Chlorolissoclimides: New inhibitors of eukaryotic protein synthesis
- Francis Robert1,
- Hong Qing Gao1,
- Marwa Donia2,
- William C. Merrick3,
- Mark T. Hamann2, and
- Jerry Pelletier1,4
- 1Department of Biochemistry
- 4McGill Cancer Center, McGill University, Montreal, Quebec, Canada H3G 1Y6
- 2Department of Pharmacognosy, Pharmacology, Chemistry, and Biochemistry and National Center for the Development of Natural Products, The University of Mississippi, Oxford, Mississippi, USA
- 3Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-4935, USA
Abstract
Lissoclimides are cytotoxic compounds produced by shell-less molluscs through chemical secretions to deter predators. Chlorinated lissoclimides were identified as the active component of a marine extract from Pleurobranchus forskalii found during a high-throughput screening campaign to characterize new protein synthesis inhibitors. It was demonstrated that these compounds inhibit protein synthesis in vitro, in extracts prepared from mammalian and plant cells, as well as in vivo against mammalian cells. Our results suggest that they block translation elongation by inhibiting translocation, leading to an accumulation of ribosomes on mRNA. These data provide a rationale for the cytotoxic nature of this class of small molecule natural products.
Footnotes
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Reprint requests to: Jerry Pelletier, McIntyre Medical Sciences Building, Room 810, 3655 Promenade Sir William Osler, McGill University, Montreal, Quebec, Canada H3G 1Y6; e-mail: jerry.pelletier{at}mcgill.ca; fax: (514) 398-7384.
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Article published online ahead of print. Article and publication date are at http://www.rnajournal.org/cgi/doi/10.1261/rna.2346806.
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- Received December 29, 2005.
- Accepted January 19, 2006.
- Copyright © 2006 RNA Society
