PURPOSE: Carboxylesterases are important in the detoxification of drugs, pesticides and other xenobiotics. This study was to evaluate a series of substrates and inhibitors for characterizing these enzymes. METHODS: A series of novel aliphatic esters and thioesters were used in spectral assays to monitor human, murine and porcine esterases. A series of transition state mimics were evaluated as selective esterase inhibitors. RESULTS: Several alpha-alkyl thioacetothioates were found to be approximately 2 to 11-fold superior to commonly used substrates for monitoring carboxylesterase activity. Insertion of a heteroatom in the acid portion of these esters in the beta or gamma position relative to the carbonyl had a dramatic effect on enzyme activity with S or O substituents often improving the kCAT/K(M) ratio of the substrate and N decreasing it. Several alpha,alpha'-bis (2-oxo-3,3,3-trifluoropropylthio)alkanes proved to be potent selective transition state mimics of the esterase activity with IC50's from 10(-5) to 10(-9)M. CONCLUSIONS: This library of substrates and inhibitors are useful research tools for characterizing the numerous isozymes of carboxylesterases present in mammalian tissues.
PURPOSE: Carboxylesterases are important in the detoxification of drugs, pesticides and other xenobiotics. This study was to evaluate a series of substrates and inhibitors for characterizing these enzymes. METHODS: A series of novel aliphatic esters and thioesters were used in spectral assays to monitor human, murine and porcine esterases. A series of transition state mimics were evaluated as selective esterase inhibitors. RESULTS: Several alpha-alkyl thioacetothioates were found to be approximately 2 to 11-fold superior to commonly used substrates for monitoring carboxylesterase activity. Insertion of a heteroatom in the acid portion of these esters in the beta or gamma position relative to the carbonyl had a dramatic effect on enzyme activity with S or O substituents often improving the kCAT/K(M) ratio of the substrate and N decreasing it. Several alpha,alpha'-bis (2-oxo-3,3,3-trifluoropropylthio)alkanes proved to be potent selective transition state mimics of the esterase activity with IC50's from 10(-5) to 10(-9)M. CONCLUSIONS: This library of substrates and inhibitors are useful research tools for characterizing the numerous isozymes of carboxylesterases present in mammalian tissues.
Authors: B F McCutchen; T Uematsu; A Székács; T L Huang; T Shiotsuki; A Lucas; B D Hammock Journal: Arch Biochem Biophys Date: 1993-12 Impact factor: 4.013
Authors: E V Rudakova; G F Makhaeva; T G Galenko; A Yu Aksinenko; V B Sokolov; I V Martynov Journal: Dokl Biochem Biophys Date: 2013-05-09 Impact factor: 0.788
Authors: Varnavas D Mouchlis; Christophe Morisseau; Bruce D Hammock; Sheng Li; J Andrew McCammon; Edward A Dennis Journal: Bioorg Med Chem Date: 2016-05-10 Impact factor: 3.641
Authors: Craig E Wheelock; Kosuke Nishi; Andy Ying; Paul D Jones; Michael E Colvin; Marilyn M Olmstead; Bruce D Hammock Journal: Bioorg Med Chem Date: 2007-11-26 Impact factor: 3.641