Abstract：
We report a collision-induced dissociation (CID) based gas phase rearrangement study using quadrupole time-of-flight mass spectrometry coupled with liquid chromatography on a novel endothelin and angiotensin II receptor antagonist, sparsentan. We performed tandem mass spectrometry to identify precursor and fragment ion relationships and assigned structures for major fragment ions. We propose a benzyl migration mechanism based on bond length measurements in density functional theory (B3LYP/6-31+G*) optimized geometries of protonated sparsentan and its m/z 547 fragment. Protonated sparsentan undergoes loss of ethanol, which yields a resonance-stabilized benzylic cation with m/z 547, which further fragments into m/z 353 via benzyl migration, where the benzylic cation migrates to one of the nucleophilic nitrogen atoms followed by proton transfer from the sulfonamide nitrogen to a carbonyl oxygen, resulting in a neutral loss of mass 194. Further fragmentation of m/z 353 results in m/z 258, which undergoes radical and neutral loss to yield m/z 193 and 194, respectively. The proposed mechanism of generation of m/z 353 was confirmed by CID of deuterated sparsentan. Considering the importance of gas phase rearrangements of organic molecules in structural identifications as well as the novelty of the molecule, these findings will be helpful for future studies to predict gas phase benzyl migration in sparsentan analogs and for degradation product and metabolite identification of sparsentan and its analogs using LC-MS.
摘要：
我们报告了一种基于碰撞诱导解离（CID）的气相重排研究，该研究使用四极杆飞行时间质谱结合液相色谱对新型内皮素和血管紧张素II受体拮抗剂进行，Sparsentan.我们进行了串联质谱分析，以识别前体和碎片离子关系，并为主要碎片离子分配结构。我们提出了一种基于密度泛函理论（B3LYP/6-31G*）中的键长测量值的苄基迁移机制，优化了质子化sparsentan及其m/z547片段的几何形状。质子化的斯帕生坦经历了乙醇的损失，这产生共振稳定的苄基阳离子与m/z547，其进一步片段为m/z353通过苄基迁移，其中苄基阳离子迁移到亲核氮原子之一，然后质子转移从磺酰胺氮转移到羰基氧，导致质量194的中性损失。m/z353的进一步碎裂导致m/z258,其经历自由基和中性损失以分别产生m/z193和194。所提出的m/z353的产生机制已通过氘代斯波生坦的CID得到证实。考虑到有机分子气相重排在结构鉴定中的重要性以及分子的新颖性，这些发现将有助于未来的研究，以预测sparsentan类似物中的气相苄基迁移，以及使用LC-MS鉴定sparsentan及其类似物的降解产物和代谢物。
