The syntheses, antiviral activities, and partition coefficients (P) of 3'‐O‐(1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyl)‐coupled nucleosides are described. These novel compounds were designed in an effort to enhance the lipophilicity, and thereby the delivery to the CNS, without compromising the anti‐HSV‐1 activity of the parental nucleosides. We have previously reported the synthesis of 3'‐O‐(1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyl) analogs of 5‐iodo‐(5), 5‐vinyl‐(6), and (E)‐5‐(2‐iodovinyl)‐2'‐deoxyuridines (7). We now report the synthesis of 5‐iodo‐3'O‐(1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyl)‐5'‐O‐acetyl‐2'‐deoxyuridine (15) and 3'‐O‐(1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyl)‐2'‐deoxyuridine (17). Quarternization of the 3'‐O‐(3‐pyridylcarbonyl) compounds (10,12) using iodomethane afforded the corresponding 1‐methyl pyridinium salts (13,14) which were reduced with sodium dithionite to yield the corresponding 3'‐O‐1‐methyl‐1,4‐dihy‐dropyridyl‐3‐carbonyl compounds (15,16). The deprotection of 3'‐O‐(1‐methyl‐1,4‐dihy‐dropyridyl‐3‐carbonyl)‐5'‐O‐t‐butyldimethylsilyl‐2'‐deoxyuridine (16) with Bu4N+F‐ afforded 3'‐O‐(1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyl)‐2'‐deoxyuridine (17). Compounds 5‐7 and 15 were evaluated for their antiviral activity in vitro against HSV‐1, HSV‐2, HCMV, and VZV, and were found to retain anti‐HSV‐1, HSV‐2 and VZV activity as compared to their parental nucleosides (1—3). In addition, the cellular toxicity of 3'‐O‐(1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyl)‐coupled compounds (5—7 and 15) was found to be lower than the parent nucleosides. The lipophilicity of compounds (5—7,15,17) are enhanced substantially, compared to the parent nucleosides, as indicated by an increase in corresponding P values (1‐octanol‐water) upon replacement of the C‐3' hydroxyl by 1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyl moiety.

中文翻译：

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5-取代嘧啶核苷与二氢吡啶/吡啶盐氧化还原化学递送系统偶联的合成和生物学研究

描述了 3'-O-（1-甲基-1,4-二氢吡啶基-3-羰基）-偶联核苷的合成、抗病毒活性和分配系数 (P)。这些新化合物的设计旨在提高亲脂性，从而在不影响亲本核苷的抗 HSV-1 活性的情况下向 CNS 递送。我们之前已经报道了 5-iodo- (5)、5-vinyl- (6) 和 (E) 的 3'-O- (1-methyl-1,4-dihydropyridyl-3-carbonyl) 类似物的合成 - 5-（2-碘乙烯基）-2'-脱氧尿苷 (7)。我们现在报告合成 5-iodo-3'O- (1-methyl-1,4-dihydropyridyl-3-carbonyl) -5'-O-acetyl-2'-deoxyuridine (15) 和 3'-O- (1-甲基-1,4-二氢吡啶基-3-羰基)-2'-脱氧尿苷(17)。3'-O-(3-吡啶基羰基)化合物的季铵化 (10, 12) 使用碘甲烷得到相应的 1-甲基吡啶鎓盐 (13,14)，用连二亚硫酸钠还原得到相应的 3'-O-1-甲基-1,4-二氢吡啶基-3-羰基化合物 (15 , 16)。3'-O-(1-甲基-1,4-二氢吡啶基-3-羰基)-5'-O-叔丁基二甲基甲硅烷基-2'-脱氧尿苷(16)与Bu4N+F-脱保护得到3'-O - (1-甲基-1,4-二氢吡啶基-3-羰基)-2'-脱氧尿苷(17)。对化合物 5-7 和 15 的体外抗 HSV-1、HSV-2、HCMV 和 VZV 抗病毒活性进行了评估，发现与其亲本相比保留了抗 HSV-1、HSV-2 和 VZV 的活性核苷 (1-3)。此外，发现 3'-O-（1-甲基-1,4-二氢吡啶基-3-羰基）-偶联化合物（5-7 和 15）的细胞毒性低于母体核苷。