fumagillin
{{short description|Chemical compound}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 443641231
| 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
| image = Fumagillin_structure.svg
| width = 250
| tradename =
| Drugs.com = {{drugs.com|international|fumagillin}}
| pregnancy_category =
| legal_status =
| routes_of_administration =
| bioavailability =
| protein_bound =
| metabolism =
| elimination_half-life =
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 23110-15-8
| ATC_prefix = P01
| ATC_suffix = AX10
| ATC_supplemental = {{ATCvet|P51|AX23}}
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 48635
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = DB02640
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 32838
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 7OW73204U1
| PubChem = 6917655
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 5292885
| 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
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = NGGMYCMLYOUNGM-CSDLUJIJSA-N
| C=26 | H=34 | O=7
}}
Fumagillin is a complex biomolecule and used as an antimicrobial agent. It was isolated in 1949 from the microbial organism Aspergillus fumigatus.F. R. Hanson, T. E. Elbe, J. Bacteriol. 1949, 58, 527
Uses
=In animals=
It was originally used against microsporidian parasites Nosema apis infections in honey bees.{{cn|date=December 2022}}
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.{{cn|date=December 2022}}
There are reports that fumagillin controls Nosema ceranae,{{cite journal | vauthors = Williams GR, Sampson MA, Shutler D, Rogers RE | title = Does fumagillin control the recently detected invasive parasite Nosema ceranae in western honey bees (Apis mellifera)? | journal = Journal of Invertebrate Pathology | volume = 99 | issue = 3 | pages = 342–344 | date = November 2008 | pmid = 18550078 | doi = 10.1016/j.jip.2008.04.005 | bibcode = 2008JInvP..99..342W }} which has recently been hypothesized as a possible cause of colony collapse disorder.
{{cite news
|url=http://www.sfgate.com/cgi-bin/article.cgi?file=/c/a/2007/04/26/MNGK7PFOMS1.DTL
|title=UCSF scientist tracks down suspect in honeybee deaths
|author=Sabin Russell
|date=2007-04-26
|publisher=San Francisco Chronicle
|url=http://www.ecbc.army.mil/pr/download/042507_honey_bee_pathogens.pdf
|title=Scientists Identify Pathogens That May Be Causing Global Honeybee Deaths
|date=2007-04-25
|publisher=Edgewood Chemical Biological Center
|access-date=2009-12-30
|archive-date=2011-07-22
|archive-url=https://web.archive.org/web/20110722175623/http://www.ecbc.army.mil/pr/download/042507_honey_bee_pathogens.pdf
|url-status=dead
}}{{check|date=December 2009}}
The latest report, however, has shown it to be ineffective against N. ceranae.{{cite journal | vauthors = Huang WF, Solter LF, Yau PM, Imai BS | title = Nosema ceranae escapes fumagillin control in honey bees | journal = PLOS Pathogens | volume = 9 | issue = 3 | pages = e1003185 | date = March 2013 | pmid = 23505365 | pmc = 3591333 | doi = 10.1371/journal.ppat.1003185 | veditors = Schneider DS | doi-access = free }}
Fumagillin is also investigated as an inhibitor of malaria parasite growth.{{cite journal | vauthors = Chen X, Xie S, Bhat S, Kumar N, Shapiro TA, Liu JO | title = Fumagillin and fumarranol interact with P. falciparum methionine aminopeptidase 2 and inhibit malaria parasite growth in vitro and in vivo | journal = Chemistry & Biology | volume = 16 | issue = 2 | pages = 193–202 | date = February 2009 | pmid = 19246010 | doi = 10.1016/j.chembiol.2009.01.006 | doi-access = free }}{{cite journal | vauthors = 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 | display-authors = 6 | title = Antiparasitic activities of novel, orally available fumagillin analogs | journal = Bioorganic & Medicinal Chemistry Letters | volume = 19 | issue = 17 | pages = 5128–5131 | date = September 2009 | pmid = 19648008 | pmc = 2745105 | doi = 10.1016/j.bmcl.2009.07.029 }}
=In humans=
Fumagillin has been used in the treatment of microsporidiosis.{{cite journal | vauthors = 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 | display-authors = 6 | title = Microsporidiosis in solid organ transplant recipients: two Enterocytozoon bieneusi cases and review | journal = Transplant Infectious Disease | volume = 11 | issue = 1 | pages = 83–88 | date = February 2009 | pmid = 18803616 | doi = 10.1111/j.1399-3062.2008.00347.x | s2cid = 205423324 }}{{cite journal | vauthors = Molina JM, Tourneur M, Sarfati C, Chevret S, de Gouvello A, Gobert JG, Balkan S, Derouin F | display-authors = 6 | title = Fumagillin treatment of intestinal microsporidiosis | journal = The New England Journal of Medicine | volume = 346 | issue = 25 | pages = 1963–1969 | date = June 2002 | pmid = 12075057 | doi = 10.1056/NEJMoa012924 | doi-access = free }} It is also an amebicide.{{cite journal | vauthors = Lefkove B, Govindarajan B, Arbiser JL | title = Fumagillin: an anti-infective as a parent molecule for novel angiogenesis inhibitors | journal = Expert Review of Anti-Infective Therapy | volume = 5 | issue = 4 | pages = 573–579 | date = August 2007 | pmid = 17678422 | doi = 10.1586/14787210.5.4.573 | s2cid = 41794515 }}
Fumagillin can block blood vessel formation by binding to an enzyme methionine aminopeptidase 2
{{cite journal | vauthors = Gilbert MA, Granath WO | title = Whirling disease of salmonid fish: life cycle, biology, and disease | journal = The Journal of Parasitology | volume = 89 | issue = 4 | pages = 658–667 | date = August 2003 | pmid = 14533670 | doi = 10.1645/GE-82R | s2cid = 8950955 }} and for this reason, the compound, together with semisynthetic derivatives, are investigated as an angiogenesis inhibitor{{cite journal | vauthors = Ingber D, Fujita T, Kishimoto S, Sudo K, Kanamaru T, Brem H, Folkman J | title = Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth | journal = Nature | volume = 348 | issue = 6301 | pages = 555–557 | date = December 1990 | pmid = 1701033 | doi = 10.1038/348555a0 | s2cid = 1020594 | bibcode = 1990Natur.348..555I }} in the treatment of cancer.
