Word man

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Structural formula
Structural formula of the Wortmannin
General
Surname Word man
other names
  • (1 R , 3 R , 5 S , 9 R , 18 S ) -18- (methoxymethyl) -1,5-dimethyl-6,11,16-trioxo-13,17-dioxapentacyclo [10.6.1.0 2.10 . 0 5.9 0 15.19 ] -nonadeca-2 (10), 12 (19), 14-trien-3-yl acetate ( IUPAC )
  • KY 12420
Molecular formula C 23 H 24 O 8
External identifiers / databases
CAS number 19545-26-7
EC number 606-337-5
ECHA InfoCard 100.112.065
PubChem 5691
ChemSpider 5489
Wikidata Q423565
properties
Molar mass 428.43 g mol −1
Physical state

firmly

Melting point

240 ° C

safety instructions
GHS labeling of hazardous substances
06 - Toxic or very toxic

danger

H and P phrases H: 300-310-330
P: 260-264-280-284-302 + 350-310
Toxicological data
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Wortmannin is a mycotoxin . The compound is named after the German mycologist Julius Wortmann (1856–1925).

Occurrence

Wortmannin is formed from colonies of the molds Fusarium oxysporum , Fusarium avenaceum , Fusarium sambucinum and the tube fungus Penicillium funiculosum , from which it can be isolated.

Pharmacological effect

Wortmannin has no antibacterial properties, but it is a highly potent fungicide . It is also a highly potent PI3K - inhibitor and was the first identified PI3K inhibitor. It binds covalently to a lysine in position 802 via the furan ring. The IC 50 value is 30 nmol. In addition, wortmannin in higher concentrations is able to inhibit mTOR , DNA-dependent protein kinase (DNA-PK), phosphatidylinositol-4-kinases , myosin light chain kinase and mitogen-activated protein kinase (MAP-kinase). It has immunosuppressive and powerful anti-inflammatory effects.

Wortmannin's high liver toxicity is unfavorable, which is why the pure substance has not yet found clinical use. One way of suppressing this undesirable side effect is to conjugate Wortmannin to a monoclonal antibody .

PX-866 is a synthetically modified derivative of Wortmannin and is currently (as of June 2011) as an experimental active ingredient in three oncological phase II studies ( glioblastoma , colorectal carcinoma, head and neck carcinoma .)

further reading

Individual evidence

  1. ↑ a b Wortmannin from Penicillium funiculosum. (PDF; 97 kB) Product Information, Sigma-Aldrich, accessed on June 13, 2011.
  2. ↑ a b c d e data sheet Wortmannin from Penicillium funiculosum at Sigma-Aldrich , accessed on October 23, 2016 ( PDF ).
  3. ↑ N. Magan, M. Olsen: Mycotoxins in food: detection and control. Woodhead Publishing, 2004, ISBN 1-855-73733-7 , p. 412. Limited preview in Google Book Search
  4. ↑ T. Korzybski, Z. Owszyk-Gindifer, W. Kuryłowicz: Antibiotics - Origin, Nature, and Properties. Volume 3, ISBN 0-914-82614-X , p. 1797.
  5. ^ A b O. Müller, C. Wagener: Molecular oncology: emergence, progression, clinical aspects. Georg Thieme Verlag, 2009, ISBN 3-131-03513-7 , p. 238. Restricted preview in the Google book search.
  6. ↑ MP Wymann, G. Bulgarelli-Leva, MJ Zvelebil, L. Pirola, B. Vanhaesebroeck, MD Waterfield, G. Panayotou: Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction . In: Molecular and cellular biology Volume 16, Number 4, April 1996, pp. 1722-1733, ISSN  0270-7306 . PMID 8657148 . PMC 231159 (free full text).
  7. ↑ EF Blommaart, U. Krause, JP Schellens, H. Vreeling-Sindelárová, AJ Meijer: The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. In: European Journal of Biochemistry Volume 243, Number 1-2, January 1997, pp 240-246, ISSN  0014-2956 . PMID 9030745 .
  8. ↑ I. Ferby, I. Waga, K. Kume, C. Sakanaka, T. Shimizu: PAF-induced MAPK activation is inhibited by Wortmannin in neutrophils and macrophages. In: Advances in Experimental Medicine and Biology Volume 416, 1996, pp. 321-326, ISSN  0065-2598 . PMID 9131167 .
  9. ^ I. Vetter, BD Wyse, SJ Roberts-Thomson, GR Monteith, PJ Cabot: Mechanisms involved in potentiation of transient receptor potential vanilloid 1 responses by ethanol. In: European journal of pain (London, England) Volume 12, Number 4, May 2008, pp. 441-454, ISSN  1532-2149 . doi : 10.1016 / j.ejpain.2007.07.001 . PMID 17826200 .
  10. ^ R. Gunther, PN Kishore, HK Abbas, CJ Mirocha: Immunosuppressive effects of dietary wortmannin on rats and mice. In: Immunopharmacology and Immunotoxicology Volume 11, Number 4, 1989, pp. 559-570, ISSN  0892-3973 . doi : 10.3109 / 08923978909005385 . PMID 2628478 .
  11. ^ D. Wiesinger, HU Gubler, W. Haefliger, D. Hauser: Antiinflammatory activity of the new mold metabolite 11-desacetoxy-wortmannin and of some of its derivatives. In: Experientia Volume 30, Number 2, February 1974, pp. 135-136, ISSN  0014-4754 . PMID 4814585 .
  12. ^ RA Smith, H. Yuan, R. Weissleder, LC Cantley, L. Josephson: A wortmannin-cetuximab as a double drug. In: Bioconjugate Chemistry Volume 20, Number 11, November 2009, pp. 2185-2189, ISSN  1520-4812 . doi : 10.1021 / bc900176a . PMID 19883074 .
  13. ↑ oncothyreon.com: PI 3 Kinase Inhibitor. Retrieved June 18, 2011.
  14. ↑ clinicaltrials.gov: A Study of PX-866 in Patients With Glioblastoma Multiforme at Time of First Relapse or Progression. Retrieved June 18, 2011.
  15. ↑ HS Gwak, T. Shingu, V. Chumbalkar, YH Hwang, R. DeJournett, K. Latha, D. Koul, WK Alfred Yung, G. Powis, NP Farrell, O. Bögler: Combined action of the dinuclear platinum compound BBR3610 with the PI3-K inhibitor PX-866 in glioblastoma. In: International Journal of Cancer . Volume 128, Number 4, February 2011, pp. 787-796, ISSN  1097-0215 . doi : 10.1002 / ijc.25394 . PMID 20473884 . PMC 299081 (free full text).
  16. ↑ D. Koul, R. Shen, YW Kim, Y. Kondo, Y. Lu, J. Bankson, SM Ronen, DL Kirkpatrick, G. Powis, WK Yung: Cellular and in vivo activity of a novel PI3K inhibitor, PX- 866, against human glioblastoma. In: Neuro-Oncology Volume 12, Number 6, June 2010, pp. 559-569, ISSN  1523-5866 . doi : 10.1093 / neuonc / nop058 . PMID 20156803 . PMC 294063 (free full text).
  17. ↑ clinicaltrials.gov: Phase 1 and 2 Study of PX-866 and Cetuximab. dated June 18, 2011.
  18. ↑ clinicaltrials.gov: Study of PX-866 and Docetaxel in Solid Tumors. dated June 18, 2011.

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