Bisphosphonate derivatives of nucleoside antimetabolites:: Hydrolytic stability and hydroxyapatite adsorption of 5′-β,γ-methylene and 5′-β,γ-(1-hydroxyethylidene) triphosphates of 5-fluorouridine and ara-cytidine
Bisphosphonate derivatives of nucleoside antimetabolites:: Hydrolytic stability and hydroxyapatite adsorption of 5′-β,γ-methylene and 5′-β,γ-(1-hydroxyethylidene) triphosphates of 5-fluorouridine and ara-cytidine
复制标题
DOI：
10.1021/jo800317e
复制
发表时间：
2008-06-06
影响因子：
3.6
通讯作者：
Lonnberg, Harri
中科院分区：
文献类型：
--
作者：
Ora, Mikko;Lonnberg, Tuomas;Lonnberg, Harri
核苷抗代谢物的四种双膦酸酯衍生物的水解反应动力学，即 5-氟尿苷 5'-β,γ-(1-羟基亚乙基) 三磷酸 (4)、5-氟尿苷 5'-β,γ-亚甲基三磷酸 (5)、ara-胞苷 5'-β,γ-(1-羟基亚乙基) 三磷酸 (6) 和ara-胞苷 5'-β,γ-亚甲基三磷酸 (7) 已在 90 摄氏度下在较宽的 pH 范围 (pH 1.0-8.5) 下进行了研究。对于每种化合物，起始原料的消失都伴随着相应核苷 5'-单磷酸的形成，β,γ-(1-羟基亚乙基) 衍生物 (4, 6) 的反应速度比它们的反应快 2 个数量级β,γ-亚甲基对应物 (5, 7)。对于化合物7，胞嘧啶碱基的脱氨基作用与pH 3-6 下的磷酸盐水解竞争。在 37 摄氏度（pH 7.4）不存在和存在二价碱土金属离子（Mg2+ 和 Ca2+）的情况下进行的测量没有显示金属离子催化的迹象。在这些条件下，初始产物核苷 5'-单磷酸快速去磷酸化为相应的核苷。 β,γ-亚甲基衍生物 (5, 7) 水解成相应的核苷 5'-单磷酸在小鼠血清中比在水性缓冲液 (pH 7.4) 中明显更快，5 和 7 的速率加速分别为 5600 倍和 3150 倍。在人血清中，与缓冲液相比，加速度分别是 800 倍和 450 倍。与此形成鲜明对比的是，β,γ-(1-羟基亚乙基)衍生物的水解稳定性并未出现类似的下降。人血清中的稳定性与水性缓冲液中的稳定性相当（tau(1/2) = 17 和 33 小时，分别为 4 和 6 小时），并且油进入小鼠血清，观察到 2 至 4 倍的加速。为了阐明 4-7 的矿物质结合特性，研究了它们在羟基磷灰石柱上的保留，并与唑来膦酸盐 (1a) 和核苷单磷酸、二磷酸和三磷酸进行比较。
Kinetics of the hydrolytic reactions of four bisphosphonate derivatives of nucleoside anti metabolites, viz., 5-fluorouridine 5'-beta,gamma-(1-hydroxyethylidene) triphosphate (4), 5-fluorouridine 5'-beta,gamma-methylene triphosphate (5), ara-cytidine 5'-beta,gamma-(1-hydroxyethylidene) triphosphate (6), and ara-cytidine 5'-beta,gamma-methylene triphosphate (7), have been studied over a wide pH range (pH 1.0-8.5) at 90 degrees C. With each compound, the disappearance of the starting material was accompanied by formation of the corresponding nucleoside 5'-monophosphate, the reaction being up to 2 orders of magnitude faster with the beta,gamma-(1-hydroxyethylidene) derivatives (4, 6) than with their beta,gamma-methylene counterparts (5, 7). With compound 7, deamination of the cytosine base competed with the phosphate hydrolysis at pH 3-6. The measurements at 37 degrees C (pH 7.4) in the absence and presence of divalent alkaline earth metal ions (Mg2+ and Ca2+) showed no sign of metal ion catalysis. Under these conditions, the initial product, nucleoside 5'-monophosphate, underwent rapid dephosphorylation to the corresponding nucleoside. Hydrolysis of the beta,gamma-methylene derivatives (5, 7) to the corresponding nucleoside 5'-monophosphates was markedly faster in mouse serum than in aqueous buffer (pH 7.4), the rate-acceleration being 5600- and 3150-fold with 5 and 7, respectively. In human serum, the accelerations were 800- and 450-fold compared to buffer. In striking contrast, the beta,gamma-(1-hydroxyethylidene) derivatives did not experience a similar decrease in hydrolytic stability. The stability in human serum was comparable to that in aqueous buffer (tau(1/2) = 17 and 33 h with 4 and 6, respectively), and oil going to mouse serum, a 2- to 4-fold acceleration was observed. To elucidate the mineral-binding properties of 4-7, their retention on a hydroxyapatite column was studied and compared to that of zoledronate (1a) and nucleoside mono-, di-, and triphosphates.