Asymmetric Synthesis of Biologically Active Marine Natural Products

描述（由申请人提供）：我们的目标是合成具有潜在临床应用的海洋代谢物。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-咪唑类生物碱，特别是新发现的香叶基香叶基转移酶I型（GGTase I）抑制剂马萨定。马塞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、心血管疾病以及真菌和病毒感染的潜在治疗方法。为此，我们设计了一个自由基级联环化和一个氧化重排反应来构建马尾苋的关键骨架。我们将探讨这两种方法的范围和普遍性。我们将利用这些方法合成马萨定并制备各种马萨定类似物，以促进其生物学研究和临床评价。我们相信这一研究不仅将为马尾草胺的合成提供解决方案，而且还将为其他如帕劳胺、axinellamine、ageliferin和nagelamide的合成提供解决方案。这个项目是我们朝着构建具有所有立体化学可能性的天然和非天然邻避二聚体迈出的第一步。我们希望建立一个集中的oroidin二聚体库，以填补自然界在立体化学多样性方面的空白。结合德克萨斯大学西南分校未来的合作生物学研究，我们希望能够帮助推进基于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，这些方法将在制药工业中得到应用。最终的目标是利用从自然物质中吸取的教训来发现新的治疗方法。

DESCRIPTION (provided by applicant): 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.