Comparison of the Reactivity of Trapping Reagents toward Electrophiles: Cysteine Derivatives Can Be Bifunctional Trapping Reagents
Comparison of the Reactivity of Trapping Reagents toward Electrophiles: Cysteine Derivatives Can Be Bifunctional Trapping Reagents
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DOI：
10.1021/acs.chemrestox.5b00129
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发表时间：
2015-08-01
影响因子：
4.1
通讯作者：
Kusano, Kazutomi
中科院分区：
文献类型：
--
作者：
Inoue, Kazuko;Fukuda, Katsuyuki;Kusano, Kazutomi
捕获试剂是检测不稳定活性代谢物的有力工具。有多种基于亲电体化学反应性的捕获试剂，我们研究了硫醇和胺捕获试剂对代谢产生的亲电体和市售亲电化合物的反应性。谷胱甘肽（GSH）和N-乙酰半胱氨酸（Nac）捕获软亲电试剂，胺衍生物如氨基脲（SC）和甲氧基胺（MeA）作为硬亲核试剂捕获醛作为亚胺衍生物。半胱氨酸（Cys）和高半胱氨酸（HCys）捕获软亲电体和硬亲电醛两者。在Cys、HCys、GSH和Nac之间捕获软亲电体没有定性差异，尽管捕获软亲电体的定量反应性可能取决于其巯基的pK（a）值而变化。在与醛的反应性中，Cys和HCys显示出相对较低的反应性，与SC和MeA相比。尽管如此，它们可以捕获醛，并且所得缀合物是稳定的，并且容易检测，因为它们的氨基与醛反应后形成亚胺，其被分子内巯基连续攻击以形成稳定的环状结构。本报告表明，Cys和HCys的独特结构特征有利于在药物发现的早期评估许多候选药物的软亲电体和环糊精型衍生物的形成。
Trapping reagents are powerful tools to detect unstable reactive metabolites. There are a variety of trapping reagents based on chemical reactivity to electrophiles, and we investigated the reactivity of thiol and amine trapping reagents to metabolically generated electrophiles and commercially available electrophilic compounds. Glutathione (GSH) and N-acetylcysteine (Nac) trapped soft electrophiles, and amine derivatives such as semicarbazide (SC) and methoxyamine (MeA) reacted as hard nudeophiles to trap aldehydes as imine derivatives. Cysteine (Cys) and homocysteine (HCys) captured both soft electrophiles and hard electrophilic aldehydes. There were no qualitative differences in trapping soft electrophiles among Cys, HCys, GSH, and Nac, although quantitative reactivity to trap soft electrophiles varied likely depending on the pK(a) values of their thiol group. In the reactivity with aldehydes, Cys and HCys showed relatively lower reactivity as compared with SC and MeA. Nonetheless, they can trap aldehydes, and the resulting conjugates were stable and detected easily because their amino group formed imines after reaction with aldehydes, which are successively attacked by the intramolecular thiol group to form stable ring structures. This report demonstrated that Cys and HCys are advantageous to evaluate the formations of both soft electrophiles and aldehyde-type derivatives from a lot of drug candidates at early drug discovery by their unique structural characteristics.