title: Synthesis of a new trifluoromethylketone analogue of l-arginine and contrasting inhibitory activity against human arginase I and histone deacetylase 8.
abstract: 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.
authors.affiliation: Department of Chemistry, Drexel University, Philadelphia, PA 19104-2875, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Ilies
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Dowling
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Lombardi
authors.forename: David W
authors.initials: DW
authors.lastname: Christianson
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001119:Arginase / Q000037:antagonists & inhibitors*; D020134:Catalytic Domain; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006655:Histone Deacetylases; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000378:metabolism; D007659:Ketones / Q000737:chemistry; D008670:Metals / Q000737:chemistry; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000517:prevention & control; D011994:Recombinant Proteins; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C571361:2-amino-8,8,8-trifluoro-7-oxooctanoic acid; D000596:Amino Acids; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D007659:Ketones; D008670:Metals; D011994:Recombinant Proteins; D012097:Repressor Proteins; C409470:HDAC8 protein, human; D006655:Histone Deacetylases; D001119:Arginase