Fumagillin

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Fumagillin
Fumagillin structure.svg
Clinical data
AHFS/Drugs.comInternational Drug Names
ATC code
Identifiers
  • (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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.041.288 Edit this at Wikidata
Chemical and physical data
FormulaC26H34O7
Molar mass458.551 g·mol−1
3D model (JSmol)
  • CC(=CC[C@@H]1[C@@](O1)(C)[C@H]2[C@@H]([C@@H](CC[C@]23CO3)OC(=O)/C=C/C=C/C=C/C=C/C(=O)O)OC)C
  • InChI=1S/C26H34O7/c1-18(2)13-14-20-25(3,33-20)24-23(30-4)19(15-16-26(24)17-31-26)32-22(29)12-10-8-6-5-7-9-11-21(27)28/h5-13,19-20,23-24H,14-17H2,1-4H3,(H,27,28)/b7-5+,8-6+,11-9+,12-10+/t19-,20-,23-,24-,25+,26+/m1/s1 ☒N
  • Key:NGGMYCMLYOUNGM-CSDLUJIJSA-N ☒N
 ☒NcheckY (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 microsporidian parasites Nosema apis infections in honey bees.[citation needed]

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.[citation needed]

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 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.

The company Zafgen conducted clinical trials using the fumagillin analog beloranib for weight loss,[13] but they were unsuccessful.[14]

Fumagillin is toxic to erythrocytes in vitro at concentrations greater than 10 μM.[15]

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.[16][17][18][19][20][21][22][23][24]

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" (PDF). Edgewood Chemical Biological Center. 2007-04-25.[verification needed]
  5. ^ Huang, Wei-Fone; Leellen Solter; Peter Yau; Brian Imai (7 March 2013). Schneider, David S (ed.). "Nosema ceranae Escapes Fumagillin Control in Honey Bees". PLOS Pathogens. 9 (3): e1003185. doi:10.1371/journal.ppat.1003185. PMC 3591333. PMID 23505365.
  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): 193–202. doi:10.1016/j.chembiol.2009.01.006. PMID 19246010.
  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.
  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. S2CID 205423324.
  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. S2CID 41794515.
  11. ^ Gilbert, M. A.; Granath, W.O. Jr. (2003). "Whirling disease and salmonid fish: life cycle, biology, and disease". Journal of Parasitology. 89 (4): 658–667. doi:10.1645/GE-82R. PMID 14533670. S2CID 8950955.
  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. S2CID 1020594.
  13. ^ "Zafgen Announces Positive Topline Phase 1b Data for ZGN-433 in Obesity". MedNews. Drugs.com. 5 January 2011.
  14. ^ "Zafgen Halts Development of Beloranib, to Cut Jobs by ~34%". nasdaq.com. July 20, 2016.
  15. ^ 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.
  16. ^ 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.
  17. ^ 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.
  18. ^ 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[dead link]
  19. ^ Martin Hutchings*, D. M. (2001). "A Concise Synthesis of Fumagillol". Synlett. 2001 (5): 0661–0663. doi:10.1055/s-2001-13359.
  20. ^ Taber, D. F.; Christos, T. E. (1999). "Synthesis of (−)-Fumagillin". Journal of the American Chemical Society. 121 (23): 5589. doi:10.1021/ja990784k. S2CID 95897985.
  21. ^ 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.
  22. ^ 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.
  23. ^ 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 Edition in English. 45 (5): 789–793. doi:10.1002/anie.200502826. PMID 16365904.
  24. ^ Yamaguchi, J.; Hayashi, Y. (2010). "Syntheses of Fumagillin and Ovalicin". Chemistry: A European Journal. 16 (13): 3884–3901. doi:10.1002/chem.200902433. PMID 20209516.
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