Selective Native N_(in)-H Bond Activation in Peptides with Metallaphotocatalysis

Autor(es)

Delgado, Jose A. C. ; Amaral, JessicaC. ; Penteado, Paula S. ; Ferreira, Antonio G. ; da Silva, Maria FatimaG. F. ; Koenig, Burkhard ; Paixao, Marcio W.

• Tipo de documento: Artigo Científico
• Fonte: JACS AU; v. N/A, p. 7-pg., 2025-03-28.

Resumo

The development of chemical methods enabling site-selective incorporation of noncanonical amino acids into peptide backbones with precise functional tailoring remains a critical challenge. Particularly compelling is the use of underexplored endogenous amino acid hotspots, such as the N- (in) of tryptophan, as versatile anchors for diversification. Herein, we report a chemoselective N(sp(2))-H bond activation strategy targeting native tryptophan residues within peptide frameworks, exemplified by GLP-1 (7-37), using nickel metallaphotocatalysis under postsynthetic solid-phase conditions. This selective N- (in)-arylation reaction proceeds efficiently within 3 h of light irradiation in highly functionalized heterogeneous environments, employing minimal excesses of electrophile and base, alongside catalytic quantities of nickel, ligand, and photocatalyst. The method affords homogeneous peptide products with high chemoselectivity and operational simplicity. We envision that this strategy could contribute to advancing the design of the next-generation long-acting class II G protein-coupled receptor agonist therapeutics. (AU)

• Processo FAPESP: 24/09943-0 - Desenvolvimento Sustentável de Fármacos com Calcogênios: Da Síntese à Aplicação
• Beneficiário: Márcio Weber Paixão
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 21/06099-5 - Desenvolvimento de novas metodologias fotoquímicas para síntese de pequenas moléculas e modificações de biomoléculas
• Beneficiário: Márcio Weber Paixão
• Modalidade de apoio: Auxílio à Pesquisa - Regular