Saturday, October 24, 2020

Systematic Study of the Glutathione (GSH) Reactivity of N-Phenylacrylamides: 2. Effects of Acrylamide Substitution

Adam Birkholz, David J. Kopecky, Laurie P. Volak, Michael D. Bartberger, Yuping Chen, Christopher M. Tegley, Tara Arvedson, John D. McCarter, Christopher Fotsch, and Victor J. Cee

Journal of Medicinal Chemistry 2020 63 (20), 11602-11614
DOI: 10.1021/acs.jmedchem.0c00749

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 α- and β-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 β-position, aminomethyl substituents with amine pKa’s > 7 accelerate, while those with pKa’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.

Covalent drug discovery using sulfur(VI) fluoride exchange warheads

Huang Huang, Lyn H. Jones Expert Opinion on Drug Discovery , 2023 Covalent drug discovery has ...