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The Carmaphycins: New Proteasome Inhibitors Exhibiting an α,β-Epoxyketone Warhead from a Marine Cyanobacterium

  1. Dr. Alban R. Pereira1,
  2. Andrew J. Kale1,
  3. Dr. Andrew T. Fenley2,
  4. Tara Byrum1,
  5. Dr. Hosana M. Debonsi1,3,
  6. Dr. Michael K. Gilson2,
  7. Dr. Frederick A. Valeriote4,
  8. Dr. Bradley S. Moore1,2,
  9. Dr. William H. Gerwick1,2,*

Article first published online: 1 MAR 2012

DOI: 10.1002/cbic.201200007

Issue

ChemBioChem

ChemBioChem

Volume 13, Issue 6, pages 810–817, April 16, 2012

Additional Information

How to Cite

Pereira, A. R., Kale, A. J., Fenley, A. T., Byrum, T., Debonsi, H. M., Gilson, M. K., Valeriote, F. A., Moore, B. S. and Gerwick, W. H. (2012), The Carmaphycins: New Proteasome Inhibitors Exhibiting an α,β-Epoxyketone Warhead from a Marine Cyanobacterium. ChemBioChem, 13: 810–817. doi: 10.1002/cbic.201200007

Author Information

  1. 1

    Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, 9500 Gilman Drive, La Jolla, CA 92093-0212 (USA)

  2. 2

    Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0736 (USA)

  3. 3

    Departamento de Física e Química, Universidade de São Paulo, Ribeirão Preto, São Paulo 14040903 (Brazil)

  4. 4

    Henry Ford Health System, Department of Internal Medicine, Josephine Ford Cancer Center, 440 Burroughs, Room 415, Detroit, MI 48202 (USA)

*Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, 9500 Gilman Drive, La Jolla, CA 92093-0212 (USA)

Publication History

  1. Issue published online: 11 APR 2012
  2. Article first published online: 1 MAR 2012
  3. Manuscript Received: 5 JAN 2012

Funded by

  • FAPESP
  • NIH. Grant Numbers: NCI CA100851, CA127622, GM61300

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Keywords:

  • anticancer;
  • cyanobacteria;
  • proteasome inhibitors;
  • structural biology;
  • total synthesis

Abstract

Two new peptidic proteasome inhibitors were isolated as trace components from a Curaçao collection of the marine cyanobacterium Symploca sp. Carmaphycin A (1) and carmaphycin B (2) feature a leucine-derived α,β-epoxyketone warhead directly connected to either methionine sulfoxide or methionine sulfone. Their structures were elucidated on the basis of extensive NMR and MS analyses and confirmed by total synthesis, which in turn provided more material for further biological evaluations. Pure carmaphycins A and B were found to inhibit the β5 subunit (chymotrypsin-like activity) of the S. cerevisiae 20S proteasome in the low nanomolar range. Additionally, they exhibited strong cytotoxicity to lung and colon cancer cell lines, as well as exquisite antiproliferative effects in the NCI60 cell-line panel. These assay results as well as initial structural biology studies suggest a distinctive binding mode for these new inhibitors.

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