FUNGICIDAL AND NEUROTOXIC MARINE NATURAL PRODUCTS

杀菌和神经毒性海洋天然产品

• 批准号: 6342954
• 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/6342954
• 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.

海洋环境不断为我们提供各种各样的资源 具有生物学和建筑学意义的天然产品。 不幸的是，我们无法分离出足够数量的许多 对这些生物活性化合物进行全面评估。本文概述的是 我们计划通过合成生物活性物质来改善现状 海洋毒素的新开发和改进（更高效 合成技术。生物活性海洋天然物质的合成 本提案中描述的产品不仅提供 目前无法提供大量材料，但仅此而已 通过这些努力，真正了解这些特性 分子将变得可用。 我们被两个目标所吸引。其中之一，pinnatoxin A，是一种强效的 神经毒素被认为是季节性食物爆发的原因 亚洲各地因摄入贝类而中毒。另一个， 冈比亚酸 A 是已知最有效的抗菌剂之一 男人。据信，这两种物种以及其他类似物种都会出现 来自甲藻的物质可能至少部分地导致了红色 潮汐灾难。我们的pinnatoxin A 合成将包括许多新颖的 转化，包括通过自由基方法合成螺稠环， 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 羽鱼毒素A的合成 我们打算在综合过程中回答几个重要问题 首先，可以采用烯醇醚的迭代策略 环氧化和闭环复分解用于生成稠合醚 海洋“阶梯毒素”中存在的各种环尺寸？还， 该策略是否适合在坚实的支撑上使用？一旦这最后一次 目标已经达到，可以想象图书馆 药理学相关的稠环醚可能会变得可用。在 除了通过我们的迭代策略进行综合之外，我们还 对稠合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。