SYNTHESIS AND BIOLOGICAL EVALUATION OF C-DISACCHARIDES

该计划的主要目标是合成类似物 糖苷间氧原子被取代的双糖 亚甲基及其作为糖苷酶的活性评价 抑制剂。该计划的范围将在下一年期间扩大 预算期间，到一类新的假二糖，即氮杂-C-糖- 二糖，其中环氧原子的“非还原”单元 被亚氨基(-NH-)取代(相当于难以捉摸的诺吉霉素- 二糖)。 下一个预算期的具体目标是：(1)编制 特定支链C-二糖(例如，C-乳糖胺)，(2) 氮杂-C-二糖高效合成方法的研究进展 (例如氮杂-C-麦芽糖)，以及(3)制备以下物质的第一实例 假三糖(C，O和O，C-三糖)。 作为化学惰性和结构极其相似的类似物 几种糖苷酶的天然底物，建议的 伪低聚糖可能表现出同样的效力，严格地说 这些化合物催化的水解过程的竞争性抑制物 酵素。麦芽糖类似物尤其重要。 作为潜在碳水化合物代谢调节剂的靶点：高度 消化道α-葡萄糖苷酶的选择性抑制剂， 这些化合物可能提供了一种控制肠道的方法 葡萄糖摄取，因此被证明在治疗代谢疾病中很有用 糖尿病等疾病。此外，作为潜在的抑制剂， 参与黄连加工过程中的“修剪”糖苷酶 糖蛋白的寡糖链(例如 人类HIV病毒的包膜糖蛋白)，建议 假二糖(如氮杂-C-曲二糖)也可能具有 显著的抗病毒活性。 合成碳水化合物化学中的一个主要挑战是合成 C-二糖需要两个糖单元通过C-C键偶联 形成反应。基于极性(米曲醇)的高效方法学 和基本(SRN1)工艺已经开发并提供了 直链“C-二糖”的快速合成 二糖的制备将通过SRN1-偶联过程和氮杂-氮杂环己烷-氮杂环己烷偶联反应的方式进行。 C-二糖通过自由基偶联或极性偶联过程。 拟低聚糖的生物活性将被测定。 在我们实验室使用简单的糖苷酶，并在专门的 使用α和β-葡聚糖酶的实验室(与Dr。 首页--期刊主要分类--期刊细介绍--期刊题录与文摘--期刊详细文摘内容 )。

The principal objectives of this program are the synthesis of analogs of disaccharides in which the interglycosidic oxygen atom is replaced by a methylene group, and the evaluation of their activity as glycosidase inhibitors. The scope of the program will be extended, during the next budget period, to a new class of pseudodisaccharides, namely aza-C- disaccharides, in which the ring oxygen atom of the "non-reducing" unit is replaced by an imino (-NH-) group (equivalent to elusive nojirimycin- disaccharides). The specific aims for the next budget period are (1) the preparation of specific branched C-disaccharides (e.g., C-lactosamine), (2) the development of efficient synthetic approaches to aza-C-disaccharides (e.g., aza-C-maltose), and (3) the preparation first examples of pseudotrisaccharides (C,O and O,C-trisaccharides). As chemically inert and structurally extremely similar analogs of the natural substrates of several types of glycosidase, the proposed pseudeooligosaccharides are likely to behave as potent, strictly competitive inhibitors of the hydrolytic process catalyzed by these enzymes. Maltose analogs, in particular, are especially significant targets as potential modulators of carbohydrate metabolism: as highly selective inhibitors of the alpha-glucosidases of the digestive tract, these compounds might provide a means of controlling the intestinal glucose uptake and thus prove useful in the treatment of metabolic diseases such as diabetes mellitus. Furthermore, as potential inhibitors of the "trimming" glycosidase involved in the processing of the oligosaccharide chains of glycoproteins (such as for example of the envelope glycoprotein of the human HIV virus), the proposed pseudodisaccharides (e.g., aza-C- kojibiose) might also posses significant antiviral activities. A major challenge in synthetic carbohydrate chemistry, the synthesis of C-disaccharides require the coupling of two sugar units by a C-C bond forming reaction. Efficient methodologies based on polar (mitroaldol) and radical (SRN1) processes have been developed and have provided expeditious syntheses of linear" C-disaccharides. "Branched" C- disaccharides will be prepared by way of SRN1-coupling processes and aza- C-disaccharides by way of radical or polar coupling processes. The biological activity of the pseudooligosaccharides will be determined in our laboratory using simple glycosidase, and in specialized laboratories using alpha and Beta-glucanases (in collaboration with Dr. H. Driguez, CNRS-Grenoble, and Dr. M. Claeyssens, University of Gent, respectively).