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Field desorption mass spectrometric characterization of thiol conjugates related to the oxidative metabolism of the anticancer drug 4′‐(9‐acridinylamino)‐methanesulfon‐ m ‐anisidide
Author(s) -
Gaudich K.,
Przybylski M.
Publication year - 1983
Publication title -
biomedical mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 121
eISSN - 1096-9888
pISSN - 0306-042X
DOI - 10.1002/bms.1200100412
Subject(s) - chemistry , thioether , glutathione , cysteamine , moiety , acridine , aniline , thiol , stereochemistry , medicinal chemistry , organic chemistry , enzyme
Conjugation products with glutathione (GSH) and other endogenous thiol derivatives related to the oxidative metabolism of the anticancer drug, 4′‐(9‐acridinlyamino) methanesulfon‐ m ‐anisidide ( m ‐AMSA) were synthesized and characterized by field desorption mass spectrometry. The primary microsomal oxidation product of m ‐AMSA, m ‐AQDI, was prepared by MnO 2 oxidation of the parent drug and reacted with equimolar GSH, cysteine, N ‐acetylcysteine and N ‐acetylcysteine methyl ester to form m ‐AMSA‐(5′)‐thiol conjugates linkedat the aniline ring, as major products. Field desorption mass spectra of the conjugates provided abundant [MH] plus; ions, and characteristic fragment ions by cleavage at the thioether bonds and at the γ‐Glu‐Cys linkage. The assignment of the 5′‐position of the thioether linkage at the aniline ring was ascertained by 1 H nuclear magnetic resonance spectra. However, the reaction of m ‐AQDI with increased molar amounts of thiol, and with cysteamine as a bifunctional nucleophile at equimolar amounts afforded the concurrent formation of conjugation products by nucleophilic displacement at the acridine moiety of m ‐AMSA. In the reaction with cysteamine, a ‘dimeric’ adduct of cysteamine linked to both the aniline and the acridine of cysteamine linked to both the aniline and the acridine moiety of moiety of m ‐AMSA was separated as a major product by thin‐layer chromatography and identified by field desorption mass spectrometry. m ‐AMSA‐GSH, a major biliary metabolite of m ‐AMSA in the rat undergoes with excess GSH in aqueous solution a thiolytic cleavage to yield S ‐(9‐acridinyl)‐GSH (ACR‐GSH) and S [(4‐amino‐3‐methoxymethanesulfonanilide‐5‐yl]‐GSH (MSA‐GSH) as established by thin‐layer chromatography, reversephase high‐performance liquid chromatography and mass spectral analysis. These results suggest that the formation of m ‐AMSA‐thiol (aniline ring) v. thiolysis (acridine ring) conjugates may depend on the rate of enzymatic oxidation of m ‐AMSA and GSH levels in vivo , and may explain the different pattern of biliary metabolites found in previous studies.