Pichon, Maeva M., Drelinkiewicz, Dawid, Lozano mena, David, Moraru, Ruxandra, Hayward, Laura Jane, Jones, Megan, McCoy, Michael Arron, Allstrum-Graves, Samuel Charles John, Balourdas, Dimitrios-Ilias, Joerger, Andreas C., Whitby, Richard J., Goldup, Stephen, Wells, Neil J., Langley, G. John, Herniman, Julie and Baud, Matthias G.J. (2023) Structure–reactivity studies of 2-sulfonylpyrimidines allow selective protein arylation. Bioconjugate Chemistry, 34 (9), 1679–1687. (doi:10.1021/acs.bioconjchem.3c00322).
Abstract
Protein arylation has attracted much attention for developing new classes of bioconjugates with improved properties. Here, we have evaluated 2-sulfonylpyrimidines as covalent warheads for the mild, chemoselective, and metal free cysteine S-arylation. 2-Sulfonylpyrimidines react rapidly with cysteine, resulting in stable S-heteroarylated adducts at neutral pH. Fine tuning the heterocyclic core and exocyclic leaving group allowed predictable SNAr reactivity in vitro, covering >9 orders of magnitude. Finally, we achieved fast chemo- and regiospecific arylation of a mutant p53 protein and confirmed arylation sites by protein X-ray crystallography. Hence, we report the first example of a protein site specifically S-arylated with iodo-aromatic motifs. Overall, this study provides the most comprehensive structure–reactivity relationship to date on heteroaryl sulfones and highlights 2-sulfonylpyrimidine as a synthetically tractable and protein compatible covalent motif for targeting reactive cysteines, expanding the arsenal of tunable warheads for modern covalent ligand discovery.
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