Asymmetric Synthesis of Biologically Active Marine Natural Products

生物活性海洋天然产物的不对称合成

基本信息

批准号：
7544944
负责人：
CHUO CHEN
金额：
$ 26.85万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7544944
关键词：
Alkaloids Antibiotics Biological Biological Factors Biological Process Cardiovascular Diseases Chemicals Chemistry Complex Cyclization DNA Sequence Rearrangement Development Drug Industry Evaluation Family Future Goals Imidazole Immunosuppressive Agents Learning Libraries Marines Methodology Methods Modeling Modification Molecular Nature One-Step dentin bonding system Palau&apos amine Pathway interactions Property Pyrroles Reaction Reporting Research Research Personnel Route Skeleton Solutions Structure Structure-Activity Relationship Therapeutic Therapeutic Uses Variant Virus Diseases analog base cancer therapy chemical synthesis clinical application dimer drug development functional group inhibitor/antagonist marine natural product massadine member novel novel therapeutics oroidin programs protein geranylgeranyltransferase research clinical testing small molecule tool

项目摘要

We aim to synthesize marine metabolites with potential clinical applications. The focus of this research is the synthesis of biologically significant and synthetically challenging natural pyrrole-imidazole alkaloids, in particular, massadine, a newly discovered geranylgeranyltransferase type I (GGTase I) inhibitor. Massadine is a valuable synthetic target because selective GGTase I inhibitors are potential treatments for cancer, cardiovascular disease as well as fugal and viral infection. Toward this end, we have devised a radical cascade cyclization and an oxidative rearrangement reaction to construct the key skeleton of massadine. We will explore the scope and generality of the two approaches. We will utilize these approaches to synthesize massadine and prepare a variety of massadine analogs to facilitate its biological study and clinical evaluation. We believe this research will provide a solution not only to the massadine synthesis, but the synthesis of other oroidin dimers, such as palau'amine, axinellamine, ageliferin and nagelamide. This project serves as our first step toward the construction of both natural and unnatural oroidin dimers with all stereochemical possibilities. We wish to create a focused oroidin dimer library and fill nature's gap in stereochemical diversity. Combining with future collaborative biological studies at UT Southwestern, we wish to help advance oroidin dimer-based drug development. This research program involves development of new chemical methods, which will find applications in pharmaceutical industry. The ultimate goal is to discover new therapeutics using the lessons learned from natural substances.

我们的目标是合成具有潜在临床应用的海洋代谢物。这项研究的重点是合成具有生物学意义和合成挑战性的天然吡咯-咪唑生物碱，特别是massadine，一种新发现的香叶基香叶基转移酶I型（GGTase I）抑制剂。马萨丁是一个有价值的合成靶点，因为选择性 GGT 酶 I 抑制剂是癌症的潜在治疗方法，心血管疾病以及真菌和病毒感染。为此，我们设计了一个激进的方案级联环化和氧化重排反应构建了massadine的关键骨架。我们将探讨这两种方法的范围和通用性。我们将利用这些方法来合成马萨丁并制备多种马萨丁类似物以促进其生物学研究和临床评估。我们相信这项研究不仅将为马萨丁的合成提供解决方案，而且还将为马萨丁的合成提供解决方案。其他 oroidin 二聚体的合成，如 palau'amine、axinellamine、ageliferin 和 nagelamide。这个项目这是我们构建天然和非天然蝴蝶苷二聚体的第一步立体化学的可能性。我们希望创建一个集中的兰花甙二聚体库并填补自然界的空白立体化学多样性。结合德州大学西南分校未来的合作生物学研究，我们希望帮助推进基于 Oroidin 二聚体的药物开发。该研究计划涉及新化学方法的开发，将在以下领域找到应用：制药业。最终目标是利用从中吸取的经验教训来发现新的治疗方法天然物质。