INHIBITION OF COMPLEX CARBOHYDRATE BIOSYNTHESIS

该建议描述了几类新结构的合成 专门设计用于抑制生物学上重要的糖苷酶 （糖基水解酶）。 预测糖和端基异构体的基本原理 特异性是基于（1）酶的工作假设 机制和（2）与先前已知的抑制剂的结果。 目标 结构通常是多羟基化的环胺，其将被 通过新方法由D-己糖制备对映体纯形式。 糖苷酶在自然界中普遍存在，是正常代谢所必需的。 所有生物的生长和发育。 糖苷酶参与了一种 各种重要的细胞功能，包括分解 碳水化合物食品，真核糖蛋白的加工，以及 多糖和糖复合物的催化剂。 One系列 糖基化酶在复杂的大脑的生物合成和分解中起作用 和神经系统鞘脂称为神经节苷脂。 障碍 神经节苷脂分解，如Tay-Sachs，Sandhoff，Gaucher，Fabry和 克拉布氏病是遗传性的，是由于缺乏 特异性糖苷酶。 这些酶的抑制剂可用于诱导 实验动物的疾病症状，从而便于临床研究。 一般而言，糖苷酶抑制剂将可用于研究 多糖和糖缀合物的生物合成。 他们应该找到宽 在微生物学、病毒学、细胞生物学、免疫学、 发育生物学和医学。

This proposal describes the synthesis of several classes of new structures designed specifically to inhibit biologically important glycosidases (glycosyl hydrolases). A rationale for predicting sugar and anomer specificity is presented based on (1) a working hypothesis of enzyme mechanism and (2) results with previously known inhibitors. Target structures are typically polyhydroxylated cyclic amines, which will be prepared in enantiomerically pure form by a new method from D-hexoses. Glycosidases are ubiquitous in nature, being essential for the normal growth and development of all organisms. Glycosidases are involved in a variety of important cellular functions including the breakdown of carbohydrate foodstuffs, the processing of eucaryotic glycoproteins, and the catabolism of polysaccharides and glycoconjugates. One family of glycosidases functions in the biosynthesis and breakdown of complex brain and nervous system sphingolipids known as gangliosides. Disorders of ganglioside breakdown such as Tay-Sachs, Sandhoff's, Gaucher's, Fabry's and Krabbe's diseases are genetically inherited and result from deficiencies of specific glycosidases. Inhibitors of these enzymes could be used to induce disease symptoms in experimental animals, thus facilitating clinical study. In general, glycosidase inhibitors would be useful in studying the biosynthesis of polysaccharides and glycoconjugates. They should find wide application in microbiology, virology, cell biology, immunology, developmental biology and medicine.