Ketenimine Multicomponent Strategy for Multifaceted Amidine Functionalization of Peptides on the Solid Phase

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Peptide Chemistry

Background:

• Amidine derivatives are proteolytically stable bioisosteres of peptide bonds.
• Incorporating amidines into peptides imparts unique chemical and biological properties.
• Existing methods for amidine-containing peptide synthesis can be limited in scope and efficiency.

Purpose of the Study:

• To develop an efficient, solid-phase-compatible synthesis of amidine-containing peptides.
• To leverage ketenimine intermediates generated in situ for peptide modification.
• To expand the chemical space for peptide-based therapeutics and diagnostics.

Main Methods:

• Copper-catalyzed multicomponent reaction (MCR) utilizing ketenimine intermediates.
• On-resin synthesis involving sulfonyl azides, terminal alkynes, and amines.
• Solid-phase peptide synthesis protocols adapted for amidine incorporation.

Main Results:

• Robust synthesis of diverse amidine-containing peptides, including modified amino acids and arginine isologues.
• Successful generation of fluorescently labeled peptides, drug-peptide hybrids, and PEGylated derivatives.
• Demonstrated compatibility with various peptide modifications like macrocyclization and scaffold incorporation.

Conclusions:

• The ketenimine-based MCR offers a versatile platform for advanced peptide modification.
• This strategy significantly broadens the accessibility of complex peptide motifs for medicinal chemistry.
• The methodology supports the development of novel peptide therapeutics and imaging agents.