Fumagillin

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

Fumagillin
Clinical data
AHFS/Drugs.comInternational Drug Names
ATC code
Identifiers
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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.041.288
Chemical and physical data
FormulaC26H34O7
Molar mass458.551 g·mol−1
3D model (JSmol)
SMILES
  • 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
  • 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
 NY (what is this?)  (verify)

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]

References
  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.
  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
  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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