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Requirements for mammalian carboxylesterase inhibition by substituted ethane-1,2-diones.

Bioorganic & medicinal chemistry (2011-07-08)
Elizabeth I Parkinson, M Jason Hatfield, Lyudmila Tsurkan, Janice L Hyatt, Carol C Edwards, Latorya D Hicks, Bing Yan, Philip M Potter
ABSTRACT

Carboxylesterases (CE) are ubiquitous enzymes found in both human and animal tissues and are responsible for the metabolism of xenobiotics. This includes numerous natural products, as well as a many clinically used drugs. Hence, the activity of these agents is likely dependent upon the levels and location of CE expression. We have recently identified benzil is a potent inhibitor of mammalian CEs, and in this study, we have assessed the ability of analogues of this compound to inhibit these enzymes. Three different classes of molecules were assayed: one containing different atoms vicinal to the carbonyl carbon atom and the benzene ring [PhXC(O)C(O)XPh, where X=CH₂, CHBr, N, S, or O]; a second containing a panel of alkyl 1,2-diones demonstrating increasing alkyl chain length; and a third consisting of a series of 1-phenyl-2-alkyl-1,2-diones. In general, with the former series of molecules, heteroatoms resulted in either loss of inhibitory potency (when X=N), or conversion of the compounds into substrates for the enzymes (when X=S or O). However, the inclusion of a brominated methylene atom resulted in potent CE inhibition. Subsequent analysis with the alkyl diones [RC(O)C(O)R, where R ranged from CH₃ to C₈H₁₇] and 1-phenyl-2-alkyl-1,2-diones [PhC(O)C(O)R where R ranged from CH₃ to C₆H₁₃], demonstrated that the potency of enzyme inhibition directly correlated with the hydrophobicity (clogP) of the molecules. We conclude from these studies that that the inhibitory power of these 1,2-dione derivatives depends primarily upon the hydrophobicity of the R group, but also on the electrophilicity of the carbonyl group.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Benzil, 98%
Sigma-Aldrich
2,3-Butanedione, 97%
Supelco
2,3-Butanedione, analytical standard
Sigma-Aldrich
3,4-Hexanedione, 95%
Sigma-Aldrich
1-Phenyl-1,2-propanedione, 98%, FG
Sigma-Aldrich
3,4-Hexanedione, ≥95%, FG

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