Jump to content

User:Marcipangris/Sandbox

From Wikipedia, the free encyclopedia
Dictyostatin
Dictyostatin
Names
IUPAC name
(3Z,5E,7R,8S,10S,11Z,13S,14R,15S,17S,20R,21S,22S)-22-[(2S,3Z)-hexa-3,

5-dien-2-yl]-8,10,14,20-tetrahydroxy-7,13,15,17,

21-pentamethyl-1-oxacyclodocosa-3,5,11-trien-2-one
Identifiers
3D model (JSmol)
ChemSpider
UNII
  • InChI=1S/C31H50O6/c1-7-8-11-23(4)29-20-27(33)16-14-21(2)18-25(6)31(36)24(5)15-17-26(32)19-28(34)22(3)12-9-10-13-30(35)37-29/h7-13,15,17,21-29,31-34,36H,1,14,16,18-20H2,2-6H3/b11-8-,12-9+,13-10-,17-15-/t21-,22+,23-,24-,25-,26+,27+,28-,29+,31-/m1/s1 checkY
    Key: HXOISBRUAVVASX-LYEDGMQBSA-N checkY
  • InChI=1/C31H50O6/c1-7-8-11-23(4)29-20-27(33)16-14-21(2)18-25(6)31(36)24(5)15-17-26(32)19-28(34)22(3)12-9-10-13-30(35)37-29/h7-13,15,17,21-29,31-34,36H,1,14,16,18-20H2,2-6H3/b11-8-,12-9+,13-10-,17-15-/t21-,22+,23-,24-,25-,26+,27+,28-,29+,31-/m1/s1
    Key: HXOISBRUAVVASX-LYEDGMQBBQ
  • C[C@@H]1CC[C@@H](C[C@H](OC(=O)/C=C\C=C\[C@@H]([C@@H](C[C@H](/C=C\[C@H]([C@H]([C@@H](C1)C)O)C)O)O)C)[C@H](C)/C=C\C=C)O
Properties
C31H50O6
Molar mass 518.73 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

(+)-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

[edit]

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 and structure

[edit]

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 paclitaxel- and in epothilone-resistant cancer cells.[7]. Discodermolide also seems to demonstrate a remarkably consistent 3D molecular conformation in the solid-state, in solution and when bound to tubulin; molecules with the conformational flexibility of discodermolide usually present very different conformations in different environments[8].

Biosynthesis

[edit]

Many marine-derived polyketides that are often found in sponges cannot be cultured out of their natural environment.Finding the genes responsible for the biosynthesis of a sponge derived polyketides is a difficult task to accomplish because of the sponges’ colonial nature.[citation needed] Scientists are not yet able to culture the sponges; therefore, the genes for the biosynthesis of (+)-discodermolide have not yet been discovered.[1]

Total syntheses

[edit]

Several total syntheses have been published to date by Schreiber[9][10], Smith[11][12][13], Paterson[14], Marshall[15], and Myles[16]. A review of the various synthetic approaches has also been published.[17][2]

Clinical development

[edit]

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 toxicity.[18] Amos B. Smith's research group, in collaboration with Kosan Biosciences, has a preclinical drug development program ongoing.[19]

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.[20][21]

The chemistry of palladium-catalyzed reactions developed by professor Richard F. Heck, Ei-ichi Negishi and Akira Suzuki, allowed chemists to carry out key coupling steps on-route to the final product; discodermolide. These three gentelmen were recognized for their ground breaking work with the Nobel prize in 2010.

See also

[edit]

References

[edit]
  1. ^ Shaw, S. J.; Zhang, D.; Sundermann, K. F.; Myles, D. C. Fragment Assembly: An Alternative Approach to Generating Complex Polyketides. Synthetic Commun. 2005, 35, 1735-1743.
  2. ^ Roche, C.; Roux, R. L.; Haddad, m.; Phansavath, P.; Genet, J.-P. A Ruthenium-Mediated Asymmetric Hydrogenation Approach to the Synthesis of Discodermolide Subunits. SYNLETT 2009, 4, 573-576.
  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. ^ Jogalekar, A. S.; Kriel, F. H.; Shi, Q.; Cornett, B.; Cicero, D.; Snyder, J. P. J. Med. Chem. 2010, 53, 155-165. (doi:10.1021/jm9015284)
  9. ^ Nerenberg, J. B.; Hung, D. T.; Somers, P. K.; Schreiber, S. L. J. Am. Chem. Soc. 1993, 115, 12621-12622. (doi:10.1021/ja00079a066)
  10. ^ Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 11054-11080. (doi:10.1021/ja961374o)
  11. ^ Smith, A. B. III. et al. J. Am. Chem. Soc. 1995, 117, 12011-12012. (doi:10.1021/ja00153a030)
  12. ^ 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)
  13. ^ Smith, A. B.; Freeze, B. S.; Xian, M.; Hirose, T. Org. Lett. 2005, 7, 1825-1828.
  14. ^ Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P. Angew. Chem. Int. Ed. Engl. 2000, 39, 377. (Article)
  15. ^ Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885-7892. (doi:10.1021/jo9811423)
  16. ^ Harried, S. S.; Yang, G.; Strawn, M. A.; Myles, D. C. J. Org. Chem. 1997, 62, 6098-6099. (doi:10.1021/jo9708093)
  17. ^ Smith, A. B., III; Freeze, B. S. Tetrahedron 2008, 64, 261-298.
  18. ^ 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)
  19. ^ Amos B. Smith, III Current Research Projects
  20. ^ Mickel, S. J. et al. Org. Process Res. Dev. 2004, 8, 92, 101, 107, 113 and 122.
  21. ^ Wulff research group (PDF)
[edit]
Retrieved from "https://en.wikipedia.org/w/index.php?title=User:Marcipangris/Sandbox&oldid=1118581970"