Publication details
Isoform-selective HDAC1/16/8 inhibitors with an imidazo-ketopiperazine cap containing stereochemical diversity
| Authors | |
|---|---|
| Year of publication | 2018 |
| Type | Article in Periodical |
| Magazine / Source | PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES |
| MU Faculty or unit | |
| Citation | |
| Web | https://royalsocietypublishing.org/doi/10.1098/rstb.2017.0364 |
| Doi | http://dx.doi.org/10.1098/rstb.2017.0364 |
| Keywords | zinc metalloenzymes; epigenetics; histone deacetylases; enzyme inhibitors; peptidomimetics |
| Description | A series of hvdroxamic acids linked by different lengths to a chiral imidazo-ketopiperazine scaffold were synthesized. The compounds with linker lengths of 6 and 7 ca vb on 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 hvdroxamic 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'. |