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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：
10594458
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/10594458
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 Charge Clinic Clinical Clinical Research Clinical Trials Computational Technique 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 Natural Extract 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 Synthesis Inhibition Proteins Reporting Ribosomal RNA Route Site Structure Sulfate Technology Therapeutic Thrombocytopenia Time Translating Translations Trisaccharides Umbilicus angiogenesis apramycin 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.

项目摘要乙酰肝素酶被认为是癌症侵袭性表型的主要调节因子，这是癌症患者预后不良的重要原因，也是治疗的主要目标。虽然已经开发了基于碳水化合物的乙酰肝素酶，但没有一种被翻译成在诊所使用。由于它是抗癌治疗的理想和可药物化的靶标，许多人认为它是抗癌治疗的理想靶点。分子已经被开发出来，但只有四种碳水化合物进入了临床试验。由于它们的肝素基性质，这些分子在尺寸和硫酸化方面是异质的导致非特异性结合和不可预见的不良影响的模式，因此停止其转化为临床应用。我们在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- 定义的硫酸化模式，同时通过能够支持随后，规模扩大。氨基糖苷类在这方面是有吸引力的，可用且便宜。氨基糖苷类药物靶向16 S细菌核糖体RNA并抑制蛋白质合成。它们在生理pH下是聚阳离子假寡糖。一种方法是将带正电荷的氨基糖苷类转化为一类新的带负电荷的氨基糖苷类。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。在Aim中 1，我们提出了加速和可扩展的硫酸化糖共聚物合成的策略，从巴龙霉素和新霉素，具有相似的结构和多价性质，在天然存在的HS多糖中发现。在目标2中，我们在商业上确定了可用且低成本的安普霉素是修饰产生硫酸化的理想候选药物假寡糖作为潜在的乙酰肝素酶抑制剂。在目标3中，我们提出了以下战略：通过重组3-氨基糖单元加速合成硫酸化假寡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增稠HS寡糖相似的结构和性质。