In:
Philosophical Transactions of the Royal Society B: Biological Sciences, The Royal Society, Vol. 373, No. 1748 ( 2018-06-05), p. 20170364-
Abstract:
A series of hydroxamic acids linked by different lengths to a chiral imidazo-ketopiperazine scaffold were synthesized. The compounds with linker lengths of 6 and 7 carbon atoms were the most potent in histone deacetylase (HDAC) inhibition, and were specific submicromolar inhibitors of the HDAC1, HDAC6 and HDAC8 isoforms. A docking model for the binding mode predicts binding of the hydroxamic acid to the active site zinc cation and additional interactions between the imidazo-ketopiperazine and the enzyme rim. The compounds were micromolar inhibitors of the MV4-11, THP-1 and U937 cancer cell lines. Increased levels of histone H3 and tubulin acetylation support a cellular mechanism of action through HDAC inhibition. This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.
Type of Medium:
Online Resource
ISSN:
0962-8436
,
1471-2970
DOI:
10.1098/rstb.2017.0364
Language:
English
Publisher:
The Royal Society
Publication Date:
2018
detail.hit.zdb_id:
1462620-2
SSG:
12
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