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

submitted on 10.01.2018, 14:41 and posted on 10.01.2018, 16:21 by James Leighton, 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
With an average GI50 value against the NCI panel of 60 human cancer cell lines of 0.12 nM, 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. It is unavailable from natural sources and its size and complex stereostructure render chemical synthesis highly time- and resource-intensive, however, and its development requires more efficient and step-economical synthetic access. Using novel and uniquely enabling direct complex fragment coupling alkallyl- and crotylsilylation reactions, we have developed a 22-step synthesis of a rationally designed D-ring modified analog of spongistatin 1 that is equipotent with the natural product, and have used that synthesis to establish that the C(15) acetate may be replaced with a linker functional group-bearing ester with only minimal reductions in potency.





  • Organic Synthesis and Reactions
  • Natural Products
  • Stereochemistry

Email Address of Submitting Author


Columbia University



ORCID For Submitting Author


Declaration of Conflict of Interest

The authors declare no conflicts of interest.


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