Antineoplastic agents. 599. Total synthesis of dolastatin 16.

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.

• Authors: George R Pettit, Thomas H Smith, Pablo M Arce, Erik J Flahive, Collin R Anderson, Jean-Charles Chapuis, Jun-Ping Xu, Thomas L Groy, Paul E Belcher, Christian B Macdonald
• Journal: Journal of natural products (J Nat Prod) Vol. 78 Issue 3 Pg. 476-85 (Mar 27 2015) ISSN: 1520-6025 [Electronic] United States
• PMID: 25689568 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 2-methyl-6-nitrobenzoic anhydride
• Anhydrides
• Antineoplastic Agents
• Depsipeptides
• Nitrobenzoates
• dolastatin 16

Topics

• Anhydrides (chemistry)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Depsipeptides (chemical synthesis, chemistry, pharmacology)
• Drug Screening Assays, Antitumor
• Humans
• Molecular Conformation
• Molecular Structure
• Nitrobenzoates (chemistry)
• Nuclear Magnetic Resonance, Biomolecular
• Tumor Cells, Cultured