Mechanistic Analysis of 5-Hydroxy š¯›¾-Pyrones as Michael Acceptor Prodrugs

30 May 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Substituted 5-hydroxy Ī³-pyrones have shown promise as covalent inhibitor leads against cysteine proteases and tran- scription factors, but their hydrolytic instability has hindered optimization efforts. Previous mechanistic proposals have suggested that these molecules function as Michael acceptor prodrugs, releasing a leaving group to generate an ortho quinone methideā€“like structure. Addition to this electrophile by either water or an active site cysteine was purported to lead to inhibitor hydrolysis or enzyme inhibition, respectively. Through the use of kinetic NMR experiments, Hammett analysis, kinetic isotope effect studies, and density functional theory calculations, our findings suggest that enzyme inhibition and hydrolysis proceed by distinct pathways and are dif- ferentially influenced by substituent electronics. This mechanistic revision helps enable a more rational optimization for this class of promising compounds.

Keywords

Mechanistic Analysis
Density Functional Theory
Kinetic Isotope Effect
Hammett Studies

Supplementary materials

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Supporting Information
Description
General methods, synthetic procedures, experimental protocol for quantitative kinetic NMR assay, data from NMR experiments, computational details, computed absolute energies and thermal cor- rections, optimized Cartesian coordinates, characterization data, and copies of 1H, 13C, 19F, COSY, HSQC, HMBC spectra
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