SYNTHESIS AND BIOLOGICAL EVALUATION OF C-DISACCHARIDES

此申请是为了继续一项研究计划， 授予DK35766。 该计划的主要目标是综合 C-二糖（天然二糖的化学惰性等排体） 其中糖苷间氧原子被亚甲基，-CH 2-， 组，并评价其作为糖苷酶的生物活性 抑制剂的 这项研究将扩展到一个新的生物化学类， 高度重要的二糖类似物，其中糖苷间 在一个实施方案中，连接基是氨基亚甲基（-CHNH 2-）基团（"同型糖基胺"）。 由于它们与天然基质的结构极其相似， 某些糖苷酶及其对水解的完全惰性， 所提出的C-二糖可能作为高效的、竞争性的 这些酶催化的生化过程的抑制剂。 作为 消化道α-C二硫代磷酸酯酶的潜在抑制剂 二糖可能被证明可用于治疗糖尿病， 相关的代谢疾病，通过提供一种控制 肠葡萄糖摄取。 此外，假二糖可能是 能够干扰低聚糖的加工， 糖蛋白（例如，人的包膜糖蛋白） HIV病毒），因此也可能具有抗病毒或抗癌 活动 C-二糖的合成是合成的主要挑战。 糖类化学 1，1-和1，6-连接的快速方法 β-C二糖，基于硝基醛醇反应，已经被 开发，并将应用于制备1，4-连接的β-C- 二糖如C-乳糖。 一种新的，同样有效的方法， 被设计用于α-C- 糖基甲基汞化合物与糖硝酸盐。1，1-，1，4-也是 因为1，6-连接的α-C-二糖将通过这种短的 方法论 假双糖对葡萄糖苷的影响 水解反应由相应的α-或β- 在可能的情况下，通过特异性的二硫代磷酸酶， 考察

This application is for the continuation of a research program supported by grant DK35766. The principal objectives of this program are the synthesis of C-disaccharides (chemically inert isosters of the natural disaccharides in which the interglycosidic oxygen atom is replaced by a methylene, -CH2-, group and the evaluation of their biological activity as glycosidase inhibitors. The study will be extended to a new class of biochemically highly significant disaccharide analogs in which the interglycosidic linkage is an aminomethylene (-CHNH2-) group ("homoglycosylamines"). Owing to their extreme structural similarity to the natural substrates of certain glycosidases and to their complete inertness towards hydrolysis, the proposed C-disaccharides are likely to act as efficient, competitive inhibitors of the biochemical process catalyzed by these enzymes. As potential inhibitors of the disaccharidases of the digestive tract, alpha-C disaccharides might prove useful for the treatment of diabetes mellitus and related metabolic diseases, by providing a means of controlling the intestinal glucose uptake. Furthermore, the pseudodisaccharides might be able to interfere with the processing of the oligosaccharide chin of glycoproteins (such as, for example, the envelope glycoprotein of the human HIV virus) and therefore might possess also antiviral or anticancer activity. The synthesis of C-disaccharides is a major challenge of synthetic carbohydrate chemistry. Expeditious approaches to 1,1- and 1,6-linked beta-C disaccharides, based on the nitroaldol reaction, have been developed, and will be applied to the preparation of 1,4-linked beta-C- disaccharides such as C-lactose. A new, equally efficient methodology has been devised for the radical SRN1 reaction of an alpha-C- glycosylmethylmercury compound with a sugar nitronate. 1,1-, 1,4- as well as 1,6-linked alpha-C-disaccharides will be prepared by this short methodology. The effect of the pseudodisaccharides on the glycoside hydrolysis reaction catalyzed by the corresponding alpha- or beta- glycosidases and, when possible, by specific disaccharidases, will be examined.