FIGURE 10.10 Product-ion MS/MS spectrum and the proposed fragmentation scheme of a leu-arg adduct of an a,ft -unsaturated aldehyde intermediate from ticlopidine.
found in rat liver microsmes was formed by opening the thiophene ring following nucleophilic attack at the carbon a on the sulfur atom. The structure of this metabolite was confirmed by LC-MS and derivatization with dansylaziridine. The formation of the a, ft -unsaturated carbonyl intermediate was confirmed by trapping with leu-arg. The formation of a GSH adduct through an epoxide intermediate and the trapping of an a, ft -unsaturated carbonyl intermediate with a dipeptide could imply that the same type of binding might occur in vivo with proteins as targets. The formation of this adduct could contribute to the toxicity observed for this class of drugs. Two other thiophene analogs (5-bromo-2-thienyl-phenyl-methanone, and 2-[5-(4-methoxybenzyl)-2-thienyl] acetonitrile) with substitution on both a-carbons to sulfur in the thiophene ring were also evaluated. None of the reactive intermediates were observed. Blocking both a-carbons to sulfur in the thiophene ring prevented the formation of reactive metabolites. Medicinal chemists can use this information to block the active sites of thiophene moiety, therefore minimizing the formation of reactive metabolites.
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