Many potential therapeutic targets cannot be studied with our current arsenal of chemical tools. One method that can be used to find small-molecule binders to proteins of interest involves the covalent attachment of organic compounds to unique DNA sequences that function as amplifiable barcodes. Hits resulting from affinity chromatography-based experiments may then be used to study individual proteins or entire biological pathways. Unfortunately, the compounds in existing DNA-barcoded libraries often do not exhibit structural properties that are desirable for biological activity. DNA-barcoded compounds are often synthesized in a manner that requires the synthetic chemistry to take place in the presence of both DNA and water. Many reactions are incompatible with these conditions, so libraries often contain large numbers of structurally simple (and redundant) compounds.<br/><br/>Applying the principles of diversity-oriented synthesis (DOS) could lead to the synthesis of DNA-barcoded compounds that are better suited for the development of chemical probes and therapeutics. DOS prioritizes complexity-generating reactions that assemble chemical skeletons of intermediate complexity, which have been shown to be preferable for biological activity. Incorporating these reactions into strategically designed synthetic pathways could furnish scaffolds that are currently underrepresented (or completely absent) from current collections of DNA-barcoded compounds. By leveraging novel chemistry, we hope to develop molecules that address some of the most pressing unresolved challenges in biomedicine.<br/><br/>As a first instance of this strategy, here we describe the design, synthesis, and biological evaluation of a DNA-barcoded library comprising over 100,000 chiral azetidines and pyrrolidines. The corresponding synthetic pathway uses Pd-mediated C-H arylation chemistry to access all possible stereoisomers of 2,3-disubstituted azetidine and pyrrolidine scaffolds. This library has been validated against well-studied protein targets, and it is currently being used to search for small-molecule binders to proteins implicated in cancer, diabetes, and neurodegenerative disease, among others. As a complement to these biological experiments, cheminformatic analyses have quantified the diversity of the library and the complexity of its constituent molecules. Taken together, these results will inform best practices for future library design.

DOSEDO: Diversity-oriented synthesis encoded by DNA oligonucleotides

256th National Meeting (2018)

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