Miller Kiara T, Mruthunjaya Ashwin K V, Torriero Angel A J
School of Life and Environmental Sciences, Faculty of Science Engineering & Built Environment, Deakin University, Burwood, VIC 3125, Australia.
Molecules. 2025 Feb 25;30(5):1050. doi: 10.3390/molecules30051050.
This study investigates the electrochemical oxidation mechanisms of chlorpromazine (CPZ), revealing a novel three-electron oxidation pathway that challenges the traditionally accepted two-electron paradigm, offering new insights into CPZ oxidation pathways. Using an integrated approach combining cyclic voltammetry, bulk electrolysis, UV-Vis, FT-IR, H-NMR spectroscopy, and LC-MS/MS analysis, we demonstrate that CPZ undergoes sequential oxidation processes involving both the phenothiazine core and the tertiary amine-containing side chain. Our results highlight the critical role of side-chain oxidation in forming nor-CPZ sulfoxide, an often-overlooked metabolite, which may influence CPZ's metabolic and pharmacological behaviour. Spectroelectrochemical data reveal stable intermediate species, providing insight into the structural rearrangements accompanying oxidation. This work offers a detailed mechanistic understanding of CPZ redox behaviour, contributing to improved interpretations of its pharmacological and metabolic properties.
本研究探究了氯丙嗪（CPZ）的电化学氧化机制，揭示了一种新的三电子氧化途径，这对传统上公认的双电子模式提出了挑战，为CPZ氧化途径提供了新的见解。通过结合循环伏安法、批量电解、紫外可见光谱、傅里叶变换红外光谱、氢核磁共振光谱和液相色谱-串联质谱分析的综合方法，我们证明CPZ经历了涉及吩噻嗪核心和含叔胺侧链的连续氧化过程。我们的结果突出了侧链氧化在形成去甲氯丙嗪亚砜（一种常被忽视的代谢物）中的关键作用，这可能会影响CPZ的代谢和药理行为。光谱电化学数据揭示了稳定的中间物种，为伴随氧化的结构重排提供了见解。这项工作提供了对CPZ氧化还原行为的详细机理理解，有助于更好地解释其药理和代谢特性。
