Discodermolide

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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.

Contents 1 History 2 Mechanism of action 3 Total syntheses 4 Clinical development 5 See also 6 References 7 External links

[edit] 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.

[edit] 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. Hyper-stabilization of the mitotic spindle causes cell cycle arrest and cell death by apoptosis. Over a variety of cell lines, activity has been measured at IC₅₀ = 3-80 nM.

Discodermolide competes with paclitaxel for microtubule binding, but with higher affinity^[4][5][6] and is also effective in in paclitaxel- and epothilone-resistant cancer cells.^[7]

[edit] 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]

[edit] 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]

[edit] See also

• Dictyostatin
• Epothilone
• Eleutherobin
• Laulimalide
• Paclitaxel

[edit] 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. ^  Smith, A. B., III; Freeze, B. S. Tetrahedron 2008, 64, 261-298.
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)

[edit] External links

• Chemical and Engineering News: Scaled-Up Synthesis of Discodermolide by Michael Freemantle
• Chemistry and Biology of Discodermolide
• The Betzer and Ardisson Synthesis of (+)-Discodermolide