INHIBITION OF COMPLEX CARBOHYDRATE BIOSYNTHESIS

这份更新提案概述了研究的四个具体目标 关于碳水化合物生物合成和代谢的几个领域。它的广袤， 长期目标是推动基础化学和 对碳水化合物代谢的生化理解及其作用 各种疾病状态下的碳水化合物。具体目标包括 以下是： (1)酰胺酮类糖的合成应导致有效的 抑制碳水化合物加工的过渡态结构模拟物 被称为糖苷酶的酶。几种新的单糖酰胺类化合物 也将准备用作基因工程的配体 催化活性人工外糖苷酶和合成凝集素 结合单糖的物质。 (2)合成了几种新型的鞘糖脂类似物。 并被测试为GSL生物合成的抑制剂。这样的抑制剂应该 在阐明GSLS在癌细胞新陈代谢中的作用方面证明是有用的。 (3)提出了几种不对称的全合成方法。 糖苷酶活性强的多羟基环戊烷和环己烷 抑制剂。目标包括甘露糖他汀类A和B、别沙米丁、valienamine 和假-α-半乳吡喃糖。 (4)几种新型杂糖苷类化合物的合理手性合成 建议。这些非自然的结构预计会抑制或 根据健全的生物学原理灭活特定的糖苷酶 理由，但以不同寻常的新方式。

This renewal proposal outlines four specific objectives for research on several areas of carbohydrate biosynthesis and metabolism. Its broad, long-term objectives are to advance the fundamental chemical and biochemical understanding of carbohydrate metabolism and the role of carbohydrates in a variety of disease states. Specific aims include the following: (1)The synthesis of amidrazone sugar analogs should lead to potent transition-state structural mimics which inhibit carbohydrate-processing enzymes known as glycosidases. Several new monosaccharide amidrazones will also be prepared for use as ligands for genetic engineering of catalytically active artificial exoglycosidases and synthetic lectins which bind monosaccharides. (2)Several novel glycosphingolipid (GSL) analogs will be synthesized and tested as inhibitors of GSL biosynthesis. Such inhibitors should prove useful in elucidating the role of GSLs in cancer cell metabolism. (3)Enantioselective total syntheses are proposed for several unusual polyhydroxycyclopentanes and cyclohexanes which are potent glycosidase inhibitors. Targets include mannostatins A & B, allosamidin, valienamine and pseudo-alpha-galactopyranose. (4)Rational chiral syntheses of several novel heteroglycosides are proposed. These unnatural structures are expected to inhibit or inactivate specific glycosidases according to sound biological rationales, but in unusual new ways.