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Micelle-Mediated Sonogashira Coupling for DNA-Encoded Library Synthesis
Jessica S Graham1, Harriet A Stanway-Gordon1, Michael J Waring1
1Cancer Research Horizons Therapeutic Innovation, Newcastle Drug Discovery Group, Chemistry, School of Natural and Environmental Sciences Bedson Building, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.
Chemistry (Weinheim an Der Bergstrasse, Germany)
|May 15, 2023
Summary
DNA-Encoded Libraries (DELs) enable efficient drug discovery. Micellar technology now allows Sonogashira coupling on DNA, expanding chemical diversity for DELs.
Area of Science:
- Medicinal Chemistry
- Organic Chemistry
- Biotechnology
Background:
- DNA-Encoded Libraries (DELs) are a powerful tool for hit identification in drug discovery.
- The efficiency of DEL synthesis relies on robust chemical reactions compatible with DNA.
- Developing new on-DNA reactions is crucial for expanding the chemical space accessible in DELs.
Purpose of the Study:
- To adapt the Sonogashira coupling reaction for efficient use on DNA.
- To demonstrate the utility of micellar technology for on-DNA Sonogashira coupling.
- To enable the synthesis of diverse and drug-like DELs using this new method.
Main Methods:
- Application of a novel micellar technology for performing chemistry on DNA.
- Utilizing the Sonogashira coupling reaction to link alkynes to aryl halides on DNA scaffolds.
- Characterization of reaction efficiency and substrate scope for on-DNA Sonogashira coupling.
Main Results:
- Achieved highly efficient conversions for the Sonogashira coupling reaction on DNA.
- Demonstrated broad substrate scope, coupling various (hetero)aromatic and aliphatic alkynes to (hetero)aryl iodides and bromides.
- Successfully synthesized diverse DNA-Encoded Libraries with potential drug-like properties.
Conclusions:
- Micellar technology provides an effective platform for on-DNA Sonogashira coupling.
- This method significantly enhances the diversity of accessible DELs.
- The developed on-DNA Sonogashira coupling is a valuable addition to the toolkit for drug discovery.
