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首页> 外文期刊>Chemistry: A European journal >Hydrolytic Reactions of Thymidine 5'-O-Phenyl-N-Alkylphosphoramidates, Models of Nucleoside 5'-Monophosphate Prodrugs
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Hydrolytic Reactions of Thymidine 5'-O-Phenyl-N-Alkylphosphoramidates, Models of Nucleoside 5'-Monophosphate Prodrugs

机译：胸苷5'-O-苯基-N-烷基磷酰胺，核苷5'-单磷酸盐前药的模型的水解反应

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摘要

To obtain detailed data on the kinetics of hydrolytic reactions of triester-like nucleoside 5'-O-aryl-N-al-kylphosphoramidates, potential prodrugs of antiviral nucleoside monophosphates, the hydrolysis of diastereo-meric (R_P/S_P) thymidine 5'-{O-phenyl-N-[(1S)-2-oxo-2-methoxy-1-methyl-ethyl]phosphoramidate} (3), a phos-phoramidate derived from the methyl ester of L-alanine, has been followed by reversed-phase HPLC over the range from H_0 = 0 to pH 8 at 90 °C. According to the time-dependent product distributions, the hydrolysis of 3 proceeds at pH<4 by two parallel routes, namely by nucleophilic displacement of the alaninyl ester moiety by a water molecule and by hydrolysis of the car-boxylic ester linkage that allows intra-molecular attack of the carboxy group on the phosphorus atom, thereby resulting in the departure of either thymidine or phenol without marked accumulation of any intermediates. Both routes represent about half of the overall disappearance of 3. The departure of phenol eventually leads to the formation of thymidine 5'-phosphate. At pH > 5, the predominant reaction is hydrolysis of the carboxylic ester linkage followed by intramolecular displacement of a phenoxide ion by the carbox-ylate ion and hydrolysis of the resulting cyclic mixed anhydride into an acyclicdiester-like thymidine 5'-phosphorami-date. The latter product accumulated quantitatively without any indication of further decomposition. Hydroxide-ion-catalyzed P-OPh bond cleavage of the starting material 3 occurred as a side reaction. Comparative measurements with thymidine 5'-{N-[(1S)-2-oxo-2-me-thoxy-1-methylethyl]phosphoramidate} (4) revealed that, under acidic conditions, this diester-like compound is hy-drolyzed by P-N bond cleavage three orders of magnitude more rapidly than the triester-like 3. At pH > 5, the stability order is reversed, with 3 being hy-drolyzed six times as rapidly as 4. Mechanisms of the partial reactions are discussed.
机译：为了获得Triester样核苷5'-O-芳基-N-磷酸酯酰基磷酸酯的水解反应的动力学的详细数据，抗病毒核苷的潜在前药，单磷酸酯的水解（R_P / S_P）胸苷5' - {O-苯基-N - [（1S）-2-氧代-2-甲氧基-1-甲基 - 乙基 - 乙基 - 乙基 - 乙基]磷酸酯}（3），衍生自L-丙氨酸的甲酯的磷光酯邻烷基酯反相HPLC在90℃下的H_0 = 0至pH8的范围内。根据时间依赖的产品分布，3次通过两个平行途径在pH <4的水解中进行，即通过水分子的丙烯酸酯部分的亲核移位和允许内部 - 羧基对磷原子上的分子攻击，从而导致胸苷或苯酚的脱落，而不明显任何中间体积累。两条路线都代表了总体消失的一半。苯酚的偏离最终导致胸苷5'-磷酸盐的形成。在pH> 5时，主要反应是羧酸酯连杆的水解，然后通过羧基离子离子和所得环状混合酸酐的水解将苯氧化离子的分子内移位加入到亚氨基酯样胸苷5'-磷酰胺日。后一种产品定量累积，没有进一步分解的任何指示。原料3的氢氧 - 离子催化的P-OPH键裂解作为副反应。胸苷5'的比较测量 - {N - [（1S）-2-氧代-2-X甲氧基-1-甲基乙基]磷酸酯}（4）显示，在酸性条件下，这种二酯状化合物是Hy-Droplyed通过PN键裂解三个数量级比三酯状3更快3.在pH> 5时，稳定性顺序颠倒，3次较快地将六次六倍恢复为4.讨论了部分反应的机制。

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