Mutagenicity of N-acyloxy-N-alkoxyamides as an indicator of DNA intercalation: The role of fluorene and fluorenone substituents as DNA intercalators

Abstract

N-Acyloxy-N-alkoxyamides are direct-acting mutagens in S. typhimurium TA100 and TA98. A reliable QSAR for their activity in TA100 has been developed, which indicates reversible intercalation into the DNA helix through naphthalene substituents. In this paper, we show that fluorene as a substituent does not facilitate intercalation while fluorenone does, although the efficacy is determined by the position of substitution on the fluorenone as well as the N-acyloxy-N-alkoxyamide side chain. Where intercalation is evident, the increased binding to DNA is similar to that of naphthalene and is worth the equivalent of ca four LogP hydrophobicity units. 4-Substituted fluorenones, where the anomeric amide group is in the bay region do not intercalate, which is attributed to the requirement for a weaker edge-on, rather than an end-on intercalation. Mutagencity in S. typhimurium TA98, which detects frame shifts through intercalation, supports the findings. Fluorene appears not to intercalate, which points to the fact that the charge delocalised 2-fluorenylnitrenium ion, the ultimate metabolite from 2-aminofluorene (AF) and 2-acetylaminofluorene (AAF) is the itercalating agent responsible for frameshift mutations leading to their carcinogenicity.

Keywords: 2-Aminofluorene nitrenium ion; Bacterial mutagenicity testing; DNA intercalation; Fluorene intercalation; Fluorenone intercalation; QSAR.