GOALI: Developing New Hydrogen Isotope Exchange Strategies for Isotope Labelling of Pharmaceuticals

在化学系化学催化和化学合成项目的支持下，韦恩州立大学的罗龙博士和默克公司的李景伟博士正在开发药物氢同位素标记的新方法。利用多相光催化和电化学，罗团队寻求建立改进的化学方法，用多个氢同位素原子或在特定位置选择性标记药物及其前体。在多个位置掺入氢同位素将改善临床前和临床研究中检测和定量药物和药物代谢物的诊断信号。此外，位置选择性标记将为合成含氘药物提供新的工具。这一大学/行业综合研究计划将为研究生和本科生提供独特的学习和培训经验，为多学科和跨学科研究成为常态的未来做好准备。在这一目标奖下，韦恩州立大学的罗龙博士和默克公司的李景伟博士将从事合成方法学研究，寻求药品氢同位素标记的新方法。该团队将专注于：(1)开发多相光催化剂，以实现相对于传统分子光催化剂更多的氢同位素交换中心，利用其独特的催化剂-底物界面(例如，使用金属硫化物量子点光催化剂同时激活苄基和α-胺中心)和(2)开发电化学方法，以实现具有类似化学反应活性的中心之间的氢同位素交换中心的选择性，例如α-氨基C-H键，利用电化学提供的时间分辨的氧化还原环境来控制不同中心的反应动力学。该团队将致力于回答以下重要的科学问题：(1)如何在氢同位素交换反应中通过异相光催化剂-底物界面实现高效的氢原子转移？(2)如何通过调节电化学氧化还原环境来控制氢同位素交换反应的反应路径？该项目的影响将不仅限于药物的氢同位素标记领域，还可能为光催化和电化学反应的一般反应路径控制提供新的策略。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。

With the support of the Chemical Catalysis and Chemical Synthesis programs in the Division of Chemistry, Dr. Long Luo of Wayne State University and Dr. Jingwei Li of Merck & Co are developing new methods for hydrogen isotope labeling of pharmaceuticals. With the use of heterogeneous photocatalysis and electrochemistry, the Luo team seeks to establish improved chemical methods for labeling pharmaceuticals and their precursors with either multiple hydrogen isotope atoms or selective labeling at specific sites. Hydrogen isotope incorporation at multiple sites will improve the diagnostic signals for detecting and quantifying drugs and drug metabolites in preclinical and clinical studies. In addition, the site-selective labeling will provide new tools for synthesizing drugs containing deuterium. This integrated university/industry research program will provide unique learning and training experience for graduate and undergraduate students, preparing this “next generation workforce” for a future in which multi- and inter-disciplinary research is the norm.Under this GOALI award, Dr. Long Luo of Wayne State University and Dr. Jingwei Li of Merck & Co will engage in synthetic methodology research toward new approaches to hydrogen isotope labeling of pharmaceuticals. The team will focus on: (1) developing heterogeneous photocatalysts to enable additional hydrogen isotope exchange sites relative to the conventional molecular photocatalysts utilizing their unique catalyst-substrate interface (For example, efforts to simultaneously activate benzylic and α-amine sites using metal chalcogenide quantum dot photocatalysts) and (2) developing electrochemical methods to achieve the hydrogen isotope exchange site selectivity among sites with similar chemical reactivity such as α-amino C-H bonds, utilizing the time-resolved redox environment provided by electrochemistry to control the reaction kinetics at different sites. The team will work to answer the following important scientific questions: (1) how can one achieve efficient hydrogen atom transfer via the heterogenous photocatalyst-substrate interface during a hydrogen isotope exchange reaction? (2) how can one control the reaction pathways of hydrogen isotope exchange reactions by tuning the electrochemical redox environment? The impact of this project will not be limited to the field of hydrogen isotope labeling of pharmaceuticals but will likely also provide new strategies for controlling reaction pathways in general for photocatalytic and electrochemical reactions.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.