Kinetically guided radical-based synthesis of C(sp 3 )-C(sp 3 ) linkages on DNA.

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  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      Gene Library* ; Models, Molecular*; DNA/*chemistry; Kinetics
    • Abstract:
      DNA-encoded libraries (DEL)-based discovery platforms have recently been widely adopted in the pharmaceutical industry, mainly due to their powerful diversity and incredible number of molecules. In the two decades since their disclosure, great strides have been made to expand the toolbox of reaction modes that are compatible with the idiosyncratic aqueous, dilute, and DNA-sensitive parameters of this system. However, construction of highly important C(sp 3 )-C(sp 3 ) linkages on DNA through cross-coupling remains unexplored. In this article, we describe a systematic approach to translating standard organic reactions to a DEL setting through the tactical combination of kinetic analysis and empirical screening with information captured from data mining. To exemplify this model, implementation of the Giese addition to forge high value C-C bonds on DNA was studied, which represents a radical-based synthesis in DEL.
      Competing Interests: Conflict of interest statement: S.B., W.F., R.G.D., C.J.O., A.S.R., and P.R. are full-time employees of Pfizer Inc. D.G.B. and P.S.B. have received research funding from Pfizer Inc.
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    • Grant Information:
      R35 GM118176 United States GM NIGMS NIH HHS
    • Contributed Indexing:
      Keywords: DNA-encoded libraries; combinatorial chemistry; kinetic analysis; organic synthesis; radical reactions
    • Accession Number:
      9007-49-2 (DNA)
    • Publication Date:
      Date Created: 20180628 Date Completed: 20180910 Latest Revision: 20190110
    • Publication Date:
      20231215
    • Accession Number:
      PMC6048552
    • Accession Number:
      10.1073/pnas.1806900115
    • Accession Number:
      29946037