Fungicidal and Neurotoxic Marine Natural Products

描述（由申请人提供）：本提案中概述的研究计划体现了我们对合成建筑上具有挑战性的，具有重要意义的天然和非天然产品的承诺。我们进入这一竞技场不仅来自于对合成生物活性剂的渴望，而且来自于对简洁的有机合成策略和有效的合成方法的发展的迷恋。这些研究领域不仅会影响有机化学，还会影响新药的开发和对生物过程的理解。具体到这个计划是战略，以医学有趣的多环醚天然和非天然产品，涉及C-糖苷/酮苷合成和烯醇醚-烯烃闭环复分解。本提案的第一部分概述了我们的合成成员的海洋阶梯毒素家族，具体来说，冈比亚酸和brevenal。这些药剂是从腰鞭毛虫中分离的无毒多环醚，在初步研究中，已经证明了在没有神经毒性的情况下从其目标（电压门控钠通道）中置换短毒素之一的有点令人困惑的能力。有趣的是，这两种药物都表现出其他生物活性，可能对人类健康很重要（冈比亚酸的抗真菌活性和从绵羊肺中清除粘液的能力，作为Brevenal囊性纤维化的模型）。还概述了一个计划，旨在产生多环醚图书馆，以更好地了解其独特的生物学。本申请还包含我们将C-糖苷、复分解化学扩展到医学相关的非梯形毒素天然产物的建议。具体来说，我们感兴趣的肌动蛋白结合pectenotoxin家族。肌动蛋白结合剂已经显示出靶向缺乏p53蛋白的细胞，使得果胶毒素成为优秀的抗癌先导，我们在这一领域的努力具有潜在的重要性。

DESCRIPTION (provided by applicant): 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 and non-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.