Synthesis and Chemical Biology of Bioactive Natural Products

项目摘要/摘要 这份提案描述了我们的计划，重点是开发复杂的新型化学反应 分子合成，分子合成的创新策略，以及这些反应和应用 天然产物的抗菌策略 拟议研究的目标是开发一种可扩展的和方便的方法来处理几种生物活性 天然产品系列，并利用合成工作开发新的化学探测器和先导化合物 用于治疗发展。在过去的5年里，我们已经在这方面开发了几个项目 美国国立卫生研究院表示支持，并很高兴能够扩大我们的努力，同时推动我们现有的项目更上一层楼。的 到目前为止，人们特别感兴趣的是多环胍、恶唑烷酮、弯曲胺和阿昔米星。 抗菌和/或抗生物被膜活性。 我们期望我们的合成工作将提供新的反应来构建具有广泛用途和铅的分子。 到能够将其用作化学探针的天然产品的方法。这些综合研究是 通过内部化学生物学研究，探索天然和天然的活性和机制 针对临床相关疾病的产品和类似物。总而言之，这些努力将提供一个框架 用于开发用于治疗细菌的新的合成化学和潜在的先导化合物 随着新的活动被发现，感染以及其他疾病也是如此。

Project Summary/Abstract This proposal describes our program focused on the development of novel chemical reactions for complex molecule synthesis, innovative strategies for molecule synthesis, and the application of these reactions and strategies to antimicrobial natural products The objective of the proposed research is to develop a scalable and expedient approach to several bioactive natural product families and leverage the synthetic work to develop new chemical probes and lead compounds for therapeutic development. We have developed several programs in this regard over our previous 5 years of NIH support and are excited to expand our efforts while advancing our existing projects to the next level. Of particular interest to date are polycyclic guanidine, oxazolidinone, curvulamines and absyssomicins to explore antimicrobial and/or anti-biofilm activity. We expect that our synthetic work will provide new reactions to construct molecules of broad utility and lead to approaches to natural products that enable their use as chemical probes. These synthetic studies are complimented by in-house chemical biology studies to explore the activity and mechanism of both natural products and analogs against clinically relevant diseases. Taken together, these efforts will provide a framework for the development of new synthetic chemistry and potential lead compounds for the treatment of bacterial infections as well as other diseases as new activity is uncovered.