title: Selective Inhibitors of Human Liver Carboxylesterase Based on a β-Lapachone Scaffold: Novel Reagents for Reaction Profiling.
abstract: Carboxylesterases (CEs) are ubiquitous enzymes that are responsible for the metabolism of xenobiotics, including drugs such as irinotecan and oseltamivir. Inhibition of CEs significantly modulates the efficacy of such agents. We report here that β-lapachone is a potent, reversible CE inhibitor with Kivalues in the nanomolar range. A series of amino and phenoxy analogues have been synthesized, and although the former are very poor inhibitors, the latter compounds are highly effective in modulating CE activity. Our data demonstrate that tautomerism of the amino derivatives to the imino forms likely accounts for their loss in biological activity. A series of N-methylated amino derivatives, which are unable to undergo such tautomerism, were equal in potency to the phenoxy analogues and demonstrated selectivity for the liver enzyme hCE1. These specific inhibitors, which are active in cell culture models, will be exceptionally useful reagents for reaction profiling of esterified drugs in complex biological samples.
authors.affiliation: Department of Chemical Biology and Therapeutics, ‡Department of Structural Biology, St. Jude Children's Research Hospital , Memphis, Tennessee 38105, United States.
authors.forename: M Jason
authors.initials: MJ
authors.lastname: Hatfield
authors.affiliation: Department of Chemical Biology and Therapeutics, ‡Department of Structural Biology, St. Jude Children's Research Hospital , Memphis, Tennessee 38105, United States.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Chemical Biology and Therapeutics, ‡Department of Structural Biology, St. Jude Children's Research Hospital , Memphis, Tennessee 38105, United States.
authors.forename: Ellie M
authors.initials: EM
authors.lastname: Fratt
authors.affiliation: Department of Chemical Biology and Therapeutics, ‡Department of Structural Biology, St. Jude Children's Research Hospital , Memphis, Tennessee 38105, United States.
authors.forename: Liying
authors.initials: L
authors.lastname: Chi
authors.affiliation: Department of Chemical Biology and Therapeutics, ‡Department of Structural Biology, St. Jude Children's Research Hospital , Memphis, Tennessee 38105, United States.
authors.forename: John C
authors.initials: JC
authors.lastname: Bollinger
authors.affiliation: Department of Chemical Biology and Therapeutics, ‡Department of Structural Biology, St. Jude Children's Research Hospital , Memphis, Tennessee 38105, United States.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Binder
authors.affiliation: Department of Chemical Biology and Therapeutics, ‡Department of Structural Biology, St. Jude Children's Research Hospital , Memphis, Tennessee 38105, United States.
authors.forename: John
authors.initials: J
authors.lastname: Bowling
authors.affiliation: Department of Chemical Biology and Therapeutics, ‡Department of Structural Biology, St. Jude Children's Research Hospital , Memphis, Tennessee 38105, United States.
authors.forename: Janice L
authors.initials: JL
authors.lastname: Hyatt
authors.affiliation: Department of Chemical Biology and Therapeutics, ‡Department of Structural Biology, St. Jude Children's Research Hospital , Memphis, Tennessee 38105, United States.
authors.forename: Jerrod
authors.initials: J
authors.lastname: Scarborough
authors.affiliation: Department of Chemical Biology and Therapeutics, ‡Department of Structural Biology, St. Jude Children's Research Hospital , Memphis, Tennessee 38105, United States.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Jeffries
authors.affiliation: Department of Chemical Biology and Therapeutics, ‡Department of Structural Biology, St. Jude Children's Research Hospital , Memphis, Tennessee 38105, United States.
authors.forename: Philip M
authors.identifier: 0000-0001-8922-8535
authors.initials: PM
authors.lastname: Potter
mesh_terms: D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D000077146:Irinotecan; D008099:Liver / Q000201:enzymology; D062105:Molecular Docking Simulation; D009285:Naphthoquinones / Q000737:chemistry* / Q000494:pharmacology*; D053139:Oseltamivir / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D053139:Oseltamivir; C014638:beta-lapachone; D000077146:Irinotecan; D002265:Carboxylic Ester Hydrolases; D002166:Camptothecin