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

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 2aminofluorene (AF) and 2-acetylaminofluorene (AAF) is the itercalating agent responsible for frameshift mutations leading to their carcinogenicity.

Automated summary

The binding mechanism of fluorenes or fluorenones with DNA depends on the position of substitution and specific chemical side chains, leading to varying intercalation efficacies; some fluorene derivatives do not intercalate into DNA, possibly due to a different insertion mode; the insertion of certain substances is crucial for the detection of frameshift mutations in S. typhimurium TA98.