Fumagillin

Fumagillin

Clinical data
AHFS/Drugs.com	International Drug Names
ATC code	P01AX10 (WHO) QP51AX23 (WHO)
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	23110-15-8
PubChem (CID)	6917655
DrugBank	DB02640
ChemSpider	5292885
UNII	7OW73204U1
ChEBI	CHEBI:48635
ChEMBL	CHEMBL32838
ECHA InfoCard	100.041.288
Chemical and physical data
Formula	C26H34O7
Molar mass	458.54 g/mol
3D model (Jmol)	Interactive image
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 Key:NGGMYCMLYOUNGM-CSDLUJIJSA-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

In animals

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

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.

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 at concentrations >10uM.^[14]

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.^{[15][16][17][18][19][20][21][22][23]}

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" (Portable Document Format). 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.
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.
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): 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.
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.
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.
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.
19. Taber, D. F.; Christos, T. E. (1999). "Synthesis of (−)-Fumagillin". Journal of the American Chemical Society. 121: 5589. doi:10.1021/ja990784k.
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.
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.
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 Edition in English. 45 (5): 789–793. doi:10.1002/anie.200502826. PMID 16365904.
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.