SYNTHESIS AND BIOLOGICAL EVALUATION OF PRODRUGS OF ZIDOVUDINE
SYNTHESIS AND BIOLOGICAL EVALUATION OF PRODRUGS OF ZIDOVUDINE
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DOI：
10.1021/jm00167a034
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发表时间：
1990-05-01
影响因子：
7.3
通讯作者：
AGRAWAL, KC
中科院分区：
文献类型：
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作者：
AGGARWAL, SK;GOGU, SR;AGRAWAL, KC
为了提高艾滋病病毒1型（HIV-1）感染细胞对齐多夫定（AZT）前药的摄取，延长其血浆半衰期，合成了一系列AZT前药。在DCC和4-（二甲氨基）吡啶（DMAP）存在下，用各种酸酯化AZT的5“-OH官能团。前药部分包括（a）吗啉和N-苯基哌嗪-1-乙酸，（B）1，4-二氢-1-甲基-3-烟酸，（c）视黄酸，和（d）某些氨基酸。在外周血淋巴细胞中测定酯的抗HIV-1活性。在该系统中，AZT的IC 50为0.12 μ M，而前药的IC 50为0.05 - 0.2 μ M。除了维甲酸酯外，前药的细胞毒性一般低于AZT。在人体血浆中的各种酯的体外水解表明，这些代理商是相对稳定的血浆酯酶与t1/2范围从10至240分钟。在H9细胞与放射性标记的类似物的药物摄取研究表明，维甲酸酯实现约4倍的细胞内浓度比[3 H]AZT。然而，1，4-二氢-1-甲基-3-[（吡啶基羰基）氧基]酯（5）是该系列中活性最高的药物，并且具有比AZT更高的治疗指数。
A series of prodrugs of zidovudine (AZT) has been synthesized in an effort to enhance the uptake of the prodrugs by the HIV-1 infected cells and to increase the plasma half-life of AZT. The 5''-OH function of AZT was esterified with various acids in the presence of DCC and 4-(dimethylamino)pyridine (DMAP). The prodrug moieties included (a) morpholine and N-phenylpiperazine-1-acetic acid, (b) 1,4-dihydro-1-methyl-3-nicotinic acid, (c) retinoic acid, and (d) certain amino acids. The anti-HIV-1 activity of the esters was determined in peripheral blood lymphocytes. The IC50 for AZT in this system was 0.12 .mu.M whereas for prodrugs it ranged from 0.05 to 0.2 .mu.M. The prodrugs were generally less cytotoxic than AZT except the retinoic acid ester. In vitro hydrolysis of the various esters in human plasma indicated that these agents were relatively stable toward plasma esterases with t1/2 ranging from 10 to 240 min. Drug uptake studies in H9 cells with radiolabeled analogues demonstrated that the retinoic acid ester achieved approximately 4-fold higher intracellular concentration than [3H]AZT. However, 1,4-dihydro-1-methyl-3-[(pyridylcarbonyl)oxy] ester (5) was the most active agent of this series and had a higher therapeutic index than AZT.