Amidate Prodrugs of O-2-Alkylated Pyrimidine Acyclic Nucleosides Display Potent Anti-Herpesvirus Activity
Amidate Prodrugs of O-2-Alkylated Pyrimidine Acyclic Nucleosides Display Potent Anti-Herpesvirus Activity
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DOI：
10.1021/acsmedchemlett.0c00090
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发表时间：
2020-07-09
影响因子：
4.2
通讯作者：
Herdewijn, Piet
中科院分区：
文献类型：
--
作者：
Luo, Min;Groaz, Elisabetta;Herdewijn, Piet
3-氟-2-(膦酰基甲氧基)丙基 (FPMP)、环状 3-羟基-2-(膦酰基甲氧基丙基) (cHPMP) 和 2-(膦酰基甲氧基丙基) (PMP) 型 O-2-烷基化无环核苷的三个系列酰胺化前药，具有胞嘧啶和 5-氟胞嘧啶作为核碱基很容易合成。 (R)-O-2-烷基化 FPMPC 的天冬氨酸酯和缬氨酸酯前药均在微摩尔范围内表现出有效的抗 HCMV 和 VZV 活性。此外，5-氟胞嘧啶 (R)-O-2-烷基化 FPMP 和 (R)-O-2-烷基化 cHPMPC 的缬氨酸酯前药在摩尔浓度下对这些病毒表现出抑制活性。
Three series of amidate prodrugs of O-2-alkylated acyclic nucleosides of the 3-fluoro-2-(phosphonomethoxy)propyl (FPMP), cyclic 3-hydroxy-2-(phosphonomethoxypropyl) (cHPMP), and 2-(phosphonomethoxypropyl) (PMP)-type featuring cytosine and 5-fluorocytosine as nucleobases were readily synthesized. Both the aspartic acid ester and valine ester prodrugs of (R)-O-2-alkylated FPMPC exhibited potent anti-HCMV and VZV activity in the micromolar range. In addition, the valine ester prodrugs of 5-fluorocytosine (R)-O-2-alkylated FPMP and (R)-O-2-alkylated cHPMPC showed inhibitory activity at molar concentrations against these viruses.