New histone deacetylase inhibitors based on 4-fluoro-2-amino acid esters: Synthesis and activity

Abstract

A series of twelve fluorinated and non-fluorinated potential histone deacetylase inhibitors 25 was synthesized and their inhibitory activity was tested against rat liver histone deacetylase. The new inhibitors involve an enzyme binding element consisting of asparagine, glutamine or different short chain fluorinated or unfluorinated amino acids, a suberoyl spacer and a hydroxamic acid functionality, which is responsible for the inhibitory activity. The 4-fluoro-2-aminobutyric acid esters 1a,b, their 2-methyl derivatives 2a,b and the 2-amino-4-fluoropent-4-enoic acid esters 3a,b were synthesized by alkylation of glycine or alanine ester imides with bromofluoroethane or 2-fluoroallylbromide, respectively. Methyl 2-amino-5-fluorohex-5-enoate (4a) was prepared using 3-fluorobut-3-enyl tosylate or the iodide as alkylating reagents. An alternative pathway starting from Boc protected 3-iodo-l-alanine was more efficient. The latter method was also applied to synthesize the parent unfluorinated compound 4c using allylbromide as the alkylating reagent. The fluorinated compounds, tested as histone deacetylase inhibitors were slightly less active than comparable (S)-valine, (S)-phenylalanine or (S)-allylglycine derivatives that do not contain a fluorine atom. Interestingly, it was shown for the first time that the fluoro vinyl group which was proposed to be an aprotic amide mimic due to its electronic properties may serve as a bioisosteric replacement of a primary amide function. For the fluorinated analogs 25f (IC50 0.88μM) and 25i (IC50 1.02μM) a similar or an even enhanced inhibitory activity was observed compared to the unfluorinated parents 25g (IC50 0.67μM) and 25j (IC50 1.79μM) or the (S)-asparagine or (S)-glutamine derivatives 25l (IC50 2.10μM) and 25m (IC50 3.90μM).