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Bioorg Med Chem Lett. 2011 Oct 1;21(19):5854-8. doi: 10.1016/j.bmcl.2011.07.100. Epub 2011 Aug 3.

Synthesis of a new trifluoromethylketone analogue of l-arginine and contrasting inhibitory activity against human arginase I and histone deacetylase 8.

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Department of Chemistry, Drexel University, Philadelphia, PA 19104-2875, USA.


As part of our continuing search for new amino acid inhibitors of metalloenzymes, we now report the synthesis and biological evaluation of the trifluoromethylketone analogue of L-arginine, (S)-2-amino-8,8,8-trifluoro-7-oxo-octanoic acid (10). While this novel amino acid was initially designed as a potential inhibitor of human arginase I, it exhibits no measurable inhibitory activity against this enzyme. Surprisingly, however, 10 is a potent inhibitor of human histone deacetylase 8, with IC(50)=1.5 ± 0.2 μM. Additionally, 10 weakly inhibits the related bacterial enzyme, acetylpolyamine amidohydrolase, with IC(50)=110 ± 30 μM. The lack of inhibitory activity against human arginase I may result from unfavorable interactions of the bulky trifluoromethyl group of 10 in the constricted active site. Since the active site of histone deacetylase 8 is less constricted, we hypothesize that it accommodates 10 as the gem-diol, which mimics the tetrahedral intermediate and its flanking transition states in catalysis. Therefore, we suggest that 10 represents a new lead in the design of an amino acid or peptide-based inhibitor of histone deacetylases with simpler structure than previously studied trifluoromethylketones.

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