Characterization of reactions of antimoniate and meglumine antimoniate with a guanine ribonucleoside at different pH |
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Authors: | Cláudio dos Santos Ferreira Adriano Monteiro de Castro Pimenta Cynthia Demicheli Frédéric Frézard |
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Affiliation: | 1. Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Av. Ant?nio Carlos 6627, Pampulha, 31270-901, Belo Horizonte, MG, Brazil 2. Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Av. Ant?nio Carlos 6627, Pampulha, 31270-901, Belo Horizonte, MG, Brazil 3. Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Ant?nio Carlos 6627, Pampulha, 31270-901, Belo Horizonte, MG, Brazil
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Abstract: | It has been shown previously that SbV 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 SbV–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. |
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Keywords: | antimony kinetics leishmaniasis meglumine antimoniate nucleoside |
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