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Inhibition of alkaline phosphatase by thioureido derivatives of methylenebisphosphonic acid

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.

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Abbreviations

BSIM:

bovine small intestine mucosa

HP:

human placenta

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Correspondence to A. I. Vovk.

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Original Russian Text © A.I. Vovk, A.L. Chuiko, L.A. Kononets, V.Yu. Tanchuk, I.V. Murav’eva, M.O. Lozinsky, V.P. Kukhar, 2008, published in Bioorganicheskaya Khimiya, 2008, Vol. 34, No. 1, pp. 67–74.

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Vovk, A.I., Chuiko, A.L., Kononets, L.A. et al. Inhibition of alkaline phosphatase by thioureido derivatives of methylenebisphosphonic acid. Russ J Bioorg Chem 34, 60–66 (2008). https://doi.org/10.1134/S1068162008010081

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  • DOI: https://doi.org/10.1134/S1068162008010081

Key words

  • alkaline phosphatase
  • inhibition
  • molecular docking
  • thioureidomethylenebisphosphonates