Journal
MOLECULAR PHARMACOLOGY
Volume 71, Issue 3, Pages 713-723Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.105.021683
Keywords
-
Categories
Funding
- NCI NIH HHS [P30-CA21765, CA79763, CA98468, CA76202, CA108775] Funding Source: Medline
- NHLBI NIH HHS [F32-HL078096] Funding Source: Medline
- NIDDK NIH HHS [T32-DK07355-22] Funding Source: Medline
- NIEHS NIH HHS [P42-ES04699, P30-ES05707, P30 ES005707, R37-ES02710, R37 ES002710, P42 ES004699] Funding Source: Medline
Ask authors/readers for more resources
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. Trifluoromethyl-ketone-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 K-i 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 (r(2) ranging from 0.908-0.948), with cross-correlation coefficients (q(2)) of similar to 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available