Russian Journal of Bioorganic Chemistry

, Volume 34, Issue 1, pp 60–66

Inhibition of alkaline phosphatase by thioureido derivatives of methylenebisphosphonic acid

  • A. I. Vovk
  • A. L. Chuiko
  • L. A. Kononets
  • V. Yu. Tanchuk
  • I. V. Murav’eva
  • M. O. Lozinsky
  • V. P. Kukhar
Article
  • 63 Downloads

Abstract

A series of thioureido derivatives of methylenebisphosphonic acid were synthesized by the reaction of aminomethylenebisphosphonic acid with the corresponding isothiocyanates, and their effect on the activity of alkaline phosphatases from bovine small intestine mucosa (BSIM) and human placenta was studied. It was found that (3-phenylthioureido)methylenebisphosphonate is approximately one order of magnitude more effective in inhibiting the activity of alkaline phosphatase from BSIM than the alkyl derivatives of thioureidomethylenebisphosphonic acid with methyl, ethyl, tert-butyl, or cyclohexyl substituents. The introduction of substituents into the benzene ring of (3-phenylthioureido)methylenebisphosphonate decreased the effect of the inhibitor on the activity of the enzyme. The affinity of (3-phenylureido)methylenebisphosphonate to the alkaline phosphatase of BSIM was also weaker as compared with the corresponding thioureidomethylenebisphosphonate. The insertion of thioureidobisphosphonates into the active site of alkaline phosphatase of human placenta by the method of molecular docking indicated that the methylenebisphosphonate residue and the substituted amino groups of the inhibitor are involved in the mechanisms of complex formation with the enzyme. It is supposed that the improvement of the inhibitory activity of (3-phenylthioureido)methylenebisphosphonate toward alkaline phosphatase of BSIM is due to the additional fixation of the phenyl substituent in the active site of the enzyme.

Key words

alkaline phosphatase inhibition molecular docking thioureidomethylenebisphosphonates 

