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Biocompatible Synthesis of Macrocyclic Thiazol(in)e Peptides.
He, Junming; Nitsche, Christoph.
Afiliación
  • He J; Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia.
  • Nitsche C; Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia.
Chemistry ; 30(38): e202401716, 2024 Jul 05.
Article en En | MEDLINE | ID: mdl-38708622
ABSTRACT
Macrocyclic peptides containing a thiazole or thiazoline in the backbone are considered privileged structures in both natural compounds and drug discovery, owing to their enhanced bioactivity, stability, and permeability. Here, we present the biocompatible synthesis of macrocyclic peptides from N-terminal cysteine and C-terminal nitrile. While the N-terminal cysteine is incorporated during solid-phase peptide synthesis, the C-terminal nitrile is introduced during cleavage with aminoacetonitrile, utilizing a cleavable benzotriazole linker. This method directly yields the fully functionalized linear peptide precursor. The biocompatible cyclization reaction occurs in buffer at physiological pH and room temperature. The resulting thiazoline heterocycle remains stable in buffer but hydrolyzes under acidic conditions. While such hydrolysis enables access to macrocyclic peptides with a complete amide backbone, mild oxidation of the thiazoline leads to the stable thiazole macrocyclic peptide. While conventional oxidation strategies involve metals, we developed a protocol simply relying on alkaline salt and air. Therefore, we offer a rapid and metal-free pathway to macrocyclic thiazole peptides, featuring a biocompatible key cyclization step.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tiazoles Idioma: En Revista: Chemistry Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Alemania

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tiazoles Idioma: En Revista: Chemistry Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Alemania