Synthesis and Functionalization of Azetidine-Containing Small Macrocyclic Peptides

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Peptide Chemistry

Background:

• Cyclic peptides are vital drug candidates but face synthetic challenges.
• Efficient synthesis is crucial for developing novel cyclic peptide therapeutics.

Purpose of the Study:

• Introduce 3-aminoazetidine (3-AAz) as a novel turn-inducing element for cyclic peptide synthesis.
• Demonstrate improved cyclization efficiency and late-stage functionalization of cyclic peptides.

Main Methods:

• Incorporation of the 3-AAz subunit into linear peptide precursors.
• Standard cyclization conditions and post-cyclization deprotection strategies.
• Late-stage modification via azetidine nitrogen substitution or click chemistry.

Main Results:

• Achieved greatly improved cyclizations for tetra-, penta-, and hexapeptides (28 examples).
• Demonstrated successful post-cyclization deprotection without azetidine ring degradation.
• Enabled facile synthesis of dye and biotin-tagged macrocycles via 3-AAz functionalization.
• XRD analysis revealed azetidine promotes less stable all-trans conformations.

Conclusions:

• The 3-AAz subunit is an effective tool for efficient cyclic peptide synthesis.
• 3-AAz facilitates late-stage diversification of macrocyclic peptides.
• Incorporation of 3-AAz enhances cyclic peptide stability against proteases.