Laboratory of Organic Chemistry, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
TI-COAST, Science Park 904, 1098 XH, Amsterdam, The Netherlands.
J Am Soc Mass Spectrom. 2019 Apr;30(4):639-646. doi: 10.1007/s13361-018-2120-x. Epub 2019 Jan 7.
In drug discovery, it is important to identify phase I metabolic modifications as early as possible to screen for inactivation of drugs and/or activation of prodrugs. As the major class of reactions in phase I metabolism is oxidation reactions, oxidation of drugs with TiO photocatalysis can be used as a simple non-biological method to initially eliminate (pro)drug candidates with an undesired phase I oxidation metabolism. Analysis of reaction products is commonly achieved with mass spectrometry coupled to chromatography. However, sample throughput can be substantially increased by eliminating pretreatment steps and exploiting the potential of ambient ionization mass spectrometry (MS). Furthermore, online monitoring of reactions in a time-resolved way would identify sequential modification steps. Here, we introduce a novel (time-resolved) TiO-photocatalysis laser ablation electrospray ionization (LAESI) MS method for the analysis of drug candidates. This method was proven to be compatible with both TiO-coated glass slides as well as solutions containing suspended TiO nanoparticles, and the results were in excellent agreement with studies on biological oxidation of verapamil, buspirone, testosterone, andarine, and ostarine. Finally, a time-resolved LAESI MS setup was developed and initial results for verapamil showed excellent analytical stability for online photocatalyzed oxidation reactions within the set-up up to at least 1 h. Graphical Abstract.
在药物发现中，尽早识别 I 期代谢修饰以筛选药物失活和/或前药激活非常重要。由于 I 期代谢中的主要反应类别为氧化反应，因此可以使用 TiO 光催化氧化来作为一种简单的非生物方法，初步消除具有不良 I 期氧化代谢的（前）药物候选物。通常采用与色谱法联用的质谱法来分析反应产物。但是，可以通过消除预处理步骤并利用环境离子化质谱（MS）的潜力来大大提高样品通量。此外，以时间分辨的方式在线监测反应可以识别连续的修饰步骤。在这里，我们引入了一种新的（时间分辨）TiO 光催化激光烧蚀电喷雾电离（LAESI）MS 方法来分析药物候选物。该方法被证明与涂有 TiO 的载玻片以及含有悬浮 TiO 纳米颗粒的溶液兼容，并且结果与维拉帕米、丁螺环酮、睾丸酮、奥氮平和奥沙利文的生物氧化研究非常吻合。最后，开发了一个时间分辨的 LAESI MS 装置，并对维拉帕米进行了初步研究，结果表明该装置在线光催化氧化反应中的分析稳定性良好，在该装置中至少可以稳定 1 小时。
