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

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 () and James L. Leighton ()
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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

Nature Communications, 2018, vol. 9, issue 1, 1-8

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07259-x

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