加拿大麦吉尔大学Arndtsen, Bruce A.团队报道了羧酸碳同位素标记的金属催化官能团复分解方法。相关研究成果发表在2024年2月19日出版的国际知名学术期刊《自然—化学》。

分子在体内的分布、代谢和最终命运是药物活性的核心。然而，将放射性同位素引入药物代谢稳定的碳位点以探测这些特征通常需要有毒的放射性气体，如[¹⁴C]CO和[¹⁴C]CO₂。

该文中，研究人员描述了一种通过金属催化的官能团交换反应直接碳标记含羧酸的药物的方法，在没有放射性气体的情况下，使用易于获得和处理的羧酸¹⁴C源，在一锅中形成¹⁴C标记的含羧酸的药品。为了实现这一过程，利用镍催化剂可逆激活碳-氯键和有机分子之间交换官能团的能力，开发了酰氯官能团中碳-碳共价键的官能团复分解方法。

药物开发的适用性通过将¹⁴C标记物或¹³C标记物直接掺入复杂的芳基、烷基、乙烯基和杂环羧酸药物或候选药物的阵列中来说明，无需气体或特殊设备，在环境条件下且不损失放射性标记物。

附：英文原文

Title: A metal-catalysed functional group metathesis approach to the carbon isotope labelling of carboxylic acids

Author: Kinney, R. Garrison, Zgheib, Jos, Lagueux-Tremblay, Pierre-Louis, Zhou, Cuihan, Yang, Haifeng, Li, Jingwei, Gauthier, Donald R., Arndtsen, Bruce A.

Issue&Volume: 2024-02-19

Abstract: The distribution, metabolism and ultimate fate of molecules within the body is central to the activity of pharmaceuticals. However, the introduction of radioisotopes into the metabolically stable carbon sites on drugs to probe these features typically requires toxic, radioactive gases such as [14C]CO and [14C]CO2. Here we describe an approach to directly carbon-label carboxylic-acid-containing pharmaceuticals via a metal-catalysed functional group exchange reaction, forming 14C-labelled carboxylic-acid-containing drugs without radioactive gases, in one pot, using an easily available and handled carboxylic acid 14C source. To enable this process, a functional group metathesis of carbon–carbon covalent bonds in acid chloride functionalities is developed, exploiting the ability of nickel catalysts to both reversibly activate carbon–chloride bonds and exchange functionalities between organic molecules. The drug development applicability is illustrated by the direct incorporation of the 14C label or 13C label into an array of complex aryl, alkyl, vinyl and heterocyclic carboxylic acid drugs or drug candidates without gases or a special apparatus, at ambient conditions and without loss of the radiolabel.

DOI: 10.1038/s41557-024-01447-7

Source: https://www.nature.com/articles/s41557-024-01447-7