Total Synthesis of Bioactive Marine Natural Products

生物活性海洋天然产物的全合成

• 批准号: 8725678
• 负责人: Armen Zakarian
• 金额: $ 40.74万
• 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/8725678
• 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）：拟议的研究项目包括三个研究主题：1)开发和应用利用易于获得的手性锂酰胺作为可回收立体定向试剂的高效不对称合成方法，2)复杂生物活性分子的总合成，以及3)通过定义环亚胺（CI）毒素与烟碱乙酰胆碱受体（nAChRs）的相互作用，研究环亚胺（CI）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，已经成为我们不同研究兴趣的统一平台。在前两个领域，我们将扩展手性锂试剂在与重阴离子中间体的不对称烷基化反应中的应用。该方法构成了针对德拉马西丁D和c30倍半萜类Nuphar硫代生物碱的对体选择性制备的合成策略的基础，这些成员显示出一系列与抑制相关的生物活性