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Design and 22-step synthesis of highly potent D-ring modified and linker-equipped analogs of spongistatin 1

Author

Listed:
  • Linda M. Suen

    (Columbia University)

  • Makeda A. Tekle-Smith

    (Columbia University)

  • Kevin S. Williamson

    (Columbia University)

  • Joshua R. Infantine

    (Columbia University)

  • Samuel K. Reznik

    (Columbia University)

  • Paul S. Tanis

    (Columbia University)

  • Tyler D. Casselman

    (Columbia University)

  • Dan L. Sackett

    (National Institutes of Health)

  • James L. Leighton

    (Columbia University)

Abstract

Spongistatin 1 is among the most potent anti-proliferative agents ever discovered rendering it an attractive candidate for development as a payload for antibody–drug conjugates and other targeted delivery approaches. Unfortunately, it is unavailable from natural sources and its size and complex stereostructure render chemical synthesis highly time- and resource-intensive. As a result, the design and synthesis of more acid-stable and linker functional group-equipped analogs that retain the low picomolar potency of the parent natural product requires more efficient and step-economical synthetic access. Using uniquely enabling direct complex fragment coupling crotyl- and alkallylsilylation reactions, we report a 22-step synthesis of a rationally designed D-ring modified analog of spongistatin 1 that is characterized by GI50 values in the low picomolar range, and a proof-of-concept result that the C(15) acetate may be replaced with linker functional group-bearing esters with only minimal reductions in potency.

Suggested Citation

  • Linda M. Suen & Makeda A. Tekle-Smith & Kevin S. Williamson & Joshua R. Infantine & Samuel K. Reznik & Paul S. Tanis & Tyler D. Casselman & Dan L. Sackett & James L. Leighton, 2018. "Design and 22-step synthesis of highly potent D-ring modified and linker-equipped analogs of spongistatin 1," Nature Communications, Nature, vol. 9(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07259-x
    DOI: 10.1038/s41467-018-07259-x
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