Strategies for Expedited Synthesis of Sulfated Aminoglycans

硫酸化氨基聚糖的快速合成策略

• 批准号: 10371884
• 负责人: Hien M Nguyen
• 金额: $ 34.3万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371884
• 关键词: 4T1; Active Sites; Adverse effects; Affinity; Amines; Amino Sugars; Aminoglycoside Antibiotics; Aminoglycosides; Anticoagulants; Beta-glucuronidase; Binding; Binding Proteins; Breast Carcinoma; Cancer Patient; Carbohydrates; Cations; Charge; Clinic; Clinical; Clinical Research; Clinical Trials; Computational Technique; Crystallization; Disaccharides; Disease; Endothelial Cells; Enzymes; Evaluation; Extracellular Matrix; Goals; Grant; Growth Factor; Heparanase inhibitors; Heparin; Heparin Binding; Heparitin Sulfate; Human; Hydrolysis; Hydroxyl Radical; Inflammation; Injection Site Reaction; Kanamycin; Ligands; Light; Malignant Epithelial Cell; Malignant Neoplasms; Modification; Nature; Neomycin; Neoplasm Metastasis; Normal tissue morphology; Oligosaccharides; Outcome; P-Selectin; PF4 Gene; Paromomycin; Pattern; Pharmacologic Substance; Phenotype; Physiological; Polymers; Polysaccharides; Preparation; Prognosis; Property; Protein Biosynthesis; Proteins; Reporting; Ribosomal RNA; Route; Site; Structure; Sulfate; Technology; Therapeutic; Thrombocytopenia; Time; Translating; Translations; Trisaccharides; angiogenesis; apramycin; base; cancer therapy; clinical development; computer studies; cost; cost effective; design; druggable target; glycomimetics; heparanase; innovation; lipophilicity; novel; phase I trial; preclinical development; scale up; small molecule; targeted treatment; tumor; tumor behavior

PROJECT SUMMARY Heparanase is recognized as a master regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients and a prime target for therapy. Although carbohydrate-based heparanase have been developed, but none were translated into use in the clinic. Due to its being a desirable and druggable target for anti-cancer therapy, many molecules have been developed, but only four carbohydrates have advanced to clinical trials. Owing to their heparin-based nature, these molecules are heterogeneous in size and sulfation pattern leading to nonspecific binding and unforeseen adverse effects, therefore halting their translation into clinical use. Our goal in this grant is to develop cost-effective strategies, aided by computational technique, for rapidly generating glycopolymers and oligosacharides with well- defined sulfation pattern and at the same time via a synthetic route that is capable of supporting subsequent scale up. Aminoglycosides are attractive in this light as they are commercially available and inexpensive. Aminoglycosides target 16S bacterial ribosomal RNA and inhibit protein synthesis. They are poly-cationic pseudo-oligosaccharides at physiological pH. Our approach is to transform positively charged aminoglycosides into a novel class of negatively charged aminoglycans, which no longer bind to rRNA, but can interact with heparanase. In Aim 1, we propose strategies for expedited and scalable synthesis of sulfated glycopolymers, derived from paromomycin and neomycin, which possess similar structures and multivalent properties found in the naturally existing HS polysaccharides. In Aim 2, we have identified commercially available and low-cost apramycin as an ideal candidate for modification to produce the sulfated pseudo-oligosaccharides as potential heparanase inhibitors. In Aim 3, we propose strategies for expedited synthesis of sulfated pseudo-oligosaccharides by recombining 3-aminosugar unit of kanamycin with its corresponding pseudo-disaccharide unit. These pseudo- oligosaccharides possess similar structure and properties of the naturally existiing HS oligosaccharides.

项目概要 乙酰肝素酶被认为是癌症侵袭性表型的主要调节因子， 癌症患者预后不良的重要因素，也是治疗的主要目标。 虽然基于碳水化合物的乙酰肝素酶已经被开发出来，但没有被转化为 在临床上使用。由于它是抗癌治疗的理想且可药物化的靶点，许多 分子已经开发出来，但只有四种碳水化合物进入了临床试验。 由于其基于肝素的性质，这些分子的大小和硫酸化程度不同 导致非特异性结合和不可预见的不利影响的模式，因此停止它们 转化为临床应用。我们这笔赠款的目标是制定具有成本效益的战略， 计算技术，用于快速生成具有良好性能的糖聚合物和寡糖 定义的硫酸化模式，同时通过能够支持的合成路线 随后扩大规模。从这个角度来看，氨基糖苷类很有吸引力，因为它们是商业化的 可用且便宜。氨基糖苷类靶向 16S 细菌核糖体 RNA 并抑制 蛋白质合成。它们在生理pH值下是聚阳离子假寡糖。我们的 方法是将带正电荷的氨基糖苷类转化为一类新型的带负电荷的氨基糖苷类药物。 带电荷的氨基聚糖，不再与 rRNA 结合，但可以与乙酰肝素酶相互作用。瞄准 1，我们提出了加速和规模化合成硫酸化糖聚合物的策略，衍生 来自巴龙霉素和新霉素，具有相似的结构和多价特性 存在于天然存在的 HS 多糖中。在目标 2 中，我们已经确定了商业化 可用且低成本的安普霉素作为修饰生产硫酸化物的理想候选者 假低聚糖作为潜在的乙酰肝素酶抑制剂。在目标 3 中，我们提出了以下策略： 通过重组3-氨基糖单元加速合成硫酸化假低聚糖 卡那霉素及其相应的假二糖单元。这些假寡糖 具有与天然存在的HS低聚糖相似的结构和特性。