Macrocycle synthesis strategy based on step-wise "adding and reacting" three components enables screening of large...

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Macrocycles are valuable for drug development but library generation is limited.
• Efficient synthesis of diverse macrocyclic ligands is crucial for targeting new biological targets.

Purpose of the Study:

• To develop a novel, efficient, and combinatorial strategy for synthesizing large macrocycle libraries.
• To demonstrate the utility of this approach by generating and screening a library against thrombin.

Main Methods:

• A solution-phase synthesis strategy coupling three building blocks sequentially via alkylation reactions.
• Combinatorial reaction of 15 tripeptide building blocks, 42 amines, and 6 cyclization linkers.
• Screening the generated library against thrombin and subsequent structure-activity relationship and X-ray crystallography analysis.

Main Results:

• A 3780-compound macrocycle library was synthesized with minimal effort and no purification required.
• A potent and selective thrombin inhibitor (Ki = 4.2 ± 0.8 nM) was identified.
• Structure-activity relationship and crystallography revealed synergistic interactions of building blocks and highlighted the importance of combinatorial screening.

Conclusions:

• The developed three-component library synthesis is a general and powerful method for generating macrocycle ligands.
• This approach significantly accelerates the discovery of macrocyclic drug candidates.
• The strategy offers a promising avenue for developing ligands against various biological targets.