Fungicidal and Neurotoxic Marine Natural Products

杀菌和神经毒性海洋天然产品

• 批准号: 6687824
• 负责人: JON Douglas RAINIER
• 金额: $ 22.43万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6687824
• 关键词: Fungicidal; Neurotoxic; Marine; Natural; Products

DESCRIPTION (provided by applicant): Natural products that have been isolated from the marine environment show promise as pharmacological agents. However, because of the supply problems associated with their isolation, a thorough evaluation of their properties requires their chemical synthesis. This proposal describes the chemical synthesis of three biologically important marine natural products. The first of these is gambierol, a marine ladder toxin associated with ciguatera poisoning. The second is armatol A, a polycyclic ether that has demonstrated interesting cytotoxicity in preliminary testing. The third is halichondrin B, a potent anticancer agent that has been recommended for preclinical trials in spite of its short supply. Gambierol, armatol A, and halichondrin B have in common a fused polycyclic ether skeleton. This proposal outlines the chemical synthesis of these agents centered around carbon-glycosides. As carbon-glycosides have been demonstrated to be important, not only in synthetic chemistry, but also in medicinal chemistry, we believe that this strategy might have broad implications. In addition, by coupling our carbon-glycoside forming chemistry with efficient annulation protocols, we believe that we will be able to efficiently generate polycyclic ethers including the natural products listed above. Furthermore, these efforts will undoubtedly lead to the generation of a number of interesting and biologically important analogs whose properties will be evaluated.

描述（由申请人提供）：已从海洋环境中隔离的天然产品显示出作为药理剂的希望。但是，由于与它们隔离相关的供应问题，对其性质的彻底评估需要其化学合成。该提案描述了三种具有生物学重要海洋天然产品的化学合成。首先是Gambierol，这是一种与Ciguatera中毒有关的海洋梯子毒素。第二个是Armatol A，一种多环节，在初步测试中表现出有趣的细胞毒性。第三个是Halichondrin B，这是一种有效的抗癌剂，尽管其供应量短，但已推荐用于临床前试验。 Gambierol，Armatol A和Halichondrin B具有融合的多环芳烃骨架。该提议概述了这些因子围绕碳糖苷的化学合成。由于碳糖苷不仅在合成化学中，而且在药用化学中也很重要，因此我们认为该策略可能具有广泛的影响。此外，通过将形成化学形成化学的碳糖苷与有效的营养方案耦合，我们相信我们将能够有效地生成多环醚，包括上面列出的天然产品。此外，这些努力无疑将导致将评估这些特性的许多有趣且具有生物学上重要的类似物。