Characterization of reactions of antimoniate and meglumine antimoniate with a guanine ribonucleoside at different pH.
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.
dos Santos Ferreira
Cláudio
C
Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Pampulha, 31270-901, Belo Horizonte, MG, Brazil.
de Castro Pimenta
Adriano Monteiro
AM
Demicheli
Cynthia
C
Frézard
Frédéric
F
D000818:Animals; D000965:Antimony / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D000981:Antiprotozoal Agents / Q000378:metabolism*; D006157:Guanosine Monophosphate / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007896:Leishmaniasis / Q000188:drug therapy; D008536:Meglumine / Q000378:metabolism* / Q000627:therapeutic use; D000077485:Meglumine Antimoniate; D019906:Nuclear Magnetic Resonance, Biomolecular; D009942:Organometallic Compounds / Q000378:metabolism* / Q000627:therapeutic use; D021241:Spectrometry, Mass, Electrospray Ionization; D013816:Thermodynamics
D000981:Antiprotozoal Agents; D009942:Organometallic Compounds; D008536:Meglumine; D000077485:Meglumine Antimoniate; D006157:Guanosine Monophosphate; D000965:Antimony