Abstract
A series of substituted trifluoroketones were tested as inhibitors of mammalian liver microsomal carboxylesterase(s) hydrolyzing a variety of substrates including malathion, diethylsuccinate (DES) and p-nitrophenyl acetate (p-NpAc). The trifluoroketones used were very potent "transition state" inhibitors of crude mouse and human liver microsomal carboxylesterases as well as commercial porcine liver carboxylesterase (Sigma EC 3.1.1.1 Type I). These enzymes were found to differ in their sensitivity to the inhibitors employed, and some compounds caused dramatic activation of the hydrolysis of DES. In some but not all cases, a thioether beta to the carbonyl increased the inhibitory potency of the compound. Structure-activity relationships also were evaluated among aliphatic versus substituted and unsubstituted aromatic trifluoroketones. Kinetic parameters [i.e. Km, Vmax and (T 1 2)e] for the mouse liver microsomes and the porcine carboxylesterase hydrolyzing DES were determined. Apparent high-and low-affinity forms were observed with each preparation. 3-Nonylthio-1,1,1-trifluoropropan-2-one was synthesized by the reaction of the corresponding thiol with 3-bromo-1,1,1-trifluoroacetone, and apparent synergism was observed when it was coadministered i.p. with malathion to mice.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1869-1879 |
| Number of pages | 11 |
| Journal | Biochemical Pharmacology |
| Volume | 36 |
| Issue number | 12 |
| DOIs | |
| State | Published - Jun 15 1987 |
Fingerprint
ASJC Scopus subject areas
- Pharmacology
Cite this
Substituted trifluoroketones as potent, selective inhibitors of mammalian carboxylesterases. / Ashour, Mohamed Bassem A; Hammock, Bruce D.
In: Biochemical Pharmacology, Vol. 36, No. 12, 15.06.1987, p. 1869-1879.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Substituted trifluoroketones as potent, selective inhibitors of mammalian carboxylesterases
AU - Ashour, Mohamed Bassem A
AU - Hammock, Bruce D.
PY - 1987/6/15
Y1 - 1987/6/15
N2 - A series of substituted trifluoroketones were tested as inhibitors of mammalian liver microsomal carboxylesterase(s) hydrolyzing a variety of substrates including malathion, diethylsuccinate (DES) and p-nitrophenyl acetate (p-NpAc). The trifluoroketones used were very potent "transition state" inhibitors of crude mouse and human liver microsomal carboxylesterases as well as commercial porcine liver carboxylesterase (Sigma EC 3.1.1.1 Type I). These enzymes were found to differ in their sensitivity to the inhibitors employed, and some compounds caused dramatic activation of the hydrolysis of DES. In some but not all cases, a thioether beta to the carbonyl increased the inhibitory potency of the compound. Structure-activity relationships also were evaluated among aliphatic versus substituted and unsubstituted aromatic trifluoroketones. Kinetic parameters [i.e. Km, Vmax and (T 1 2)e] for the mouse liver microsomes and the porcine carboxylesterase hydrolyzing DES were determined. Apparent high-and low-affinity forms were observed with each preparation. 3-Nonylthio-1,1,1-trifluoropropan-2-one was synthesized by the reaction of the corresponding thiol with 3-bromo-1,1,1-trifluoroacetone, and apparent synergism was observed when it was coadministered i.p. with malathion to mice.
AB - A series of substituted trifluoroketones were tested as inhibitors of mammalian liver microsomal carboxylesterase(s) hydrolyzing a variety of substrates including malathion, diethylsuccinate (DES) and p-nitrophenyl acetate (p-NpAc). The trifluoroketones used were very potent "transition state" inhibitors of crude mouse and human liver microsomal carboxylesterases as well as commercial porcine liver carboxylesterase (Sigma EC 3.1.1.1 Type I). These enzymes were found to differ in their sensitivity to the inhibitors employed, and some compounds caused dramatic activation of the hydrolysis of DES. In some but not all cases, a thioether beta to the carbonyl increased the inhibitory potency of the compound. Structure-activity relationships also were evaluated among aliphatic versus substituted and unsubstituted aromatic trifluoroketones. Kinetic parameters [i.e. Km, Vmax and (T 1 2)e] for the mouse liver microsomes and the porcine carboxylesterase hydrolyzing DES were determined. Apparent high-and low-affinity forms were observed with each preparation. 3-Nonylthio-1,1,1-trifluoropropan-2-one was synthesized by the reaction of the corresponding thiol with 3-bromo-1,1,1-trifluoroacetone, and apparent synergism was observed when it was coadministered i.p. with malathion to mice.
UR - http://www.scopus.com/inward/record.url?scp=0023264158&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0023264158&partnerID=8YFLogxK
U2 - 10.1016/0006-2952(87)90483-7
DO - 10.1016/0006-2952(87)90483-7
M3 - Article
C2 - 3593399
AN - SCOPUS:0023264158
VL - 36
SP - 1869
EP - 1879
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 12
ER -