The company Zafgen conducted clinical trials using the fumagillin analog beloranib for weight loss,{{cite web | url = https://www.drugs.com/clinical_trials/zafgen-announces-positive-topline-phase-1b-data-zgn-433-obesity-10955.html | title = Zafgen Announces Positive Topline Phase 1b Data for ZGN-433 in Obesity | date = 5 January 2011 | work = MedNews | publisher = Drugs.com }} but they were unsuccessful.{{cite news | url = http://www.nasdaq.com/article/zafgen-halts-development-of-beloranib-to-cut-jobs-by-34-cm651992 | publisher = nasdaq.com | title = Zafgen Halts Development of Beloranib, to Cut Jobs by ~34% | date = July 20, 2016}}
Fumagillin is toxic to erythrocytes in vitro at concentrations greater than 10 μM.{{cite journal | vauthors = Zbidah M, Lupescu A, Jilani K, Lang F | title = Stimulation of suicidal erythrocyte death by fumagillin | journal = Basic & Clinical Pharmacology & Toxicology | volume = 112 | issue = 5 | pages = 346–351 | date = May 2013 | pmid = 23121865 | doi = 10.1111/bcpt.12033 | doi-access = free }}
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.{{cite journal | vauthors = Corey EJ, Snider BB | title = A total synthesis of (+-)-fumagillin | journal = Journal of the American Chemical Society | volume = 94 | issue = 7 | pages = 2549–2550 | date = April 1972 | pmid = 5016935 | doi = 10.1021/ja00762a080 | bibcode = 1972JAChS..94.2549C }}{{Cite journal | vauthors = Kim D, Ahn SK, Bae H, Choi WJ, Kim HS | doi = 10.1016/S0040-4039(97)00925-8| title = An asymmetric total synthesis of (−)-fumagillol | year = 1997 | journal = Tetrahedron Letters| volume = 38| issue = 25| pages = 4437–4440 }}{{cite journal | vauthors = Vosburg DA, Weiler S, Sorensen EJ | title = A Concise Synthesis of Fumagillol | journal = Angewandte Chemie | volume = 38 | issue = 7 | pages = 971–974 | date = April 1999 | pmid = 29711854 | doi = 10.1002/(SICI)1521-3773(19990401)38:7<971::AID-ANIE971>3.0.CO;2-W }}{{cite journal| vauthors = Hutchings M, Moffat D, Simpkins NS | title = A Concise Synthesis of Fumagillol | journal = Synlett | volume = 2001 |year=2001|issue=5 |pages=0661–0663 | doi = 10.1055/s-2001-13359| s2cid = 196782462 }}{{Cite journal| doi = 10.1021/ja990784k| title = Synthesis of (−)-Fumagillin| year = 1999| vauthors = Taber DF, Christos TE, Rheingold AL, Guzei IA | s2cid = 95897985| journal = Journal of the American Chemical Society| volume = 121| issue = 23|page=5589 | bibcode = 1999JAChS.121.5589T}}{{cite journal | vauthors = Boiteau JG, Van de Weghe P, Eustache J | title = A new, ring closing metathesis-based synthesis of (-)-fumagillol | journal = Organic Letters | volume = 3 | issue = 17 | pages = 2737–2740 | date = August 2001 | pmid = 11506622 | doi = 10.1021/ol016343z }}{{Cite journal| doi = 10.1002/ejoc.200400262| title = A Stereoselective Formal Synthesis of (−)-Fumagillol| year = 2004| vauthors = Bedel O, Haudrechy A, Langlois Y | journal = European Journal of Organic Chemistry| volume = 2004| issue = 18|page=3813 }}{{cite journal | vauthors = Yamaguchi J, Toyoshima M, Shoji M, Kakeya H, Osada H, Hayashi Y | title = Concise enantio- and diastereoselective total syntheses of fumagillol, RK-805, FR65814, ovalicin, and 5-demethylovalicin | journal = Angewandte Chemie | volume = 45 | issue = 5 | pages = 789–793 | date = January 2006 | pmid = 16365904 | doi = 10.1002/anie.200502826 }}{{cite journal | vauthors = Yamaguchi J, Hayashi Y | title = Syntheses of fumagillin and ovalicin | journal = Chemistry: A European Journal | volume = 16 | issue = 13 | pages = 3884–3901 | date = April 2010 | pmid = 20209516 | doi = 10.1002/chem.200902433 | doi-access = free }}