ANTIMETASTATIC OLIGOSACCHARIDES FROM HYALURONIC ACID

描述：(首席调查员)这项建议的主要目的是 为了研究已经观察到的抗肿瘤转移作用 由透明质酸裂解酶(EC 4.2.2.1)作用产生的寡糖 透明质酸(HA)。利用从这些研究中收集的信息， 设计和合成代谢稳定的合成努力 将对这些低聚糖进行模拟。 该提案有三个具体目标：(L)隔离、净化和 透明质酸衍生的抗肿瘤寡糖的表征 裂解酶(EC 4.2.2.1)降解HA。分子量的测定， DP和结构对于开发任何结构活性都是重要的 关系(SAR)。(2)研究其他HA降解酶，其中 其中来自睾丸组织(EC 3.2.1.35)和水蚤的透明质酸酶 (EC 3.2.1.36)提供的产品在结构上与 裂解酶的消化液。这些人将接受筛选，以确定 抗转移活性，并将得到充分的描述。 (3)使用根据(1)和(2)中的研究开发的SAR，低聚糖 他们的-O-键战略上被-CH2-和-S取代 设计、综合和评估。我们的战略是利用C-和 S-可糖苷O连接的二糖提供 适当大小的寡糖，以最大限度地发挥抗转移活性。

DESCRIPTION: (Principal Investigator's) The major aims of this proposal are to investigate the antimetastatic effect that has been observed for certain oligosaccharides derived by the action of hyaluronate lyase (EC 4.2.2.1) on hyaluronic acid (HA). Using information to be gleaned from these studies, a synthetic effort toward designing and synthesizing metabolically stable mimics of these oligosaccharides will be undertaken. The proposal has three Specific Aims: (l) To isolate, purify, and characterize the antimetastatic oligosaccharides derived by hyaluronate lyase (EC 4.2.2.1) degradation of HA. Determination of molecular weight, dp, and structure are important for developing any structure-activity relationships (SAR). (2) To investigate other HA-degrading enzymes, among them hyaluronidases from testicular tissue (EC 3.2.1.35) and from leeches (EC 3.2.1.36) that give products that are different in structure from those of the lyase digests. These will be subjected to screening for antimetastatic activity and will be fully characterized. (3) Using SAR developed from the studies in (1) and (2), oligosaccharides having their -O-linkages strategically replaced by -CH2- and -S- will be designed, synthesized, and evaluated. Our strategy is to make use of C- and S-disaccharides that can be glycosidically O-linked to provide oligosaccharides of appropriate size to maximize antimetastatic activity.