Abstract
Carboxylesterases (CE) are ubiquitous enzymes that hydrolyze numerous ester-containing xenobiotics, including complex molecules, such as the anticancer drugs irinotecan (CPT-11) and capecitabine and the pyrethroid insecticides. Because of the role of CEs in the metabolism of many exogenous and endogenous ester-containing compounds, a number of studies have examined the inhibition of this class of enzymes. Trifluoromethylketone-containing (TFK) compounds have been identified as potent CE inhibitors. In this article, we present inhibition constants for 21 compounds, including a series of sulfanyl, sulfinyl, and sulfonyl TFKs with three mammalian CEs, as well as human acetyl- and butyrylcholinesterase. To examine the nature of the slow tight-binding inhibitor/enzyme interaction, assays were performed using either a 5-min or a 24-h preincubation period. Results showed that the length of the preincubation interval significantly affects the inhibition constants on a structurally dependent basis. The TFK-containing compounds were generally potent inhibitors of mammalian CEs, with Ki values as low as 0.3 nM observed. In most cases, thioether-containing compounds were more potent inhibitors then their sulfinyl or sulfonyl analogs. QSAR analyses demonstrated excellent observed versus predicted values correlations (r2 ranging from 0.908–0.948), with cross-correlation coefficients (q2) of ∼0.9. In addition, pseudoreceptor models for the TKF analogs were very similar to structures and models previously obtained using benzil- or sulfonamide-based CE inhibitors. These studies indicate that more potent, selective CE inhibitors, containing long alkyl or aromatic groups attached to the thioether chemotype in TFKs, can be developed for use in in vivo enzyme inhibition.
Footnotes
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This work was supported in part by National Institutes of Health (NIH) grants CA76202, CA79763, CA98468, CA108775, Cancer Center Core grant P30-CA21765, National Institute of Environmental Health Sciences (NIEHS) grant R37-ES02710, NIEHS Superfund grant P42-ES04699, NIEHS Center for Environmental Health Sciences grant P30-ES05707, and by the American Lebanese Syrian Associated Charities. C.E.W. was supported by a Japanese Society for the Promotion of Science (JSPS) postdoctoral fellowship and NIH postdoctoral training grant T32-DK07355-22. P.D.J. was supported by NIH/National Heart, Lung, and Blood Institute Ruth L. Kirschstein National Research Service Award grant F32-HL078096.
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.105.021683.
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ABBREVIATIONS: CE, carboxylesterase; CPT-11, irinotecan; TFK, trifluoromethyl ketone; AChE, acetylcholinesterase; QSAR, quantitative structure-activity relationship; 3D, three-dimensional; BChE, butylcholinesterase; h, human; r, rabbit; Mp, melting point; o-NPA, o-nitrophenyl acetate.
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↵1 Current affiliation: Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden.
- Received December 13, 2005.
- Accepted December 12, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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