Received for publication December 15, 2005.
Revised December 12, 2006.
Accepted for publication December 12, 2006.

Analysis of mammalian carboxylesterase inhibition by trifluoromethylketone-containing compounds

Abstract

Carboxylesterases (CE) are ubiquitous enzymes that hydrolyze numerous ester-containing xenobiotics including complex molecules such as the anticancer drugs, CPT-11 and capecitabine, and the pyrethroid insecticides. Due to 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 3 mammalian CEs, as well as human acetyl- and butyrylcholinesterase. In order to examine the nature of the slow tight-binding inhibitor/enzyme interaction, assays were performed using either a 5 min or a 24 hour 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.

Key words: Structure-activity relationships and modeling, Carboxylesterase, Structure/function/mechanism