Electrocatalysis for the synthesis of chiral and PET imaging pharmaceuticals

电催化合成手性和 PET 成像药物

• 批准号: 10661909
• 负责人: Christian Malapit
• 金额: $ 24.9万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661909
• 关键词: Alkenes; Amides; Amines; Amino Acids; Carbon Dioxide; Carboxylic Acids; Catalysis; Cathodes; Cell Nucleus; Chemicals; Cobalt; Collaborations; Complex; Coupling; Data Science; Detection; Development; Electricity; Electrochemistry; Electrodes; Electrolyses; Electrolytes; Electrons; Excision; Goals; Grant; Label; Ligands; Medical; Mentors; Methods; Modification; Nitriles; Optics; Organic Chemistry; Organic Synthesis; Organometallic Chemistry; Oxidants; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiologic pulse; Positron-Emission Tomography; Preparation; Process; Proline; Radioactive; Radioactive Elements; Radioactivity; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Reaction; Reaction Time; Reagent; Reducing Agents; Research; Series; Solid; System; Techniques; Temperature; Time; Tracer; Transition Elements; Work; base; bioimaging; carboxylation; catalyst; chemical reaction; chiral molecule; design; disorder prevention; drug discovery; functional group; imaging agent; improved; interdisciplinary approach; novel; novel strategies; peptide synthase; polypeptide; prevent; programs; toxic metal

Project Summary/Abstract Chiral drugs and radiolabelled compounds are two general classes of highly sought molecules for the detection, treatment, and prevention of disease. Chiral compounds are present in the majority of complex bioactive drugs. On the other hand, radiolabeled compounds are widely used as imaging agents for positron emission tomography (PET). Despite the many recent advancements in synthetic organic chemistry, such as in transition-metal (TM) catalysis, the incorporation of functional groups to construct stereogenic centers and/or install radioactive nuclei in a safe and sustainable method remains challenging. Thus, providing opportunities to develop novel approaches in organic synthesis relevant to drug discovery. Electrosyntheses have shown application in organic synthesis; however, it suffers from achieving product selectivity and lacks the ability to construct stereogenic centers. The overall goal of this project is to integrate electrochemistry and transition-metal catalysis to provide solutions on the challenges in organic synthesis particularly in the assembly of chiral and radiolabeled drugs. This grant builds on existing collaboration between the Minteer Lab (electrocatalysis, electroanalysis) and the Sigman Lab (asymmetric catalysis, data science) in the development of electroactive compounds for battery and synthesis applications. Integration of my expertise (organic chemistry, transition metal catalysis, and organometallic chemistry) with Minteer and Sigman will bring a collective capability to accomplish the overall goal. The central hypothesis of this application is that through the use of electrochemical energy, non-toxic TM can be used as electrocatalysts to selectively install functional groups/atoms that are often used as radioactive elements in PET tracers while generating a stereogenic center. Specifically, we will (Aim 1) develop cobalt electrocatalytic asymmetric reactions to convert organohalides into chiral carboxylic acids, nitriles, and fluorinated compounds. This electrocatalytic approach will also allow us to discover new reactions that are valuable in medical applications. Through catalyst design and electroanalysis, we will develop (Aim 2) TM-electrocatalysts capable of activating and functionalizing inert amide bonds (most represented polar bond in organic and biomolecules). This will provide a late-stage functionalization in amide-containing marine products and polypeptides. Radiopharmaceuticals for PET imaging require rapid preparation and delivery to patients due to their short-lived radioactivity (t1/2 = 20.4 and 110 min for 11C and 18F radionuclide, respectively). For the first time, we will use the strategic merger of electrochemistry and TM-catalysis to provide a new synthetic approach to deliver chiral radiopharmaceuticals (Aim 3). The transformations in Aims 1 and 2 were carefully chosen based on their high potential to be adapted for the assembly of radiopharmaceuticals. Overall, this project will deliver unique, organic transformations that will directly impact the complex process of drug discovery.

项目概要/摘要 手性药物和放射性标记化合物是两类备受追捧的分子 疾病的检测、治疗和预防。手性化合物存在于大多数配合物中 生物活性药物。另一方面，放射性标记化合物广泛用作正电子成像剂 发射断层扫描（PET）。尽管合成有机化学最近取得了许多进展，例如 如在过渡金属 (TM) 催化中，掺入官能团以构建立体中心 和/或以安全且可持续的方法安装放射性核仍然具有挑战性。因此，提供 开发与药物发现相关的有机合成新方法的机会。电合成 已在有机合成中显示出应用；然而，它在实现产品选择性方面存在问题，并且缺乏 构建立体中心的能力。 该项目的总体目标是将电化学和过渡金属催化结合起来，提供 有机合成挑战的解决方案，特别是手性和放射性标记药物的组装。 这笔赠款建立在 Minteer 实验室（电催化、电分析）和 西格曼实验室（不对称催化、数据科学）开发电活性化合物 电池和合成应用。整合我的专业知识（有机化学、过渡金属催化、 和有机金属化学）与 Minteer 和 Sigman 将带来集体能力来实现 总体目标。该应用的中心假设是通过使用电化学能量， 无毒的TM可以用作电催化剂来选择性地安装经常使用的官能团/原子 用作 PET 示踪剂中的放射性元素，同时产生立体中心。具体来说，我们将（目标 1）开发钴电催化不对称反应，将有机卤化物转化为手性羧酸， 腈类和氟化物。这种电催化方法也将使我们能够发现新的 在医学应用中有价值的反应。通过催化剂设计和电解分析，我们将 开发（目标 2）能够激活和功能化惰性酰胺键（大多数 代表有机和生物分子中的极性键）。这将提供后期功能化 含酰胺的海产品和多肽。用于 PET 成像的放射性药物需要快速 由于其放射性寿命短（t1/2 = 20.4，11C 为 110 分钟， 18F放射性核素，分别）。我们将首次采用电化学与电化学的战略合并 TM 催化提供一种新的合成方法来提供手性放射性药物（目标 3）。这 目标 1 和 2 中的转型是根据其适应的巨大潜力而​​精心选择的 放射性药物的组装。总体而言，该项目将带来独特的、有机的转变， 直接影响药物发现的复杂过程。