Substituent effects on the bioactivation of 2-(N-hydroxyacetamido)fluorenes by N-arylhydroxamic acid N,O-acyltransferase

Abstract

A series of 7-substituted analogues of 2-(N-hydroxyacetamido)fluorene (1) was subjected to bioactivation by a partially purified preparation of hamster hepatic AHAT, and the rates of methylthio adduct formation resulting from the reaction of the activated intermediates with N-acetylmethionine were determined. Electronegative substituents enhanced the amount of adduct formed; this finding contrasted with the results of a previous study in which it was found that electron-donating substituents facilitated the mechanism-based inactivation of AHAT by analogues of 1. The structures of the adducts formed from reaction of the activated forms of several of the 7-substituted compounds with N-acetylmethionine and with 2'-deoxyguanosine were determined; the types of adducts formed were similar to those formed with electrophiles generated by the AHAT-catalyzed activation of 1. Electronegative substituents enhanced the amount of adducts formed in the reaction with 2'-deoxyguanosine as well as with N-acetylmethionine.