Luo Min, Groaz Elisabetta, Snoeck Robert, Andrei Graciela, Herdewijn Piet
Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49 box 1041, 3000 Leuven, Belgium.
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Herestraat 49 box 1043, 3000 Leuven, Belgium.
ACS Med Chem Lett. 2020 Jun 24;11(7):1410-1415. doi: 10.1021/acsmedchemlett.0c00090. eCollection 2020 Jul 9.
Three series of amidate prodrugs of -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 ()--2-alkylated FPMPC exhibited potent anti-HCMV and VZV activity in the micromolar range. In addition, the valine ester prodrugs of 5-fluorocytosine ()--2-alkylated FPMP and ()--2-alkylated cHPMPC showed inhibitory activity at molar concentrations against these viruses.
易于合成出三类以胞嘧啶和5-氟胞嘧啶作为碱基的含3-氟-2-(膦酰甲氧基)丙基(FPMP)、环状3-羟基-2-(膦酰甲氧基丙基)(cHPMP)和2-(膦酰甲氧基丙基)(PMP)类型的-2-烷基化无环核苷的酰胺基前药。( )--2-烷基化FPMPC的天冬氨酸酯和缬氨酸酯前药在微摩尔范围内均表现出强效的抗人巨细胞病毒(HCMV)和水痘带状疱疹病毒(VZV)活性。此外，5-氟胞嘧啶( )--2-烷基化FPMP和( )--2-烷基化cHPMPC的缬氨酸酯前药在摩尔浓度下对这些病毒显示出抑制活性。
