Strategies towards the Synthesis of Azetidine-Containing Metabolites Produced by Pseudomonas aeruginosa

铜绿假单胞菌产生的含氮杂环丁烷代谢物的合成策略

基本信息

批准号：
10679580
负责人：
Stanna Dorn
金额：
$ 6.87万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679580
关键词：
Address Affect Alcohols Alkenes Behavior Biochemical Pathway Biological Biological Process Biomimetics Carbamates Chemicals Chemistry Complex Creativeness Cyclization Development Future Geometry Glycine Goals Health Human Ions Literature Methodology Methods Microbial Biofilms Mission Modernization Natural Products Organic Chemistry Organometallic Chemistry Oxidation-Reduction Pathway interactions Periodicity Physical condensation Pigments Production Pseudomonas aeruginosa Pseudomonas aeruginosa infection Pyridones Reaction Research Risk Role Route System Training Translating United States National Institutes of Health Variant Virulence adverse outcome azetidine bioactive natural products career chemical synthesis cystic fibrosis patients design interest member novel novel strategies oxidation pathogenic bacteria peptide synthase professor quorum sensing risk mitigation scaffold success

项目摘要

Project Summary/Abstract Total syntheses of novel azetidine-containing metabolites (azetidomonamide A, azetidopyridone, and diazetidomonapyridone) from Pseudomonas aeruginosa do not exist, and are sorely needed so their biological functions in quorum-sensing behavior can be evaluated. In particular, the exact mode of their production from the non-ribosomal peptide synthetase (NRPS) enzymatic cluster is unknown; furthermore, elucidating the exact role of these metabolites in modulating quorum-sensing behavior in P. aeruginosa is not currently possible due to the minute quantities of metabolites produced in the natural bacterial system. Additionally, these metabolites affect overall bacterial biofilm formation and the production of redox-active metabolites, which are partially implicated in adverse outcomes for cystic fibrosis patients infected with P. aeruginosa. Thus, total syntheses of these metabolites are highly needed and will have a broader impact on human health through expanding our understanding of biofilm formation by P. aeruginosa, and potentially allowing for development of anti-virulence treatments for it in the long term. The studies described in this proposal seek to develop strategies for synthesis of these novel azetidine- containing metabolites. Importantly, we propose orthogonal approaches that mitigate the risk of the overall goal while still pushing chemical boundaries by leveraging modern chemistry in complex contexts. For the synthesis of azetidomonamide A (Aim1), our design involves accessing and employing a unique ynamide cascade to cyclize the system; a second approach utilizes enzymatic biocatalysis to install the alcohol stereocenter. For the synthesis of diazetidomonapyridone (Aim 2), we first propose strategies for accessing the azetidopyridone precursor. The initial approach would build on existing chemistry by utilizing a Pd-catalyzed cascade cyclization with CO in a complex setting; an alternative approach alleviates the risk of the former approach by employing condensation reactivity to install the requisite cyclic system. To access diazetidomonapyridone from the azetidopyridone, we envision two approaches. The first employs a biomimetic reflection of literature precedent by directly subjecting azetidopyridone to azetidomonamide A, which undergo spontaneous reaction under basic conditions to access the target metabolite. Additionally, we propose accessing diazetidomonapyridone via a bio-inspired approach that leverages ring formation to control alkene geometry. Overall, the proposed research is significant because it provides creative strategies to establish the first total syntheses of azetidomonamide A, azetidopyridone, which will enable their biological study. More broadly, these strategies can be used to access similar scaffolds in other bacterial metabolites that have yet to be synthesized. Performing this research in Prof. Reisman’s group at Caltech aligns well with their current success in the efficient total synthesis of complex natural products and will augment my prior training in organometallic chemistry to prepare me for a future academic career as a professor.

项目概要/摘要新型含氮杂环丁烷代谢物（氮杂环丁酰胺 A、氮杂环吡啶酮和铜绿假单胞菌中的二氮杂莫纳吡啶酮（diazetidomonapyridone）并不存在，而且是迫切需要的，因此它们的生物可以评估群体感知行为中的功能，特别是其产生的确切模式。非核糖体肽合成酶（NRPS）酶簇尚不清楚，进一步阐明了确切的原因；这些代谢物在调节铜绿假单胞菌群体感应行为中的作用目前尚不可能，因为天然细菌系统中产生的微量代谢物。影响整体细菌生物膜的形成和氧化还原活性代谢物的产生，这些代谢物部分地涉及铜绿假单胞菌感染的囊性纤维化患者的不良后果。这些代谢物是非常需要的，并将通过扩大我们的研究范围对人类健康产生更广泛的影响了解铜绿假单胞菌生物膜的形成，并有可能促进抗毒力的发展对其进行长期治疗。该提案中描述的研究旨在开发合成这些新型氮杂环丁烷的策略重要的是，我们提出了减轻总体目标风险的正交方法。同时在复杂的环境中利用现代化学来突破化学界限。氮杂单酰胺 A (Aim1) 的设计涉及访问和采用独特的 ynamide 级联环化系统；第二种方法利用酶生物催化来安装醇立体中心。对于二氮杂单吡啶酮的合成（目标 2），我们首先提出了获取最初的方法将利用钯催化的现有化学方法。在复杂环境中与 CO 进行级联环化；另一种方法可以减轻前者的风险通过利用缩合反应性来安装必要的循环系统的方法。我们设想了两种方法：第一种方法采用仿生方法。文献先例的反映，将氮杂吡啶酮直接与氮杂单酰胺 A 反应，经过此外，我们建议在基本条件下发生自发反应来获取目标代谢物。二氮杂莫吡啶酮通过生物启发的方法，利用环的形成来控制烯烃的几何形状。总体而言，拟议的研究意义重大，因为它提供了建立第一个氮杂单酰胺 A、氮杂吡啶酮的全合成，这将使他们能够进行更广泛的生物学研究。这些策略可用于获取其他尚未被研究的细菌代谢物中的类似支架。加州理工学院 Reisman 教授小组进行的这项研究与他们目前的成功非常吻合。复杂天然产物的高效全合成，并将增强我之前在有机金属方面的培训化学为我未来作为教授的学术生涯做好准备。