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Comparison of the Reactivity of Trapping Reagents toward Electrophiles: Cysteine Derivatives Can Be Bifunctional Trapping Reagents

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Drug Metabolism and Pharmacokinetics Japan, Eisai Product Creation Systems, Eisai Co., Ltd., Tsukuba, Japan
*5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. Tel: +81-29-847-5684. Fax: +81-29-847-5672. E-mail: [email protected]
Cite this: Chem. Res. Toxicol. 2015, 28, 8, 1546–1555
Publication Date (Web):July 14, 2015
https://doi.org/10.1021/acs.chemrestox.5b00129
Copyright © 2015 American Chemical Society
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    Abstract

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    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 nucleophiles 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 pKa 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.

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    Disappearance curves of MCB, BHBA, NBPC, and 4HN as results of reactions with or without nucleophiles (GSH, Nac, Cys, HCys, and SMCys for MCB, and GSH, Nac, Cys, HCys, SMCys, Lys, SC, and MeA for BHBA, NBPC, and 4HN) and mass spectra of parent ions of adducts discussed in this study and included in Table 1. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.chemrestox.5b00129.

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