SYNTHESIS OF HYALURONIC ACID MIMETICS TO PREVENT METASTASIS

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 透明质酸（HA）是由葡萄糖醛酸和N-乙酰葡糖胺的重复二糖单元组成的多糖。它是各种哺乳动物组织中细胞外基质的一种成分，也存在于某些细菌（尤其是致病性细菌）周围的荚膜物质中。虽然它被称为润滑剂和减震器，但透明质酸也被证明参与细胞信号传导。我们寻求进一步了解的正是后者的功能及其在癌症转移中的作用。 来自动物模型的结果表明，单剂量的HA 10-mer将抑制转移持续24-48小时的时间。我们研究的主要目标之一是通过合成那些HA寡聚体的S/O连接的模拟物来增加功效的长度。这应该使这些模拟物不太容易受到透明质酸酶降解的影响，并增加试剂的活力。我们的研究将从合成HA模拟物开始，其中1 - 4糖苷键中的氧已被硫原子取代。所得寡糖将用于产生树枝状聚合物，其将被检查治疗功效。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hyaluronic acid (HA) is a polysaccharide composed of repeating disaccharide units of glucuronic acid and N-acetylglucosamine. It is a component of the extracellular matrix in various mammalian tissues and is also found in the capsular material surrounding certain bacteria, especially pathogenic ones. While it is known to serve as a lubricant and shock absorber, hyaluronic acid has also been shown to be involved in cell signaling. It is this latter function and its role in the metastasis of cancer that we seek to further understand. Results from animal models suggest that a single dose of HA 10-mers will inhibit metastasis for a period of 24-48 hours. One of the main goals of our research will be to increase the length of efficacy by synthesizing S/O-linked mimetics of those HA oligomers. This should render those mimetics less susceptible to hyaluronidase degradation and increase the viability of the agent. Our study will begin with the synthesis of the HA mimetics in which the oxygen in the 1¿ 4 glycosidic bond has been replaced with a sulfur atom. The resulting oligosaccharides will be used to create a dendrimer which will be examined for therapeutic efficacy.