Lactam based 7-amino suberoylamide hydroxamic acids as potent HDAC inhibitors

被引：21

作者：

Taddei, Maurizio ^{[1
]}

Cini, Elena ^{[1
]}

Giannotti, Luca ^{[1
]}

Giannini, Giuseppe ^{[2
]}

Battistuzzi, Gianfranco ^{[2
]}

Vignola, Davide ^{[2
]}

Vesci, Loredana ^{[2
]}

Cabri, Walter ^{[2
]}

机构：

[1] Univ Siena, Dipartimento Biotecnol Chim & Farm, I-53100 Siena, Italy

[2] R&D Sigma Tau Ind Farmaceut Riunite SpA, I-00040 Rome, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 01期

关键词：

HDAC; Anticancer; Pan-inhibitor; Hydroxamic acid; Heterocycles; HISTONE DEACETYLASE INHIBITORS; DESIGN; VORINOSTAT; ANALOGS;

D O I：

10.1016/j.bmcl.2013.11.072

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of SAHA-like molecules were prepared introducing different lactam-carboxyamides in position 7 of the suberoylanilide skeleton. The activity against different HDAC isoforms was tested and the data compared with the corresponding linear products, without substituent in position 7. In general, this modification provided an effective reinforcement of in vitro activity. While the lactam size or the CO/NH group orientation did not strongly influence the inhibition, the contemporary modification of the suberoylamide fragment gave vary active variants in the lactam series, with compound 28 (ST8078AA1) that showed IC50 values between 2 and 10 nM against all Class I HDAC isoforms, demonstrating it to be a large spectrum pan-inhibitor. This strong affinity with HDAC was also confirmed by the value of IC50 = 0.5 mu M against H460 cells, ranking 28 as one of the most potent HDAC inhibitors described so far. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：61 / 64

页数：4