Jump to main content
Jump to site search

Issue 5, 2016
Previous Article Next Article

Intrinsic reactivity profile of electrophilic moieties to guide covalent drug design: N-α-acetyl-l-lysine as an amine nucleophile

Author affiliations

Abstract

Covalent drugs contain a reactive electrophilic moiety or covalent reactive group (CRG), which forms an irreversible bond between the drug and a biological target. Consequently, the intrinsic reactivity of the CRG is an important consideration in the design of irreversible inhibitors. Although reactivity assessments of CRGs with sulfur nucleophiles, such as glutathione and cysteine have been reported, reactivity of these moieties with amine-containing nucleophiles is not well described. In this study, intrinsic reactivities were determined for a series of electrophiles (acrylamides, nitriles, cyanamides, sulfones, and sulfonamides) using N-α-acetyl-L-lysine as a model amine-based nucleophile and compared with results using glutathione (GSH). Since the ε-amine of N-α-acetyl-L-lysine is protonated at neutral pH, reactions were carried out at pH 10.2. In addition to reporting rate data for reactions of CRGs with N-α-acetyl-L-lysine, elements of selectivity relative to thiol-containing nucleophiles are also be discussed.

Graphical abstract: Intrinsic reactivity profile of electrophilic moieties to guide covalent drug design: N-α-acetyl-l-lysine as an amine nucleophile

Back to tab navigation

Supplementary files

Article information


Submitted
08 Jan 2016
Accepted
13 Feb 2016
First published
16 Feb 2016

Med. Chem. Commun., 2016,7, 864-872
Article type
Research Article
Author version available

Intrinsic reactivity profile of electrophilic moieties to guide covalent drug design: N-α-acetyl-L-lysine as an amine nucleophile

U. P. Dahal, A. M. Gilbert, R. S. Obach, M. E. Flanagan, J. M. Chen, C. Garcia-Irizarry, J. T. Starr, B. Schuff, D. P. Uccello and J. A. Young, Med. Chem. Commun., 2016, 7, 864
DOI: 10.1039/C6MD00017G

Search articles by author

Spotlight

Advertisements