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Novel isosorbide-based substrates for human butyrylcholinesterase
J F Gilmer1, M N Lally, P Gardiner
1School of Pharmacy, Trinity College Dublin, Ireland.
Chemico-Biological Interactions
|November 4, 2005
Summary
Butyrylcholinesterase (BuChE) rapidly and selectively hydrolyzes isosorbide esters, particularly at the 2-position. The 5-position group influences binding and hydrolysis rates, revealing new insights into BuChE activity.
Area of Science:
- Biochemistry
- Enzymology
- Drug Discovery
Background:
- Butyrylcholinesterase (BuChE) is a widely distributed enzyme with incompletely understood functions.
- BuChE is known to detoxify xenobiotics and release drugs from prodrugs.
Purpose of the Study:
- To investigate the hydrolysis of isosorbide esters catalyzed by BuChE.
- To determine the regioselectivity and kinetics of BuChE-mediated hydrolysis of isosorbide diesters.
Main Methods:
- Synthesis of a series of isosorbide esters.
- Measurement of hydrolysis rates using High-Performance Liquid Chromatography (HPLC) after incubation in diluted plasma.
Main Results:
- BuChE exhibited rapid hydrolysis of the 2-ester group in isosorbide diesters.
- Hydrolysis of the 5-ester group was generally minimal.
- The identity of the substituent at the 5-position significantly influenced the hydrolysis rate of the 2-ester group.
Conclusions:
- BuChE demonstrates significant regioselectivity in hydrolyzing isosorbide esters.
- The 5-ester group, while not readily hydrolyzed, is crucial for the productive binding of BuChE to isosorbide diesters.
- These findings contribute to understanding BuChE's role in xenobiotic metabolism and prodrug activation.