MacroEvoLution: A New Method for the Rapid Generation of Novel Scaffold-Diverse Macrocyclic Libraries

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Chemical Biology

Background:

• Macrocycles are crucial in medicinal chemistry, but generating diverse structures remains challenging.
• Existing methods lack flexibility for rapid, large-scale synthesis of novel macrocyclic scaffolds.

Purpose of the Study:

• To develop an efficient and flexible method for generating structurally diverse macrocyclic peptide-based scaffolds.
• To enable scalable synthesis and late-stage diversification of novel macrocyclic architectures.

Main Methods:

• A cyclization screening approach termed 'MacroEvoLution' was employed.
• Building blocks were classified into pools to ensure orthogonally addressable functionalities.
• The method focuses on generating novel macrocyclic peptide-based scaffolds.

Main Results:

• The MacroEvoLution method provides reliable access to novel macrocyclic architectures.
• Scaffolds with orthogonally addressable functionalities facilitate the creation of diverse compound libraries.
• The process allows for rapid access to novel scaffolds with scalable synthesis (multi-gram scale).
• Late-stage diversification is readily achievable.

Conclusions:

• MacroEvoLution offers an efficient route to novel macrocyclic scaffolds for medicinal chemistry.
• The method supports scalable synthesis and late-stage diversification, accelerating drug discovery.
• The approach is adaptable for synthesizing systems with reduced peptidic character.