Lead Diversification through a Prins-Driven Macrocyclization Strategy: Application to C13-Diversified Bryostatin
Paul A Wender1, Kelvin L Billingsley2
1Department of Chemistry, Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305-5080, USA, Fax +1(650)7250259.
Synthesis
|March 28, 2014
Summary
Researchers developed new bryostatin analogues with C13 modifications. This diversification strategy allows for tuning biological activity, offering potential therapeutic applications.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Pharmacology
Background:
- Bryostatins are a class of natural products with significant biological activity.
- Developing synthetic analogues is crucial for understanding structure-activity relationships and therapeutic potential.
- Late-stage diversification strategies are valuable for rapidly generating compound libraries.
Purpose of the Study:
- To design and synthesize novel C13-diversified bryostatin analogues.
- To establish a general synthetic strategy for late-stage diversification of the bryostatin scaffold.
- To evaluate the biological activity of the synthesized analogues.
Main Methods:
- Utilized a Prins macrocyclization-nucleophilic trapping cascade for synthesis.
- Employed late-stage diversification at the C13 position.
- Conducted in vitro biological evaluation of selected library members.
Main Results:
- Successfully synthesized a novel class of C13-diversified bryostatin analogues.
- Demonstrated the utility of a Prins macrocyclization-nucleophilic trapping cascade for diversification.
- Identified that C13 modifications can modulate biological activity.
Conclusions:
- The C13 position serves as a key diversification handle in bryostatin analogues.
- The developed strategy enables the regulation of biological activity through scaffold modification.
- These findings contribute to the development of new bryostatin-based therapeutics.
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