New Directions for Redox-Active Ligands: Ratiometric Sensors for H2O2 with 19F and 1H MRI Outputs and Functional Mimics of Superoxide Dismutase with Non-Enzymatic Metals

氧化还原活性配体的新方向：具有 19F 和 1H MRI 输出的 H2O2 比例传感器以及具有非酶金属的超氧化物歧化酶功能​​模拟物

• 批准号: 1954336
• 负责人: Christian Goldsmith
• 金额: $ 42万
• 依托单位: Auburn University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1954336&HistoricalAwards=false
• 关键词: New; Directions; Redox; Active; Ligands

The overproduction of reactive oxygen species (ROS) has been linked to a wide array of health conditions, including many cardiovascular, neurological, and inflammatory disorders. Currently, it is difficult to assess the concentrations of ROS in vivo. The lack of reliable imaging techniques makes it difficult to understand the roles of ROS in the human body. A pattern of oxidative stress may be used to distinguish disorders that give rise to similar clinically observable symptoms, and the ability to detect ROS overproduction in vivo could potentially diagnose these conditions more quickly and accurately. In this project funded by the Chemical Structure, Dynamics, and Mechanisms-B Program of the Chemistry Division, Dr. Christian R. Goldsmith of Auburn University is developing small molecule sensors for the ROS hydrogen peroxide (H2O2) that gives rise to two distinct magnetic resonance imaging (MRI) signals before and after their reaction with H2O2. By comparing the signals, one may be able to directly assess the concentration of H2O2 in a particular region of the body. Dr. Goldsmith is also interested in observing how antioxidants interact with ROS. Dr. Goldsmith is also engaged in outreach activities that heighten the involvement of undergraduate students in science, technology, engineering, and mathematics (STEM). These activities include giving research talks at local colleges and providing summer research internships in Dr. Goldsmith’s laboratory. These activities are designed to improve both undergraduate science education in the East Alabama area and the diversity of the future STEM workforce.Dr. Christian R. Goldsmith is developing new transition metal complexes that can detect and degrade reactive oxygen species (ROS). The research produces redox-responsive contrast agents for magnetic resonance imaging (MRI) and functional mimics of superoxide dismutase (SOD) enzymes. The new MRI contrast agents are iron complexes with fluorinated redox-active quinol-containing ligands. In their reduced Fe(II)-quinol forms, these give rise to weak H-1 and strong F-19 MRI signals. After oxidation by H2O2, the Fe(III)-para-quinone products display weak F-19 MRI but strong H-1 signals, with the enhancement in H-1 MRI deriving from the increased paramagnetism and higher aquation of the metal center. The contrast agents are therefore bimodal ratiometric sensors for H2O2. The superoxide dismutase (SOD) mimics consist of quinol-containing ligands coordinated to redox-inactive transition metal ions, specifically Zn(II) and Ga(III). These complexes use the quinol/para-quinone redox couple to alternatively reduce and oxidize superoxide and bypass the need for a potentially harmful redox-active transition metal ion. New quinol-containing ligands increase the catalytic activity by enabling superoxide to more readily access the metal center. Given the involvement of ROS in disease, these complexes may lead to improved diagnostic options for several health conditions. The project’s reliance on inorganic chemistry, organic chemistry, and biochemistry teach undergraduate and graduate students a broad array of skills. Dr. Goldsmith’s laboratory are also presenting research seminars at primarily undergraduate institutions in the East Alabama area and enable their students to participate in cutting-edge scientific research by providing two summer internships per year of the project.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

