Structure–Reactivity Studies of 2‑Sulfonylpyrimidines Allow Selective Protein Arylation

• Published in: Bioconjugate chemistry Vol. 34; no. 9; pp. 1679 - 1687
• Main Authors: Pichon, Maëva M., Drelinkiewicz, Dawid, Lozano, David, Moraru, Ruxandra, Hayward, Laura J., Jones, Megan, McCoy, Michael A., Allstrum-Graves, Samuel, Balourdas, Dimitrios-Ilias, Joerger, Andreas C., Whitby, Richard J., Goldup, Stephen M., Wells, Neil, Langley, Graham J., Herniman, Julie M., Baud, Matthias G. J.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 20.09.2023; Amer Chemical Soc
• Subjects: Adducts; Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry; Chemistry, Multidisciplinary; Chemistry, Organic; Covalence; Crystallography; Cysteine; Life Sciences & Biomedicine; p53 Protein; Physical Sciences; Proteins; Reactivity; Science & Technology; Sulfones; Warheads; X-ray crystallography; CYSTEINE; THIOL; MUTATIONS; RESIDUES; P53
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/acs.bioconjchem.3c00322

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 S N Ar 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.