Asymmetric Synthesis of Biologically Active Marine Natural Products

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 具有生物意义和合成挑战性的天然吡咯咪唑生物碱的合成 特别是马萨定，一种新发现的香叶基香叶基转移酶I(GGTase I)抑制剂。马萨丁 是一个有价值的合成靶点，因为选择性GGTase 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 级联环化和氧化重排反应以构建马萨定的关键骨架。我们 我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合成 并制备多种马萨定类似物，方便其生物学研究和临床应用 评估。我们相信，这项研究不仅将为马萨定的合成提供解决方案，而且将为 其他山梨素二聚体的合成，如帕劳胺、紫杉胺、洋参皂苷和橙皮酰胺。这个项目 是我们向构建天然和非天然的Oroidin二聚体迈出的第一步 立体化学的可能性。我们希望创建一个集中的oroidin二聚体文库，并填补自然的空白 立体化学多样性。结合德克萨斯大学西南分校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。 这项研究计划涉及开发新的化学方法，这将在 制药业。最终目标是利用从中学到的经验发现新的治疗方法 天然物质。

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.