Gambino J, Focher F, Hildebrand C, Maga G, Noonan T, Spadari S, Wright G
Department of Pharmacology, University of Massachusetts Medical School, Worcester 01655.
J Med Chem. 1992 Aug 7;35(16):2979-83. doi: 10.1021/jm00094a007.
Quantitative structure-activity relationships of the Hansch-type were developed to account for inhibition of thymidine kinases from Herpes simplex viruses types 1 and 2 (HSV1,2) by N2-phenylguanines. Derivatives with meta and/or para substituents on the phenyl ring display a wide range of overlapping, but not identical, potencies as inhibitors of the enzymes. IC50 values for 36 (HSV1) and 35 inhibitors (HSV2) were used to develop equations using hydrophobic (pi), electronic (sigma, R), and group size (MR) parameters. Equations 1 and 2 with correlation coefficients of 0.797 and 0.805, respectively, were obtained for inhibitors of the types 1 and 2 enzymes. Potencies were correlated positively with pi values of meta substituents but negatively with pi values of para substituents in the phenyl ring. Positive correlations were also obtained with the resonance parameter R of para substituents and with sigma constants of meta substituents. The most potent inhibitor of both enzymes was N2-[m-(trifluoromethyl)phenyl]guanine, although HSV2 thymidine kinase was more sensitive to certain compounds than the HSV1 enzyme.
为了解释 N2-苯基鸟嘌呤对 1 型和 2 型单纯疱疹病毒（HSV1、2）胸苷激酶的抑制作用，建立了 Hansch 型定量构效关系。苯环上带有间位和/或对位取代基的衍生物作为酶抑制剂表现出广泛的重叠但不相同的效力。使用 36 种（HSV1）和 35 种抑制剂（HSV2）的 IC50 值，利用疏水（π）、电子（σ、R）和基团大小（MR）参数建立方程。分别得到了针对 1 型和 2 型酶抑制剂的方程 1 和方程 2，相关系数分别为 0.797 和 0.805。效力与苯环中间位取代基的π值呈正相关，但与对位取代基的π值呈负相关。对位取代基的共振参数 R 和间位取代基的σ常数也呈正相关。两种酶最有效的抑制剂是 N2-[间-（三氟甲基）苯基]鸟嘌呤，尽管 HSV2 胸苷激酶对某些化合物比 HSV1 酶更敏感。
