Multicomponent Reaction Toolbox for Peptide Macrocyclization and Stapling.

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Chemical Biology

Background:

• Peptide macrocyclization is crucial for developing novel therapeutics.
• Traditional cyclization methods have limitations in scope and efficiency.
• Multicomponent reactions (MCRs) have emerged as a powerful alternative.

Purpose of the Study:

• To provide a historical and modern overview of peptide macrocyclization using MCRs.
• To highlight the advantages of MCRs over classic peptide cyclization techniques.
• To showcase the potential of MCRs in drug discovery and chemical biology.

Main Methods:

• Review of literature on MCRs for peptide macrocyclization.
• Analysis of MCRs for cyclizing peptides via termini or side chains.
• Discussion of MCRs for generating diversity in cyclic peptides.

Main Results:

• MCRs enable rapid creation of skeletal complexity and diversity with low synthetic cost.
• MCRs offer advantages in chemical efficiency and synthetic scope compared to classic methods.
• MCRs allow exploration of cyclic peptide chemotypes at both sequence and ring-forming moieties.
• MCRs facilitate diversity generation in both endo- and exo-cyclic fragments, ideal for library creation.

Conclusions:

• Peptide multicomponent macrocyclization is a competitive strategy for cyclic peptide synthesis.
• MCRs provide a unique advantage for exploring cyclic peptide diversity.
• This strategy holds significant promise for drug discovery and chemical biology applications.