FUNGICIDAL AND NEUROTOXIC MARINE NATURAL PRODUCTS

杀菌和神经毒性海洋天然产品

• 批准号: 2763568
• 负责人: JON Douglas RAINIER
• 金额: $ 18.18万
• 依托单位: UNIVERSITY OF ARIZONA
• 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 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2763568
• 关键词: antifungal agents; chemical structure; chemical synthesis; marine toxins; neurotoxins; silicon; stereochemistry

The marine environment continues to provide us with a wide variety of biologically and architecturally interesting natural products. Unfortunately, we are unable to isolate sufficient quantities of many of these bioactive compounds for their full evaluation. Outlined herein are our plans to improve the status quo through the synthesis of bioactive marine toxins and the development of new and improve (more efficient synthetic techniques. The synthesis of the bioactive marine natural products that are described in this proposal will not only provide quantities of materials that are not currently available but it is only through these efforts that a true understanding of the properties of these molecules will become available. We are drawn to two targets. One of these, pinnatoxin A, is a potent neurotoxin though to be responsible for seasonal outbreaks of food poisoning from the ingestion of shellfish throughout Asia. The other, gambieric acid A, is among the most potent antimicrobial agents known to man. Both of these, as well as other similar species, are believed to come from dinoflagellates are probably at least partially responsible for red tide catastrophes. Our synthesis of pinnatoxin A will include many novel transformations including free-radical approaches to spiro-fused rings, macrocylic rings and bis-ketal rings as well as free-radical coupling reactions which utilize silicon as a stereo-and regio-controlling feature. We anticipate that these studies will have implications far beyond the synthesis of pinnatoxin A. We intend to answer several important questions during the synthesis of gambieric acid A. First, can an iterative strategy employing enol ether epoxidation and ring closing metathesis be used to generated fused ethers of various ring sizes as are present in the marine "ladder toxins"? Also, is this strategy amenable to its use on a solid support? Once this last goal has been achieved, it is conceivable that libraries of pharmacologically relevant fused cyclic ethers could become available. In addition to their synthesis through our iterative strategy, we are also interested in the biosynthesis of fused cyclic ethers and plan to explore polyepoxide cyclizations towards their synthesis.

海洋环境继续为我们提供各种各样的 生物学和建筑学上有趣的天然产物。 不幸的是，我们无法分离出足够数量的 这些生物活性化合物进行全面评估。本文概述了 我们计划通过合成生物活性物质来改善现状， 海洋毒素和开发新的和改善（更有效 合成技术具有生物活性的海洋天然产物的合成 本提案中描述的产品不仅提供 目前还没有的材料数量，但它只是 通过这些努力，一个真正的了解这些属性， 分子将变得可用。 我们被两个目标吸引。其中之一，pinnatoxin A，是一种有效的 神经毒素虽然负责季节性爆发的食物 全亚洲因食用贝类而中毒。另一个， 冈比亚酸A是已知的最有效的抗微生物剂之一， 伙计这两个物种，以及其他类似的物种，被认为是来自 可能至少是造成红色的部分原因 潮汐灾害我们对羽叶毒素A的合成将包括许多新的 包括自由基方法到螺稠环的转化， 大环和双缩酮环以及自由基偶联 利用硅作为立体和区域控制特征的反应。 我们预计，这些研究的影响将远远超出 羽叶毒素A合成 我们打算在综合过程中回答几个重要问题， 甘比尔酸A.第一，使用烯醇醚的迭代策略 环氧化和闭环复分解反应可用于生成稠醚 海洋“阶梯毒素”中存在的不同大小的环？还有， 这一战略是否适合在坚实的支持下使用？一旦这最后 目标已经实现，可以想象， 相关的稠环醚可能变得可用。在 除了通过我们的迭代策略进行综合之外，我们还 对稠环醚的生物合成感兴趣，并计划探索 多环氧化物环化以实现其合成。