Mechanistic Analysis of 5-Hydroxy γ-Pyrones as Michael Acceptor Prodrugs

被引:0
|
作者
Leung, Clifford [1 ]
Bashir, Umyeena M. [1 ]
Karney, William L. [1 ]
Swanson, Mark G. [2 ]
Nikolayevskiy, Herman [1 ]
机构
[1] Univ San Francisco, Dept Chem, San Francisco, CA 94117 USA
[2] San Francisco State Univ, Dept Chem & Biochem, San Francisco, CA 94132 USA
来源
JOURNAL OF ORGANIC CHEMISTRY | 2024年 / 89卷 / 17期
基金
美国国家科学基金会;
关键词
DENSITY FUNCTIONALS; VERTICIPYRONE; INHIBITORS; HYDROGEN; SORTASE;
D O I
10.1021/acs.joc.4c01377
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
Substituted 5-hydroxy gamma-pyrones have shown promise as covalent inhibitor leads against cysteine proteases and transcription 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 o-quinone methide-like structure. Addition to this electrophile of either water or an active site cysteine was purported to lead to inhibitor hydrolysis or enzyme inhibition, respectively. Through the use of kinetic nuclear magnetic resonance 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 differentially influenced by substituent electronics. This mechanistic revision helps enable a more rational optimization for this class of promising compounds.
引用
收藏
页码:12432 / 12438
页数:7
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