Department of Chemistry, Faculty of Engineering, Gifu University, Gifu, Japan.
Bioorg Med Chem Lett. 2010 Dec 15;20(24):7269-73. doi: 10.1016/j.bmcl.2010.10.085. Epub 2010 Oct 23.
Various 4-deoxy-4-fluoro-xylosides were prepared using click chemistry for evaluating their potential utility as inhibitors of glycosaminoglycan biosynthesis. 2,3-Di-O-benzoyl-4-deoxy-4-fluoro-β-D-xylopyranosylazide, obtained from L-arabinopyranose by six steps, was treated with a wide variety of azide-reactive triple bond-containing hydrophobic agents in the presence of Cu(2+) salt/ascorbic acid, a step known as click chemistry. After click chemistry, benzoylated derivatives were deprotected under Zemplén conditions to obtain 4-deoxy-4-fluoro-xyloside derivatives. A mixture of α:β-isomers of twelve derivatives were then separated on a reverse phase C18 column using HPLC and the resulting twenty four 4-deoxy-4-fluoro-xylosides were evaluated for their ability to inhibit glycosaminoglycan biosynthesis in endothelial cells. We identified two xyloside derivatives that selectively inhibit heparan sulfate and chondroitin sulfate/derman sulfate biosynthesis without affecting cell viability. These novel derivatives can potentially be used to define the biological actions of proteoglycans in model organisms and also as therapeutic agents to combat various human diseases in which glycosaminoglycans participate.
使用点击化学方法制备了各种 4-脱氧-4-氟木糖苷，以评估它们作为糖胺聚糖生物合成抑制剂的潜在用途。由 L-阿拉伯吡喃糖经六步反应得到的 2,3-二-O-苯甲酰基-4-脱氧-4-氟-β-D-木吡喃糖基叠氮化物，在 Cu(2+)盐/抗坏血酸存在下与各种叠氮反应性叁键含疏水试剂反应，这一步骤称为点击化学。点击化学后，在 Zemplén 条件下脱保护得到 4-脱氧-4-氟木糖苷衍生物。然后，将十二种衍生物的混合物在反相 C18 柱上通过 HPLC 分离，得到二十四种 4-脱氧-4-氟木糖苷，并评估它们抑制内皮细胞糖胺聚糖生物合成的能力。我们鉴定了两种木糖苷衍生物，它们选择性地抑制肝素硫酸盐和软骨素硫酸盐/真皮硫酸盐的生物合成，而不影响细胞活力。这些新型衍生物可能可用于在模式生物中定义蛋白聚糖的生物学作用，也可作为治疗剂来对抗各种参与糖胺聚糖的人类疾病。
