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 ;
CompTox Dashboard (EPA)	DTXSID7040736 ;
ECHA InfoCard	100.041.288
Chemical and physical data
Formula	C26H34O7
Molar mass	458.551 g·mol−1
3D model (JSmol)	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 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

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

^ F. R. Hanson, T. E. Elbe, J. Bacteriol. 1949, 58, 527
^ Williams GR, Sampson MA, Shutler D, Rogers RE (November 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. Bibcode:2008JInvP..99..342W. doi:10.1016/j.jip.2008.04.005. PMID 18550078.
^ Sabin Russell (2007-04-26). "UCSF scientist tracks down suspect in honeybee deaths". San Francisco Chronicle.
^ "Scientists Identify Pathogens That May Be Causing Global Honeybee Deaths" (PDF). Edgewood Chemical Biological Center. 2007-04-25. Archived from the original (PDF) on 2011-07-22. Retrieved 2009-12-30.^{[verification needed]}
^ Huang WF, Solter LF, Yau PM, Imai BS (March 2013). Schneider DS (ed.). "Nosema ceranae escapes fumagillin control in honey bees". PLOS Pathogens. 9 (3): e1003185. doi:10.1371/journal.ppat.1003185. PMC 3591333. PMID 23505365.
^ Chen X, Xie S, Bhat S, Kumar N, Shapiro TA, Liu JO (February 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.
^ 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, et al. (September 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.
^ Lanternier F, Boutboul D, Menotti J, Chandesris MO, Sarfati C, Mamzer Bruneel MF, et al. (February 2009). "Microsporidiosis in solid organ transplant recipients: two Enterocytozoon bieneusi cases and review". Transplant Infectious Disease. 11 (1): 83–88. doi:10.1111/j.1399-3062.2008.00347.x. PMID 18803616. S2CID 205423324.
^ Molina JM, Tourneur M, Sarfati C, Chevret S, de Gouvello A, Gobert JG, et al. (June 2002). "Fumagillin treatment of intestinal microsporidiosis". The New England Journal of Medicine. 346 (25): 1963–1969. doi:10.1056/NEJMoa012924. PMID 12075057.
^ Lefkove B, Govindarajan B, Arbiser JL (August 2007). "Fumagillin: an anti-infective as a parent molecule for novel angiogenesis inhibitors". Expert Review of Anti-Infective Therapy. 5 (4): 573–579. doi:10.1586/14787210.5.4.573. PMID 17678422. S2CID 41794515.
^ Gilbert MA, Granath WO (August 2003). "Whirling disease of salmonid fish: life cycle, biology, and disease". The Journal of Parasitology. 89 (4): 658–667. doi:10.1645/GE-82R. PMID 14533670. S2CID 8950955.
^ Ingber D, Fujita T, Kishimoto S, Sudo K, Kanamaru T, Brem H, Folkman J (December 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.
^ "Zafgen Announces Positive Topline Phase 1b Data for ZGN-433 in Obesity". MedNews. Drugs.com. 5 January 2011.
^ "Zafgen Halts Development of Beloranib, to Cut Jobs by ~34%". nasdaq.com. July 20, 2016.
^ Zbidah M, Lupescu A, Jilani K, Lang F (May 2013). "Stimulation of suicidal erythrocyte death by fumagillin". Basic & Clinical Pharmacology & Toxicology. 112 (5): 346–351. doi:10.1111/bcpt.12033. PMID 23121865.
^ Corey EJ, Snider BB (April 1972). "A total synthesis of (+-)-fumagillin". Journal of the American Chemical Society. 94 (7): 2549–2550. Bibcode:1972JAChS..94.2549C. doi:10.1021/ja00762a080. PMID 5016935.
^ Kim D, Ahn SK, Bae H, Choi WJ, Kim HS (1997). "An asymmetric total synthesis of (−)-fumagillol". Tetrahedron Letters. 38 (25): 4437–4440. doi:10.1016/S0040-4039(97)00925-8.
^ Vosburg DA, Weiler S, Sorensen EJ (April 1999). "A Concise Synthesis of Fumagillol". Angewandte Chemie. 38 (7): 971–974. doi:10.1002/(SICI)1521-3773(19990401)38:7<971::AID-ANIE971>3.0.CO;2-W. PMID 29711854.
^ Hutchings M, Moffat D, Simpkins NS (2001). "A Concise Synthesis of Fumagillol". Synlett. 2001 (5): 0661–0663. doi:10.1055/s-2001-13359. S2CID 196782462.
^ Taber DF, Christos TE, Rheingold AL, Guzei IA (1999). "Synthesis of (−)-Fumagillin". Journal of the American Chemical Society. 121 (23): 5589. Bibcode:1999JAChS.121.5589T. doi:10.1021/ja990784k. S2CID 95897985.
^ Boiteau JG, Van de Weghe P, Eustache J (August 2001). "A new, ring closing metathesis-based synthesis of (-)-fumagillol". Organic Letters. 3 (17): 2737–2740. doi:10.1021/ol016343z. PMID 11506622.
^ 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.
^ Yamaguchi J, Toyoshima M, Shoji M, Kakeya H, Osada H, Hayashi Y (January 2006). "Concise enantio- and diastereoselective total syntheses of fumagillol, RK-805, FR65814, ovalicin, and 5-demethylovalicin". Angewandte Chemie. 45 (5): 789–793. doi:10.1002/anie.200502826. PMID 16365904.
^ Yamaguchi J, Hayashi Y (April 2010). "Syntheses of fumagillin and ovalicin". Chemistry. 16 (13): 3884–3901. doi:10.1002/chem.200902433. PMID 20209516.

