Fumagillin Explained

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

Uses

In animals

It was originally used against microsporidian 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

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

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]

Notes and References

  1. F. R. Hanson, T. E. Elbe, J. Bacteriol. 1949, 58, 527
  2. Williams GR, Sampson MA, Shutler D, Rogers RE . Does fumagillin control the recently detected invasive parasite Nosema ceranae in western honey bees (Apis mellifera)? . Journal of Invertebrate Pathology . 99 . 3 . 342–344 . November 2008 . 18550078 . 10.1016/j.jip.2008.04.005 .
  3. News: UCSF scientist tracks down suspect in honeybee deaths . Sabin Russell . 2007-04-26 . .
  4. News: Scientists Identify Pathogens That May Be Causing Global Honeybee Deaths . 2007-04-25 . . 2009-12-30 . 2011-07-22 . https://web.archive.org/web/20110722175623/http://www.ecbc.army.mil/pr/download/042507_honey_bee_pathogens.pdf . dead .
  5. Huang WF, Solter LF, Yau PM, Imai BS . Nosema ceranae escapes fumagillin control in honey bees . PLOS Pathogens . 9 . 3 . e1003185 . March 2013 . 23505365 . 3591333 . 10.1371/journal.ppat.1003185 . Schneider DS . free .
  6. Chen X, Xie S, Bhat S, Kumar N, Shapiro TA, Liu JO . 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 . February 2009 . 19246010 . 10.1016/j.chembiol.2009.01.006 . free .
  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 PA, Contonio BD, Morgan BA, O'Donovan G, Paradise CL, Skinner SR, Sluboski B, Svendsen JL, White KF, Debnath A, Gut J, Wilson N, McKerrow JH, DeRisi JL, Rosenthal PJ, Chiang PK . 6 . Antiparasitic activities of novel, orally available fumagillin analogs . Bioorganic & Medicinal Chemistry Letters . 19 . 17 . 5128–5131 . September 2009 . 19648008 . 2745105 . 10.1016/j.bmcl.2009.07.029 .
  8. Lanternier F, Boutboul D, Menotti J, Chandesris MO, Sarfati C, Mamzer Bruneel MF, Calmus Y, Mechaï F, Viard JP, Lecuit M, Bougnoux ME, Lortholary O . 6 . Microsporidiosis in solid organ transplant recipients: two Enterocytozoon bieneusi cases and review . Transplant Infectious Disease . 11 . 1 . 83–88 . February 2009 . 18803616 . 10.1111/j.1399-3062.2008.00347.x . 205423324 .
  9. Molina JM, Tourneur M, Sarfati C, Chevret S, de Gouvello A, Gobert JG, Balkan S, Derouin F . 6 . Fumagillin treatment of intestinal microsporidiosis . The New England Journal of Medicine . 346 . 25 . 1963–1969 . June 2002 . 12075057 . 10.1056/NEJMoa012924 . free .
  10. Lefkove B, Govindarajan B, Arbiser JL . Fumagillin: an anti-infective as a parent molecule for novel angiogenesis inhibitors . Expert Review of Anti-Infective Therapy . 5 . 4 . 573–579 . August 2007 . 17678422 . 10.1586/14787210.5.4.573 . 41794515 .
  11. Gilbert MA, Granath WO . Whirling disease of salmonid fish: life cycle, biology, and disease . The Journal of Parasitology . 89 . 4 . 658–667 . August 2003 . 14533670 . 10.1645/GE-82R . 8950955 .
  12. Ingber D, Fujita T, Kishimoto S, Sudo K, Kanamaru T, Brem H, Folkman J . Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth . Nature . 348 . 6301 . 555–557 . December 1990 . 1701033 . 10.1038/348555a0 . 1020594 . 1990Natur.348..555I .
  13. Web site: Zafgen Announces Positive Topline Phase 1b Data for ZGN-433 in Obesity . 5 January 2011 . MedNews . Drugs.com .
  14. News: Zafgen Halts Development of Beloranib, to Cut Jobs by ~34% . nasdaq.com . July 20, 2016.
  15. Zbidah M, Lupescu A, Jilani K, Lang F . Stimulation of suicidal erythrocyte death by fumagillin . Basic & Clinical Pharmacology & Toxicology . 112 . 5 . 346–351 . May 2013 . 23121865 . 10.1111/bcpt.12033 . free .
  16. Corey EJ, Snider BB . A total synthesis of (+-)-fumagillin . Journal of the American Chemical Society . 94 . 7 . 2549–2550 . April 1972 . 5016935 . 10.1021/ja00762a080 .
  17. Kim D, Ahn SK, Bae H, Choi WJ, Kim HS . 10.1016/S0040-4039(97)00925-8. An asymmetric total synthesis of (−)-fumagillol . 1997 . Tetrahedron Letters. 38. 25. 4437–4440 .
  18. Vosburg DA, Weiler S, Sorensen EJ . A Concise Synthesis of Fumagillol . Angewandte Chemie . 38 . 7 . 971–974 . April 1999 . 29711854 . 10.1002/(SICI)1521-3773(19990401)38:7<971::AID-ANIE971>3.0.CO;2-W .
  19. Hutchings M, Moffat D, Simpkins NS . A Concise Synthesis of Fumagillol . Synlett . 2001 . 2001. 5 . 0661–0663 . 10.1055/s-2001-13359. 196782462 .
  20. 10.1021/ja990784k. Synthesis of (−)-Fumagillin. 1999. Taber DF, Christos TE, Rheingold AL, Guzei IA . 95897985. Journal of the American Chemical Society. 121. 23. 5589 .
  21. Boiteau JG, Van de Weghe P, Eustache J . A new, ring closing metathesis-based synthesis of (-)-fumagillol . Organic Letters . 3 . 17 . 2737–2740 . August 2001 . 11506622 . 10.1021/ol016343z .
  22. 10.1002/ejoc.200400262. A Stereoselective Formal Synthesis of (−)-Fumagillol. 2004. Bedel O, Haudrechy A, Langlois Y . European Journal of Organic Chemistry. 2004. 18. 3813 .
  23. Yamaguchi J, Toyoshima M, Shoji M, Kakeya H, Osada H, Hayashi Y . Concise enantio- and diastereoselective total syntheses of fumagillol, RK-805, FR65814, ovalicin, and 5-demethylovalicin . Angewandte Chemie . 45 . 5 . 789–793 . January 2006 . 16365904 . 10.1002/anie.200502826 .
  24. Yamaguchi J, Hayashi Y . Syntheses of fumagillin and ovalicin . Chemistry . 16 . 13 . 3884–3901 . April 2010 . 20209516 . 10.1002/chem.200902433 . free .

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