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 Citations (Scopus)

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

Fingerprint

Antineoplastic Agents
Biological Products
Depsipeptides
Cell growth
Conformations
Crystal structure
X-Rays
Amino Acids
X rays
Growth
dolastatin 16
dolastatin 1
Neoplasms
2-methyl-6-nitrobenzoic anhydride

ASJC Scopus subject areas

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

Cite this

Pettit, G., Smith, T. H., Arce, P. M., Flahive, E. J., Anderson, C. R., Chapuis, J., ... 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

Antineoplastic agents. 599. Total synthesis of dolastatin 16. / Pettit, George; Smith, Thomas H.; Arce, Pablo M.; Flahive, Erik J.; Anderson, Collin R.; Chapuis, Jean; Xu, Jun-Ping; Groy, Thomas L.; Belcher, Paul E.; Macdonald, Christian B.

In: Journal of Natural Products, Vol. 78, No. 3, 27.03.2015, p. 476-485.

Research output: Contribution to journalArticle

Pettit, G, Smith, TH, Arce, PM, Flahive, EJ, Anderson, CR, Chapuis, J, Xu, J-P, Groy, TL, Belcher, PE & Macdonald, CB 2015, 'Antineoplastic agents. 599. Total synthesis of dolastatin 16', Journal of Natural Products, vol. 78, no. 3, pp. 476-485. https://doi.org/10.1021/np500925y
Pettit, George ; Smith, Thomas H. ; Arce, Pablo M. ; Flahive, Erik J. ; Anderson, Collin R. ; Chapuis, Jean ; Xu, Jun-Ping ; Groy, Thomas L. ; Belcher, Paul E. ; Macdonald, Christian B. / Antineoplastic agents. 599. Total synthesis of dolastatin 16. In: Journal of Natural Products. 2015 ; Vol. 78, No. 3. pp. 476-485.
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