Fungicidal and Neurotoxic Marine Natural Products

描述（由申请人提供）：从海洋环境中分离出来的天然产物显示出作为药理药物的前景。然而，由于与它们的分离有关的供应问题，要彻底评价它们的性质，就需要对它们进行化学合成。本文介绍了三种重要的海洋天然产物的化学合成。第一种是甘比罗尔，一种与雪卡毒素中毒有关的海洋阶梯毒素。第二种是芳香醇A，一种多环醚，在初步测试中显示出有趣的细胞毒性。第三种是软海绵素B，这是一种有效的抗癌药物，尽管供不应求，但仍被推荐用于临床前试验。甘比醇、香甲醇A和软海绵素B具有共同的熔融多环醚骨架。本提案概述了以碳糖苷为中心的这些试剂的化学合成。由于碳糖苷不仅在合成化学中，而且在药物化学中也被证明是重要的，我们相信这种策略可能具有广泛的意义。此外，通过将我们的碳糖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包括上述天然产物在内的多环醚。此外，这些努力无疑将导致产生许多有趣的和生物学上重要的类似物，其性质将被评估。

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.