Total Synthesis of Bioactive Marine Natural Products

生物活性海洋天然产物的全合成

基本信息

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
项目类别：
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

项目摘要

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）使用容易获得的手性锂酰胺作为可恢复的立体调节试剂的有效不对称合成方法的开发和应用，2）总合成复杂的生物活性分子的总合成，以及通过ci的各个方面（CI）互动（CI）的影响（3））烟碱乙酰胆碱受体（NACHRS）。复杂天然产品的总合成，尤其是CI毒素，已成为我们多样化研究兴趣的统一平台。在前两个区域内，我们将扩展手性锂试剂的效用，用于与狄安离子中间体的不对称烷基化反应。该方法构成了针对龙霉素D的对映选择性制备的合成策略的基础，以及C30-静态的几名成员，C30-静态苯甲酰类thioalkaloids，这些thioalkaloid显示出与抑制的生物学活性相关的一系列生物学活性 NFKB调节的途径。在第三区域，我们引入了CI毒素可扩展合成的专业知识，以产生亚型选择性探针和放射性示例，以研究NACHRS。 CI毒素是一群新兴的海洋毒素，具有全球分布和未知的人类健康风险。我们将使用电生理学，放射性置换和其他功能研究进行有关CI毒素与单个NACHR的选定亚型相互作用的全面功能研究。使用总合成产生的放射性标记的CI毒素，我们将研究这些海洋毒素的体内生物分布及其使用雏鸡胚胎作为模型的发育生物学作用。从这个意义上讲，合成的CI毒素将成为独特的工具，有望丰富我们对这一重要类别的离子型受体的了解，包括长期对代谢流动和NACHR对神经退行性疾病的更广泛影响的额外见解。