Selective inhibition of carboxylesterases by isatins, indole-2,3-diones.
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.
Hyatt
Janice L
JL
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.
Moak
Teri
T
Hatfield
M Jason
MJ
Tsurkan
Lyudmila
L
Edwards
Carol C
CC
Wierdl
Monika
M
Danks
Mary K
MK
Wadkins
Randy M
RM
Potter
Philip M
PM
D000110:Acetylcholinesterase / Q000737:chemistry; D002091:Butyrylcholinesterase / Q000737:chemistry; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007510:Isatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D007510:Isatin; D002265:Carboxylic Ester Hydrolases; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase