Sekiyama T, Hatsuya S, Tanaka Y, Uchiyama M, Ono N, Iwayama S, Oikawa M, Suzuki K, Okunishi M, Tsuji T
Central Research Laboratories, Ajinomoto Company, Inc., 1-1 Suzuki-cho, Kawasaki 210, Japan.
J Med Chem. 1998 Apr 9;41(8):1284-98. doi: 10.1021/jm9705869.
A series of acyclic nucleosides with two hydroxymethyl groups mimicking the 3'- and 5'-hydroxyl groups of the 2'-deoxyribose moiety were prepared and evaluated for their antiherpetic activity. Among those, 9-[[cis-1', 2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanine (3) showed extremely potent antiviral activity against herpes simplex virus type-1 (HSV-1) with good selectivity. Both enantiomers of 3 were synthesized starting from chiral epichlorohydrins, and only one of the enantiomers with 1'S,2'R-configuration (3a) exhibited strong antiherpetic activity (IC50 of 0.020 microg/mL against HSV-1 Tomioka vs 0.81 microg/mL for acyclovir). Enantiomer 3a was also more inhibitory than acyclovir against varicella-zoster virus (VZV) but ineffective against human immunodeficiency virus (HIV). Compound 3a is phosphorylated by HSV-1 thymidine kinase (TK) very efficiently. The relationship between conformation and antiherpetic activity in this series of compounds is discussed.
制备了一系列具有两个羟甲基的无环核苷，它们模拟2'-脱氧核糖部分的3'-和5'-羟基，并对其抗疱疹活性进行了评估。其中，9-[[顺式-1',2'-双（羟甲基）环丙-1'-基]甲基]鸟嘌呤（3）对单纯疱疹病毒1型（HSV-1）显示出极强的抗病毒活性，且具有良好的选择性。3的两种对映体均从手性环氧氯丙烷开始合成，只有具有1'S,2'R-构型的对映体之一（3a）表现出较强的抗疱疹活性（对HSV-1富冈株的IC50为0.020μg/mL，而阿昔洛韦为0.81μg/mL）。对映体3a对水痘带状疱疹病毒（VZV）的抑制作用也比阿昔洛韦更强，但对人类免疫缺陷病毒（HIV）无效。化合物3a能被HSV-1胸苷激酶（TK）非常有效地磷酸化。讨论了该系列化合物的构象与抗疱疹活性之间的关系。
