Arylhydroxamic acid bioactivation via acyl group transfer. Structural requirements for transacylating and electrophile-generating activity of N-(2-fluorenyl)hydroxamic acids and related compounds

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Abstract
The synthesis of a series of 12 N-(2-fluorenyl)hydroxamic acids, N-(2-fluorenyl)-N-hydroxyureas and N-(2-fluorenyl)-N-hydroxycarbamates is reported. The compounds were evaluated for their ability to serve as substrates for a partially purified hamster hepatic arylhydroxamic acid N,O-acyltransferase preparation. Transacylating activity was measured spectrophotometrically with 4-aminoazobenzene as the acyl group acceptor, and electrophile-generating activity, which is thought to be responsible for the toxic and carcinogenic activity of this compound, was quantified by the N-acetylmethionine trapping assay. Only the N-acetyl, N-propionyl and N-methoxyacetyl derivatives exhibited relatively high levels of activity as measured by either of the assay methods. These results are generally consistent with previously reported conclusions regarding the steric and electronic characteristics of acyl groups that are required for activation by this enzyme system. N,O-Acyltransferase inactivation by N-hydroxy-2-acetamidofluorene depressed the bioactivation of the N-acetyl compound to a greater extent than the N-propionyl or N-methyloxyacetyl derivative.