Strategies for Expedited Synthesis of Sulfated Aminoglycans

项目总结 乙酰肝素酶被认为是癌症侵袭性表型的主要调节因子， 是导致癌症患者预后不佳的重要因素，也是治疗的主要目标。 虽然基于碳水化合物的肝素酶已经被开发出来，但没有一种被翻译成 在临床上使用。由于它是抗癌治疗的理想和可用药靶点，许多 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。 由于它们基于肝素的性质，这些分子在大小和硫酸盐化方面是不同的。 导致非特定约束和不可预见的不利影响的模式，因此阻止其 转化为临床应用。我们在这笔赠款中的目标是开发具有成本效益的策略，并得到 计算技术，用于快速生成具有良好结构的糖共聚物和低聚糖 定义的硫化模式，同时通过能够支持的合成路线 随后进行扩展。在这一点上，氨基糖苷类药物很有吸引力，因为它们具有商业价值 可供选择且价格不贵。氨基糖苷类药物靶向16S细菌核糖体RNA及其抑制作用 蛋白质合成。在生理pH下，它们是多阳离子拟低聚糖。我们的 方法是将带正电荷的氨基糖苷类化合物转化为一类新的负电荷。 荷电的氨基聚糖，不再与rRNA结合，但可以与乙酰肝素酶相互作用。在AIM 1，我们提出了快速和可扩展地合成硫酸酯糖共聚物的策略，衍生 从具有相似结构和多价性质的帕罗霉素和新霉素中分离得到 在天然存在的HS多糖中发现。在目标2中，我们已经在商业上确定了 可获得的低成本的安普霉素作为一种理想的改性候选者来生产硫酸盐化 拟低聚糖作为潜在的乙酰肝素酶抑制剂。在目标3中，我们提出了以下战略 通过重组3-氨基糖单元加速合成硫化拟低聚糖 卡那霉素及其相应的伪二糖单元。这些拟低聚糖 具有与天然存在的HS寡糖相似的结构和性质。

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.