Diversity-oriented synthesis as a tool to expand the chemical space of DNA-encoded libraries

DNA-encoded libraries (DEL) represent a powerful technology for generating compound collections for drug discovery campaigns, that have allowed for the selection of many hit compounds over last three decades. However, the application of split-and-pool combinatorial methodologies, as well as the limitation imposed by DNA-compatible chemistry, has often brought to a limited exploration of the chemical space, with an overrepresentation of flat aromatic or peptide-like structures, whereas a higher scaffold complexity is generally associated with a more successful biological activity of the library. In this context, the application of DiversityOriented Synthesis, capable of creating sp3-rich molecular entities even starting from simple flat building blocks, can represent an efficient strategy to significantly broaden the chemical space explored by DELs. In this review, we present selected examples of DNA-compatible complexity-generating reactions that can be applied for the generation of DNA-encoded DOS libraries, including: (i) multicomponent reactions; (ii) C-H/C-X functionalization; (iii) tandem approaches; (iv) cycloadditions; (v) reactions introducing privileged elements. Also, selected case studies on the generation of DELs with high scaffold diversity are discussed, reporting their application in drug discovery programs.

Automated summary

DNA-encoded libraries (DEL) are a powerful technology for drug discovery, but their exploration of chemical space is limited by DNA-compatible chemistry and synthetic methodologies, while the application of Diversity-Oriented Synthesis can significantly broaden this space.