CHEMICAL AND BIOLOGICAL OXIDATION OF THIOPHENE - PREPARATION AND COMPLETE CHARACTERIZATION OF THIOPHENE S-OXIDE DIMERS AND EVIDENCE FOR THIOPHENE S-OXIDE AS AN INTERMEDIATE IN THIOPHENE METABOLISM IN-VIVO AND IN-VITRO

Direct evidence for the involvement of thiophene S-oxide as a key prim ary reactive intermediate in the metabolism of thiophene (1) in rats w as obtained from the isolation of two diastereoisomeric thiophene S-ox ide dimers, 4a and 4b, both in vitro (oxidation of thiophene with rat liver microsomes) and in vivo (isolation of 4a from rat urine). The st ructure of these dimers was established after an original preparation of identical samples by oxidation of thiophene with H2O2 and CF3COOH. In fact, the H2O2/CF3COOH system appeared to be the best oxidizing age nt for the selective transformation of thiophene to its S-oxide. The c omplete determination of the structures of 4a and 4b was carried out f or the first time by X-ray diffraction for the former and by a sequenc e of chemical reactions for the latter. The reported results indicate two fates for thiophene S-oxide in vivo: (i) its dimerization via a Di els-Alder reaction and (ii) its reaction with nucleophiles such as glu tathione leading eventually to mercapturates. These results together w ith recent literature data on thiophene derivatives suggest that thiop hene S-oxides, a class of reactive intermediates whose chemistry is st ill not well-known, could play a central role in the metabolism and to xic effects of thiophenes in mammals. This situation would be differen t from that observed in the metabolism of other aromatic compounds, su ch as benzene or furan, in which arene oxides are predominant intermed iates.