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.

根据这项拨款进行的研究主要有四个范畴： 1)完成降血糖药沙特的全合成工作 (1)测试1及其前体，以确定药效团；以及 如果可能的话，确定降血糖作用的机制 启发(与Sandoz研究所合作)；准备 前述研究所保证的适当类似物； 2)继续开展路易斯酸催化应用方面的工作 (+)-Laurencin(2)和(+)-Laurencin的不对称[2+2]环加成反应 Laurenyne(3)，它采用了一种新的复古-克莱森重排来创建 所需的对映体纯形式的六茂铁环体系； 3)继续最近开始的针对 新型角鲨烯合成酶抑制剂(+)-扎拉戈齐酸的制备 C，一组新的抗真菌酶抑制剂之一，称为 葛兰素史克和默克分离的角鲨素1-3和Zaraczic酸A-C 组。该方法利用了一种新的网络应用[4-3] 环加成反应构建新型角鲨烯合成酶的核心 抑制剂萨拉戈齐酸C(4)；以及， 4)启动针对UCT4B(6)的合成研究，最近的一个 表征了DNA旋转酶抑制剂，它既是一种 抗生素和潜在的抗肿瘤药物。UCT4B(6)是一个 具有生物活性的二萜衍生物，数量虽少，但仍在不断增长 还包括克洛西丁和松油菌素。一种新的保护方案 使用手性二醇缩醛的设想是允许控制 关键的不对称中心存在于非环链中，并提供方便的 接触到灵敏的α-酮醛装置的直接前体。