5-AZACYTIDINE HYDROLYSIS KINETICS MEASURED BY HIGH-PRESSURE LIQUID-CHROMATOGRAPHY AND C-13-NMR SPECTROSCOPY
5-AZACYTIDINE HYDROLYSIS KINETICS MEASURED BY HIGH-PRESSURE LIQUID-CHROMATOGRAPHY AND C-13-NMR SPECTROSCOPY
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DOI：
10.1002/jps.2600680705
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发表时间：
1979-01-01
影响因子：
3.8
通讯作者：
SADEE, W
中科院分区：
文献类型：
--
作者：
CHAN, KK;GIANNINI, DD;SADEE, W
采用高压液相色谱（HPLC）和13C-NMR方法测定了5-氮杂胞苷（5-azacytidine）在水缓冲液中的水解作用。利用6- 13c -5-氮杂胞苷和核磁共振光谱技术明确地确定了水解序列以及不稳定中间体n -甲酰基鸟酰核苷脲的存在。n -甲酰基胍核脲可逆开环步骤，平衡常数为0.58 +-。pH值在5.6 ~ 8.5之间为0.03，在此基础上不可逆地生成了胍基核苷脲。这些数据证实了先前对水解动力学的假设。考察了水解的pH依赖性，水解曲线呈正常的V型，pH为7.0时最稳定。可以配制出相当稳定的静脉剂型。
Hydrolysis of 5-azacytidine, an experimental anticancer drug, in aqueous buffers was measured using a high-pressure liquid chromatographic (HPLC) procedure and a 13C-NMR method. The hydrolysis sequence as well as the existence of a labile intermediate, N-formylguanylribosylurea, was unequivocally established using 6-13C-5-azacytidine and NMR spectral techniques. A reversible ring opening step to the N-formylguanylribosylurea with an equilibrium constant of 0.58 .+-. 0.03 between pH 5.6 and 8.5, followed by an irreversible formation of guanylribosylurea, was found by HPLC. The data confirm previous assumptions on the hydrolytic kinetics. The pH dependency of hydrolysis was examined, and the hydrolysis profile gave a normal V shape with the most stable pH at 7.0. Rather stable i.v. dosage forms can be formulated.