Kreis W, Damin L, Colacino J, Lopez C
Biochem Pharmacol. 1982 Mar 1;31(5):767-73. doi: 10.1016/0006-2952(82)90461-0.
Phosphorylation of 1-beta-D-2'-F-arabino-5-iodocytosine (FIAC), a newly synthesized pyrimidine nucleoside with potent antiherpesvirus activity, was compared with that of its parent compound, 1-beta-D-arabinofuranosylcytosine (ara-C). While ara-C was phosphorylated extensively by homogenates of normal, rapidly proliferating mouse tissues, FIAC was a poor substrate for the nucleoside kinase occurring in such normal tissues. With cell homogenates of noninfected Vero cells, thymidine (TdR) was phosphorylated about fifty and twenty times more efficiently than FIAC and ara-C, while infection of Vero cells with Herpes Simplex Virus Type 1 (HSV-1) resulted in a 23-fold increase of TdR- and a 1270-fold increase of FIAC phosphorylation. In contrast, phosphorylation of ara-C was increased only by a factor of 2.6. While the reaction products obtained with homogenates of normal mouse tissues were 5'-mono-, di- and triphosphates of ara-C and FIAC, the reaction products with noninfected and infected Vero cell homogenates were predominantly monophosphates. In contrast, TdR was efficiently phosphorylated to its 5'-mono-, di- and triphosphates by such homogenates. In intact HSV-1-infected Vero cells. FIAC was rapidly taken up and phosphorylated to FIACMP and to an as yet unidentified metabolite. In contrast, TdR was taken up and phosphorylated to 5'-mono-, di- and triphosphates and ara-C was taken up moderately but metabolized poorly to its 5'-mono-, di- and triphosphates. Thus, in normal tissues, FIAC was a poorer substrate than ara-C for nucleoside kinases, but in intact HSV- 1-infected Vero cells FIAC was efficiently phosphorylated and thus behaved like a TdR analog, except that it was phosphorylated only to the 5'-monophosphate and a hitherto unidentified metabolite. The greatly increased phosphorylation of FIAC by HSV-1-infected Vero cells probably accounts, at least in part, for its great selectivity of action.
1-β-D-2'-氟阿拉伯糖基-5-碘胞嘧啶（FIAC）是一种新合成的具有强大抗疱疹病毒活性的嘧啶核苷，将其磷酸化作用与其母体化合物1-β-D-阿拉伯呋喃糖基胞嘧啶（ara-C）的磷酸化作用进行了比较。虽然ara-C能被正常的、快速增殖的小鼠组织匀浆大量磷酸化，但FIAC却是这类正常组织中存在的核苷激酶的不良底物。对于未感染的非洲绿猴肾（Vero）细胞匀浆，胸苷（TdR）的磷酸化效率比FIAC和ara-C分别高约五十倍和二十倍，而用1型单纯疱疹病毒（HSV-1）感染Vero细胞后，TdR的磷酸化增加了23倍，FIAC的磷酸化增加了1270倍。相比之下，ara-C的磷酸化仅增加了2.6倍。正常小鼠组织匀浆产生的反应产物是ara-C和FIAC的5'-单磷酸、二磷酸和三磷酸，而未感染和感染的Vero细胞匀浆产生的反应产物主要是单磷酸。相比之下，TdR能被这类匀浆高效磷酸化为其5'-单磷酸、二磷酸和三磷酸。在完整的HSV-1感染的Vero细胞中，FIAC被迅速摄取并磷酸化为FIACMP和一种尚未鉴定的代谢产物。相比之下，TdR被摄取并磷酸化为5'-单磷酸、二磷酸和三磷酸，ara-C被适度摄取但代谢为其5'-单磷酸、二磷酸和三磷酸的效率较低。因此，在正常组织中，FIAC作为核苷激酶的底物比ara-C差，但在完整的HSV-1感染的Vero细胞中，FIAC能被有效磷酸化，因此表现得像一种TdR类似物，只是它仅被磷酸化为5'-单磷酸和一种迄今未鉴定的代谢产物。HSV-1感染的Vero细胞对FIAC磷酸化的大幅增加可能至少部分解释了其强大的作用选择性。
