INHIBITION OF COMPLEX CARBOHYDRATE BIOSYNTHESIS

该方案描述了几类新结构的合成 专为抑制具有生物重要性的糖苷酶而设计 (糖基水解酶)。预测糖分和异构体的理论基础 特异性是基于(1)酶的工作假说而提出的 作用机理和(2)已知的抑制剂的结果。目标 结构通常是多羟基环胺，它将是 通过D-己糖的一种新方法制备对映体纯净的形式。 糖苷酶在自然界中无处不在，是正常生命所必需的 所有有机体的生长和发育。糖苷酶参与一种 各种重要的细胞功能，包括细胞的崩溃 碳水化合物食品，真核糖蛋白的加工，以及 多糖和糖偶联物的分解代谢。一个家庭 糖苷酶在复合脑生物合成和分解中的作用 和神经系统神经鞘糖脂称为神经节苷脂。精神障碍 神经节苷脂分解，如泰-萨克斯、桑德霍夫、高谢尔、法布里和 Krabbe病是遗传的，是由于缺乏 特定的糖苷酶。这些酶的抑制剂可以用来诱导 实验动物的疾病症状，从而方便了临床研究。 总体而言，糖苷酶抑制剂将有助于研究 多糖和糖偶联物的生物合成。他们应该找到更宽的 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.