Total Synthesis of Bioactive Marine Natural Products

生物活性海洋天然产物的全合成

• 批准号: 8578008
• 负责人: Armen Zakarian
• 金额: $ 49.09万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-10 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8578008
• 关键词: Alkaloids; Alkylation; Amides; Area; Autoradiography; Biodistribution; Biological; Biological Factors; Biology; Carbon Dioxide; Carboxylic Acids; Chick Embryo; Collaborations; Communicable Diseases; Complex; Development; Developmental Biology; Electrophysiology (science); Embryo; Embryonic Development; Exposure to; Goals; Health; Human; Imines; Individual; Indoles; Investigation; Knowledge; Lead; Lithium; Malignant Neoplasms; Marine Toxins; Metabolic; Methodology; Methods; Modeling; Nature; Neurodegenerative Disorders; Nicotinic Receptors; Nuphar; Organic Synthesis; Pathway interactions; Preparation; Process; Radiolabeled; Reaction; Reagent; Research; Risk; Roentgen Rays; Signal Transduction; Solutions; Structure; Testing; Therapeutic; Toxin; Universities; base; chemical synthesis; cholinergic; developmental disease; drug development; empowered; fascinate; in vivo; insight; interest; marine natural product; member; method development; n-butyllithium; nervous system disorder; neurotoxic; neurotoxicity; novel; pinnatoxin A; programs; public health relevance; radioligand; radiotracer; receptor; tetramethylenedisulfotetramine; tool; transmission process

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.

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）开发和应用使用现成的手性氨基锂作为可回收的立体定向试剂进行有效不对称合成的方法，2）复杂生物活性分子的全合成，以及3）通过定义环亚胺（CI）毒素与胆碱能传递的相互作用来研究环亚胺（CI）毒素对胆碱能传递各个方面的影响。 烟碱乙酰胆碱受体（nAChR）。复杂天然产物（特别是 CI 毒素）的全合成已成为我们不同研究兴趣的统一平台。在前两个领域中，我们将扩展手性锂试剂在双阴离子中间体的不对称烷基化反应中的应用。该方法构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，这些生物碱表现出一系列与抑制相关的生物活性。 NFkB 调节途径。在第三个领域，我们利用 CI 毒素可扩展合成方面的专业知识来生产用于 nAChR 研究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，分布于全球，对人类健康风险未知。我们将利用电生理学、放射性配体置换和其他功能研究，对 CI 毒素与单个 nAChR 的选定亚型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，以鸡胚为模型，研究这些海洋毒素的体内生物分布及其对发育生物学的影响。从这个意义上说，合成 CI 毒素将作为独特的工具，有望丰富我们对这一类重要的离子型受体的了解，包括从长远来看，进一步了解代谢周转以及 nAChR 对神经退行性疾病的更广泛影响。