Przybylski M, Cysyk R L, Shoemaker D, Adamson R H
Biomed Mass Spectrom. 1981 Oct;8(10):485-91. doi: 10.1002/bms.1200081004.
Conjugation and cleavage products in the thiolytic metabolism of the anticancer drug 4'-(9-acridinylamino)methanesulfon-m-anisidide were identified primarily by high-pressure liquid chromatography in combination with field desorption mass spectrometry. The spontaneous metabolic pathway of the drug, as related to its susceptibility to nucleophilic attack by endogenous thiols at the 9-carbon atom of the acridine moiety, has been studied. Among the metabolite fraction of 4'-(9-acridinylamino)methanesulfon-m-anisidide excreted in rat bile after administration of a therapeutic dose, a conjugate was identified as the 9-acridinyl thioether of glutathione. This conjugation product and the corresponding 9-acridinyl conjugates were formed spontaneously after incubation of 4'-(9-acridinylamino)methanesulfon-m-anisidide with glutathione, cysteine and N-acetylcysteine in sodium phosphate buffer and other aqueous media, as established by high-pressure liquid chromatography and field desorption mass spectra. The thiolytic pathway results in the release 4-amino-3-methoxymethanesulfonanilide which was identified in all in vitro experiments and in rat serum after intravenous 4'-(9-acridinylamino)methanesulfon-m-anisidide. 9(10H)-Acridone, 9-aminoacridine and other acridine derivatives which occur as minor products during the thiolytic cleavage in vitro were identified by field desorption and partially by high resolution electron impact mass spectrometry.
主要通过高压液相色谱结合场解吸质谱法，对抗癌药物4'-（9-吖啶基氨基）甲磺酰间茴香胺硫解代谢中的共轭物和裂解产物进行了鉴定。研究了该药物的自发代谢途径，该途径与其在吖啶部分的9-碳原子上受到内源性硫醇亲核攻击的敏感性有关。在给予治疗剂量后，大鼠胆汁中排泄的4'-（9-吖啶基氨基）甲磺酰间茴香胺代谢物部分中，一种共轭物被鉴定为谷胱甘肽的9-吖啶基硫醚。通过高压液相色谱和场解吸质谱确定，在磷酸钠缓冲液和其他水性介质中，4'-（9-吖啶基氨基）甲磺酰间茴香胺与谷胱甘肽、半胱氨酸和N-乙酰半胱氨酸孵育后，会自发形成这种共轭产物和相应的9-吖啶基共轭物。硫解途径会释放出4-氨基-3-甲氧基甲磺酰苯胺，在所有体外实验以及静脉注射4'-（9-吖啶基氨基）甲磺酰间茴香胺后的大鼠血清中都鉴定出了该物质。通过场解吸以及部分通过高分辨率电子轰击质谱法，鉴定出了9(10H)-吖啶酮、9-氨基吖啶以及其他在体外硫解裂解过程中作为次要产物出现的吖啶衍生物。
