Oxadiazole grafts in peptide macrocycles

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Peptide Chemistry

Background:

• Controlling macrocycle conformation and reducing peptide bond polarity are crucial for discovering novel bioactive molecules.
• Existing synthetic methods often face limitations in achieving both conformational control and polarity mitigation.

Purpose of the Study:

• To develop a novel, single-step macrocyclization reaction for synthesizing head-to-tail cyclic peptidomimetics.
• To explore the utility of the new method for creating diverse macrocyclic structures with potential therapeutic applications.

Main Methods:

• A one-step macrocyclization reaction involving a linear peptide, an aldehyde, and (N-isocyanimino)triphenylphosphorane.
• Synthesis of 15-, 18-, 21-, and 24-membered cyclic peptidomimetics.
• Characterization of the resulting macrocycles, focusing on their structural features and conformational properties.

Main Results:

• The developed method efficiently generates head-to-tail cyclic peptidomimetics.
• The synthesized macrocycles contain a 1,3,4-oxadiazole and a tertiary amine, forming a non-canonical backbone.
• These structures promote unique intramolecular hydrogen-bond networks, leading to conformationally rigid turn structures.
• The method demonstrated tolerance to variations in peptide and aldehyde components.

Conclusions:

• The novel macrocyclization strategy provides a facile route to conformationally constrained cyclic peptidomimetics.
• The resulting oxadiazole-containing macrocycles exhibit high passive membrane permeability, suggesting potential for developing orally bioavailable peptide therapeutics.
• This approach offers a valuable tool for the discovery of new bioactive molecules with improved drug-like properties.