Tzioumaki Niki, Tsoukala Evangelia, Manta Stella, Kiritsis Christos, Balzarini Jan, Komiotis Dimitri
Department of Biochemistry and Biotechnology, Laboratory of Organic Chemistry, University of Thessaly, 26 Ploutonos Str., 41221 Larissa, Greece.
Carbohydr Res. 2011 Feb 1;346(2):328-33. doi: 10.1016/j.carres.2010.10.019. Epub 2010 Oct 30.
A novel series of exomethylene- and keto-exomethylene-d-glucopyranonucleosides with thymine, uracil, and 5-fluorouracil as heterocyclic bases have been designed and synthesized. Wittig condensation of the 3-keto glucoside 1 gave the corresponding 1,2:5,6-di-O-isopropylidene-3-deoxy-3-methylene-d-glucofuranose (2), which after hydrolysis and acetylation led to the precursor 1,2,4,6-tetra-O-acetyl-3-deoxy-3-methylene-d-glucopyranose (4). Compound 4 was condensed with silylated thymine, uracil, and 5-fluorouracil, respectively, deacetylated and acetalated to afford 1-(3'-deoxy-4',6'-O-isopropylidene-3'-methylene-β-d-glucopyranosyl)pyrimidines 7a-c. Oxidation of the free hydroxyl group in the 2'-position of the sugar moiety led to the formation of the labile 1-(3'-deoxy-4',6'-O-isopropylidene-3'-methylene-β-d-glucopyranosyl-2'-ulose)pyrimidines 8a-c. Finally, deisopropylidenation of the resulted derivatives 8a-c afforded the diol nucleosides 9a-c. The target keto-exomethylene analogs 9a-c were more cytostatic against a variety of tumor cell lines than the corresponding saturated-hydroxy-exomethylene derivatives 6. In particular, the 5-fluorouracil derivative 9c was highly cytostatic at an IC(50) (50% inhibitory concentration) ranging between 0.56 and 9.4 microg/mL, which was comparable to the free parental 5-fluorouracil base.
设计并合成了一系列以胸腺嘧啶、尿嘧啶和5-氟尿嘧啶为杂环碱基的新型亚甲基-和酮亚甲基-d-吡喃葡萄糖核苷。3-酮糖苷1的维蒂希缩合反应得到相应的1,2:5,6-二-O-异亚丙基-3-脱氧-3-亚甲基-d-呋喃葡萄糖（2），其经水解和乙酰化后得到前体1,2,4,6-四-O-乙酰基-3-脱氧-3-亚甲基-d-吡喃葡萄糖（4）。化合物4分别与硅烷化的胸腺嘧啶、尿嘧啶和5-氟尿嘧啶缩合，脱乙酰化并缩醛化，得到1-(3'-脱氧-4',6'-O-异亚丙基-3'-亚甲基-β-d-吡喃葡萄糖基)嘧啶7a - c。糖部分2'-位游离羟基的氧化导致不稳定的1-(3'-脱氧-4',6'-O-异亚丙基-3'-亚甲基-β-d-吡喃葡萄糖基-2'-酮)嘧啶8a - c的形成。最后，所得衍生物8a - c的去异亚丙基化反应得到二醇核苷9a - c。目标酮亚甲基类似物9a - c对多种肿瘤细胞系的细胞毒性比相应的饱和羟基亚甲基衍生物6更强。特别是，5-氟尿嘧啶衍生物9c在IC(50)（50%抑制浓度）为0.56至9.4μg/mL时具有高度细胞毒性，这与游离的母体5-氟尿嘧啶碱基相当。
