Antineoplastic agents. 599. Total synthesis of dolastatin 16

George Pettit, Thomas H. Smith, Pablo M. Arce, Erik J. Flahive, Collin R. Anderson, Jean Chapuis, Jun-Ping Xu, Thomas L. Groy, Paul E. Belcher, Christian B. Macdonald

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

The first 23-step total synthesis of the cyclodepsipeptide dolastatin 16 (1) has been achieved. Synthesis of the dolaphenvaline and dolamethylleuine amino acid units using simplified methods improved the overall efficiency. The formation of the 25-membered macrocycle employing lactonization with 2-methyl-6-nitrobenzoic anhydride completed a key step in the synthesis. Regrettably, the synthetic dolastatin 16 (1), while otherwise identical (by X-ray crystal structure and spectral analyses) with the natural product, did not reproduce the powerful (nanomolar) cancer cell growth inhibition displayed by the natural isolate. Presumably this result can be attributed to conformation(s) of the synthetic dolastatin 16 (1) or to a chemically undetected component isolated with the natural product.

Original languageEnglish (US)
Pages (from-to)476-485
Number of pages10
JournalJournal of Natural Products
Volume78
Issue number3
DOIs
StatePublished - Mar 27 2015

ASJC Scopus subject areas

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

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    Pettit, G., Smith, T. H., Arce, P. M., Flahive, E. J., Anderson, C. R., Chapuis, J., Xu, J-P., Groy, T. L., Belcher, P. E., & Macdonald, C. B. (2015). Antineoplastic agents. 599. Total synthesis of dolastatin 16. Journal of Natural Products, 78(3), 476-485. https://doi.org/10.1021/np500925y