Biocompatible Synthesis of Macrocyclic Thiazol(in)e Peptides.
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.
Palabras clave
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