Fan Xuesen, Zhang Xinying, Zhou Longhu, Keith Kathy A, Kern Earl R, Torrence Paul F
Department of Chemistry and Biochemistry, Northern Arizona University, Flagstaff, Arizona 86011, USA.
J Med Chem. 2006 Jun 1;49(11):3377-82. doi: 10.1021/jm0601710.
To provide potential new leads for the treatment of orthopoxvirus infections, the 5-position of the pyrimidine nucleosides have been modified with a gem diether moiety to yield the following new nucleosides: 5-(dimethoxymethyl)-2'-deoxyuridine (2b), 5-(diethoxymethyl)-2'-deoxyuridine (3b), 5-formyl-2'-deoxyuridine ethylene acetal (4b), and 5-formyl-2'-deoxyuridine propylene acetal (5b). These were evaluated in human foreskin fibroblast cells challenged with the vaccinia virus or cowpox virus. Of the four gem diether nucleosides, only the dimethyl gem diether congener showed significant antiviral activity against both viruses. This antiviral activity did not appear to be related to the decomposition to the 5-formyl-2'-deoxyuridine, which was itself devoid of anti-orthopoxvirus activity in these assays. Moreover, at the pH of the in vitro assays, 2b was very stable with a decomposition (to aldehyde) half-life of >15 d. The anti-orthopoxvirus activity of pyrimidine may be favored by the introduction of hydrophilic moieties to the 5-position side chain.
为了为正痘病毒感染的治疗提供潜在的新线索，嘧啶核苷的5位已用偕二醚部分修饰，以产生以下新核苷：5-（二甲氧基甲基）-2'-脱氧尿苷（2b）、5-（二乙氧基甲基）-2'-脱氧尿苷（3b）、5-甲酰基-2'-脱氧尿苷乙烯缩醛（4b）和5-甲酰基-2'-脱氧尿苷丙烯缩醛（5b）。在用人包皮成纤维细胞接种痘苗病毒或牛痘病毒的实验中对这些核苷进行了评估。在这四种偕二醚核苷中，只有二甲基偕二醚同系物对两种病毒均表现出显著的抗病毒活性。这种抗病毒活性似乎与分解为5-甲酰基-2'-脱氧尿苷无关，在这些实验中5-甲酰基-2'-脱氧尿苷本身没有抗正痘病毒活性。此外，在体外实验的pH值条件下，2b非常稳定，分解（生成醛）的半衰期>15天。嘧啶的抗正痘病毒活性可能因在5位侧链引入亲水性部分而增强。
