Drug Discovery 2022: driving the next life science revolution

New Approaches to the Synthesis and Application of DNA-Encoded Libraries

Tue4  Oct02:35pm(30 mins)
Where:
Auditorium 2
Miss Jessica Graham
Dr Harriet Stanway-Gordon

Abstract

DNA-Encoded Libraries (DELs) facilitate rapid construction of large numbers of structures and have emerged as a promising method for the identification of biologically active compounds. DELs consist of chemically synthesised molecules tagged with a coding DNA-strand that identifies their structure; in this manner, the tag acts as a barcode for the molecule that it is attached to. Whilst advantageous over more traditional methods of hit discovery in terms of both the scale of the libraries that can be constructed, alongside the speed at which this can be achieved, DELs suffer from several limitations relating to the chemistry that can be performed in the presence of the DNA tag. Accordingly, many of the current chemistries available for use within DELs suffer from variable product formation, resulting in low fidelity libraries.

Micellar catalysis is an established technique within conventional organic chemistry, allowing for a wide range of reactions to be conducted within primarily aqueous systems in high yields across broad substrate scopes. Employing the commercially available surfactant TPGS-750-M, we have applied this approach to the development of multiple DNA-compatible synthetic procedures including Suzuki-Miyaura1,2, amide coupling3, transfer hydrogenation4 and Buchwald-Hartwig5 reactions. In all instances, the optimised conditions provide highly efficient methods to conduct their respective transformations and show broad substrate scope and functional group compatibility. Through the implementation of this approach, DELs can be utilised to explore an expanded region of chemical space, in addition to improving the reliability of the hits obtained.

1. https://doi.org/10.1021/acs.bioconjchem.9b00838 (Suzuki-Miyaura)
2. https://doi.org/10.1021/acs.joc.1c02259 (Suzuki-Miyaura follow-up work)
3. https://doi.org/10.1039/D1SC03007H (Amide coupling)
4. https://doi.org/10.1002/ange.202111927 (Hydrogenation)
5. https://doi.org/10.1021/acs.joc.1c02325 (Buchwald-Hartwig)

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