Chemoselective, Oxidation-Induced Macrocyclization of Tyrosine-Containing Peptides

Area of Science:

• Organic Chemistry
• Peptide Chemistry
• Biochemistry

Background:

• Nature utilizes oxidation-induced modifications for cross-linking and cyclization in peptides.
• Tyrosine (Tyr) and other phenolic residues are key targets for such modifications.

Purpose of the Study:

• To develop a selective chemical strategy for preparing tyrosine-linked cyclic peptides.
• To mimic natural cross-linking mechanisms for peptide synthesis.

Main Methods:

• Utilized N4-substituted 1,2,4-triazoline-3,5-diones (TADs) as electrophiles for chemoselective reaction with tyrosine.
• Constructed a urazole precursor on solid-supported peptides, followed by oxidation to generate TAD intermediates.
• Performed selective oxidation under mild, peptide-compatible conditions in aqueous media.

Main Results:

• Successfully synthesized Tyr-linked cyclic peptides with a stable C-N1 bond.
• Demonstrated the method's tolerance for native amino acid side chains.
• Produced cyclic peptides with 3- to 11-residues (16- to 38-atom cycles).
• Confirmed the Tyr-linkage structure via NMR spectroscopy.
• Applied the method to create biologically active cyclic peptides, including those with the RGDf epitope.

Conclusions:

• The developed strategy provides efficient access to Tyr-linked cyclic peptides.
• This method offers a versatile tool for peptide engineering and drug discovery.
• The approach is inspired by nature and applicable to biologically relevant peptide structures.