Chemistry and Biological Activity of the Anti‐HIV Prodrug N4‐Dimethylaminomethylene‐2′,3′‐Dideoxy‐3′‐Fluorocytidine (DDFC) a
Chemistry and Biological Activity of the Anti‐HIV Prodrug N4‐Dimethylaminomethylene‐2′,3′‐Dideoxy‐3′‐Fluorocytidine (DDFC) a
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抗 HIV 前药 N4-二甲基氨基亚甲基-2,3-二脱氧-3-氟胞苷 (DDFC) 的化学和生物活性
DOI：
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发表时间：
1990
期刊：
影响因子：
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通讯作者：
A. V. Reddy
中科院分区：
文献类型：
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作者：
T. Kalman;A. V. Reddy
这项工作是为了证明前药方法的可行性，以改善现有的抗HIV双脱氧核苷的治疗效果，旨在更有效地渗透到中枢神经系统，延长作用时间，并降低细胞和全身毒性。DDFC（NSC-614898）的设计和选择作为这类代理1的代表，使用反相HPLC的二甲氨基亚甲基侧链的水解动力学进行了研究。在37°C和pH 7.4的磷酸盐缓冲液中，DDFC的半衰期为4.8小时。观察到含有保留时间为4.4分钟的共轭侧链的中间体快速地乳化，在1.5小时内达到10%的最大值。根据其紫外光谱（在HPLC分析期间通过二极管阵列检测器测定）与N4乙酰胞苷的相似性，将中间体鉴定为N4-甲酰基-3 '-F-ddC。与我们的结果一致，先前考虑的二甲氨基亚甲基侧链水解的合理机制2概述如下：
This work was undertaken to demonstrate the feasibility of a prodrug approach to the improvement of the therapeutic effectiveness of existing anti-HIV dideoxynucleosides, aiming at more effective penetration into the central nervous system, prolonged duration of action, and decreased cellular and systemic toxicities. DDFC (NSC-614898) was designed and chosen as a representative of this class of agents1 The kinetics of the hydrolysis of the dimethylaminomethylene side chain was investigated using reverse-phase HPLC. At 37°C and pH 7.4 in phosphate buffer, DDFC had a half-life of 4.8 hours. An intermediate containing a conjugated side chain with a retention time of 4.4 min, was observed to rapidly accummulate, reaching a maximum of 10% within 1.5 hours. On the basis of the similarity of its ultraviolet spectrum (determined by a diode-array detector during HPLC analysis) to that of N4acetylcytidine, the intermediate was identified as N4-formyl-3’-F-ddC. A plausible mechanism previously considered2 for the hydrolysis of the dimethylaminomethylene side chain, consistent with our results, is outlined below: