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具有建筑挑战性，药理意义的天然和非天然产品的承诺。我们进入这一领域不仅是出于合成生物活性制剂的愿望，也是出于对简明有机合成策略和高效合成方法发展的着迷。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。具体到这个项目是有医学意义的多环醚天然和非天然产物的策略，包括c -糖苷/酮苷合成和烯醇醚-烯烃闭环复合。本建议的第一部分概述了我们对海洋阶梯毒素家族成员的合成，特别是冈比亚酸和布雷凡纳酸。这些药物是从鞭毛藻中分离出来的无毒多环醚，在初步研究中，已经证明了在没有神经毒性的情况下，从其靶标（电压门控钠通道）中取代一种短毒素的令人困惑的能力。有趣的是，这两种药物都显示出其他可能对人类健康很重要的生物活性（冈比亚酸的抗真菌活性和清除绵羊肺部粘液的能力，作为短暂性囊性纤维化的模型）。还概述了一个针对多环醚库生成的程序，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，转化化学扩展到医学相关的非阶梯毒素天然产物的建议。具体来说，我们对肌动蛋白结合pectenotoxin家族感兴趣。肌动蛋白结合物已经被证明可以靶向缺乏p53蛋白的细胞，这使得pectenotoxins成为优秀的抗癌药物，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.