Correlation Engine 2.0
Clear Search sequence regions

filter terms:
  • acrylamides (3)
  • amine (4)
  • thiol (1)
  • Sizes of these terms reflect their relevance to your search.

    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.


    Adam Birkholz, David J Kopecky, Laurie P Volak, Michael D Bartberger, Yuping Chen, Christopher M Tegley, Tara Arvedson, John D McCarter, Christopher Fotsch, Victor J Cee. Systematic Study of the Glutathione Reactivity of N-Phenylacrylamides: 2. Effects of Acrylamide Substitution. Journal of medicinal chemistry. 2020 Oct 22;63(20):11602-11614

    Expand section icon Mesh Tags

    Expand section icon Substances

    PMID: 32965113

    View Full Text