Small Molecule Pharmaceutical Sciences, Genentech Inc., South San Francisco, CA 94080, United States.
Small Molecule Pharmaceutical Sciences, Genentech Inc., South San Francisco, CA 94080, United States.
J Pharm Biomed Anal. 2022 Mar 20;211:114622. doi: 10.1016/j.jpba.2022.114622. Epub 2022 Jan 26.
In pharmaceutical development, structural elucidation of small molecules from process related impurities and degradation products is an essential component. As one of the most important methods in the toolbox, high resolution mass spectrometry (HRMS) and specifically tandem mass spectrometry (MS/MS) often provide fast and informative structural insights. However, many small molecule drugs containing certain biological relevant pharmacophores result in limited numbers of fragments when using traditional collision based fragmentation techniques, such as higher energy collisional dissociation (HCD), due to its inherent preference of cleaving the weakest bond first. As an alternative, ultraviolet photodissociation (UVPD), which irradiates the precursor ion with high energy photons, can lead to more extensive fragmentation from the readily UV absorbing small molecules. Here, we showcase the advantage of UVPD over HCD on pyrrolidine and piperidine containing molecules derivatized from a model compound, telmisartan. While HCD only yielded a single, highly abundant ion resulting from the pyrrolidine and pipieridine ring cleavage, UVPD generated rich and structurally informative fragment ions. UVPD is an attractive and powerful alternative for traditional fragmentation techniques for small molecule structural elucidation.
在药物研发中，从小分子的工艺相关杂质和降解产物中推断其结构是必不可少的。高分辨质谱（HRMS），特别是串联质谱（MS/MS）作为工具包中最重要的方法之一，通常可以快速提供有价值的结构信息。然而，许多含有某些生物相关药效团的小分子药物，由于其优先切割最弱键的固有特性，使用传统的基于碰撞的碎裂技术（如高能碰撞解离（HCD））时，得到的碎片数量有限。作为替代方法，紫外光解离（UVPD）用高能光子照射前体离子，可以导致更容易被紫外光吸收的小分子产生更广泛的碎裂。在这里，我们展示了在从模型化合物替米沙坦衍生的含吡咯烷和哌啶的分子中，UVPD 相对于 HCD 的优势。虽然 HCD 仅产生一个单一的、高度丰富的离子，是由吡咯烷和哌啶环断裂产生的，但 UVPD 产生了丰富且具有结构信息的碎片离子。对于小分子结构解析，UVPD 是一种有吸引力且强大的传统碎裂技术替代方法。
