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Two-Step Synthesis of Complex Artificial Macrocyclic Compounds
Rudrakshula Madhavachary1, Eman M M Abdelraheem1,2, Arianna Rossetti1
1Drug Design, University of Groningen, Address Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
Angewandte Chemie (International Ed. in English)
|July 11, 2017
Summary
Researchers developed a rapid, two-step Ugi-reaction method to create novel artificial macrocycles. This efficient synthesis enables access to diverse macrocyclic structures for targeting challenging biological targets.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
- Chemical Biology
Background:
- Artificial macrocycles are promising scaffolds for targeting challenging biological targets.
- Conventional drug-like compounds often fail to effectively modulate complex protein-protein interactions.
- Developing efficient synthetic routes to novel macrocyclic structures is crucial for drug discovery.
Purpose of the Study:
- To develop a novel, efficient, and versatile synthetic strategy for head-to-tail linked artificial macrocycles.
- To explore the substrate scope and functional group tolerance of the developed synthetic method.
- To investigate the potential of the synthesized macrocycles in targeting undruggable biological targets, exemplified by p53-MDM2 antagonism.
Main Methods:
- Utilized the Ugi-reaction for the rapid, head-to-tail linkage of molecular components.
- Employed a two-step synthetic sequence to generate diverse macrocyclic structures.
- Systematically varied reaction conditions to assess medium and macrocyclic loop size compatibility (≥8-12).
Main Results:
- Successfully synthesized 39 novel artificial macrocycles using a highly efficient, two-step Ugi-reaction approach.
- Demonstrated exceptional substrate scope and functional group tolerance in the macrocyclization process.
- Identified potent p53-MDM2 antagonism as a key application of the synthesized artificial macrocycles.
Conclusions:
- The developed Ugi-reaction-based strategy provides an unprecedentedly short and efficient route to artificial macrocycles.
- The synthesized macrocycles exhibit properties suitable for targeting challenging biological targets, including protein-protein interactions.
- This methodology opens new avenues for the discovery of novel therapeutics against previously undruggable targets, such as the p53-MDM2 interaction.
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