Fungicidal and Neurotoxic Marine Natural Products

本提案中概述的研究计划体现了我们对建筑合成的承诺。 具有挑战性、药理意义重大的天然和非天然产品。我们进入这个竞技场 不仅来自于对合成生物活性物质的渴望，也来自于对发展的迷恋 简明的有机合成策略和高效的合成方法。这些研究领域不仅将 影响着有机化学，也影响着新药的发展和对生物学的认识 流程。具体到这个计划是战略，以医学上的兴趣多环醚天然和非- 天然产物，涉及C-糖苷/酮苷合成和烯醇醚-烯烃开环歧化反应。 该提案的第一部分概述了我们合成的海洋阶梯毒素家族成员， 具体地说，是冈比亚酸和棕榈酸。这些试剂是无毒的多环醚，分离自 在初步研究中，已经显示出令人费解的取代甲藻的能力 在没有神经毒性的情况下，从其靶标(电压门控钠通道)中分离出短杆菌毒素。 有趣的是，这两种制剂都显示出了其他生物活性，这些活性可能被证明是 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 肺作为囊性纤维化的动物模型)。还概述了一个计划，目标是生成 多环醚文库，以更好地了解它们独特的生物学特性。 本申请还包含我们的建议，将C-糖苷、歧化化学扩展到医学上 相关非阶梯毒素天然产物。具体地说，我们对肌动蛋白结合果胶毒素感兴趣 一家人。肌动蛋白结合蛋白被证明是缺乏P53蛋白的靶细胞，从而产生果胶毒素。 优秀的抗癌线索和我们在这一领域的努力具有潜在的重要意义。

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.