Total synthesis of bioactive natural products

生物活性天然产物的全合成

基本信息

批准号：
10000922
负责人：
DENIS SERVENT
金额：
$ 44.66万
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 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10000922
关键词：
Alkaloids Alkylation Amides Area Biodistribution Biological Biology Carboxylic Acids Chick Embryo Collaborations Communicable Diseases Complex Development Developmental Biology Duocarmycin Electrophysiology (science)Embryo Embryonic Development Exposure to Goals Health Heterocyclic Compounds Human Imines Impairment Individual Investigation Knowledge Lead Lithium Malignant Neoplasms Marine Toxins Metabolic Methodology Methods Modeling Morphine Natural Products Nature Neurodegenerative Disorders Nicotinic Receptors Organic Synthesis Penetration Periodicity Physiological Preparation Process Radiolabeled Reaction Reagent Research Risk Roentgen Rays Signal Transduction Therapeutic Toxin Universities base bioactive natural products chemical synthesis cholinergic developmental disease drug development empowered fascinate imaging probe in vivo in vivo evaluation insight interest marine natural product method development nervous system disorder neurotoxic neurotoxicity novel pinnatoxin A programs radioligand radiotracer receptor tool transmission process

项目摘要

Abstract 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 with momoanionic and dianionic intermediates. This methodology forms the basis of synthesis strategies directed at the enantioselective preparation of duocarmycin alkaloids and a morphine and related alkaloids by a shortest synthetic sequence to date. 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 uncertain 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.

抽象的拟议的研究计划结合了三个研究主题：1）开发和应用方法为了使用随时可用的手性锂酰胺作为有效的不对称合成，作为可回收的立体导向试剂，2）复杂生物活性分子的总合成，3）研究环状亚胺（CI）的作用通过定义与烟碱乙酰胆碱的相互作用，胆碱能传播的各个方面的毒素受体（NACHR）。复杂天然产物的总合成，尤其是CI毒素，已成为统一平台为我们多样化的研究兴趣。在前两个区域内，我们将扩展手性的效用锂试剂与Momoanionic和Dianionic中间体不对称烷基化反应。这方法论构成了针对对映选择性准备的合成策略的基础迄今为止，Duocarmycin生物碱和吗啡和相关的生物碱。在第三区域，我们引入了CI毒素可伸缩合成的专业知识，以产生亚型选择性探针和用于研究NACHR的放射性示例。 CI毒素是一组新兴的海洋毒素，具有全球分布和不确定的人类健康风险。我们将进行有关CI相互作用的全面功能研究具有电生理学，放射性置换和单个NACHR的选定亚型的毒素其他功能研究。使用总合成产生的放射性标记的CI毒素，我们将在体内研究这些海洋毒素的生物分布及其使用小鸡胚作为模型的发育生物学作用。从这个意义上讲，合成CI毒素将成为有望丰富我们对此知识的独特工具重要类的离子受体，包括长期对代谢流失和的额外见解 NACHR对神经退行性疾病的更广泛影响。