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.

项目摘要/摘要 手性药物和放射性标记的化合物是两种一般性的高度受欢迎的分子 检测，治疗和预防疾病。大多数复合物中都存在手性化合物 生物活性药物。另一方面，放射性标记的化合物被广泛用作正电子的成像剂 排放断层扫描（PET）。尽管最近在合成有机化学方面取得了许多进步，但 与过渡金属（TM）催化一样，将官能团纳入构建立体中心 和/或以安全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方法的新方法的机会。电气合成 已经在有机合成中显示了应用；但是，它遭受了实现产品选择性的痛苦，并且缺乏 构建立体中心的能力。 该项目的总体目标是整合电化学和过渡金属催化以提供 关于有机合成挑战的解决方案，特别是在手性和放射标记药物的组装中。 这项赠款是建立在Minteer Lab（电催化，电分析）和 Sigman Lab（不对称催化，数据科学）在开发的电活性化合物中 电池和合成应用。我的专业知识的整合（有机化学，过渡金属催化， 和有机金属化的化学）用薄荷和西格曼（Sigman）带来集体能力来完成 总体目标。该应用的中心假设是通过使用电化学， 无毒的TM可以用作电催化剂，以选择性安装通常是的功能组/原子 在产生立体中心的同时，用作宠物示踪剂的放射性元素。具体来说，我们将 1）开发钴电催化不对称反应，将有机果仁转化为手性羧酸， 硝酸盐和氟化化合物。这种电催化方法也将使我们发现新的 在医疗应用中有价值的反应。通过催化剂设计和电分析，我们将 开发（AIM 2）能够激活和功能化惰性酰胺键的TM - 电催化剂（大多数 代表有机和生物分子中的极性键）。这将在 含酰胺的海洋产品和多肽。用于PET成像的放射性药物需要快速 由于其短寿命的放射性（T1/2 = 20.4和110分钟）的准备和分娩，11C和110分钟 分别为18F放射性核素）。我们将第一次使用电化学的战略合并和 TM催化提供了一种新的合成方法来提供手性放射性药物（AIM 3）。这 AIM 1和2中的转换是根据其高潜力适应其的高潜力的仔细选择的 放射性药物的组装。总体而言，该项目将提供独特的有机转型 直接影响了复杂的药物发现过程。