Carbon Dioxide Activation Center (CADIAC), Novo Nordisk Foundation CO2 Research Center, Interdisciplinary Nanoscience Center, Department of Chemistry, Aarhus University, Gustav Wieds Vej 14, Aarhus C, Denmark.
Early Chemical Development, Pharmaceutical Sciences R&D AstraZeneca, Gothenburg, Sweden.
Nat Commun. 2024 Mar 22;15(1):2592. doi: 10.1038/s41467-024-46820-9.
Carbon isotope labelling of bioactive molecules is essential for accessing the pharmacokinetic and pharmacodynamic properties of new drug entities. Aryl carboxylic acids represent an important class of structural motifs ubiquitous in pharmaceutically active molecules and are ideal targets for the installation of a radioactive tag employing isotopically labelled CO. However, direct isotope incorporation via the reported catalytic reductive carboxylation (CRC) of aryl electrophiles relies on excess CO, which is incompatible with carbon-14 isotope incorporation. Furthermore, the application of some CRC reactions for late-stage carboxylation is limited because of the low tolerance of molecular complexity by the catalysts. Herein, we report the development of a practical and affordable Pd-catalysed electrocarboxylation setup. This approach enables the use of near-stoichiometric CO generated from the primary carbon-14 source BaCO, facilitating late-stage and single-step carbon-14 labelling of pharmaceuticals and representative precursors. The proposed isotope-labelling protocol holds significant promise for immediate impact on drug development programmes.
生物活性分子的碳同位素标记对于了解新药实体的药代动力学和药效动力学特性至关重要。芳基羧酸代表了一类在药物活性分子中普遍存在的重要结构基序，是用同位素标记的 CO 安装放射性标记的理想目标。然而，通过报道的芳基亲电试剂的催化还原羧化（CRC）进行直接同位素掺入依赖于过量的 CO，这与碳-14 同位素掺入不兼容。此外，由于催化剂对分子复杂性的低容忍度，一些 CRC 反应在后期的羧化应用受到限制。在此，我们报告了一种实用且经济实惠的 Pd 催化电羧化装置的开发。这种方法可以使用来自主要碳-14 源 BaCO 的近乎化学计量的 CO，促进药物和代表性前体的后期和单步碳-14 标记。所提出的同位素标记方案有望对药物开发计划产生直接影响。
