Systematic Study of the Glutathione Reactivity of N-Phenylacrylamides: 2. Effects of Acrylamide Substitution
Systematic Study of the Glutathione Reactivity of N-Phenylacrylamides: 2. Effects of Acrylamide Substitution
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DOI：
10.1021/acs.jmedchem.0c00749
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发表时间：
2020-10-22
影响因子：
7.3
通讯作者：
Cee, Victor J.
中科院分区：
文献类型：
--
作者：
Birkholz, Adam;Kopecky, David J.;Cee, Victor J.
全面了解结构-活性关系对于半胱氨酸靶向共价抑制剂的设计和优化至关重要。在这里，我们报道了N-苯基丙烯酰胺的谷胱甘肽(GSH)反应速率，在丙烯酰胺部分的α和β位置有不同的取代。我们发现，GSH反应速率一般可以用取代基的供电子或取电子能力来理解。当氨甲基与胺PK(A)‘S和7安装在β位置时，与氢取代基相比，带有PK(A)’S和7的氨甲基取代基加速了谷胱甘肽的加成速率。尽管计算模型只能近似地捕捉实验反应趋势，但我们的计算并不支持协同的胺/硫醇质子转移和C-S键形成的常见机制，而是认为质子化的氨甲基起到了一个吸电子基团的作用，以降低丙烯酰胺上硫酸盐加成的势垒。
A comprehensive understanding of structure-reactivity relationships is critical to the design and optimization of cysteine-targeted covalent inhibitors. Herein, we report glutathione (GSH) reaction rates for N-phenyl acrylamides with varied substitutions at the alpha- and beta-positions of the acrylamide moiety. We find that the GSH reaction rates can generally be understood in terms of the electron donating or withdrawing ability of the substituent. When installed at the beta-position, aminomethyl substituents with amine pK(a)'s > 7 accelerate, while those with pK(a)'s < 7 slow the rate of GSH addition at pH 7.4, relative to a hydrogen substituent. Although a computational model was able to only approximately capture experimental reactivity trends, our calculations do not support a frequently invoked mechanism of concerted amine/thiol proton transfer and C-S bond formation and instead suggest that protonated aminomethyl functions as an electron-withdrawing group to reduce the barrier for thiolate addition to the acrylamide.