Development of Catalytic Glycosylations and Biologically Important Glycosaminoglycans

项目总结 这项建议中的工作建立在我们在催化立体选择性糖基化方面的专业知识基础上，以导致 构建具有挑战性的糖苷键的有效合成方法。我们最近 发现易得的邻菲咯啉、刚性和平面有机化合物中含有两个吡啶 环融合到苯环上，有效地作为亲核催化剂促进立体选择性的1，2- 醇亲核试剂与吡喃糖基和呋喃糖基溴供体的顺式糖基化反应。 邻菲咯啉催化体系提供了大量1，2-顺式吡喃糖苷和 含有C2-氧、-叠氮和-氟官能团的呋喃糖苷在温和和可操作条件下 条件很简单。邻菲咯啉催化的方法学代表了长期存在的合成 高度可取的糖基化以产生具有生物重要性的寡糖和 糖肽，以促进对其生物学功能的了解。在这笔35卢比的赠款中，我们继续 揭示邻菲咯啉催化剂的简单性和多功能性，为 具有挑战性的α-2-脱氧糖苷的立体选择性构建。精确定制的邻菲罗啉 催化剂可以同时激活醇类亲核试剂和糖基卤化物亲电试剂。 我们还将研究邻菲咯啉催化剂控制中心位置的双重活化机理。 多元醇亲核试剂的选择性偶联和丝氨酸残基羟基的化学选择性偶联 在含有半胱氨酸多肽的硫醇存在下。此外，我们将应用邻菲咯啉 乙酰肝素酶抑制剂类硫酸乙酰肝素低聚糖的合成催化剂平台， 这是抗癌治疗的一个可用药靶点。我们还将开发硫酸乙酰肝素库 与所有可能的O-和N-硫化基序从现成的氨基糖苷类到 促进对硫酸糖胺多聚糖在许多生物系统中的作用的了解。在……里面 特别是，我们将研究这些结构上定义良好的硫酸乙酰肝素模拟物作为潜在的 临床上重要的成纤维细胞生长因子的结合剂。

PROJECT SUMMARY The work in this proposal builds on our expertise in catalytic stereoselective glycosylations to result in efficient synthetic methodologies for construction of the challenging glycosidic bonds. We recently discovered that readily available phenanthrolines, rigid and planar organic compound with two pyridine rings fused to a benzene ring, effectively act as nucleophilic catalysts to promote stereoselective 1,2- cis glycosylation reactions of alcohol nucleophiles with both pyranosyl and furanosyl bromide donors. The phenanthroline catalytic system provides efficient access to a myriad of 1,2-cis pyranosides and furanosides bearing the C2-oxygen, -azido and -fluoro functional groups under mild and operationally simple conditions. The phenanthroline-catalyzed methodologies represent long standing synthetic challenges for highly desirable glycosylations to generate biologically important oligosaccharides and glycopeptides to advance an understanding of their biological functions. In this R35 grant, we continue uncovering the simplicity and versatility of phenanthroline catalysts to provide a new principle for the stereoselective construction of the challenging α-2-deoxy glycosides. Precisely tailored phenanthroline catalysts can activate both the alcohol nucleophile and the glycosyl halide electrophile simultaneously. We will also investigate the dual activation mechanism of the phenanthroline catalysts to control site- selective coupling of polyol nucleophiles and chemoselective coupling of the hydroxyl of serine residue in the presence of the thiol of cysteine-containing peptides. Further, we will apply the phenanthroline catalyst platform to the synthesis of heparan sulfate-like oligosaccharides as inhibitors of heparanase, which is a druggable target for anticancer therapy. We will also develop the library of heparan sulfate mimetics with all of the possible O- and N-sulfation motifs from readily available aminoglycosides to advance an understanding of the role of sulfated glycosaminoglycans in many biological systems. In particular, we will investigate these structurally well-defined heparan sulfate mimetics as the potential binders of clinically important fibroblast growth factors.