title: Identification and characterization of novel benzil (diphenylethane-1,2-dione) analogues as inhibitors of mammalian carboxylesterases.
abstract: Carboxylesterases (CE) are ubiquitous enzymes responsible for the metabolism of xenobiotics. Because the structural and amino acid homology among esterases of different classes, the identification of selective inhibitors of these proteins has proved problematic. Using Telik's target-related affinity profiling (TRAP) technology, we have identified a class of compounds based on benzil (1,2-diphenylethane-1,2-dione) that are potent CE inhibitors, with K(i) values in the low nanomolar range. Benzil and 30 analogues demonstrated selective inhibition of CEs, with no inhibitory activity toward human acetylcholinesterase or butyrylcholinesterase. Analysis of structurally related compounds indicated that the ethane-1,2-dione moiety was essential for enzyme inhibition and that potency was dependent on the presence of, and substitution within, the benzene ring. 3D-QSAR analyses of these benzil analogues for three different mammalian CEs demonstrated excellent correlations of observed versus predicted K(i) (r(2) > 0.91), with cross-validation coefficients (q(2)) of 0.9. Overall, these results suggest that selective inhibitors of CEs with potential for use in clinical applications can be designed.
authors.affiliation: Department of Chemistry and Biochemistry, University of Mississippi, University, Mississippi 38677, USA.
authors.forename: Randy M
authors.initials: RM
authors.lastname: Wadkins
authors.forename: Janice L
authors.initials: JL
authors.lastname: Hyatt
authors.forename: Xin
authors.initials: X
authors.lastname: Wei
authors.forename: Kyoung Jin P
authors.initials: KJ
authors.lastname: Yoon
authors.forename: Monika
authors.initials: M
authors.lastname: Wierdl
authors.forename: Carol C
authors.initials: CC
authors.lastname: Edwards
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Morton
authors.forename: John C
authors.initials: JC
authors.lastname: Obenauer
authors.forename: Komath
authors.initials: K
authors.lastname: Damodaran
authors.forename: Paul
authors.initials: P
authors.lastname: Beroza
authors.forename: Mary K
authors.initials: MK
authors.lastname: Danks
authors.forename: Philip M
authors.initials: PM
authors.lastname: Potter
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry; D000818:Animals; D002091:Butyrylcholinesterase / Q000737:chemistry; D043182:Carboxylesterase / Q000037:antagonists & inhibitors*; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry; D002800:Cholinesterase Inhibitors / Q000737:chemistry; D016208:Databases, Factual; D006801:Humans; D007422:Intestines / Q000201:enzymology; D008958:Models, Molecular; D010658:Phenylglyoxal / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D013329:Structure-Activity Relationship; D014468:Umbelliferones / Q000737:chemistry
chemical_list: D002800:Cholinesterase Inhibitors; D014468:Umbelliferones; C032078:4-methylumbelliferyl acetate; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; D043182:Carboxylesterase; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D010658:Phenylglyoxal; C006697:benzil