Center for Analysis and Synthesis, Chemical Center, Lund University, Lund, Sweden.
Bioorg Med Chem. 2011 Jul 1;19(13):4114-26. doi: 10.1016/j.bmc.2011.05.007. Epub 2011 May 10.
Proteoglycans (PG) are polyanionic proteins consisting of a core protein substituted with carbohydrate chains, that is, glycosaminoglycans (GAG). The biosynthesis of GAG can be manipulated by simple xylosides carrying hydrophobic aglycons, which can enter the cell and initiate the biosynthesis. While the importance of the aglycon is well investigated, there is far less information on the effect of modifications in the xylose residue. We have developed a new synthetic protocol, based on acetal protection and selective benzylation, for modification of the three hydroxyl groups in xylose. Thus we have synthesized twelve analogs of 2-naphthyl β-d-xylopyranoside (XylNap), where each hydroxyl group has been epimerized or replaced by methoxy, fluoro, or hydrogen. To gain more information about the properties of xylose, conformational studies were made on some of the analogs. It was found that the (4)C(1) conformation is highly predominant, accompanied by a nonnegligible population of the (2)S(0) conformation. However, deoxygenation at C3 results in a large portion of the (1)C(4) conformation. The GAG priming ability and proliferation activity of the twelve analogs, were investigated using a matched pair of human breast fibroblasts and human breast carcinoma cells. None of the analogs initiated the biosynthesis of GAG, but an inhibitory effect on endogenous PG production was observed for analogs fluorinated or deoxygenated at C4. From our data it seems reasonable that all three hydroxyl groups in XylNap are essential for the priming of GAG chains and for selective toxicity for tumor cells.
蛋白聚糖（PG）是由核心蛋白取代碳水化合物链组成的多阴离子蛋白，即糖胺聚糖（GAG）。通过携带疏水性非糖部分的简单木糖苷，可以操纵 GAG 的生物合成，这些木糖苷可以进入细胞并启动生物合成。虽然非糖部分的重要性已经得到了很好的研究，但关于木糖残基修饰的影响的信息要少得多。我们开发了一种新的合成方案，基于缩醛保护和选择性苄基化，用于修饰木糖中的三个羟基。因此，我们合成了十二种 2-萘基 β-d-吡喃木糖苷（XylNap）的类似物，其中每个羟基都被差向异构化或被甲氧基、氟或氢取代。为了获得更多关于木糖性质的信息，我们对一些类似物进行了构象研究。结果发现，（4）C（1）构象高度占主导地位，同时存在不可忽略的（2）S（0）构象。然而，C3 的去氧会导致大量的（1）C（4）构象。我们使用一对匹配的人乳腺成纤维细胞和人乳腺癌细胞研究了这 12 种类似物的 GAG 引发能力和增殖活性。没有一种类似物能够引发 GAG 的生物合成，但在 C4 被氟化或去氧的类似物中观察到对内源性 PG 产生的抑制作用。从我们的数据来看，XylNap 中的三个羟基对于 GAG 链的引发以及对肿瘤细胞的选择性毒性都是必不可少的，这似乎是合理的。
