Larsson A, Alenius S, Johansson N G, Oberg B
Antiviral Res. 1983 Aug;3(2):77-86. doi: 10.1016/0166-3542(83)90028-1.
9-(4-Hydroxybutyl)guanine was synthesized and tested for antiherpes activity. In cell cultures, different strains of herpes simplex virus type 1 (HSV-1) and type 2(HSV-2) were inhibited by 50% at 2-14 microM of 9-(4-hydroxybutyl)guanine, while a HSV-1 mutant lacking thymidine kinase (HSV-1 TK-) was resistant. Linear competitive inhibition of purified HSV-1-induced thymidine kinase (TK) with thymidine as a variable substrate was observed for 9-(4-hydroxybutyl)guanine with an apparent Ki value of 2.06 microM while the corresponding Ki value for the cellular TK was greater than 250 microM. By using high performance liquid chromatography, the formation of 9-(4-hydroxybutyl)guanine monophosphate by HSV-1 TK was measured and the rate of product formation was found to be about 10% of that found by using thymidine as a substrate. A selective inhibition of HSV-1 DNA synthesis by 9-(4-hydroxybutyl)guanine was observed in infected Vero cells. 9-(4-Hydroxybutyl)guanine had a low cellular toxicity. A weak therapeutic effect on herpes keratitis in rabbits was observed whereas cutaneous HSV-1 infection in guinea pigs and systemic HSV-2 infection in mice were not affected by this compound.
合成了9-(4-羟基丁基)鸟嘌呤并对其抗疱疹活性进行了测试。在细胞培养中，1型单纯疱疹病毒（HSV-1）和2型单纯疱疹病毒（HSV-2）的不同毒株在9-(4-羟基丁基)鸟嘌呤浓度为2-14微摩尔时被50%抑制，而缺乏胸苷激酶的HSV-1突变株（HSV-1 TK-）具有抗性。以胸苷为可变底物，观察到9-(4-羟基丁基)鸟嘌呤对纯化的HSV-1诱导的胸苷激酶（TK）有线性竞争性抑制作用，其表观Ki值为2.06微摩尔，而细胞TK的相应Ki值大于250微摩尔。通过高效液相色谱法，测定了HSV-1 TK形成9-(4-羟基丁基)鸟嘌呤单磷酸的情况，发现产物形成速率约为以胸苷为底物时的10%。在感染的Vero细胞中观察到9-(4-羟基丁基)鸟嘌呤对HSV-1 DNA合成有选择性抑制作用。9-(4-羟基丁基)鸟嘌呤具有低细胞毒性。观察到该化合物对兔疱疹性角膜炎有微弱的治疗作用，而对豚鼠皮肤HSV-1感染和小鼠全身性HSV-2感染无影响。
