Synthesis of New Carboxylesterase Inhibitors and Evaluation of Potency and Water Solubility
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- 作者：Craig E. Wheelock ; Tonya F. Severson ; and Bruce D. Hammock
- 刊名：Chemical Research in Toxicology
- 出版年：2001
- 出版时间：December 2001
- 年：2001
- 卷：14
- 期：12
- 页码：1563 - 1572
- 全文大小：92K
- 年卷期：v.14,no.12(December 2001)
- ISSN：1520-5010
文摘
Carboxylesterases are essential enzymes in the hydrolysis and detoxification of numerouspharmaceuticals and pesticides. They are vital in mediating organophosphate toxicity and inactivating many prodrugs such as the chemotherapeutic agent CPT-11. It is therefore importantto study the catalytic mechanism responsible for carboxylesterase-induced hydrolysis, whichcan be accomplished through the use of potent and selective inhibitors. Trifluoromethyl ketone(TFK)-containing compounds are the most potent esterase inhibitors described to date. Theinclusion of a thioether moiety 
to the carbonyl further increased TFK inhibitor potency. Inthis study, we have synthesized the sulfone analogues of a series of aliphatic and aromaticsubstituted thioether TFKs to evaluate their potency and solubility properties. This structuralchange shifted the keto/hydrate equilibrium from <9% hydrate to >95% hydrate, formingalmost exclusively the gem-diol. These new compounds were evaluated for their inhibition ofcarboxylesterase activity in three different systems, rat liver microsomes, commercial porcineesterase, and juvenile hormone esterase in cabbage looper (Trichoplusia ni) hemolymph. Themost potent inhibitor of rat liver carboxylesterase activity was 1,1,1-trifluoro-3-(decane-1-sulfonyl)-propan-2,2-diol, which inhibited 50% of the enzyme activity (IC50) at 6.3 ± 1.3 nMand was 18-fold more potent than its thioether analogue. However, the sulfone derivativeswere consistently poorer inhibitors of porcine carboxylesterase activity and juvenile hormoneesterase activity, with IC50 values ranging from low micromolar to millimolar. The compound1,1,1-trifluoro-3-(octane-1-sulfonyl)-propan-2,2-diol was shown to have a 10-fold greater watersolubility than its thioether analogue, 1,1,1-trifluoro-3-octylsulfanyl-propan-2-one (OTFP). Thesenovel compounds provide further evidence of the differences between esterase orthologs,suggesting that additional development of esterase inhibitors may ultimately provide a batteryof ortholog and/or isoform selective inhibitors analogous to those available for other complexenzyme families with overlapping substrate specificity.
to the carbonyl further increased TFK inhibitor potency. Inthis study, we have synthesized the sulfone analogues of a series of aliphatic and aromaticsubstituted thioether TFKs to evaluate their potency and solubility properties. This structuralchange shifted the keto/hydrate equilibrium from <9% hydrate to >95% hydrate, formingalmost exclusively the gem-diol. These new compounds were evaluated for their inhibition ofcarboxylesterase activity in three different systems, rat liver microsomes, commercial porcineesterase, and juvenile hormone esterase in cabbage looper (Trichoplusia ni) hemolymph. Themost potent inhibitor of rat liver carboxylesterase activity was 1,1,1-trifluoro-3-(decane-1-sulfonyl)-propan-2,2-diol, which inhibited 50% of the enzyme activity (IC50) at 6.3 ± 1.3 nMand was 18-fold more potent than its thioether analogue. However, the sulfone derivativeswere consistently poorer inhibitors of porcine carboxylesterase activity and juvenile hormoneesterase activity, with IC50 values ranging from low micromolar to millimolar. The compound1,1,1-trifluoro-3-(octane-1-sulfonyl)-propan-2,2-diol was shown to have a 10-fold greater watersolubility than its thioether analogue, 1,1,1-trifluoro-3-octylsulfanyl-propan-2-one (OTFP). Thesenovel compounds provide further evidence of the differences between esterase orthologs,suggesting that additional development of esterase inhibitors may ultimately provide a batteryof ortholog and/or isoform selective inhibitors analogous to those available for other complexenzyme families with overlapping substrate specificity.