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.

本提案中概述的研究计划体现了我们对综合建筑学的承诺 具有挑战性的、具有药理意义的天然和非天然产品。我们进入这个舞台来了 不仅出于合成生物活性剂的愿望，而且还出于对开发的迷恋 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的理解 流程。该计划的具体策略是药用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。 该提案的第一部分概述了我们对海洋梯毒素家族成员的合成， 具体地，甘比亚酸和布雷纳尔。这些试剂是从其中分离出的无毒多环醚 在初步研究中，甲藻已经证明了一种令人费解的取代一种甲藻的能力。 在没有神经毒性的情况下，从其目标（电压门控钠通道）中去除短链毒素。 有趣的是，这两种药物都表现出其他生物活性，可能被证明是 对人类健康很重要（冈比亚酸的抗真菌活性和清除绵羊粘液的能力 肺作为 brevenal 囊性纤维化的模型）。还概述了一项旨在产生 多环醚库，以更好地了解其独特的生物学特性。 该申请还包含我们将 C-糖苷复分解化学扩展到药用的建议 相关非阶梯毒素天然产物。具体来说，我们对肌动蛋白结合果胶毒素感兴趣 家庭。肌动蛋白结合剂已被证明可以靶向缺乏 p53 蛋白的细胞，从而产生果胶毒素 出色的抗癌领先优势以及我们在这一领域的努力可能很重要。