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

Abstract

Direct evidence for the involvement of thiophene S-oxide as a key primary reactive intermediate in the metabolism of thiophene (1) in rats was obtained from the isolation of two diastereoisomeric thiophene S-oxide dimers, 4a and 4b, both in vitro (oxidation of thiophene with rat liver microsomes) and in vivo (isolation of 4a from rat urine). The structure 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 agent for the selective transformation of thiophene to its S-oxide. The complete determination of the structures of 4a and 4b was carried out for the first time by X-ray diffraction for the former and by a sequence of chemical reactions for the latter. The reported results indicate two fates for thiophene S-oxide in vivo: (i) its dimerization via a Diels−Alder reaction and (ii) its reaction with nucleophiles such as glutathione leading eventually to mercapturates. These results together with recent literature data on thiophene derivatives suggest that thiophene S-oxides, a class of reactive intermediates whose chemistry is still not well-known, could play a central role in the metabolism and toxic effects of thiophenes in mammals. This situation would be different from that observed in the metabolism of other aromatic compounds, such as benzene or furan, in which arene oxides are predominant intermediates.

Pharmacokinetics and tissue distribution of the anticholinergics tiotropium and ipratropium in the rat and dog

“…Later, evidence was provided that thiophene-S-oxides are formed as intermediates which quickly underwent further reactions [29]. Treiber [30] described the two fates for thiophene-S-oxide in vivo: (1) its dimerisation via a Diels-Alder reaction and (b) its reaction with nucleophiles such as glutathione leading eventually to mercapturates. It could be speculated that tiotropium and ipratropium have different metabolic pathways due to the presence of thiophene rings in the tiotropium molecule carrying the potential for cytochrome P-450-mediated oxidation and/or conjugation reactions with endogenous nucleophiles such as glutathione or cysteine.…”

Scientific Opinion on Flavouring Group Evaluation 21, Revision 3 (FGE.21Rev3): Thiazoles, thiophenes, thiazoline and thienyl derivatives from chemical groups 29 and 30

“…The formation of the dimers may result from a Diels−Alder reaction. Thus, the metabolic fate for the thiophene S-oxide in vivo involves predominantly reaction with nucleophiles such as glutathione (catalysed by glutathione S-transferase) leading eventually to mercapturate derivatives that are excreted in the urine, or to a lesser extent it involves dimerization and the resulting dimer is also excreted via the urine (Treiber et al, 1997).…”

Inactivation of Cytochrome P450 (P450) 3A4 but not P450 3A5 by OSI-930, a Thiophene-Containing Anticancer Drug

“…Several publications describe evidence for the formation of thiophene sulfoxides as a primary intermediate in the oxidative metabolism of two thiophene derivatives Dansette et al, 1992;Valadon et al, 1996;Treiber et al, 1997). These sulfoxides react rapidly with various nucleophiles by a Michael-type addition at position 5 of the thiophene ring; reactions with nucleophilic residues of proteins result in covalent binding to proteins (Valadon et al, 1996).…”