Synthesis and evaluation of S-acyl-2-thioethyl esters of modified nucleoside 5'-monophosphates as inhibitors of hepatitis C virus RNA replication
Synthesis and evaluation of S-acyl-2-thioethyl esters of modified nucleoside 5'-monophosphates as inhibitors of hepatitis C virus RNA replication
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DOI：
10.1021/jm0495172
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发表时间：
2005-02-24
影响因子：
7.3
通讯作者：
Bhat, B
中科院分区：
文献类型：
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作者：
Prakash, TP;Prhavc, M;Bhat, B
几种修饰核苷的三磷酸（1-6）被鉴定为丙型肝炎病毒RNA依赖性RNA聚合酶（RdRp）的抑制剂（IC 50 = 0.08 - 3.8 μ M）。虽然通过确定三磷酸抑制HCV RdRp体外活性的能力而开发的初始SAR鉴定了几种有效的抑制剂，但在基于细胞的复制子测定中，相应的核苷均未表现出显著的抑制效力。为了改善活性，合成了双（tBu-S-酰基-2-硫代乙基）核苷5 '-单磷酸酯（7-12），并且这些衍生物在基于细胞的测定中与相应的核苷相比表现出改善的效力。细胞内代谢分析表明，S-酰基-2-硫代乙基（SATE）前药代谢为5 '-三磷酸的效率是相应核苷的40- 155倍。涉及双（tBuSATE）胞苷5 '-单磷酸酯的前药方法显著降低了胞苷衍生物通过细胞脱氨酶的脱氨作用。此外，在细胞中使用SATE前药进行的染色体畸变研究显示，与同期对照相比，畸变无统计学相关增加。
Several triphosphates of modified nucleosides (1-6) were identified as inhibitors (IC50 = 0.083.8 muM) of hepatitis C virus RNA-dependent RNA polymerase (RdRp). Although the initial SAR developed by determining the ability of the triphosphates to inhibit the in vitro activity of the HCV RdRp identified several potent inhibitors, none of the corresponding nucleosides exhibited significant inhibitory potency in a cell-based replicon assay. To improve upon the activity, bis(tBu-S-acyl-2-thioethyl) nucleoside 5'-monophosphate esters (7-12) were synthesized, and these derivatives exhibited improved potency compared to the corresponding nucleosides in the cell-based assay. Analysis of the intracellular metabolism demonstrated that the S-acyl-2-thioethyl (SATE) prodrug is metabolized to the 5'-triphosphate 40- to 155-fold more efficiently compared to the corresponding nucleoside. The prodrug approach involving bis(tBuSATE)cytidine 5'-monophosphate ester significantly reduced the deamination of cytidine derivatives by cellular deaminases. Additionally, chromosomal aberration studies with the SATE prodrug in cells showed no statistically relevant increase in aberrations compared to the concurrent controls.