Synthesis and Chemical Biology of Bioactive Natural Products

项目概要/摘要 该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 抗菌天然产物的策略 拟议研究的目的是开发一种可扩展的和权宜之计的方法，以几种生物活性 天然产物家族，并利用合成工作开发新的化学探针和先导化合物 用于治疗发展。在过去的5年里，我们在这方面制定了几个方案， NIH的支持，并很高兴扩大我们的努力，同时推进我们现有的项目到一个新的水平。的 迄今为止，特别感兴趣的是多环胍、恶唑烷酮、弯孢胺和absyssomicins以供探索 抗微生物和/或抗生物膜活性。 我们希望我们的合成工作将提供新的反应，以构建具有广泛用途和领导作用的分子。 涉及使其能够用作化学探针的天然产物的方法。这些综合研究是 辅以内部化学生物学研究，以探索天然药物和天然药物的活性和机制。 用于治疗临床相关疾病的产品和类似物。这些努力将提供一个框架， 用于开发新的合成化学和潜在的先导化合物，用于治疗细菌感染。 感染以及其他疾病的新活动被发现。

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.