fumagillin

Fumagillin
Systematic (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
Clinical data
AHFS/Drugs.com	International Drug Names
Identifiers
CAS Number	23110-15-8
ATC code	P01AX10 QP51AX23
PubChem	CID: 6917655
DrugBank	DB02640
ChemSpider	5292885
UNII	7OW73204U1
ChEBI	CHEBI:48635
ChEMBL	CHEMBL32838
Chemical data
Formula	C26H34O7
Molecular mass	458.54 g/mol
	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 ;
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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/12/01 14:14:55」(JST)

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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.^[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

^ F. R. Hanson, T. E. Elbe, J. Bacteriol. 1949, 58, 527
^ 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.
^ 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" (Portable Document Format). Edgewood Chemical Biological Center. 2007-04-25. ^{[verification needed]}
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ Gilbert, M. A. & Granath, W.O. Jr. (2003). "Whirling disease and salmonid fish: life cycle, biology, and disease". Journal of Parasitology 89 (4): pp. 658–667. doi:10.1645/GE-82R. PMID 14533670. CS1 maint: Extra text (link)
^ 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.
^ "Zafgen Announces Positive Topline Phase 1b Data for ZGN-433 in Obesity". MedNews. Drugs.com. 5 January 2011.
^ 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.
^ 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.
^ 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.
^ 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
^ Martin Hutchings*, D. M. (2001). "A Concise Synthesis of Fumagillol". Synlett (5): 0661–0663. doi:10.1055/s-2001-13359.
^ Taber, D. F.; Christos, T. E. (1999). "Synthesis of (−)-Fumagillin". Journal of the American Chemical Society 121: 5589. doi:10.1021/ja990784k.
^ 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.
^ 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. (2006). "Concise enantio- and diastereoselective total syntheses of fumagillol, RK-805, FR65814, ovalicin, and 5-demethylovalicin". Angewandte Chemie (International ed. in English) 45 (5): 789–793. doi:10.1002/anie.200502826. PMID 16365904.
^ 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.

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 微胞子虫症 microsporidiosis
2. 血管新生阻害剤の概要 overview of angiogenesis inhibitors
3. 抗原虫治療 antiprotozoal therapies
4. エイズ関連カポジ肉腫：病期分類および治療 aids related kaposi sarcoma staging and treatment
5. 肝線維症の新しい治療法 emerging therapies for hepatic fibrosis

English Journal

Fumagillin, a potent angiogenesis inhibitor, induces Kaposi sarcoma-associated herpesvirus replication in primary effusion lymphoma cells.

Kanno T1, Uehara T2, Osawa M2, Fukumoto H1, Mine S1, Ueda K3, Hasegawa H1, Katano H4.
Biochemical and biophysical research communications.Biochem Biophys Res Commun.2015 Aug 7;463(4):1267-72. doi: 10.1016/j.bbrc.2015.06.100. Epub 2015 Jun 18.
Kaposi sarcoma and primary effusion lymphoma cells are infected with Kaposi sarcoma-associated herpesvirus (KSHV), predominantly in the latent form, and KSHV replication is observed rarely. Angiogenesis plays a crucial role in the pathogenesis of both Kaposi sarcoma and primary effusion lymphoma. In
PMID 26093300

Stability of dicyclohexylamine and fumagillin in honey.

van den Heever JP1, Thompson TS2, Curtis JM3, Pernal SF4.
Food chemistry.Food Chem.2015 Jul 15;179:152-8. doi: 10.1016/j.foodchem.2015.01.111. Epub 2015 Jan 31.
Fumagillin is extensively used to control nosema disease in apiculture. In the commercial formulation, fumagillin is present as a salt in an equimolar quantity with dicyclohexylamine (DCH). In this study DCH was observed to be significantly more resistant to degradation in honey than fumagillin usin
PMID 25722149

Synthesis of Daumone Derivatives and their Antiangiogenic Activities on Chorioallantoic Membrane.

Ricci J, Min D, Oh M, Lim H, Chung WY, Park KK, Jung M1.
Medicinal chemistry (Shariqah (United Arab Emirates)).Med Chem.2015 May 13. [Epub ahead of print]
Daumone, a dauer-inducing pheromone and a series of lipid derivatives were synthesized from daumone to investigate structure-activity trends. Lipid derivatives demonstrated potent in vivo antiangiogenic activity on the chorioallantoic membrane, which exceeded that of fumagillin and thalidomide as re
PMID 25974079

Japanese Journal

Fumagillin inhibits colorectal cancer growth and metastasis in mice : In vivo and in vitro study of anti-angiogenesis

Pathology international 59(7), 448-461, 2009-07-01
NAID 10027380653

Effect of four antimicrobials against an Encephalitozoon sp. (Microsporidia) in a grasshopper host

Parasitology international : official journal of the Japanese Society of Parasitology 57(3), 362-367, 2008-09-01
NAID 10025328789

Design, Synthesis, and Antiangiogenic Effects of a Series of Potent Novel Fumagillin Analogues

Chemical & pharmaceutical bulletin 55(7), 1024-1029, 2007-07-01
NAID 110006317166

Related Pictures

[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. ^{[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.

[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.

[pmid18803616-8] 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.

[pmid12075057-9] 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.

[pmid17678422-10] 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): pp. 658–667. doi:10.1645/GE-82R. PMID 14533670. CS1 maint: Extra text (link)

[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 ed. 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.

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