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

Abstract

<p><i>N</i>-Acyloxy-<i>N</i>-alkoxyamides are direct-acting mutagens in <i>S. typhimurium</i> 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 <i>N</i>-acyloxy-<i>N</i>-alkoxyamide side chain. Where intercalation is evident, the increased binding to DNA is similar to that of naphthalene and is worth the equivalent of <i>ca</i> four Log<i>P</i> 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 <i>S. typhimurium</i> 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.</p>