Several novel 2,4-disubstituted-7-(2-deoxy-2-fluoro-beta-D- arabinofuranosyl)pyrrolo[2,3-d]pyrimidines have been synthesized and evaluated for their anti-human cytomegalovirus (HCMV), anti-hepatitis B virus (HBV), and anti-herpes simplex virus (HSV) activities in vitro. These nucleosides were prepared starting from 2-amino-4-chloro-7-(2-deoxy-2-fluoro- 3,5-di-O-benzoyl-beta-D-arabinofuranosyl)pyrrolo[2,3-d]pyrimidine (3), which in turn was synthesized by direct glycosylation of the sodium salt of 2-amino-4-chloropyrrolo[2,3-d]pyrimidine (1) with 2-deoxy-2-fluoro-3,5-di-O-benzoyl-alpha-D-arabinofuranosyl bromide (2). Displacement of the 4-chloro group of 3 with OH, NH2, NHOH, SH, and SeH nucleophiles furnished the corresponding nucleosides 6-8, 12, and 14, respectively. The 3'-deoxygenation of 2-amino-4-chloro-7- (2-deoxy-2-fluoro-beta-D-arabinofuranosyl)pyrrolo[2,3-d]pyrimidine (4) and subsequent amination gave 2,4-diamino-2',3'-dideoxy derivative 19. Catalytic hydrogenation of 3 followed by debenzoylation afforded 2-aminopyrrolo[2,3-d]pyrimidine nucleoside 23. Among the compounds evaluated for their ability to inhibit the growth of HCMV (strain AD169) in MRC-5 cells using a plaque reduction assay, only 7 was significantly active in vitro with a 50% inhibitory concentration (IC50) of 3.7 micrograms/mL (TI > 125), whereas the IC50 value of ganciclovir (DHPG) was 3.2 micrograms/mL. Strain D16 of HCMV was more resistant to 7 (IC50 11 micrograms/mL) than the AD169 strain. When 7 was tested in combination with DHPG, the resultant anti-HCMV activity was found to be moderately synergistic with no evidence of antagonism. Nucleoside 7 also reduced episomal HBV replication in human hepatoblastoma 2.2.15 cells with an IC50 of 0.7 micrograms/mL (TI > 143). Development of cells harboring HBV which had become resistant to the drug was not observed with 7. Compound 7 also exhibited significant activity against herpes simplex virus types 1 and 2 (IC50 of 4.1 and 6.3 micrograms/mL, respectively) in Vero cells.

中文翻译：

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某些2,4-二取代-7-（2-脱氧-2-氟-β-D-阿拉伯呋喃糖基）吡咯并[2,3-dd嘧啶核苷的合成及体外抗DNA病毒活性。

几种新颖的2,4-二取代-7-（2-脱氧-2-氟-β-D-阿拉伯呋喃糖基）吡咯并[2,3-d]嘧啶已被合成并评估了其抗人巨细胞病毒（HCMV），抗-乙型肝炎病毒（HBV）和抗单纯疱疹病毒（HSV）的体外活性。这些核苷由2-氨基-4-氯-7-（2-脱氧-2-氟-3,5-二-O-苯甲酰基-β-D-阿拉伯呋喃糖基）吡咯并[2,3-d]嘧啶制备（3），其通过2-氨基-4-氯吡咯并[2,3-d]嘧啶（1）的钠盐与2-脱氧-2-氟-3,5-二-的直接糖基化反应合成。 O-苯甲酰基-α-D-阿拉伯呋喃糖基溴化物（2）。用OH，NH2，NHOH，SH和SeH亲核试剂置换3的4-氯基团分别提供了相应的核苷6-8、12和14。3' -2-氨基-4-氯-7-（2-脱氧-2-氟-β-D-阿拉伯呋喃糖基）吡咯并[2,3-d]嘧啶（4）的脱氧并随后胺化得到2,4-二氨基- 2'，3'-二脱氧衍生物19.催化3的氢化反应，然后进行脱苯甲酰化，得到2-氨基吡咯并[2,3-d]嘧啶核苷23。评价其中的化合物抑制HCMV（菌株AD169）生长的能力。使用斑块减少试验的MRC-5细胞，在体外只有7个具有50％抑制浓度（IC50）3.7微克/毫升（TI> 125）的显着活性，而更昔洛韦（DHPG）的IC50值为3.2微克/毫升毫升 HCMV的D16菌株比AD169菌株对7的抗性更高（IC50为11微克/ mL）。当将7与DHPG结合测试时，结果发现所得的抗HCMV活性具有中等协同作用，没有拮抗作用的证据。核苷7还减少了人肝母细胞瘤2.2.15细胞中的游离HBV复制，IC50为0.7微克/毫升（TI> 143）。用7未观察到已具有对该药耐药性的带有HBV的细胞的发育。化合物7在Vero细胞中还表现出对1型和2型单纯疱疹病毒的显着活性（IC50分别为4.1和6.3微克/ mL）。