THIOPHENE SULFOXIDES AS REACTIVE METABOLITES - FORMATION UPON MICROSOMAL OXIDATION OF A 3-AROYLTHIOPHENE AND FATE IN THE PRESENCE OF NUCLEOPHILES IN-VITRO AND IN-VIVO

Oxidative metabolism of a 3-aroylthiophene, 1, by rat liver microsomes in the presence of mercaptoethanol as a trapping agent led to the iso lation of four main compounds, 2-5, which have been isolated and chara cterized by UV, H-1 NMR, and mass spectroscopy. They all derive from t wo primary metabolites, 2 and 3, which result from the nucleophilic ad dition of mercaptoethanol to a reactive, very electrophilic intermedia te formed by sulfoxidation of the thiophene ring of 1. Further reactio ns of diastereoisomers 2 and 3 with mercaptoethanol led to compound 4 that is opened at the level of its thiophene ring and, eventually, to a final metabolite 5 resulting formally from the addition of mercaptoe thanol on the 4,5-double bond of the thiophene ring of 1. Compound 5 i s very stable even in the presence of a 1 of mercaptoethanol. Similar reactions were observed upon microsomal oxidation of 1 in the presence of another thiol, N-acetylcysteine. Final metabolites 8a and 8b equiv alent to 5 except for the replacement of its mercaptoethanol substitue nt with an N-acetylcysteinyl group were isolated and characterized by UV, H-1 NMR, and mass spectroscopy. Interestingly, after treatment of rats with 1, metabolites 8a and 8b could be detected in urine, indicat ing that the successive reactions, that were observed in, vitro after microsomal oxidation of 1 in the presence of a thiol-containing trappi ng agent, also occur in vivo, glutathione acting as a nucleophile in e lectrophilic thiophene sulfoxide in metabolic sulfoxides, whose chemis try is poorly known, and on their fates in living organisms.