Macrocyclization of Unprotected Peptide Isocyanates.

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Biochemistry

Background:

• Peptide macrocyclization is crucial for developing therapeutics.
• Existing methods often require protection of functional groups.
• Facile synthesis of complex cyclic peptides remains a challenge.

Purpose of the Study:

• To describe a novel two-component macrocyclization strategy.
• To enable the synthesis of unprotected peptide isocyanates.
• To explore the biological activities of novel macrocyclic peptide analogues.

Main Methods:

• Utilizing peptides with two glutamic acid γ-hydrazide residues.
• Accessing isocyanates and cyclizing them with dicarboxylic acid hydrazides.
• Employing a nucleophilic linker for property modulation.

Main Results:

• A facile two-component macrocyclization of unprotected peptide isocyanates was achieved.
• Four cyclic NYAD-1 analogues were successfully synthesized.
• The synthesized analogues exhibited a range of biological activities.

Conclusions:

• The described chemistry provides a versatile route to macrocyclic peptides.
• This method allows for facile modulation of biochemical properties.
• The novel analogues show potential for further therapeutic development.