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Characterization of reactions of antimoniate and meglumine antimoniate with a guanine ribonucleoside at different pH.

Abstract
It has been shown previously that Sb(V) forms mono- and bis-adducts with adenine and guanine ribonucleosides, suggesting that ribonucleosides may be a target for pentavalent antimonial drugs in the treatment of leishmaniasis. In the present work, the reactions of antimoniate (KSb(OH)(6)) and meglumine antimoniate (MA) with guanosine 5'-monophosphate (GMP) have been characterized at 37 degrees C in aqueous solution and two different pH (5 and 6.5), using ESI(-)-MS and (1)H NMR. Acid and base species for both 1:1 and 1:2 Sb(V)-GMP complexes were identified by ESI(-)-MS. The (1)H NMR anomeric region was explored for determining the concentrations of mono- and bis-adducts. This allows for the determination of stability constants for these complexes (5,900 L mol(-1) for 1:1 complex and 370 L mol(-1) for 1:2 complex, at pD 5 and 37 degrees C). Kinetic studies at different pH indicated that formation and dissociation of both 1:1 and 1:2 Sb-GMP complexes are slow processes and favored at acidic pH (2,150 L mol(-1) h(-1) for the rate constant of 1:1 complex formation and 0.25 h(-1) for the rate constant of 1:1 complex dissociation, at pD 5 and 37 degrees C). When MA was used, instead of antimoniate, formation of 1:1 Sb-GMP complex occurred, but with a slower rate constant. Assuming that MA consists essentially of a 1:1 Sb-meglumine complex, a stability constant for MA could also be estimated (8,600 L mol(-1) at pD 5 and 37 degrees C). Thermodynamic and kinetic data are consistent with the formation of 1:1 Sb-ribonucleoside complexes in vertebrate hosts, following treatment with pentavalent antimonial drugs.
AuthorsCláudio dos Santos Ferreira, Adriano Monteiro de Castro Pimenta, Cynthia Demicheli, Frédéric Frézard
JournalBiometals : an international journal on the role of metal ions in biology, biochemistry, and medicine (Biometals) Vol. 19 Issue 5 Pg. 573-81 (Oct 2006) ISSN: 0966-0844 [Print] Netherlands
PMID16937264 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antiprotozoal Agents
  • Organometallic Compounds
  • Meglumine
  • Meglumine Antimoniate
  • Guanosine Monophosphate
  • Antimony
Topics
  • Animals
  • Antimony (chemistry, metabolism, therapeutic use)
  • Antiprotozoal Agents (metabolism)
  • Guanosine Monophosphate (metabolism)
  • Hydrogen-Ion Concentration
  • Leishmaniasis (drug therapy)
  • Meglumine (metabolism, therapeutic use)
  • Meglumine Antimoniate
  • Nuclear Magnetic Resonance, Biomolecular
  • Organometallic Compounds (metabolism, therapeutic use)
  • Spectrometry, Mass, Electrospray Ionization
  • Thermodynamics

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