Fungicidal and Neurotoxic Marine Natural Products

杀菌和神经毒性海洋天然产品

• 批准号: 7544487
• 负责人: JON Douglas RAINIER
• 金额: $ 26.91万
• 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 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7544487
• 关键词: Acids; Actins; Alkenes; Anhydrides; Antidotes; Antifungal Agents; Area; Binding; Binding Sites; Biological; Biological Factors; Biological Process; Biology; Brevenal; C-glycoside; Carbon; Cells; Chemistry; Ciguatera Poisoning; Coupling; Cystic Fibrosis; Development; Dinophyceae; Ethers; Family; Family member; Gambierdiscus toxicus; Generations; Health; Human; Industrial fungicide; Ion Channel; Lead; Libraries; Lung; Marines; Medicine; Methodology; Modeling; Molecular; Mucous body substance; Neurotoxins; Organic Chemistry; Organic Synthesis; Organism; Positioning Attribute; Protein p53; Publications; Research; Series; Sheep; Site; Skeleton; Sodium Channel; Source; Toxin; Work; analog; brevetoxin; brevetoxin PbTx-3; enol; gambierol; interest; marine natural product; member; neurotoxic; neurotoxicity; programs; small molecule; voltage

The research program outlined in this proposal embodies our commitment to the synthesis of architecturally challenging, pharmacologically significant natural and non-natural products. Our entry into this arena comes not only from a desire to synthesize bioactive agents but also from a fascination with the development of concise organic synthesis strategies and efficient synthetic methodology. These areas of study will not only impact organic chemistry but also the development of new medicines and the understanding of biological processes. Specific to this program are strategies to medicinally interesting polycyclic ether natural andnon- natural products that involve C-glycoside/ketoside synthesis and enol ether-olefin ring-closing metathesis. The first part of this proposal outlines our synthesis of members of the marine ladder toxin family, specifically, gambieric acid and brevenal. These agents are non-toxic polycyclic ethers isolated from dinoflagellates that, in preliminary studies, have demonstrated the somewhat puzzling ability to displace one of the brevetoxins from its target (voltage gated sodium channels) in the absence of neurotoxicity. Interestingly, both of these agents have demonstrated other biological activity that could prove to be important to human health (anti-fungal activity for gambieric acid and the ability to clear mucous from sheep lungs as a model for cystic fibrosis for brevenal). Also outlined is a program targeting the generation of polycyclic ether libraries in an effort to gain a better understanding of their unique biology. This application also contains our proposal to expand the C-glycoside, metathesis chemistry to medicinally relevant non-ladder toxin natural products. Specifically, we are interested in the actin binding pectenotoxin family. That actin binders have been shown to target cells lacking the p53 protein makes the pectenotoxins excellent anticancer leads and our efforts in this area potentially important.

在这份建议书中概述的研究计划体现了我们对建筑综合的承诺， 具有挑战性的，重要的天然和非天然产品。我们进入这个竞技场 这不仅是因为希望合成生物活性剂，而且也是因为对开发 简洁的有机合成策略和高效的合成方法。这些研究领域不仅 影响有机化学，也影响新药的开发和对生物化学的理解。 流程.具体到这个计划是战略医学有趣的多环醚天然和非- 涉及C-糖苷/酮苷合成和烯醇醚-烯烃闭环复分解的天然产物。 本提案的第一部分概述了我们对海洋梯形毒素家族成员的合成， 具体地说，是冈比亚酸和Brevenal。这些试剂是从以下物质中分离的无毒多环醚： 在初步研究中，已经证明了这种有点令人费解的能力， 在不存在神经毒性的情况下，从其靶点（电压门控钠通道）释放短毒素。 有趣的是，这两种药物都表现出了其他生物活性， 对人体健康很重要（抗真菌活性的甘比酸和能力，以清除粘液从羊 肺作为Brevenal的囊性纤维化模型）。还概述了一个方案， 多环醚图书馆，以更好地了解其独特的生物学。 本申请还包含我们的建议，以扩大C-糖苷，复分解化学药用 相关的非梯形毒素天然产物。具体地说，我们感兴趣的是肌动蛋白结合果胶毒素 家人肌动蛋白结合剂已经显示出靶向缺乏p53蛋白的细胞， 优秀的抗癌线索和我们在这方面的努力可能是重要的。