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 °C in aqueous solution and two different pH (5 and 6.5), using ESI(−)-MS and ¹H NMR. Acid and base species for both 1:1 and 1:2 Sb^V–GMP complexes were identified by ESI(−)-MS. The ¹H 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 (5900 L mol⁻¹ for 1:1 complex and 370 L mol⁻¹ for 1:2 complex, at pD 5 and 37 °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 (2150 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 °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 (8600 L mol⁻¹ at pD 5 and 37 °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.