[1] F. R. Hanson, T. E. Elbe, J. Bacteriol. 1949, 58, 527

[2] Williams GR, Sampson MA, Shutler D, Rogers RE (November 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. Bibcode:2008JInvP..99..342W. 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. Archived from the original (PDF) on 2011-07-22. Retrieved 2009-12-30.^{[verification needed]}

[5] Huang WF, Solter LF, Yau PM, Imai BS (March 2013). Schneider DS (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] Chen X, Xie S, Bhat S, Kumar N, Shapiro TA, Liu JO (February 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 PA, Contonio BD, Morgan BA, O'Donovan G, Paradise CL, et al. (September 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.

[pmid18803616-8] Lanternier F, Boutboul D, Menotti J, Chandesris MO, Sarfati C, Mamzer Bruneel MF, et al. (February 2009). "Microsporidiosis in solid organ transplant recipients: two Enterocytozoon bieneusi cases and review". Transplant Infectious Disease. 11 (1): 83–88. doi:10.1111/j.1399-3062.2008.00347.x. PMID 18803616. S2CID 205423324.

[pmid12075057-9] Molina JM, Tourneur M, Sarfati C, Chevret S, de Gouvello A, Gobert JG, et al. (June 2002). "Fumagillin treatment of intestinal microsporidiosis". The New England Journal of Medicine. 346 (25): 1963–1969. doi:10.1056/NEJMoa012924. PMID 12075057.

[pmid17678422-10] Lefkove B, Govindarajan B, Arbiser JL (August 2007). "Fumagillin: an anti-infective as a parent molecule for novel angiogenesis inhibitors". Expert Review of Anti-Infective Therapy. 5 (4): 573–579. doi:10.1586/14787210.5.4.573. PMID 17678422. S2CID 41794515.

[11] Gilbert MA, Granath WO (August 2003). "Whirling disease of salmonid fish: life cycle, biology, and disease". The 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 (December 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.

[nasdaq-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 (May 2013). "Stimulation of suicidal erythrocyte death by fumagillin". Basic & Clinical Pharmacology & Toxicology. 112 (5): 346–351. doi:10.1111/bcpt.12033. PMID 23121865.

[16] Corey EJ, Snider BB (April 1972). "A total synthesis of (+-)-fumagillin". Journal of the American Chemical Society. 94 (7): 2549–2550. Bibcode:1972JAChS..94.2549C. doi:10.1021/ja00762a080. PMID 5016935.

[17] Kim D, Ahn SK, Bae H, Choi WJ, Kim HS (1997). "An asymmetric total synthesis of (−)-fumagillol". Tetrahedron Letters. 38 (25): 4437–4440. doi:10.1016/S0040-4039(97)00925-8.

[pmid29711854-18] Vosburg DA, Weiler S, Sorensen EJ (April 1999). "A Concise Synthesis of Fumagillol". Angewandte Chemie. 38 (7): 971–974. doi:10.1002/(SICI)1521-3773(19990401)38:7<971::AID-ANIE971>3.0.CO;2-W. PMID 29711854.

[19] Hutchings M, Moffat D, Simpkins NS (2001). "A Concise Synthesis of Fumagillol". Synlett. 2001 (5): 0661–0663. doi:10.1055/s-2001-13359. S2CID 196782462.

[20] Taber DF, Christos TE, Rheingold AL, Guzei IA (1999). "Synthesis of (−)-Fumagillin". Journal of the American Chemical Society. 121 (23): 5589. Bibcode:1999JAChS.121.5589T. doi:10.1021/ja990784k. S2CID 95897985.

[21] Boiteau JG, Van de Weghe P, Eustache J (August 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 (January 2006). "Concise enantio- and diastereoselective total syntheses of fumagillol, RK-805, FR65814, ovalicin, and 5-demethylovalicin". Angewandte Chemie. 45 (5): 789–793. doi:10.1002/anie.200502826. PMID 16365904.

[24] Yamaguchi J, Hayashi Y (April 2010). "Syntheses of fumagillin and ovalicin". Chemistry. 16 (13): 3884–3901. doi:10.1002/chem.200902433. PMID 20209516.

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