A comparison of phosphonothioic acids with phosphonic acids as phosphatase inhibitors

J Med Chem. 2003 Aug 14;46(17):3703-8. doi: 10.1021/jm030106f.


Phosphorothioates, analogues of phosphate esters in which a sulfur replaces an oxygen atom in the phosphoryl group, are competent surrogate substrates for a number of phosphatases. In some cases the thio analogues show similar binding (as estimated by K(m)) while other phosphatases show quite different K(m) values for phosphate compared to phosphorothioate esters. On this basis it was hypothesized that there might be different inhibitory tendencies by the nonhydrolyzable analogues, phosphonothioic acids compared with phosphonic acids. A series of phosphonothioic acids and corresponding phosphonic acids were synthesized and their inhibitory properties were compared toward human placental and E. coli alkaline phosphatases, the protein-tyrosine phosphatase from Yersinia, and the serine/threonine protein phosphatases PP2C and lambda. Sulfur substitution for oxygen gives the phosphonothioic acids pK(a) values that are close to those of phosphate esters, in contrast to the higher pK(a) values typical of phosphonic acids. Despite different steric requirements and differences in charge distribution in the anions of phosphonothioic acids compared with phosphonic acids, it was found that, with some exceptions, differences in inhibitory properties were modest.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkaline Phosphatase / antagonists & inhibitors
  • Alkaline Phosphatase / chemistry
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Escherichia coli / enzymology
  • Humans
  • Organophosphonates / chemical synthesis
  • Organophosphonates / chemistry
  • Organophosphorus Compounds / chemical synthesis*
  • Organophosphorus Compounds / chemistry
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Phosphoprotein Phosphatases / chemistry
  • Placenta / enzymology
  • Protein Phosphatase 2C
  • Protein Tyrosine Phosphatases / antagonists & inhibitors
  • Protein Tyrosine Phosphatases / chemistry
  • Structure-Activity Relationship
  • Yersinia / enzymology


  • Enzyme Inhibitors
  • Organophosphonates
  • Organophosphorus Compounds
  • Alkaline Phosphatase
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2C
  • Protein Tyrosine Phosphatases