Selective inhibition of carboxylesterases by isatins, indole-2,3-diones.

Selective inhibition of carboxylesterases by isatins, indole-2,3-diones. Research Abstract Details 

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Selective inhibition of carboxylesterases by isatins, indole-2,3-diones. Abstract Text:

Janice L Hyatt,Teri Moak,M Jason Hatfield,Lyudmila Tsurkan,Carol C Edwards,Monika Wierdl,Mary K Danks,Randy M Wadkins,Philip M Potter,

Carboxylesterases (CE) are ubiquitous enzymes thought to be responsible for the metabolism and detoxification of xenobiotics. Numerous clinically used drugs including Demerol, lidocaine, capecitabine, and CPT-11 are hydrolyzed by these enzymes. Hence, the identification and application of selective CE inhibitors may prove useful in modulating the metabolism of esterified drugs in vivo. Having recently identified benzil (diphenylethane-1,2-dione) as a potent selective inhibitor of CEs, we sought to evaluate the inhibitory activity of related 1,2-diones toward these enzymes. Biochemical assays and kinetic studies demonstrated that isatins (indole-2,3-diones), containing hydrophobic groups attached at a variety of positions within these molecules, could act as potent, specific CE inhibitors. Interestingly, the inhibitory potency of the isatin compounds was related to their hydrophobicity, such that compounds with clogP values of <1.25 were ineffective at enzyme inhibition. Conversely, analogs demonstrating clogP values>5 routinely yielded Ki values in the nM range. Furthermore, excellent 3D QSAR correlates were obtained for two human CEs, hCE1 and hiCE. While the isatin analogues were generally less effective at CE inhibition than the benzils, the former may represent valid lead compounds for the development of inhibitors for use in modulating drug metabolism in vivo.

Selective inhibition of carboxylesterases by isatins, indole-2,3-diones. Publishing Authors By Initials

JL Hyatt,T Moak,MJ Hatfield,L Tsurkan,CC Edwards,M Wierdl,MK Danks,RM Wadkins,PM Potter,

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Selective inhibition of carboxylesterases by isatins, indole-2,3-diones. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Journal of medicinal chemistry

VOLUME: 50

Page Numbers: 1876-85

Journal Abbreviation:

ISSN: 0022-2623

DAY: 23

MONTH: 03

YEAR: 2007

Selective inhibition of carboxylesterases by isatins, indole-2,3-diones. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 9716531

Selective inhibition of carboxylesterases by isatins, indole-2,3-diones. Keywords Mesh Terms:

KEYWORDS: Quantitative Structure-Activity Relation

MESH TERMS: chemistry

Chemical & Substance for Abstract: Selective inhibition of carboxylesterases by isatins, indole-2,3-diones. Information

Substance Name: Acetylcholinesterase

Registry Number: EC 3.1.1.7

Grant and Affiliation Information for Selective inhibition of carboxylesterases by isatins, indole-2,3-diones.

AFFILIATION: Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, and Department of Chemistry and Biochemistry, University of Mississippi, University, Mississippi 38677, USA.

Country: United States

AGENCY: United States NCI

GRANT: P30 CA 21765

ACRONYM: CA

MEDLINETA: J Med Chem

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