[1
]}

Ferrigno, Federica ^{[1
]}

Lo Surdo, Paola ^{[1
]}

Ontoria, Jesus M. ^{[1
]}

Rowley, Michael ^{[1
]}

Scarpelli, Rita ^{[1
]}

Schultz-Fademrecht, Carsten ^{[1
]}

Steinkuehler, Christian ^{[1
]}

机构：

[1] Merck Res Labs, IRBM, I-00040 Pomezia, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 11期

关键词：

histone deacetylase; HDAC; trifluoroacetyl ketones; hydrated ketones;

D O I：

10.1016/j.bmcl.2008.02.026

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The identification of class II HDAC inhibitors has been hampered by lack of efficient enzyme assays, in the preceding paper two assays have been developed to improve the efficiency of these enzymes: mutating an active site histidine to tyrosine, or by the use of a trifluoroacetamide lysine substrate, allowing screening to identify class II HDAC inhibitors. Herein, 2-trifluoroacetylthiophenes have been demonstrated to inhibit class II HDACs, resulting in the development of a series of 5-(trifluoroacetyl) thiophene-2-carboxamides as novel, potent and selective class II HDAC inhibitors. X-ray crystal structures of the HDAC 4 catalytic domain with a bound inhibitor demonstrate these compounds are active site inhibitors and bind in their hydrated form. (c) 2008 Elsevier Ltd. All rights reserved.

引用

页码：3456 / 3461

页数：6

共 11 条

[1]

BOTTOMLEY MJ, UNPUB STRUCTURE

[2] Acetylation and chromosomal functions [J].