Efficient discovery of bioactive scaffolds by activity-directed synthesis

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Natural products inspire drug discovery, with their biosynthetic pathways evolving to provide functional benefits.
• Existing methods often lack a direct link between synthetic routes and the discovery of bioactive molecules.

Purpose of the Study:

• To develop a novel 'activity-directed synthesis' approach for discovering bioactive small molecules and their associated synthetic pathways.
• To identify novel ligands with submicromolar activity against the androgen receptor.

Main Methods:

• Performed arrays of catalyzed reactions using α-diazo amides, with outcomes dependent on reaction conditions.
• Assayed reaction products at decreasing concentrations, using results to refine subsequent reaction designs.
• Scaled up promising reactions and purified compounds to identify active ligands.

Main Results:

• Discovered submicromolar ligands targeting the androgen receptor based on two novel scaffolds.
• Demonstrated the tandem discovery of bioactive small molecules and efficient synthetic routes.
• Successfully steered catalyzed reactions towards functional products through iterative design.

Conclusions:

• Activity-directed synthesis enables the parallel discovery of bioactive molecules and synthetic pathways, mimicking natural product evolution.
• This approach provides a powerful strategy for identifying new drug candidates and optimizing their synthesis.
• The identified ligands represent promising starting points for further development in androgen receptor-related therapeutics.