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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.

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 MnO2 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 1H 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.