Abbreviations

BSIM

bovine small intestine mucosa

HP

human placenta

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Le Du, M.H. and Millan, J.L., J. Biol. Chem., 2002, vol. 277, pp. 49 808–49 814.Google Scholar
  2. 2.
    Zhang, L., Balcerzak, M., Radisson, J., Thouverey, C., Pikula, S., Azzar, G., and Buchet, R., J. Biol. Chem., 2005, vol. 280, pp. 37 289–37 296.Google Scholar
  3. 3.
    Whyte, M.P., Landt, M., Ryan, L.M., Mulivor, R.A., Henthorn, P.S., Fedde, K.N., Mahuren, J.D., and Coburn, S.P., J. Clin. Invest., 1995, vol. 95, pp. 1440–1445.CrossRefPubMedGoogle Scholar
  4. 4.
    Rezende, A.A., Pizauro, J.M., Ciancaglini, P., and Leone, F.A., Biochem. J., 1994, vol. 301, pp. 517–522.PubMedGoogle Scholar
  5. 5.
    Petitclerc, C. and Plante, G.E., Can. J. Physiol. Pharmacol., 1981, vol. 59, pp. 311–323.PubMedGoogle Scholar
  6. 6.
    Hessle, L., Johnson, K.A., Anderson, H.C., Narisawa, S., Sali, A., Goding, J.W., Terkeltaub, R., and Millan, J.L., Proc. Natl. Acad. Sci. USA, 2002, vol. 99, pp. 9445–9449.CrossRefPubMedGoogle Scholar
  7. 7.
    Sanchez de Medina, F., Martinez-Augustin, O., Gonzalez, R., Ballester, I., Nieto, A., Galvez, J., and Zarzuelo, A., Biochem. Pharmacol., 2004, vol. 68, pp. 2317–2326.CrossRefPubMedGoogle Scholar
  8. 8.
    Tung, C.B., Tung, C.F., Yang, D.Y., Hu, W.H., Hung, D.Z., Peng, Y.C., and Chang, C.S., Hepatogastroenterology, 2005, vol. 52, pp. 1347–1350.PubMedGoogle Scholar
  9. 9.
    Mathieu, P., Voisine, P., Pepin, A., Shetty, R., Savard, N., and Dagenais, F., J. Heart Valve Dis., 2005, vol. 14, pp. 353–357.PubMedGoogle Scholar
  10. 10.
    Kozlenkov, A., Le Du. M.H., Cuniasse. P., Ny. T., Hoylaerts. M.F., Millan, J.L., J. Bone Miner. Res., 2004, vol. 19, pp. 1862–1872.CrossRefPubMedGoogle Scholar
  11. 11.
    Negrão, M.R., Mota, A., Azevedo, I., and Martins, M.J., Medical Hypotheses, 2006, vol. 67, pp. 524–528.CrossRefPubMedGoogle Scholar
  12. 12.
    Reszka, A.A. and Rodan, G.A., Mini Rev. Med. Chem., 2004, vol. 4, pp. 711–719.PubMedGoogle Scholar
  13. 13.
    Vaisman, D.N., McCarthy, A.D., and Cortizo, A.M., Biol. Trace Elem. Res., 2005, vol. 104, pp. 131–140.CrossRefPubMedGoogle Scholar
  14. 14.
    Engel, R, in The role of phosphonates in living systems, Hilderbrand, R.L., Ed., Rosa Baton, FL: CRC, 1983.Google Scholar
  15. 15.
    Aminophosphonic and Aminophosphinic Acids: Chemistry and Biological Activity / Kukhar, V.P. and Hudson, H.R., Eds., J. Wiley & Sons, 2000.Google Scholar
  16. 16.
    Bergstrom, J.D., Bostedor, R.G., Masarachia, P.J., Reszka, A.A., and Rodan, G., Arch. Biochem. Biophys., 2000, vol. 373, pp. 231–241.CrossRefPubMedGoogle Scholar
  17. 17.
    Bukowski, J.F. Dascher, C.C., and Das, H, Biochem. Biophys. Res. Commun., 2005, vol. 328, pp. 746–750.CrossRefPubMedGoogle Scholar
  18. 18.
    Rogers, M.J., Gordon, S., Benford, H.L., Coxon, F.P., Luckman, S.P., Monkkonen, J., and Frith, J.C., Cancer, 2000, vol. 88, pp. 2961–2978.CrossRefPubMedGoogle Scholar
  19. 19.
    Myers, J.K., Antonelli, S.M., and Widlanski, T.S., J. Am. Chem. Soc., 1997, vol. 119, pp. 3163–3164.CrossRefGoogle Scholar
  20. 20.
    Vovk, A.I., Kalchenko, V.I., Cherenok, S.A., Kukhar, V.P., Muzychka, O.V., and Lozynsky, M.O., Org. Biomol. Chem., 2004, vol. 2, pp. 3162–3166.CrossRefPubMedGoogle Scholar
  21. 21.
    Cherenok, S., Vovk, A., Muravyova, I., Shivanyuk, A., Kukhar, V., Lipkowski, J., and Kalchenko, V., Org. Lett., 2006, vol. 8, pp. 549–552.CrossRefPubMedGoogle Scholar
  22. 22.
    Holtz, K.M., Stec, B., Myers, J.K., Antonelli, S.M., Widlanski, T.S., and Kantrowitz, E.R., Protein Sci., 2000, vol. 9, pp. 907–915.CrossRefPubMedGoogle Scholar
  23. 23.
    Chuiko, A.L., Filonenko, L.P., Borisevich, A.N., and Lozinskii, M.O., Zh. Org. Khim., 1991, vol. 61, pp. 2552–2557.Google Scholar
  24. 24.
    Chuiko, A.L., Filonenko, L.P., Borisevich, A.N., and Lozinskii, M.O., Zh. Org. Khim., 1995, vol. 65, pp. 1332–1337.Google Scholar
  25. 25.
    Llinas, P., Stura, E.A., Menez, A., Kiss, Z., Stigbrand, T., Millan, J.L., and Le Du, M.H., J. Mol. Biol., 2005, vol. 350, pp. 441–451.CrossRefPubMedGoogle Scholar
  26. 26.
    Manes, T., Hoylaerts, M.F., Muller, R., Lottspeich, F., Holke, W., and Millan, J.L., J. Biol. Chem., 1998, vol. 273, pp. 23 353–23 360.CrossRefGoogle Scholar
  27. 27.
    Goldstein, D.J., Rogers, C.E., and Harris, H., Proc. Natl. Acad. Sci. USA, 1980, vol. 77, pp. 2857–2860.CrossRefPubMedGoogle Scholar
  28. 28.
    Le Du, M.H., Stigbrand, T., Taussig, M.J., Menez, A., and Stura, E.A., J. Biol. Chem., 2001, vol. 276, pp. 9158–9165.CrossRefPubMedGoogle Scholar
  29. 29.
    Kim, E.E. and Wyckoff, H.W., J. Mol. Biol., 1991, vol. 218, pp. 449–464.CrossRefPubMedGoogle Scholar
  30. 30.
    Yang, G.-F., Lu, H.-T., Xiong, Y., and Zhan, C.-G., Bioorg. Med. Chem., 2006, vol. 14, pp. 1462–1473.CrossRefPubMedGoogle Scholar
  31. 31.
    Goodsell, D.S. and Olson, A.J., Proteins: Structure, Function, and Genetics, 1990, vol. 8, pp. 195–202.CrossRefGoogle Scholar
  32. 32.
    Morris, G.M., Goodsell, D.S., Huey, R., and Olson, A.J., J. Comput. Aided Mol. Des., 1996, vol. 10, pp. 293–304.CrossRefPubMedGoogle Scholar
  33. 33.
    Morris G.M., Goodsell D.S., Halliday R.S., Huey R., Hart W.E., Belew R.K., and Olson, A.J., J. Comp. Chem., 1998, vol. 19, pp. 1639–1662.CrossRefGoogle Scholar
  34. 34.
    Stote, R.H. and Karplus, M., Proteins, 1995, vol. 23, pp. 12–31.CrossRefPubMedGoogle Scholar
  35. 35.
    Case, D.A., Pearlman, D.A., Caldwell, J.W., Cheatham III, T.E., Wang, J., Ross, W.S., Simmerling, C.L., et al., AMBER 7, University of California, San Francisco, 2002.Google Scholar
  36. 36.
    Guex, N. and Peitsch, M.C., Electrophoresis, 1997, vol. 18, pp. 2714–2723.CrossRefPubMedGoogle Scholar
  37. 37.
    Ploger, W., Schindler, N., Wollmann, K., and Worms, K.H., Z. Anorg. All. Chem., 1972, vol. 389, pp. 119–128.CrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2008

Authors and Affiliations

  • A. I. Vovk
    • 1
  • A. L. Chuiko
    • 2
  • L. A. Kononets
    • 1
  • V. Yu. Tanchuk
    • 1
  • I. V. Murav’eva
    • 1
  • M. O. Lozinsky
    • 2
  • V. P. Kukhar
    • 1
  1. 1.Institute of Bioorganic Chemistry and PetrochemistryNational Academy of Sciences of UkraineKiev-94Ukraine
  2. 2.Institute of Organic ChemistryNational Academy of Sciences of UkraineKiev-94Ukraine

Personalised recommendations