通过质谱法对 RLMs 中潜在拓扑异构酶抑制剂“吡唑啉”进行体外代谢谱研究。
In-vitro metabolic profiling study of potential topoisomerase inhibitors 'pyrazolines' in RLMs by mass spectrometry.
机构信息
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
出版信息
J Chromatogr B Analyt Technol Biomed Life Sci. 2019 May 1;1114-1115:125-133. doi: 10.1016/j.jchromb.2019.03.026. Epub 2019 Mar 23.
Taking into consideration of the cytotoxicity and topo-IIα inhibitory activity of pyrazoline derivatives (1-3) against HCT15 cells, and known topo-IIα inhibitor, etoposide, respectively, the compounds were biotransformed in rat liver microsomes. LC-MS/MS and MALDI mass spectrometric techniques has been used for analysis. All three compounds were biotransformed into demethylated metabolites. Among three compounds, compounds 1 and 2 were biotransformed into mono-hydroxylated metabolites and compound 3 biotransformed into reduced and epoxidized metabolites. Reduced and reduced along with demethylation metabolites were identified from MALDI Orbitrap spectrometric analysis. Without NADPH or microsomes no compounds (1-3) were generated metabolites, it shows CYP450 enzymes involvement in the presence of NADPH in the metabolisms.
考虑到吡唑啉衍生物 (1-3) 对 HCT15 细胞的细胞毒性和拓扑异构酶 IIα 抑制活性，以及已知的拓扑异构酶 IIα 抑制剂依托泊苷，分别在大鼠肝微粒体中对这些化合物进行了生物转化。采用 LC-MS/MS 和 MALDI 质谱技术进行分析。这三种化合物都被生物转化为去甲基代谢物。在这三种化合物中，化合物 1 和 2 被生物转化为单羟基化代谢物，而化合物 3 被生物转化为还原和环氧化代谢物。通过 MALDI Orbitrap 光谱分析鉴定了还原和还原与去甲基化代谢物。没有 NADPH 或微粒体，化合物 (1-3) 不会生成代谢物，这表明 CYP450 酶在 NADPH 存在下参与了代谢。
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