Asymmetric Synthesis of Biologically Active Marine Natural Products

生物活性海洋天然产物的不对称合成

• 批准号: 7337357
• 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
• 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/7337357
• 关键词: Alkaloids; Antibiotics; Biological; Biological Factors; Biological Process; Cardiovascular Diseases; Chemicals; Chemistry; Class; Complex; Condition; Cyclization; DNA Sequence Rearrangement; Development; Drug Industry; Evaluation; Facility Construction Funding Category; Family; Future; Goals; Imidazole; Immunosuppressive Agents; Learning; Libraries; Marines; Methodology; Methods; Modeling; Modification; Molecular; Nature; Object Attachment; One-Step dentin bonding system; Palau' 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

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价值的海洋代谢产物。本研究的重点是 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（GGT酶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，我们设计了一种激进的 级联环合和氧化重排反应构建出按摩素的关键骨架。我们 将探讨这两种方法的范围和一般性。我们将利用这些方法来综合 并制备了多种Massadine类似物，以促进其生物学研究和临床应用 评价我们相信这项研究不仅将为Massadine的合成提供解决方案， 合成其他的oroidin二聚体，例如帕劳'amine、axinellamine、ageliferin和nagelamide。这个项目 作为我们构建天然和非天然oroidin二聚体的第一步， 立体化学的可能性。我们希望建立一个集中的oroidin二聚体库，并填补自然界的空白， 立体化学多样性结合UT西南大学未来的合作生物学研究，我们希望 以帮助推进基于oroidin二聚体的药物开发。 该研究计划涉及开发新的化学方法，这些方法将在以下领域得到应用 医药行业。最终的目标是利用从研究中获得的经验发现新的疗法。 天然物质。