活性氧(ROS)的过量产生与一系列的健康状况有关，包括许多心血管、神经和炎症性疾病。目前，很难评估体内ROS的浓度。由于缺乏可靠的成像技术，很难理解ROS在人体中的作用。氧化应激的模式可能被用来区分引起类似临床可观察症状的疾病，而在体内检测ROS过量产生的能力可能会更快、更准确地诊断这些疾病。在这个由化学系化学结构、动力学和机制-B计划资助的项目中，奥本大学的Christian R.Goldsmith博士正在开发用于ROS过氧化氢(H2O2)的小分子传感器，这种传感器在它们与H2O2反应前后产生两个明显的磁共振成像(MRI)信号。通过比较信号，人们可能能够直接评估身体特定区域的过氧化氢浓度。戈德史密斯博士还对观察抗氧化剂如何与ROS相互作用感兴趣。戈德史密斯博士还从事外展活动，加强本科生对科学、技术、工程和数学(STEM)的参与。这些活动包括在当地大学进行研究讲座，以及在戈德史密斯博士的实验室提供暑期研究实习机会。这些活动旨在改善东阿拉巴马州地区的本科生科学教育和未来STEM劳动力的多样性。克里斯蒂安·R·戈德史密斯正在开发能够检测和降解活性氧物种(ROS)的新型过渡金属络合物。该研究生产用于磁共振成像(MRI)的氧化还原响应型造影剂和超氧化物歧化酶(SOD)的功能模拟物。新的MRI造影剂是带有氟化氧化还原活性喹酚配体的铁络合物。在还原的Fe(II)-Quinol形式中，这些会导致弱的H-1和强的F-19磁共振信号。经H_2O_2氧化后，Fe(III)-对苯二酚产物的F-19MRI较弱，而H-1信号较强，H-1MRI的增强源于金属中心的顺磁性增强和水合作用增强。因此，造影剂是过氧化氢的双峰比率传感器。超氧化物歧化酶(SOD)模拟物是由与氧化还原不活跃的过渡金属离子配位的含对苯二酚的配体组成的，特别是锌(II)和镓(III)。这些络合物使用对苯二酚/对苯二酚氧化还原偶合来交替还原和氧化超氧化物，并绕过了对潜在有害的氧化还原活性过渡金属离子的需要。新的含对苯二酚的配体使超氧化物更容易接近金属中心，从而提高了催化活性。鉴于ROS在疾病中的参与，这些复合体可能会改进对几种健康状况的诊断选择。该项目依赖于无机化学、有机化学和生物化学，向本科生和研究生传授广泛的技能。戈德史密斯博士的实验室还在东阿拉巴马州地区的主要本科生机构举办研究研讨会，通过每年提供两次暑期实习，使他们的学生能够参与尖端科学研究。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Recent advances in the preclinical development of responsive MRI contrast agents capable of detecting hydrogen peroxide

能够检测过氧化氢的响应性 MRI 造影剂临床前开发的最新进展

• DOI: 10.1016/j.jinorgbio.2022.111763
• 发表时间: 2022
• 期刊: Journal of Inorganic Biochemistry
• 影响因子: 3.9
• 作者: Karbalaei, Sana;Goldsmith, Christian R.
• 通讯作者: Goldsmith, Christian R.

Co(II) Complex with a Covalently Attached Pendent Quinol Selectively Reduces O 2 to H 2 O

带有共价连接的对苯二酚侧链的 Co(II) 络合物选择性地将 O 2 还原为 H 2 O

• DOI: 10.1021/jacs.2c08315
• 发表时间: 2022
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Obisesan, Segun V.;Rose, Cayla;Farnum, Byron H.;Goldsmith, Christian R.
• 通讯作者: Goldsmith, Christian R.

Diquinol Functionality Boosts the Superoxide Dismutase Mimicry of a Zn(II) Complex with a Redox-Active Ligand while Maintaining Catalyst Stability and Enhanced Activity in Phosphate Solution

二喹啉功能可增强具有氧化还原活性配体的 Zn(II) 络合物的超氧化物歧化酶模拟，同时保持催化剂稳定性并增强磷酸盐溶液中的活性

• DOI: 10.1021/acs.inorgchem.2c03256
• 发表时间: 2022
• 期刊: Inorganic Chemistry
• 影响因子: 4.6
• 作者: Moore, Jamonica L.;Oppelt, Julian;Senft, Laura;Franke, Alicja;Scheitler, Andreas;Dukes, Meghan W.;Alix, Haley B.;Saunders, Alexander C.;Karbalaei, Sana;Schwartz, Dean D.
• 通讯作者: Schwartz, Dean D.