Strategies for Expedited Synthesis of Sulfated Aminoglycans

硫酸化氨基聚糖的快速合成策略

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要肝素酶被公认为是癌症侵略性表型的主要调节剂，癌症患者预后不良的重要因素和治疗的主要靶标。尽管已经开发了基于碳水化合物的乙par菜酶，但没有人翻译成在诊所使用。由于它是抗癌治疗的理想且可药的靶标，许多已经开发了分子，但是只有四个碳水化合物已促进了临床试验。由于其基于肝素的性质，这些分子的大小和硫酸化是异质的导致非特异性结合和不可预见的不良反应的模式，因此停止了它们转化为临床用途。我们在这笔赠款中的目标是制定具有成本效益的策略计算技术，用于迅速生成糖聚合物和寡素化物具有良好的定义的硫酸化模式，同时通过能够支持的合成路线随后的比例。氨基糖苷在这一角度很有吸引力，因为它们是商业上的可用且便宜。氨基糖苷靶向16S细菌核糖体RNA并抑制蛋白质合成。它们是生理pH值的聚阳离子伪寡糖。我们的方法是将带正电的氨基糖苷转变为新颖的否定类别带电的氨基聚糖，不再与rRNA结合，但可以与乙酰肝素酶相互作用。目标 1，我们提出了加快硫化糖聚合物的加快和可扩展合成的策略，该策略得出来自偏霉素和新霉素，它们具有相似的结构和多价性能在天然现有的HS多糖中发现。在AIM 2中，我们在商业上确定了可用的和低成本的Apramycin作为修饰的理想候选者，以产生硫酸盐伪寡糖作为潜在的肝素酶抑制剂。在AIM 3中，我们提出了策略通过重新组合3-氨基糖单元的加快硫酸化伪寡糖合成卡纳霉素及其相应的伪二糖单元。这些伪寡糖具有天然存在的HS寡糖的相似结构和特性。