SYNTHESIS AND BIOLOGICAL EVALUATION OF C-DISACCHARIDES

C-二糖的合成和生物学评价

• 批准号: 3234018
• 负责人: OLIVIER R MARTIN
• 金额: $ 9.67万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-07-01 至 1993-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3234018
• 关键词: O glycosidase; beta glucuronidase; carbohydrate biosynthesis; chemical structure function; diabetes mellitus; disaccharides; enzyme inhibitors; glucose metabolism; glycoproteins; glycosides; hydrolysis; maltose; membrane activity; methylene chloride; nitro compounds; oligosaccharides; oxidation; trehalose; uronate

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.

此申请用于继续由以下机构支持的研究计划 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物 其中糖苷间氧原子被亚甲基-CH2-取代， 组及其作为糖苷酶的生物活性评价 抑制剂。 该研究将扩展到一类新的生化研究 非常重要的二糖类似物，其中糖苷间 连接是氨基亚甲基(-CHNH2-)基团(“高糖基胺”)。 由于它们与天然基质的极其相似的结构 某些糖苷酶及其对水解的完全惰性， 所提出的 C-二糖可能作为有效的、有竞争力的 这些酶催化的生化过程的抑制剂。 作为 消化道二糖酶 α-C 的潜在抑制剂 二糖可能被证明可用于治疗糖尿病 相关代谢疾病，通过提供控制手段 肠道葡萄糖摄取。 此外，假二糖可能是 能够干扰低聚糖下巴的加工 糖蛋白（例如，人类的包膜糖蛋白 HIV 病毒），因此可能还具有抗病毒或抗癌作用 活动。 C-二糖的合成是合成的一个主要挑战 碳水化合物化学。 快速实现 1,1- 和 1,6- 连接 基于硝基羟醛反应的 β-C 双糖 开发完成，将应用于1,4-连接β-C-的制备 二糖，例如C-乳糖。 一种新的、同样有效的方法 被设计用于α-C-的自由基SRN1反应 糖基甲基汞与糖硝基化合物。 1,1-, 1,4- 以及 因为 1,6-连接的 α-C-二糖将通过这个简短的过程制备 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，如果可能的话，通过特定的二糖酶，将 检查了。