Department of Biochemistry and Biotechnology, Laboratory of Organic Chemistry, University of Thessaly, 26 Ploutonos Street, 41221 Larissa, Greece.
Eur J Med Chem. 2009 Nov;44(11):4764-71. doi: 10.1016/j.ejmech.2009.06.013. Epub 2009 Jun 18.
The beta-protected nucleosides of uracil (2a), 5-fluorouracil (2b), thymine (2c), N(4)-benzoyl cytosine (2d) and N(6)-benzoyl adenine (2e) were synthesized by condensation of the peracetylated 3-deoxy-3-fluoro-D-glucopyranose (1) with the corresponding silylated bases. The nucleosides were deacetylated and several subsequent protection and deprotection steps afforded the partially acetylated analogues 6a-e. Selective iodination followed by hydrogenation gave the acetylated dideoxy analogues of uracil (8a), 5-fluorouracil (8b), thymine (8c), N(4)-benzoyl cytosine (8d) and N(6)-benzoyl adenine (8e), respectively. Finally, direct oxidation of the free hydroxyl group at the 4'-position of 8a-e, and simultaneous elimination reaction of the beta-acetoxyl group, afforded the desired unsaturated 2,6-dideoxy-3-fluoro-4-keto-beta-D-glucopyranosyl derivatives 9a-e. The new analogues were evaluated for antiviral and cytostatic activity. Compounds 9a-e were not active against a broad panel of DNA and RNA viruses at subtoxic concentrations. However, they were markedly cytostatic against a variety of tumor cell lines. The compounds should be regarded as potential new lead compounds to be further investigated for anticancer therapy.
尿嘧啶（2a）、5-氟尿嘧啶（2b）、胸腺嘧啶（2c）、N（4）-苯甲酰胞嘧啶（2d）和 N（6）-苯甲酰腺嘌呤（2e）的β-保护核苷通过将全乙酰化的 3-脱氧-3-氟-D-吡喃葡萄糖（1）与相应的硅基化碱基缩合而合成。核苷被脱乙酰化，然后进行几次后续的保护和脱保护步骤，得到部分乙酰化的类似物 6a-e。选择性碘化，然后氢化，得到尿嘧啶（8a）、5-氟尿嘧啶（8b）、胸腺嘧啶（8c）、N（4）-苯甲酰胞嘧啶（8d）和 N（6）-苯甲酰腺嘌呤（8e）的乙酰化二脱氧类似物。最后，直接氧化 8a-e 的 4′-位的游离羟基，同时β-乙酰氧基消除反应，得到所需的不饱和 2,6-二脱氧-3-氟-4-酮-β-D-吡喃葡萄糖基衍生物 9a-e。新类似物的抗病毒和细胞抑制活性进行了评估。在亚毒性浓度下，化合物 9a-e 对广泛的 DNA 和 RNA 病毒均无活性。然而，它们对多种肿瘤细胞系具有明显的细胞抑制作用。这些化合物应被视为进一步研究用于癌症治疗的潜在新先导化合物。
