The synthesis and mutagenicity of the N-formyl analog of N-hydroxyphenacetin

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Abstract
The synthesis and purification of N-hydroxy-N-formyl-p-phenetidine (N-OH-FP) is described. This new compound was subjected to mutagenicity testing using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 both in the presence and absence of the post-mitochondrial fraction of rat liver homogenate. Simultaneous mutagenicity testing of the known phenacetin metabolite, N-hydroxy-phenacetin (N-OH-AP), was conducted with the same tester strains. The N-formyl derived hydroxamic acid (N-OH-FP) was found to be a much stronger mutagen than N-hydroxy-phenacetin (N-OH-AP). Furthermore, N-OH-FP also behaved as a direct-acting mutagen unlike N-OH-AP. The chemical stabilities of N-OH-AP and N-OH-FP were studied in phosphate buffer in the pH range of 3–8; and both the hydroxamic acids were found to be stable to the conditions employed. The results of this study support the hypothesis that enzymatic deacylation is an activation process for the expression of mutagenicity by hydroxamic acids.