S-acyl-2-thioethyl phosphoramidate diester derivatives as mononucleotide prodrugs
S-acyl-2-thioethyl phosphoramidate diester derivatives as mononucleotide prodrugs
复制标题
DOI：
10.1021/jm0308444
复制
发表时间：
2003-10-09
影响因子：
7.3
通讯作者：
Périgaud, C
中科院分区：
文献类型：
--
作者：
Egron, D;Imbach, JL;Périgaud, C
本文报道了带有一个S-特戊酰基-2-硫代乙基（tBuSATE）和多个氨基酸残基的3 ′-叠氮基-2 ′，3 ′-双脱氧胸苷（AZT）的氨基磷酸酯双酯衍生物的合成及其体外抗HIV活性。这些化合物是使用酰胺化氧化步骤从H-膦酸酯策略获得的。这些衍生物中的大多数似乎抑制HIV-1复制，在胸苷激酶缺陷（TK-）细胞中微摩尔浓度的EC 50值，揭示了比以前报道的其他氨基磷酸酯前药限制性更小的细胞内分解过程。这一新系列的混合原核苷酸的拟议的分解途径可能依次涉及酯酶和磷酰胺酶水解。
The synthesis and in vitro anti-HIV activity of phosphoramidate diester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) bearing one S-pivaloyl-2-thioethyl (tBuSATE) group and various amino residues are reported. These compounds were obtained from an H-phosphonate strategy using an amidative oxidation step. Most of these derivatives appeared to inhibit HIV-1 replication, with EC50 values at micromolar concentration in thymidine kinase-deficient (TK-) cells, revealing a less restrictive intracellular decomposition process than previously reported for other phosphoramidate prodrugs. The proposed decomposition pathway of this new series of mixed pronucleotides may successively involve an esterase and a phosphoramidase hydrolysis.