Characterization of reactions of antimoniate and meglumine antimoniate with a guanine ribonucleoside at different pH
Characterization of reactions of antimoniate and meglumine antimoniate with a guanine ribonucleoside at different pH
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DOI：
10.1007/s10534-006-0001-4
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发表时间：
2006-10-01
期刊：
影响因子：
3.5
通讯作者：
Frezard, Frederic
中科院分区：
文献类型：
--
作者：
dos Santos Ferreira, Claudio;Monteiro de Castro Pimenta, Adriano;Frezard, Frederic
以前已经表明，Sb-V与腺嘌呤和鸟嘌呤核糖核苷形成单加合物和双加合物，这表明核糖核苷可能是治疗利什曼病的五价锑药物的靶点。在本工作中，锑酸钾（KSb（OH）（6））和锑酸葡甲胺（MA）与鸟苷5 '-单磷酸（GMP）的反应已在37 ℃和两种不同的pH值（5和6.5）的水溶液中进行了表征，使用ESI（-）-MS和H-1 NMR。通过ESI（-）-MS鉴定了1：1和1：2 Sb-V-GMP复合物的酸和碱物种。探索了H-1 NMR异头区域以确定单加合物和双加合物的浓度。这允许测定这些复合物的稳定常数（在pD 5和37 ℃下，1：1复合物为5900 L mol（-1），1：2复合物为370 L mol（-1））。在不同pH下的动力学研究表明，1：1和1：2 Sb-GMP复合物的形成和解离都是缓慢的过程，并且在酸性pH下更有利（在pD 5和37 ℃下，1：1复合物形成的速率常数为2150 L mol（-1）h（-1），1：1复合物解离的速率常数为0.25 h（-1））。当使用MA代替锑酸盐时，发生1：1 Sb-GMP络合物的形成，但具有较慢的速率常数。假设MA基本上由1：1的Sb-葡甲胺复合物组成，还可以估计MA的稳定常数（pD 5和37 ° C时为8600 L mol（-1））。热力学和动力学数据是一致的形成1：1锑-核糖核苷复合物在脊椎动物宿主，治疗后与五价锑药物。
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 H-1 NMR. Acid and base species for both 1:1 and 1:2 Sb-V-GMP complexes were identified by ESI(-)-MS. The H-1 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 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 (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 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 (8600 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.