Fumagillin

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Fumagillin
Fumagillin structure.svg
Systematic (IUPAC) name
(2E,4E,6E,8E)-10-{[(3R,4S,5S,6R)-5-methoxy- 4-[(2R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl]-1- oxaspiro[2.5]octan-6-yl]oxy}-10 -oxodeca-2,4,6,8-tetraenoic acid
Clinical data
AHFS/Drugs.com International Drug Names
Legal status
?
Identifiers
CAS number 23110-15-8 YesY
ATC code P01AX10 QP51AX23
PubChem CID 6917655
DrugBank DB02640
ChemSpider 5292885 N
UNII 7OW73204U1 YesY
ChEBI CHEBI:48635 N
ChEMBL CHEMBL1744445 N
Chemical data
Formula C26H34O7 
Mol. mass 458.54 g/mol
 N (what is this?)  (verify)

Fumagillin is a complex biomolecule and used as an antimicrobial agent. It was isolated in 1949 from the microbial organism Aspergillus fumigatus.[1]

Uses[edit]

In animals[edit]

It was originally used against microsporidial parasites Nosema apis infections in honey bees.

Some studies found it to be effective against some myxozoan parasites, including Myxobolus cerebralis, an important parasite of fish; however, in the more rigorous tests required for U.S. Food and Drug Administration approval, it was ineffective.

There are reports that fumagillin controls Nosema ceranae,[2] which has recently been hypothesized as a possible cause of colony collapse disorder.[3][4] The latest report, however, has shown it to be ineffective against N. ceranae.[5] Fumagillin is also investigated as an inhibitor of malaria parasite growth.[6][7]

In humans[edit]

Fumagillin has been used in the treatment of microsporidiosis.[8][9] It is also an amebicide.[10]

Fumagillin can block blood vessel formation by binding to an enzyme called methionine aminopeptidase 2.[11] and for this reason, the compound, together with semisynthetic derivatives, are investigated as an angiogenesis inhibitor [12] in the treatment of cancer.

Preliminary clinical trials are being conducted by Zafgen into using the fumagillin analog beloranib for weight loss.[13]

According to Zbidah and coworkers from Germany fumagillin is toxic to erythrocytes in vitro.[14]

Total synthesis[edit]

Fumagillin and the related fumagillol (the hydrolysis product) have been a target in total synthesis, with several reported successful strategies, racemic, asymmetric and formal.[15][16][17][18][19][20][21][22][23]

References[edit]

