Medicinal Chemistry Research

, Volume 22, Issue 3, pp 1224–1228 | Cite as

Polyoxometalates as potent inhibitors for acetyl and butyrylcholinesterases and as potential drugs for the treatment of Alzheimer’s disease

  • Jamshed Iqbal
  • Maria Barsukova-Stuckart
  • Masooma Ibrahim
  • Syed Usman Ali
  • Aftab Ahmed Khan
  • Ulrich Kortz
Original Research

Abstract

Polyoxometalates (POMs) show significant importance in medicine due to their enzyme inhibition, antiviral and anticancer properties. In this study, some polyoxotungstates were identified as potent inhibitors of acetyl and butyrylcholinesterases. Compounds [H2W12O42]10− and [TeW6O24]6− have the most potent acetylcholinesterase activity, exhibiting IC50 values of 0.29 ± 0.01 and 0.31 ± 0.01 μM, respectively. Whereas, compound [(O3PCH2PO3)4W12O36]16− was a potent and selective inhibitor of butyrylcholinesterase with IC50 value of 0.18 ± 0.05 μM. In general, POMs were found to be effective cholinesterase inhibitors in terms of efficiency as well as selectivity and represent non-classical cholinesterase inhibitors.

Keywords

Acetylcholinesterase Anti-Alzheimer Butyrylcholinesterase Enzyme Inhibition Polyoxometalates 

