Suzuki S, Izuta S, Nakayama C, Saneyoshi M
Faculty of Pharmaceutical Sciences, Hokkaido University.
J Biochem. 1987 Oct;102(4):853-7. doi: 10.1093/oxfordjournals.jbchem.a122125.
Various 5-substituted 1-beta-D-arabinofuranosyluracil 5'-triphosphates (H, methyl, ethyl, n-propyl, n-butyl, (E)-bromovinyl, styryl, and beta-phenylethyl derivatives) were prepared and their inhibitory effects on two different herpes virus-induced DNA polymerases (OMV and HCMV) were studied. These dTTP analogues inhibited the incorporation of [3H]dTMP into DNA in vitro. Among them, analogues having a vinyl group at the 5-position were strongly active against DNA polymerases induced on herpes virus infection. Kinetic analysis showed that the inhibition by the analogues was essentially competitive with respect to the substrate, dTTP. The K1 values (microM) for AraUTP (2.4), AraTTP (1.0), BVAUTP (0.8), and StUAUTP (0.8) were smaller than the Km value (microM) for dTTP (3.4), but those for AraEtUTP, AraPrUTP, and AraBuUTP (5-14) were larger than the Km for dTTP in the case of HCMV-induced DNA polymerase. In contrast to these results, OMV-induced DNA polymerase seemed to be more resistant to these inhibitors than HCMV-induced DNA polymerase. However, the mode of the structure of substituent groups at the 5-position of base moieties is almost the same for the two DNA polymerases, except for in the case of AraUTP itself.
制备了多种5-取代的1-β-D-阿拉伯呋喃糖基尿嘧啶5'-三磷酸酯（H、甲基、乙基、正丙基、正丁基、（E）-溴乙烯基、苯乙烯基和β-苯乙基衍生物），并研究了它们对两种不同疱疹病毒诱导的DNA聚合酶（OMV和HCMV）的抑制作用。这些dTTP类似物在体外抑制了[3H]dTMP掺入DNA。其中，5位带有乙烯基的类似物对疱疹病毒感染诱导的DNA聚合酶具有很强的活性。动力学分析表明，类似物的抑制作用在本质上相对于底物dTTP是竞争性的。AraUTP（2.4）、AraTTP（1.0）、BVAUTP（0.8）和StUAUTP（0.8）的K1值（微摩尔）小于dTTP（3.4）的Km值（微摩尔），但在HCMV诱导的DNA聚合酶的情况下，AraEtUTP、AraPrUTP和AraBuUTP（5-14）的K1值大于dTTP的Km值。与这些结果相反，OMV诱导的DNA聚合酶似乎比HCMV诱导的DNA聚合酶对这些抑制剂更具抗性。然而，除了AraUTP本身的情况外，两种DNA聚合酶碱基部分5位取代基的结构模式几乎相同。
