Imidazoles are Tunable Nucleofuges for Developing Tyrosine-Reactive Electrophiles.
Chembiochem
; 25(16): e202400382, 2024 Aug 19.
Article
em En
| MEDLINE
| ID: mdl-38819848
ABSTRACT
Imidazole-1-sulfonyl and -sulfonate (imidazylate) are widely used in synthetic chemistry as nucleofuges for diazotransfer, nucleophilic substitution, and cross-coupling reactions. The utility of these reagents for protein bioconjugation, in contrast, have not been comprehensively explored and important considering the prevalence of imidazoles in biomolecules and drugs. Here, we synthesized a series of alkyne-modified sulfonyl- and sulfonate-imidazole probes to investigate the utility of this electrophile for protein binding. Alkylation of the distal nitrogen activated the nucleofuge capability of the imidazole to produce sulfonyl-imidazolium electrophiles that were highly reactive but unstable for biological applications. In contrast, arylsulfonyl imidazoles functioned as a tempered electrophile for assessing ligandability of select tyrosine and lysine sites in cell proteomes and when mated to a recognition element could produce targeted covalent inhibitors with reduced off-target activity. In summary, imidazole nucleofuges show balanced stability and tunability to produce sulfone-based electrophiles that bind functional tyrosine and lysine sites in the proteome.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tirosina
/
Imidazóis
Limite:
Humans
Idioma:
En
Revista:
Chembiochem
Assunto da revista:
BIOQUIMICA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos
País de publicação:
Alemanha