Fungicidal and Neurotoxic Marine Natural Products

杀菌和神经毒性海洋天然产品

• 批准号: 7005655
• 负责人: JON Douglas RAINIER
• 金额: $ 21.9万
• 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/7005655
• 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(申请人提供)：从海洋环境中分离出来的天然产品显示出作为药理制剂的前景。然而，由于与分离相关的供应问题，彻底评估它们的性质需要它们的化学合成。这项建议描述了三种具有重要生物意义的海洋天然产物的化学合成。第一种是甘比埃罗，一种与雪卡特拉中毒有关的海洋阶梯毒素。第二种是阿马特醇A，这是一种多环醚，在初步测试中显示出了有趣的细胞毒性。第三种是灯盏花素B，这是一种有效的抗癌药物，尽管供应短缺，但仍被推荐用于临床前试验。甘草醇、阿马特醇A和灯盏花素B具有共同的稠合多环醚骨架。该提案概述了以碳苷为中心的这些试剂的化学合成。由于碳苷已被证明是重要的，不仅在合成化学中，而且在药物化学中，我们认为这一策略可能具有广泛的影响。此外，通过将我们的碳苷形成化学与有效的环化方案相结合，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物。此外，这些努力无疑将导致一些有趣的、具有生物学意义的类似物的产生，其性质将得到评估。