Development of Catalytic Glycosylations and Biologically Important Glycosaminoglycans

催化糖基化和具有生物学重要性的糖胺聚糖的发展

• 批准号: 10622180
• 负责人: Hien M Nguyen
• 金额: $ 32.58万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622180
• 关键词: Alcohols; Aminoglycosides; Benzene; Biological Process; Bromides; Carbohydrates; Clinical; Coupling; Cysteine; Development; Fibroblast Growth Factor; Glycopeptides; Glycosaminoglycans; Glycosides; Grant; Heparanase inhibitors; Heparitin Sulfate; Hydroxyl Radical; Libraries; Malignant Neoplasms; Methodology; Methods; Multiple Myeloma; Oligosaccharides; Oxygen; Peptides; Phenanthrolines; Reaction; Role; Serine; Site; Sulfate; Sulfhydryl Compounds; System; Work; biological systems; cancer therapy; catalyst; druggable target; functional group; glycosylation; mimetics; neurodevelopment; polyol; polysulfated glycosaminoglycan; pyridine

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.

项目概要 该提案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的基础上，以产生 用于构建具有挑战性的糖苷键的有效合成方法。我们最近 发现了容易获得的菲咯啉，一种带有两个吡啶的刚性平面有机化合物 与苯环稠合的环，有效地充当亲核催化剂，促进立体选择性 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。 菲咯啉催化系统可有效获取多种 1,2-顺式吡喃糖苷和 在温和且可操作的条件下，含有C2-氧、-叠氮基和-氟官能团的呋喃糖苷 条件简单。菲咯啉催化方法代表了长期存在的合成方法 高度理想的糖基化产生生物学上重要的寡糖的挑战和 糖肽以促进对其生物学功能的理解。在这笔 R35 拨款中，我们继续 揭示菲咯啉催化剂的简单性和多功能性，为催化反应提供新原理 具有挑战性的α-2-脱氧糖苷的立体选择性构建。精确定制的菲咯啉 催化剂可以同时激活醇亲核试剂和糖基卤化物亲电子试剂。 我们还将研究菲咯啉催化剂的双重活化机制以控制位点 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 在含半胱氨酸肽的硫醇存在下。此外，我们将应用菲咯啉 合成硫酸乙酰肝素类寡糖作为乙酰肝素酶抑制剂的催化剂平台， 这是抗癌治疗的药物靶标。我们还将开发硫酸乙酰肝素库 具有所有可能的 O- 和 N- 硫酸化基序的模拟物，从容易获得的氨基糖苷类到 促进对硫酸化糖胺聚糖在许多生物系统中的作用的理解。在 特别是，我们将研究这些结构明确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。