Back to Search
Start Over
Structure–Reactivity Studies of 2-Sulfonylpyrimidines Allow Selective Protein Arylation
- Source :
- Bioconjugate Chemistry; September 2023, Vol. 34 Issue: 9 p1679-1687, 9p
- Publication Year :
- 2023
-
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.
Details
- Language :
- English
- ISSN :
- 10431802 and 15204812
- Volume :
- 34
- Issue :
- 9
- Database :
- Supplemental Index
- Journal :
- Bioconjugate Chemistry
- Publication Type :
- Periodical
- Accession number :
- ejs63836591
- Full Text :
- https://doi.org/10.1021/acs.bioconjchem.3c00322