INHIBITION OF COMPLEX CARBOHYDRATE BIOSYNTHESIS

复杂碳水化合物生物合成的抑制

• 批准号: 2178023
• 负责人: BRUCE GANEM
• 金额: $ 15.1万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-01-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2178023
• 关键词: SDS polyacrylamide gel electrophoresis; affinity chromatography; antibody; carbohydrate analog; carbohydrate biosynthesis; carbohydrate metabolism; chemical kinetics; chemical synthesis; cyclization; cyclohexanes; cyclopentane; enzyme inhibitors; glycosidases; glycosides; glycosphingolipids; glycosylation; hydrolysis; lectin; oxidation; stereochemistry

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.

该更新提案概述了研究的四个特定目标 在碳水化合物生物合成和代谢的几个领域。 它广泛的 长期目标是推进基本化学物质和 对碳水化学代谢的生化理解和 各种疾病状态中的碳水化合物。 具体目的包括 下列的： （1）丙酮糖类似物的合成应导致有效 过渡状态的结构模拟物抑制碳水化合物加工 被称为糖苷酶的酶。 几种新的单糖胺 还将准备用作作为基因工程的配体 催化活性的人工外糖苷酶和合成凝集素 结合单糖。 （2）将合成几种新型糖磷脂（GSL）类似物 并作为GSL生物合成的抑制剂进行了测试。 这种抑制剂应该 事实证明，可用于阐明GSL在癌细胞代谢中的作用。 （3）提出了一些不寻常的对映选择性总合成 多羟基环戊烷和环己烯是有效的糖苷酶 抑制剂。 靶标包括甘露汀A＆B，异胺，门酰胺 和伪α-半乳吡喃糖。 （4）几种新型异质糖苷的理性性手性合成是 建议的。 这些不自然的结构有望抑制或 根据声音生物学的灭活特异性糖苷酶 理由，但以不寻常的新方式。