Expanding the small molecule toolbox through novel applications of fluorinated alkenes

抗多重耐药细菌感染的新方法和化学工具 摘要 我们实验室的中心主题围绕着小分子。我们致力于开发新方法， 获取具有生物学和医学相关性的小分子的策略，并将其用作探索 生物学问题或人类疾病。这份建议书概述了我们两个部门的持续努力和未来方向， 我们设想使用19F NMR将看似不同的程序合并到配体发现平台中。之一 我们的研究计划的重点领域是具有迷人的化学反应性组合的氟化烯烃 主要是由于极性反转特征。我们正在研究氟化的极性反转性质， 烯烃，我们认识到这将解决长期存在的问题，区域选择性氟化杂环 化合物.我们的工作证明了FA在产生区域选择性获得氮方面的适用性- 含有氟化杂环。另一个研究领域是寻找新的化学工具， 创新战略，以解决阻碍抗生素的抗药性菌株的演变 治疗，使他们无效，成本沉重的医疗保健行业。我们目前正在调查 MraY酶，细胞壁合成的关键组分，使用常规的基于结构的合理设计 靶向蛋白质降解和基于19F NMR配体的策略和非常规发现平台 筛选一个R35 MIRA奖将有助于实现我们的目标，并使我们的两个研究合并 主题.成功完成这些研究将使我们能够广泛地了解 功能、结构和使用氟化探针抑制抗菌靶标的机制，小分子 降解器和基于19F NMR的筛选平台。这些研究将导致新的化学抗菌剂 具有新的作用机制的实体，迫切需要补充我们新的和现有的 抗生素R35 MIRA奖也将促进我们在大学内现有的和新的合作， 在美国和国际上。这项研究计划将帮助参与研究的毕业生， 本科生和博士后学者提高和学习跨学科科学的新技能 同时在高度协作和多学科的环境中工作。

New Methods and Chemical Tools Against Multi Drug-resistant Bacterial Infections ABSTRACT The central theme of our lab revolves around small molecules. We contribute to developing new methods and strategies to access small molecules of biological and medicinal relevance and using them as tools to probe biological questions or human diseases. This proposal outlines our ongoing efforts and future directions of two seemingly disparate programs that we envision merging into a ligand-discovery platform using 19F NMR. One of our research program's focus areas is on fluorinated alkenes with a fascinating chemical reactivity portfolio primarily due to the polarity inversion feature. We are investigating the polarity inversion property of fluorinated alkenes, which we recognize will solve the long-standing problem of regioselectivity in fluorinated heterocyclic compounds. Our work demonstrated the applicability of FAs in generating regioselective access to nitrogen- containing fluorinated heterocycles. The other research area is focused on seeking new chemical tools and innovative strategies to address the evolution of antibiotic-resistance strains that have impeded antibiotic treatment and rendered them ineffective, costing heavily on the healthcare industry. We are currently probing the MraY enzyme, a key component of cell wall synthesis, using conventional structure-based rational design strategy and unconventional discovery platforms of targeted protein degradation and 19F NMR-based ligand screening. An R35 MIRA award would help accomplish our goals and enable the merger of our two research themes. Successful completion of these studies will allow us to contribute broadly in gaining insights into the function, structure, and mechanism of inhibition of antibacterial targets using fluorinated probes, small-molecule degraders, and a 19F NMR-based screening platform. These studies will lead to antibacterials with new chemical entities with novel mechanism of action that are urgently needed to replenish our arsenal of new and existing antibiotics. An R35 MIRA award would also foster our existing and new collaborations within the university, across the United States, and internationally. This research program will help the participating graduate, and undergraduate students and postdoctoral scholars enhance and learn new skills in interdisciplinary sciences while working in a highly collaborative and multidisciplinary environment.