biostudies-literatureLecointre BINSERMthe European Union's Seventh Framework Programme for Research, Technological Development and DemonstrationLa Ligue Contre le Cancer20170364https://www.ebi.ac.uk/biostudies/studies/S-EPMC5915728biostudies-literatureUnknown373(1748)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 chPhilosophical transactions of the Royal Society of London. Series B, Biological sciencesIsoform-selective HDAC1/6/8 inhibitors with an imidazo-ketopiperazine cap containing stereochemical diversity.PMC5915728241865 (SEtTReND) and 602080 (A-ParaDDisE)Narozny RRomier CBorrello MTSenger JGanesan AMelesina JMarek MChakrabarti AJung MLecointre BSippl WBischoff LfalseIsoform-selective HDAC1/6/8 inhibitors with an imidazo-ketopiperazine cap containing stereochemical diversity.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 ch2018-01-01T00:00:00Z2018 Jun2026-05-01T01:55:11.905Z2026-04-07T16:34:12.668ZS-EPMC59157282968596910.1098/rstb.2017.0364