Total Synthesis of Bioactive Marine Natural Products

描述(由申请人提供)：拟议的研究计划结合了三个研究主题：1)开发和应用有效的不对称合成方法，使用现成的手性锂酰胺作为可回收的立体定向试剂；2)复杂生物活性分子的全合成；3)通过确定环亚胺(CI)毒素与烟碱型乙酰胆碱受体(NAChRs)的相互作用，研究其对胆碱能传递的不同方面的影响。复杂天然产物的全合成，特别是CI毒素，已成为我们不同研究兴趣的统一平台。在前两个领域，我们将扩大手性锂试剂在与双阴离子中间体的不对称烷基化反应中的应用。这一方法学形成了合成策略的基础，该合成策略针对龙马菌素D和几个C30倍半萜类Nuphar硫代生物碱的对映选择性制备，这些成员显示出一系列与抑制 NFkB调控的信号通路。在第三个领域，我们引入了我们在可扩展合成CI毒素方面的专业知识，以生产用于研究nAChRs的亚型选择性探针和放射性示踪剂。CI毒素是一类新兴的海洋毒素，具有全球分布和未知的人类健康风险。我们将利用电生理学、放射配基置换和其他功能研究，对CI毒素与特定亚型的nAChRs的相互作用进行全面的功能研究。我们将利用全合成产生的放射性标记CI毒素，以鸡胚胎为模型，研究这些海洋毒素在体内的生物分布及其对发育生物学的影响。从这个意义上说，人工合成的CI毒素将作为一种独特的工具，有望丰富我们对这类重要的离子亲和性受体的知识，从长远来看，包括进一步了解新陈代谢和nAChRs对神经退行性疾病的更广泛影响。

DESCRIPTION (provided by applicant): The proposed research program combines three research topics: 1) development and application of methods for efficient asymmetric synthesis using readily available chiral lithium amides as recoverable stereodirecting reagents, 2) total synthesis of complex bioactive molecules, and 3) investigating effects of Cyclic Imine (CI) toxins on various aspects cholinergic transmission by defining their interaction with nicotinic acetylcholine receptors (nAChRs). Total synthesis of complex natural products, in particular CI toxins, has served as a unifying platform for our diverse research interests. Within the first two areas, we will extend the utility of chiral lithium reagents for asymmetric alkylation reactions wih dianionic intermediates. This methodology forms the basis of synthesis strategies directed at the enantioselective preparation of dragmacidin D and a several members of C30-sesquiterpenoid Nuphar thioalkaloids that display an array of biological activity associated with the inhibition of NFkB-regulated pathways. In the third area, we bring in our expertise in scalable synthesis of CI toxins to produce subtype-selective probes and radiotracers for the study of nAChRs. CI toxins are an emerging group of marine toxins with global distribution and unknown human health risks. We will carry out comprehensive functional studies on the interaction of CI toxins with selected subtypes of individual nAChRs using electrophysiology, radioligand-displacement, and other functional studies. Using radiolabeled CI toxins produced by total synthesis, we will investigate in vivo biodistribution of these marine toxins and their effect of developmental biology using chick embryo as a model. In this sense, synthetic CI toxins will serve as unique tools that promise to enrich our knowledge of this important class of ionotropic receptors, including, in long term, additional insight into metabolic turnover and broader impact of nAChRs on neurodegenerative disorders.