Gourt Home::Gourt :: Discodermolide
| Chemical name | (+)-Discodermolide |
| Chemical formula | C33H55NO8 |
| Molecular mass | 593.79 g/mol |
| CAS number | 127943-53-7 |
| Melting point | 112-113 °C |
| SMILES | O=C1*(O)*(C)* |
| Chemical infobox | |
(+)-Discodermolide is a recently discovered polyketide natural product found to be a potent inhibitor of tumor cell growth. The molecule's carbon skeleton is made up of eight polypropionate and four acetate units with 13 stereocenters.
History
Discodermolide was first isolated in 1990 from the Caribbean marine sponge Discodermia dissoluta by chemist Dr. Sarath Gunasekera and biologist, Dr. Ross Longley, scientists at the Harbor Branch Oceanographic Institution. The sponge contained 0.002% of discodermolide (7 mg/434 g of sponge). Since the compound is light-sensitive, the sponge must be harvested at a minimum depth of 33 meters. Discodermolide was initially found to have immunosuppressive and antifungal activities.
Mechanism of action
Discodermolide has been shown to inhibit the proliferation of human cells by arresting the cell cycle in G2- and M-phase. It hyper-stabilizes microtubules, especially prevalent during cell division, and competes with paclitaxel for microtubulin binding, but with higher affinity. Over a variety of cell lines, activity has been measured at IC50 = 3-80 nM.
Hyper-stabilization of the mitotic spindle causes cell cycle arrest and cell death by apoptosis.
Discodermolide is effective in paclitaxel- and epothilone-resistant cancer cells.
Total syntheses
Several total syntheses have been published to date by Schreiber, Smith, Paterson, Marshall, and Myles. A review of the various synthetic approaches has also been published.
Clinical development
As of 2005, the Harbor Branch Oceanographic Institution has licensed (+)-discodermolide to Novartis, which has begun a phase 1 clinical trial. The Amos B. Smith's research group (in collaboration with Kosan Biosciences) has a preclinical drug development program ongoing.
The compound supply necessary for complete clinical trials cannot be met by harvesting, isolation, and purfication. As of 2005, attempts at synthesis or semi-synthesis by fermentation have proven unsuccessful. As a result, all discodermolide used in preclinical studies and clinical trials has come from large-scale total synthesis.
References
- Gunasekera, S. P.; Gunasekera, M.; Longley, R. E.; Schulte, G. K. J. Org. Chem. 1990, 55, 4912-4915.
- Gunasekera, S. P.; Pomponi, S. A.; Longley, R. E.; U. S. Patent 5,840,750, November 24, 1998. (Patent text)
- Gunasekera, S. P.; Paul, G. K.; Longley, R. E.; Isbrucker, R. A.; Pomponi, S. A. J. Nat. Prod. 2002, 65, 1643.
- Hung, D. T.; Chen, J.; Schreiber, S. L. Chem Biol. 1996, 3, 287-293. (Abstract)
- Klein, L. E.; Freeze, B. S.; Smith, A. B.; Horwitz, S. B. Cell Cycle 2005, 4, 501-507. (Article)
- Jordan, M. A. Curr. Med. Chem.: Anti-Cancer Agents 2002, 2, 1.
- Nerenberg, J. B.; Hung, D. T.; Somers, P. K.; Schreiber, S. L. J. Am. Chem. Soc. 1993, 115, 12621-12622.
- Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 11054.
- Smith, A. B. III. et al. J. Am. Chem. Soc. 1995, 117, 12011.
- Smith, A. B.; Beauchamp, T. J.; LaMarche, M. J.; Kaufman, M. D.; Qiu, Y.; Arimoto, H.; Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 2000, 122, 8654-8664. (Article)
- Smith, A. B.; Freeze, B. S.; Xian, M.; Hirose, T. Org. Lett. 2005, 7, 1825-1828.
- Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P. Angew. Chem. Int. Ed. Engl. 2000, 39, 377. (Article)
- Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885.
- Harried, S. S.; Yang, G.; Strawn, M. A.; Myles, D. C. J. Org. Chem. 1997, 62, 6098.
- Paterson, I.; Florence, G. J. Eur. J. Org. Chem. 2003, 2193.
- Amos B. Smith, III Current Research Projects
- Mickel, S. J. et al. Org. Process Res. Dev. 2004, 8, 92, 101, 107, 113 and 122.
- Wulff research group (PDF)
See also
External links
- Chemical and Engineering News: Scaled-Up Synthesis of Discodermolide by Michael Freemantle
- Chemistry and Biology of Discodermolide
"Discodermolide"