Aziridine-2-carboxylic acid A reactive amino acid unit for a new class of cysteine proteinase inhibitors

Abstract

The three-membered ring of aziridine-2-carboxylic acid, which is susceptible to opening by nucleophiles, has been analyzed as a potential useful handle for the design of specific irreversible inhibitors of cysteine proteinases. For this thiol-reactive amino acid, an imino analogue of proline, a second-order rate constant of 17.07 M −1 s −1 for inactivation of papain was determined. Thus, the aziridine moiety proved to be remarkably more reactive than activated double bonds, e.g. N-ethylmaleimide, or halides such as α-iodopropionic acid or chloroacetic acid. Since it does not alkylate histidine under conditions in which quantitative alkylation occurs with N-ethyl-maleimide, it could represent an interesting reactive amino acid unit for the synthesis of a new class of irreversible inhibitors, at least in terms of specificity of the chemical reaction involved in the inactivation process.