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.

在这项资助下进行的研究分为四个主要范畴：