Structure-Reactivity Studies of 2-Sulfonylpyrimidines Allow Selective Protein Arylation

Area of Science:

• Chemical Biology
• Organic Chemistry
• Protein Chemistry

Background:

• Protein arylation is key for creating novel bioconjugates with enhanced properties.
• Cysteine residues are crucial targets for site-specific protein modification.
• Developing mild, chemoselective, and metal-free arylation methods is essential.

Purpose of the Study:

• To evaluate 2-sulfonylpyrimidines as covalent warheads for cysteine S-arylation.
• To establish structure-reactivity relationships for 2-sulfonylpyrimidines.
• To demonstrate the application of this method in protein modification.

Main Methods:

• Screening of 2-sulfonylpyrimidine derivatives for reactivity with cysteine.
• Kinetic studies to determine reaction rates and selectivity.
• Application of the optimal warhead to a mutant p53 protein.
• Confirmation of arylation sites using protein X-ray crystallography.

Main Results:

• 2-Sulfonylpyrimidines enable rapid, mild, and chemoselective cysteine S-arylation at neutral pH.
• Predictable SAr reactivity was achieved by tuning the heterocyclic core and leaving group (>9 orders of magnitude).
• Site-specific arylation of a mutant p53 protein was successfully demonstrated, with arylation sites confirmed by crystallography.

Conclusions:

• 2-Sulfonylpyrimidine is a versatile and protein-compatible covalent motif for targeting reactive cysteines.
• This study provides the most comprehensive structure-reactivity data for heteroaryl sulfones.
• The findings expand the toolkit for covalent ligand discovery and bioconjugate development.