Assembly of Complex Macrocycles by Incrementally Amalgamating Unprotected Peptides with a Designed Four-Armed Insert

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Biology

Background:

• Peptide-based macrocycles are valuable in drug discovery but their synthesis is challenging.
• Developing versatile building blocks is crucial for accessing diverse macrocyclic structures.

Purpose of the Study:

• To present a novel ω-octynoic acid derivative for synthesizing complex macrocycles.
• To demonstrate the utility of this derivative in creating peptidomimetics with unique architectures.

Main Methods:

• Asymmetric synthesis of a highly substituted ω-octynoic acid derivative.
• Orthogonal sequential reactions including scaffold ligation, macrocyclization, heterocycle embedding, and alkyne functionalization.
• Construction of a mimic of the second mitochondria derived activator of caspase.

Main Results:

• Successful synthesis of numerous polycyclic compounds with diverse macrocyclic structures.
• Identification of factors influencing reaction efficiency and selectivity.
• Demonstration of a functional peptidomimetic with altered connectivity impacting performance.

Conclusions:

• The developed chemistry provides facile and systematic access to complex peptidomimetics.
• This approach allows for direct alteration of structure and properties of peptide-based molecules.
• The methodology is a significant advancement for creating novel therapeutic agents.