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Discodermolide



Discodermolide
IUPAC name (+)-Discodermolide
Identifiers
CAS number 127943-53-7
SMILES O=C1[C@H](C)[C@@H](O)[C@@H](C)[C@H]
(C[C@H](O)/C=C\[C@H](C)[C@H](O)[C@@H]
(C)\C=C(C[C@H](C)[C@@H](O)[C@H](C)[C@@H]
(OC(N)=O)[C@@H](C)\C=C/C=C)\C)O1
Properties
Molecular formula C33H55NO8
Molar mass 593.79 g/mol
Melting point

112-113 °C

Except where noted otherwise, data are given for
materials in their standard state
(at 25 °C, 100 kPa)
Infobox disclaimer and references

(+)-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.

Additional recommended knowledge

Contents

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.[1][2][3] 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 microtubule binding, but with higher affinity.[4][5][6] 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.[7]

Total syntheses

Several total syntheses have been published to date by Schreiber[8][9], Smith[10][11][12], Paterson[13], Marshall[14], and Myles[15]. A review of the various synthetic approaches has also been published.[16]

Clinical development

The Harbor Branch Oceanographic Institution licensed (+)-discodermolide to Novartis, which began a phase 1 clinical trial in 2004. Patient accrual was halted due to drug toxicitiy.[17] The Amos B. Smith's research group (in collaboration with Kosan Biosciences) has a preclinical drug development program ongoing.[18]

The compound supply necessary for complete clinical trials cannot be met by harvesting, isolation, and purification. 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.[19][20]

See also

References

    1. ^  Gunasekera, S. P.; Gunasekera, M.; Longley, R. E.; Schulte, G. K. J. Org. Chem. 1990, 55, 4912-4915. (doi:10.1021/jo00303a029)
    2. ^  Gunasekera, S. P.; Pomponi, S. A.; Longley, R. E.; U.S. Patent 5,840,750 , November 24, 1998.
    3. ^  Gunasekera, S. P.; Paul, G. K.; Longley, R. E.; Isbrucker, R. A.; Pomponi, S. A. J. Nat. Prod. 2002, 65, 1643.
    4. ^  Ter Haar, E.; Kowalski, R. J.; Hamel, E.; Lin, C. M., Longley, R. E.; Gunasekera, S. P.; Rosenkranz, H. S.; Day, B. W. Biochemistry 1996, 35, 243-250. (Abstract)
    5. ^  Hung, D. T.; Chen, J.; Schreiber, S. L. Chem Biol. 1996, 3, 287-293. (Abstract)
    6. ^  Klein, L. E.; Freeze, B. S.; Smith, A. B.; Horwitz, S. B. Cell Cycle 2005, 4, 501-507. (Article)
    7. ^  Jordan, M. A. Curr. Med. Chem.: Anti-Cancer Agents 2002, 2, 1.
    8. ^  Nerenberg, J. B.; Hung, D. T.; Somers, P. K.; Schreiber, S. L. J. Am. Chem. Soc. 1993, 115, 12621-12622. (doi:10.1021/ja00079a066)
    9. ^  Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 11054-11080. (doi:10.1021/ja961374o)
    10. ^  Smith, A. B. III. et al. J. Am. Chem. Soc. 1995, 117, 12011-12012. (doi:10.1021/ja00153a030)
    11. ^  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)
    12. ^  Smith, A. B.; Freeze, B. S.; Xian, M.; Hirose, T. Org. Lett. 2005, 7, 1825-1828.
    13. ^  Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P. Angew. Chem. Int. Ed. Engl. 2000, 39, 377. (Article)
    14. ^  Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885-7892. (doi:10.1021/jo9811423)
    15. ^  Harried, S. S.; Yang, G.; Strawn, M. A.; Myles, D. C. J. Org. Chem. 1997, 62, 6098-6099. (doi:10.1021/jo9708093)
    16. ^  Paterson, I.; Florence, G. J. Eur. J. Org. Chem. 2003, 2193.
    17. ^  A phase I pharmacokinetic (PK) trial of XAA296A (Discodermolide) administered every 3 wks to adult patients with advanced solid malignancies. 2004 ASCO Annual Meeting (Abstract and Presentation Slides)
    18. ^  Amos B. Smith, III Current Research Projects
    19. ^  Mickel, S. J. et al. Org. Process Res. Dev. 2004, 8, 92, 101, 107, 113 and 122.
    20. ^  Wulff research group (PDF)
     
    This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Discodermolide". A list of authors is available in Wikipedia.
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