SYNTHESIS AND BIOLOGICAL EVALUATION OF C-DISACCHARIDES

这项申请是为了继续一项研究计划，该研究计划由 格兰特DK35766。这项计划的主要目标是综合 C-双糖(天然双糖的化学惰性异构体 其中，糖苷间氧原子被亚甲基，-CH2-， 群及其作为糖苷酶生物活性的评价 抑制剂。这项研究将扩展到一类新的生物化学 高度显著的二糖类似物，其中糖苷类化合物 键是氨亚甲基(-CHNH2-)基团(“高糖基胺”)。 由于它们的结构与天然底物极其相似 某些糖苷酶及其对水解性的完全惰性， 建议的C-二糖很可能作为高效的、有竞争力的 由这些酶催化的生化过程的抑制物。AS 潜在的消化道二糖酶抑制剂--α-C 双糖可能被证明对治疗糖尿病和 相关代谢性疾病，通过提供一种控制 肠道葡萄糖摄取。此外，假二糖可能是 能干扰低聚糖下巴的加工 糖蛋白(例如，人的包膜糖蛋白 HIV病毒)，因此可能还具有抗病毒或抗癌 活动。 C-二糖的合成是人工合成的一大挑战。 碳水化合物化学。快速实现1，1和1，6链接 基于硝基醛反应的β-C二糖已经被 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、同样有效的方法已经 是为α-C-的自由基SRN1反应而设计的 糖基甲基汞与硝酸糖的化合物。1，1-，1，4-也是 由于1，6-连接的α-C-二糖将由本短文制备 方法论。假二糖对糖苷的影响 由相应的α-或β-催化的水解反应 糖苷酶，并在可能的情况下，由特定的二糖酶 检查过了。

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.