References

  1. Acerete R, Server-Carrio J, Vegas A, Martinez-Ripoll M (1990) Synthesis and x-ray crystal structure determination of a novel chiral heteropolyanion: the “3:1” octadecatungstohexaphosphate. J Am Chem Soc 112:9386–9387CrossRefGoogle Scholar
  2. Alptuzun V, Prinz M, Horr V, Scheiber J, Radacki K, Fallarero A, Vuorela P, Engels B, Braunschweig H, Erciyas E, Holzgrabe U (2010) Interaction of (benzylidene-hydrazono)-1,4-dihydropyridines with beta-amyloid, acetylcholine, and butyrylcholine esterases. Bioorg Med Chem 18:2049–2059PubMedCrossRefGoogle Scholar
  3. Barnard DL, Hill CL, Gage T, Matheson JE, Huffman JH, Sidwell RW, Otto MI, Schinazi RF (1997) Potent inhibition of respiratory syncytial virus by polyoxometalates of several structural classes. Antiviral Res 34:27–37PubMedCrossRefGoogle Scholar
  4. Contant R, Klemperer WG, Yaghi O (2007) Potassium Octadecatungstodiphosphates(V) and Related Lacunary Compounds. In: Inorganic Syntheses, pp 104-111: John Wiley & Sons, IncGoogle Scholar
  5. Damonte EB (1996) Antiviral agents that act in the early phases of the viral cycle. Rev Argent Microbiol 28:204–216PubMedGoogle Scholar
  6. Dan K, Miyashita K, Seto Y, Fujita H, Yamase T (2002) The memory effect of heteropolyoxotungstate (PM-19) pretreatment on infection by herpes simplex virus at the penetration stage. Pharmacol Res 46:357–361PubMedCrossRefGoogle Scholar
  7. De Clercq E (1995) Antiviral therapy for human immunodeficiency virus infections. Clin Microbiol Rev 8:200–239PubMedGoogle Scholar
  8. De Clercq E (1997) Antiviral metal complexes. Met Based Drugs 4:173–192PubMedCrossRefGoogle Scholar
  9. Dong Z, Tan R, Cao J, Yang Y, Kong C, Du J, Zhu S, Zhang Y, Lu J, Huang B, Liu S (2011) Discovery of polyoxometalate-based HDAC inhibitors with profound anticancer activity in vitro and in vivo. Eur J Med Chem 46:2477–2484PubMedCrossRefGoogle Scholar
  10. Ellman GL, Courtney KD, Andres V Jr, Feather-Stone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95PubMedCrossRefGoogle Scholar
  11. Flutsch A, Schroeder T, Grutter MG, Patzke GR (2011) HIV-1 protease inhibition potential of functionalized polyoxometalates. Bioorg Med Chem Lett 21:1162–1166PubMedCrossRefGoogle Scholar
  12. Fukuma M, Seto Y, Yamase T (1991) In vitro antiviral activity of polyoxotungstate (PM-19) and other polyoxometalates against herpes simplex virus. Antiviral Res 16:327–339PubMedCrossRefGoogle Scholar
  13. Geisberger G, Paulus S, Carraro M, Bonchio M, Patzke GR (2011a) Synthesis, characterisation and cytotoxicity of polyoxometalate/carboxymethyl chitosan nanocomposites. Chemistry 17:4619–4625PubMedCrossRefGoogle Scholar
  14. Geisberger G, Paulus S, Gyenge EB, Maake C, Patzke GR (2011b) Targeted delivery of polyoxometalate nanocomposites. Small 7:2808–2814PubMedCrossRefGoogle Scholar
  15. Geng J, Li M, Ren J, Wang E, Qu X (2011) Polyoxometalates as inhibitors of the aggregation of amyloid beta peptides associated with Alzheimer’s disease. Angew Chem Int Ed Engl 50:4184–4188PubMedCrossRefGoogle Scholar
  16. Guo R, Cheng Y, Ding D, Li X, Zhang L, Jiang X, Liu B (2011) Synthesis and antitumoral activity of gelatin/polyoxometalate hybrid nanoparticles. Macromol Biosci 11:839–847PubMedCrossRefGoogle Scholar
  17. Hu D, Shao C, Guan W, Su Z, Sun J (2007) Studies on the interactions of Ti-containing polyoxometalates (POMs) with SARS-CoV 3CLpro by molecular modeling. J Inorg Biochem 101:89–94PubMedCrossRefGoogle Scholar
  18. Ingkaninan K, Temkitthawon P, Chuenchom K, Yuyaem T, Thongnoi W (2003) Screening for acetylcholinesterase inhibitory activity in plants used in Thai traditional rejuvenating and neurotonic remedies. J Ethnopharmacol 89:261–264PubMedCrossRefGoogle Scholar
  19. Inoue M, Suzuki T, Fujita Y, Oda M, Matsumoto N, Iijima J, Yamase T (2006a) Synergistic effect of polyoxometalates in combination with oxacillin against methicillin-resistant and vancomycin-resistant Staphylococcus aureus: a high initial inoculum of 1 x 108 cfu/ml for in vivo test. Biomed Pharmacother 60:220–226PubMedCrossRefGoogle Scholar
  20. Inoue M, Suzuki T, Fujita Y, Oda M, Matsumoto N, Yamase T (2006b) Enhancement of antibacterial activity of beta-lactam antibiotics by [P2W18O62]6-, [SiMo12O40]4-, and [PTi2W10O40]7- against methicillin-resistant and vancomycin-resistant Staphylococcus aureus. J Inorg Biochem 100:1225–1233PubMedCrossRefGoogle Scholar
  21. Judd DA, Nettles JH, Nevins N, Snyder JP, Liotta DC, Tang J, Ermolieff J, Schinazi RF, Hill CL (2001) Polyoxometalate HIV-1 protease inhibitors. A new mode of protease inhibition. J Am Chem Soc 123:886–897PubMedCrossRefGoogle Scholar
  22. Kohler D, Eckle T, Faigle M, Grenz A, Mittelbronn M, Laucher S, Hart ML, Robson SC, Muller CE, Eltzschig HK (2007) CD39/ectonucleoside triphosphate diphosphohydrolase 1 provides myocardial protection during cardiac ischemia/reperfusion injury. Circulation 116:1784–1794PubMedCrossRefGoogle Scholar
