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课题：1）使用容易获得的手性氨基锂作为可回收的立体定向试剂的有效不对称合成方法的开发和应用，2）复杂生物活性分子的全合成，（3）研究环亚胺（CI）通过定义毒素与烟碱乙酰胆碱受体（nAChRs）的相互作用，研究毒素对胆碱能传递的各个方面的影响。复杂天然产物的全合成，特别是CI毒素，已成为我们各种研究兴趣的统一平台。在前两个领域中，我们将拓展手性锂试剂在含双阴离子中间体的不对称烷基化反应中的应用。该方法形成了针对对映选择性制备dragmacidin D和C30-倍半萜类Nuphar硫代生物碱的几个成员的合成策略的基础，所述C30-倍半萜类Nuphar硫代生物碱显示出与抑制 NFkB调节途径。在第三个领域，我们将我们在CI毒素的可扩展合成方面的专业知识用于生产亚型选择性探针和放射性示踪剂，用于nAChR的研究。CI毒素是一组新兴的海洋毒素，具有全球分布和未知的人类健康风险。我们将进行全面的功能研究的相互作用的CI毒素与选定的亚型的个人nAChR使用电生理学，放射性配体置换，和其他功能的研究。利用放射性标记的全合成CI毒素，我们将研究这些海洋毒素在体内的生物分布和发育生物学效应，以鸡胚为模型。从这个意义上说，合成的Cl毒素将作为独特的工具，有望丰富我们对这类重要的离子型受体的知识，包括从长远来看，对代谢周转和nAChR对神经退行性疾病的更广泛影响的额外了解。

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.