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Journal article
Synthesis of a new trifluoromethylketone analogue of (L)-arginine and contrasting inhibitory activity against human arginase I and histone deacetylase 8
Bioorganic & medicinal chemistry letters, v 21(19), pp 5854-5858
01 Oct 2011
PMID: 21875805
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 IC50 = 1.5 +/- 0.2 mu M. Additionally, 10 weakly inhibits the related bacterial enzyme, acetylpolyamine amidohydrolase, with IC50 = 110 +/- 30 mu M. 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. (C) 2011 Elsevier Ltd. All rights reserved.
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Details
- Title
- Synthesis of a new trifluoromethylketone analogue of (L)-arginine and contrasting inhibitory activity against human arginase I and histone deacetylase 8
- Creators
- Monica Ilies - Drexel UniversityDaniel P. Dowling - University of PennsylvaniaPatrick M. Lombardi - University of PennsylvaniaDavid W. Christianson - University of Pennsylvania
- Publication Details
- Bioorganic & medicinal chemistry letters, v 21(19), pp 5854-5858
- Publisher
- Elsevier
- Number of pages
- 5
- Grant note
- GM49758 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01GM049758 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemistry
- Web of Science ID
- WOS:000294714400042
- Scopus ID
- 2-s2.0-80052586484
- Other Identifier
- 991019167975004721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Chemistry, Medicinal
- Chemistry, Organic