  23. Komloova M, Musilek K, Horova A, Holas O, Dohnal V, Gunn-Moore F, Kuca K (2011) Preparation, in vitro screening and molecular modelling of symmetrical bis-quinolinium cholinesterase inhibitors–implications for early myasthenia gravis treatment. Bioorg Med Chem Lett 21:2505–2509PubMedCrossRefGoogle Scholar
  24. Korabecny J, Musilek K, Holas O, Binder J, Zemek F, Marek J, Pohanka M, Opletalova V, Dohnal V, Kuca K (2010) Synthesis and in vitro evaluation of N-alkyl-7-methoxytacrine hydrochlorides as potential cholinesterase inhibitors in Alzheimer disease. Bioorg Med Chem Lett 20:6093–6095PubMedCrossRefGoogle Scholar
  25. Kortz U, Jameson GB, Pope MT (1994) Polyoxometalate diphosphate complexes. Folded macrocyclic dodecatungstates, [(O3PXPO3)4W12O36]16-(X = O, CH2). J Am Chem Soc 116:2659–2660CrossRefGoogle Scholar
  26. Marco JL, de los Rios C, Garcia AG, Villarroya M, Carreiras MC, Martins C, Eleuterio A, Morreale A, Orozco M, Luque FJ (2004) Synthesis, biological evaluation and molecular modelling of diversely functionalized heterocyclic derivatives as inhibitors of acetylcholinesterase/butyrylcholinesterase and modulators of Ca2 + channels and nicotinic receptors. Bioorg Med Chem 12:2199–2218PubMedCrossRefGoogle Scholar
  27. Müller CE, Iqbal J, Baqi Y, Zimmermann H, Rollich A, Stephan H (2006) Polyoxometalates–a new class of potent ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) inhibitors. Bioorg Med Chem Lett 16:5943–5947PubMedCrossRefGoogle Scholar
  28. Prudent R, Moucadel V, Laudet B, Barette C, Lafanechere L, Hasenknopf B, Li J, Bareyt S, Lacote E, Thorimbert S, Malacria M, Gouzerh P, Cochet C (2008) Identification of polyoxometalates as nanomolar noncompetitive inhibitors of protein kinase CK2. Chem Biol 15:683–692PubMedCrossRefGoogle Scholar
  29. Prudent R, Sautel CF, Cochet C (2010) Structure-based discovery of small molecules targeting different surfaces of protein-kinase CK2. Biochim Biophys Acta 1804:493–498PubMedCrossRefGoogle Scholar
  30. Rouleau J, Iorga BI, Guillou C (2011) New potent human acetylcholinesterase inhibitors in the tetracyclic triterpene series with inhibitory potency on amyloid beta aggregation. Eur J Med Chem 46:2193–2205PubMedCrossRefGoogle Scholar
  31. Samadi A, Chioua M, Bolea I, de los Ríos C, Iriepa I, Moraleda I, Bastida A, Esteban G, Unzeta M, Gálvez E, Marco-Contelles J (2011) Synthesis, biological assessment and molecular modeling of new multipotent MAO and cholinesterase inhibitors as potential drugs for the treatment of Alzheimer’s disease. Eur J Med Chem 46:4665–4668PubMedCrossRefGoogle Scholar
  32. Sarafianos SG, Kortz U, Pope MT, Modak MJ (1996) Mechanism of polyoxometalate-mediated inactivation of DNA polymerases: an analysis with HIV-1 reverse transcriptase indicates specificity for the DNA-binding cleft. Biochem J 319(Pt 2):619–626PubMedGoogle Scholar
  33. Sartorel A, Truccolo M, Berardi S, Gardan M, Carraro M, Toma FM, Scorrano G, Prato M, Bonchio M (2011) Oxygenic polyoxometalates: a new class of molecular propellers. Chem Commun (Camb) 47:1716–1718CrossRefGoogle Scholar
  34. Shigeta S, Mori S, Yamase T, Yamamoto N (2006) Anti-RNA virus activity of polyoxometalates. Biomed Pharmacother 60:211–219PubMedCrossRefGoogle Scholar
  35. Sun X, Wu Y, Gao W, Enjyoji K, Csizmadia E, Muller CE, Murakami T, Robson SC (2010) CD39/ENTPD1 expression by CD4 + Foxp3 + regulatory T cells promotes hepatic metastatic tumor growth in mice. Gastroenterology 139:1030–1040PubMedCrossRefGoogle Scholar
  36. Tasso B, Catto M, Nicolotti O, Novelli F, Tonelli M, Giangreco I, Pisani L, Sparatore A, Boido V, Carotti A, Sparatore F (2011) Quinolizidinyl derivatives of bi- and tricyclic systems as potent inhibitors of acetyl- and butyrylcholinesterase with potential in Alzheimer’s disease. Eur J Med Chem 46:2170–2184PubMedCrossRefGoogle Scholar
  37. Wall MJ, Wigmore G, Lopatar J, Frenguelli BG, Dale N (2008) The novel NTPDase inhibitor sodium polyoxotungstate (POM-1) inhibits ATP breakdown but also blocks central synaptic transmission, an action independent of NTPDase inhibition. Neuropharmacology 55:1251–1258PubMedCrossRefGoogle Scholar
  38. Yanagie H, Ogata A, Mitsui S, Hisa T, Yamase T, Eriguchi M (2006) Anticancer activity of polyoxomolybdate. Biomed Pharmacother 60:349–352PubMedCrossRefGoogle Scholar
  39. Zhang G, Keita B, Craescu CT, Miron S, de Oliveira P, Nadjo L (2007) Polyoxometalate binding to human serum albumin: a thermodynamic and spectroscopic approach. J Phys Chem B 111:11253–11259PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Jamshed Iqbal
    • 1
  • Maria Barsukova-Stuckart
    • 2
  • Masooma Ibrahim
    • 2
  • Syed Usman Ali
    • 1
  • Aftab Ahmed Khan
    • 1
  • Ulrich Kortz
    • 2
  1. 1.Department of Pharmaceutical SciencesCOMSATS Institute of Information TechnologyAbbottabadPakistan
  2. 2.School of Engineering and ScienceJacobs UniversityBremenGermany

Personalised recommendations