  1. ^ F. R. Hanson, T. E. Elbe, J. Bacteriol. 1949, 58, 527
  2. ^ Williams, G.R., Sampson, M.A., Shutler, D., Rogers, R.E.L. (2008). "Does fumagillin control the recently detected invasive parasite Nosema ceranae in western honey bees (Apis mellifera)?". Journal of Invertebrate Pathology 99 (3): 342–344. doi:10.1016/j.jip.2008.04.005. PMID 18550078. 
  3. ^ Sabin Russell (2007-04-26). "UCSF scientist tracks down suspect in honeybee deaths". San Francisco Chronicle. 
  4. ^ "Scientists Identify Pathogens That May Be Causing Global Honeybee Deaths" (Portable Document Format). Edgewood Chemical Biological Center. 2007-04-25. [verification needed]
  5. ^ Huang, Wei-Fone; Leellen Solter; Peter Yau; Brian Imai (7 March 2013). "Nosema ceranae Escapes Fumagillin Control in Honey Bees". In Schneider, David S. PLoS Pathogens 9 (3): e1003185. doi:10.1371/journal.ppat.1003185. 
  6. ^ Xiaochun Chen et al. "Fumagillin and Fumarranol Interact with P. falciparum Methionine Aminopeptidase 2 and Inhibit Malaria Parasite Growth In Vitro and In Vivo". Chemistry & Biology, Vol. 16 Nr. 2 (2009) blz. 193-202. Chen, X.; Xie, S.; Bhat, S.; Kumar, N.; Shapiro, T. A.; Liu, J. O. (2009). "Fumagillin and Fumarranol Interact with P. Falciparum Methionine Aminopeptidase 2 and Inhibit Malaria Parasite Growth in Vitro and in Vivo". Chemistry & Biology 16 (2): 193. doi:10.1016/j.chembiol.2009.01.006. PMID 19246010.  edit
  7. ^ Christopher Arico-Muendel et al. "Antiparasitic activities of novel, orally available fumagillin analogs". Bioorganic & Medicinal Chemistry Letters Vol. 19 Nr. 17 (2009), blz. 5128-5131 Arico-Muendel, C.; Centrella, P. A.; Contonio, B. D.; Morgan, B. A.; o’Donovan, G.; Paradise, C. L.; Skinner, S. R.; Sluboski, B.; Svendsen, J. L.; White, K. F.; Debnath, A.; Gut, J.; Wilson, N.; McKerrow, J. H.; Derisi, J. L.; Rosenthal, P. J.; Chiang, P. K. (2009). "Antiparasitic activities of novel, orally available fumagillin analogs". Bioorganic & Medicinal Chemistry Letters 19 (17): 5128–5131. doi:10.1016/j.bmcl.2009.07.029. PMC 2745105. PMID 19648008.  edit
  8. ^ Lanternier F, Boutboul D, Menotti J, et al. (February 2009). "Microsporidiosis in solid organ transplant recipients: two Enterocytozoon bieneusi cases and review". Transpl Infect Dis 11 (1): 83–8. doi:10.1111/j.1399-3062.2008.00347.x. PMID 18803616. 
  9. ^ Molina JM, Tourneur M, Sarfati C, et al. (June 2002). "Fumagillin treatment of intestinal microsporidiosis". N. Engl. J. Med. 346 (25): 1963–9. doi:10.1056/NEJMoa012924. PMID 12075057. 
  10. ^ Lefkove B, Govindarajan B, Arbiser JL (August 2007). "Fumagillin: an anti-infective as a parent molecule for novel angiogenesis inhibitors". Expert Rev Anti Infect Ther 5 (4): 573–9. doi:10.1586/14787210.5.4.573. PMID 17678422. 
  11. ^ Gilbert, M. A. & Granath, W.O. Jr. (2003). "Whirling disease and salmonid fish: life cycle, biology, and disease". Journal of Parasitology 89 (4): pp. 658–667. doi:10.1645/GE-82R. PMID 14533670. 
  12. ^ Ingber, D.; Fujita, T.; Kishimoto, S.; Sudo, K.; Kanamaru, T.; Brem, H.; Folkman, J. (1990). "Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth". Nature 348 (6301): 555–557. Bibcode:1990Natur.348..555I. doi:10.1038/348555a0. PMID 1701033.  edit
  13. ^ "Zafgen Announces Positive Topline Phase 1b Data for ZGN-433 in Obesity". MedNews. Drugs.com. 5 January 2011. 
  14. ^ Zbidah, M; Lupescu, A; Jilani, K; Lang, F (2013). "Stimulation of suicidal erythrocyte death by fumagillin". Basic & clinical pharmacology & toxicology 112 (5): 346–51. doi:10.1111/bcpt.12033. PMID 23121865. 
  15. ^ Corey, E. J.; Snider, B. B. (1972). "Total synthesis of (+-)-fumagillin". Journal of the American Chemical Society 94 (7): 2549–2550. doi:10.1021/ja00762a080. PMID 5016935.  edit
  16. ^ Kim, D.; Ahn, S. K.; Bae, H.; Choi, W. J.; Kim, H. S. (1997). "An asymmetric total synthesis of (−)-fumagillol". Tetrahedron Letters 38 (25): 4437–4440. doi:10.1016/S0040-4039(97)00925-8.  edit
  17. ^ A Concise Synthesis of Fumagillol David A. Vosburg, Sven Weiler, Erik J. Sorensen Angewandte Chemie International Edition Volume 38, Issue 7, Date: April 1, 1999, Pages: 971-974 DOI
  18. ^ Martin Hutchings*, D. M. (2001). "A Concise Synthesis of Fumagillol". Synlett (5): 0661–0663. doi:10.1055/s-2001-13359.  edit
  19. ^ Taber, D. F.; Christos, T. E. (1999). "Synthesis of (−)-Fumagillin". Journal of the American Chemical Society 121: 5589. doi:10.1021/ja990784k.  edit
  20. ^ Boiteau, J. G.; Van De Weghe, P.; Eustache, J. (2001). "A New, Ring Closing Metathesis-Based Synthesis of (−)-Fumagillol". Organic Letters 3 (17): 2737–2740. doi:10.1021/ol016343z. PMID 11506622.  edit
  21. ^ Bedel, O.; Haudrechy, A.; Langlois, Y. (2004). "A Stereoselective Formal Synthesis of (−)-Fumagillol". European Journal of Organic Chemistry 2004 (18): 3813. doi:10.1002/ejoc.200400262.  edit
  22. ^ Yamaguchi, J.; Toyoshima, M.; Shoji, M.; Kakeya, H.; Osada, H.; Hayashi, Y. (2006). "Concise enantio- and diastereoselective total syntheses of fumagillol, RK-805, FR65814, ovalicin, and 5-demethylovalicin". Angewandte Chemie (International ed. in English) 45 (5): 789–793. doi:10.1002/anie.200502826. PMID 16365904.  edit
  23. ^ Yamaguchi, J.; Hayashi, Y. (2010). "Syntheses of Fumagillin and Ovalicin.". Chemistry (Weinheim an der Bergstrasse, Germany) 16 (13): 3884–3901. doi:10.1002/chem.200902433. PMID 20209516.  edit