SYNTHESIS OF NOVEL BIOLOGICALLY ACTIVE NATURAL PRODUCTS

新型生物活性天然产物的合成

• 批准号: 2684735
• 负责人: ROBERT K BOECKMAN
• 金额: $ 19.12万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-09-15 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2684735
• 关键词: DNA gyrase; antifungal antibiotics; biological products; chemical addition; chemical structure function; drug design /synthesis /production; enzyme inhibitors; hypoglycemic agents; squalene; stereochemistry

The studies to be conducted under this grant fall in four major areas: 1) complete work on the total synthesis of the hypoglycemic agent Saudin (1); test 1 and its precursors to identify the pharmacophore, and determine if possible the mechanism by which the hypoglycemic effects are elicited (in collaboration with Sandoz Research Institute); prepare appropriate analogues as warranted by the preceding studies; 2) continue work directed at the application of Lewis acid catalyzed asymmetric [2+2] cycloaddition reactions to (+)-Laurencin (2) and Laurenyne (3) which employs a novel retro-Claisen rearrangement to create the required oxocene ring system in enantiomerically pure form; 3) continue preliminary studies begun recently directed toward the preparation of the novel squalene synthetase inhibitor (+)-Zaragozic Acid C, one of a group of novel antifungal enzyme inhibitors known as the squalestatins 1-3 and the Zaracozic Acids A-C isolated by Glaxo and Merck groups. The approach utilizes a novel application of a net [4-3] cycloaddition to construct the core of the novel squalene synthetase inhibitor Zaragozic Acid C (4); and, 4) initiate synthetic studies directed toward UCT4B (6), a recently characterized DNA gyrase inhibitor, which holds promise as both an antibiotic and a potentially antitumor agent. UCT4B (6) is a member of a small but growing group of biologically active diterpene derivatives which also includes Clerocidin and Terpenticin. A novel protection scheme employing a chiral diol acetal is envisioned to permit control over the key asymmetric centers present in the acyclic chain and provide convenient access to an immediate precursor of the sensitive alpha-ketoaldehyde unit.

这笔赠款下进行的研究分为四个主要领域： 1）完成降糖药Saudin的全合成工作 (1);测试 1 及其前体，用于鉴定药效团，以及 如果可能的话，确定降血糖作用的机制 引发（与山德士研究所合作）；准备 先前研究所保证的适当类似物； 2）继续针对路易斯酸催化的应用开展工作 (+)-Laurencin (2) 的不对称 [2+2] 环加成反应和 Laurenyne (3) 采用新颖的复古克莱森重排来创建 所需的对映体纯形式的氧新烯环系统； 3）继续最近开始的初步研究 新型角鲨烯合成酶抑制剂(+)-萨拉戈酸的制备 C，一组新型抗真菌酶抑制剂之一 角鲨他汀 1-3 和 Zaracozic Acids A-C，由 Glaxo 和 Merck 分离 组。 该方法利用了网络的新颖应用[4-3] 环加成构建新型角鲨烯合成酶核心 抑制剂萨拉戈酸C(4)；和， 4) 启动针对 UCT4B (6) 的综合研究，这是最近的一项研究 DNA 旋转酶抑制剂的特征，它有望作为一种 抗生素和潜在的抗肿瘤剂。 UCT4B (6) 是一个成员 一小群但不断增长的具有生物活性的二萜衍生物 还包括Clerocidin和Terpenticin。 新颖的保护方案 设想使用手性二醇缩醛来控制 无环链中存在关键的不对称中心，并提供便利 获得敏感的α-酮醛单元的直接前体。