Mechanistic Analysis of 5-Hydroxy γ-Pyrones as Michael Acceptor Prodrugs
Clifford Leung1, Umyeena M Bashir1, William L Karney1
1Department of Chemistry, University of San Francisco, San Francisco, California 94117, United States.
The Journal of Organic Chemistry
|August 23, 2024
Summary
Substituted 5-hydroxy γ-pyrones show potential as covalent inhibitors. New research reveals distinct pathways for hydrolysis and enzyme inhibition, enabling rational drug optimization.
Area of Science:
- Medicinal Chemistry
- Chemical Biology
- Biochemistry
Background:
- Substituted 5-hydroxy γ-pyrones are promising covalent inhibitor leads.
- Hydrolytic instability hinders optimization of these compounds.
- Previous mechanisms proposed Michael acceptor prodrug behavior.
Purpose of the Study:
- To elucidate the mechanism of action for substituted 5-hydroxy γ-pyrones.
- To investigate the distinct pathways for hydrolysis and enzyme inhibition.
- To guide rational optimization of these covalent inhibitor leads.
Main Methods:
- Kinetic nuclear magnetic resonance (NMR) experiments.
- Hammett analysis.
- Kinetic isotope effect studies.
- Density functional theory (DFT) calculations.
Main Results:
- Enzyme inhibition and hydrolysis proceed via distinct mechanistic pathways.
- Substituent electronics differentially influence hydrolysis and inhibition.
- Findings challenge previous mechanistic proposals.
Conclusions:
- A revised mechanism for substituted 5-hydroxy γ-pyrones is proposed.
- Understanding distinct pathways enables rational optimization.
- This work facilitates the development of improved covalent inhibitors.
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