Nitrogen Arylation for Macrocyclization of Unprotected Peptides

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Peptide Synthesis

Background:

• Macrocyclic peptides are important in drug discovery due to their stability and biological activity.
• Current methods for macrocyclic peptide synthesis often require harsh conditions or protecting groups.
• Developing mild and efficient synthetic routes is crucial for accessing novel peptide therapeutics.

Purpose of the Study:

• To establish an efficient and mild method for synthesizing macrocyclic peptides via nitrogen arylation.
• To investigate the scope and limitations of this new methodology using various precursors.
• To apply the developed method for the synthesis of a biologically relevant peptide inhibitor.

Main Methods:

• Nitrogen arylation of unprotected peptide precursors using diverse electrophiles and lysine-based nucleophiles.
• Macrocyclization scan involving 14 variants to assess reaction efficiency.
• Comparative stability studies of N-aryl versus S-aryl linked macrocycles.
• Application of the method to synthesize a p53 peptide inhibitor of MDM2.

Main Results:

• High-yielding formation of macrocyclic peptides was achieved under mild conditions.
• N-aryl macrocyclic products exhibited enhanced stability against base and oxidative degradation compared to S-aryl analogs.
• The methodology was successfully applied to a p53 peptide inhibitor, yielding a nanomolar binder.
• The resulting N-aryl macrocyclic inhibitor demonstrated improved proteolytic stability and cell permeability.

Conclusions:

• The described nitrogen arylation method provides an efficient and mild route to macrocyclic peptides from unprotected precursors.
• This methodology offers a valuable tool for generating stable and potent peptide-based therapeutics.
• The improved properties of the N-aryl macrocyclic p53 inhibitor highlight the potential of this approach in drug discovery.