中文摘要
岩藻糖化糖胺聚糖(FG)是海洋棘皮动物来源的化学结构特殊的强效内源性因子X酶(Xase)抑制剂。选择性Xase抑制剂可能具有低出血倾向的强效抗血栓活性特点,深入的FG化学及药理学研究具有重要的学术及潜在应用价值。30多年来,天然FG因其结构复杂且为多糖混合物,其确切结构(如取代基确切结构类型及连接位置)尚存疑问,构效关系研究严重受限。本课题前期在规则结构FG的纯化寡糖结构片段研究中已取得积极进展,并在复杂FG的探索研究中发现其中可能存在二糖侧链、GlcUA硫酸酯基取代等特殊的结构类型。在此基础上,本课题拟采用糖苷键选择性解聚以及寡糖纯化技术制备获得多种类型的FG的纯化寡糖片段,通过寡糖结构解析阐明天然FG的确切结构特征与类型;通过纯化寡糖构效关系研究阐明不同取代基对其Xase抑制活性的影响,以期发现结构简单的强效选择性Xase抑制剂,为低出血倾向的抗血栓药物研发及其药理研究提供科学依据。
英文摘要
Fucosylated glycosaminoglycan (FG) is a potent intrinsic Xase inhibitor with unusual structure from sea echinoderm. Since selective Xase inhibitor may be a potential type of anticoagulant with low hemorrhage tendency, it is valuable to process further studies on chemistry and pharmacology of complex FGs. However, for 30 years, studies on elucidation of the precise structure of FG and its structure-activity relationship were severely limited for the mixture property of FG, for example sulfation patterns and glycosidic linkage types of side-chain substituents are still unclear. In our earlier researches, we found that FG might have some special structural types, such as disaccharide in its side chain and sulfation of GlcUA. And we also made significant advances on selective depolymerization of glucosidic bond in FG and purification of oligosaccharides with regular well-fined structure. Based on these, we will prepare pure oligosaccharides with different structures from native FG with representative structure types and explore the precise structures by structure analysis of purified oligosaccharides. Additionally, this project is further to study the structure–activity relationships of FGs to clarify the effect of different substitute groups on Xase inhibition activity. All of these aim to discover strong selective Xase inhibitor with simple chemical structure, and to further provide valuable information for new anticoagulant drugs with low hemorrhage tendency and their pharmacology studies.
