An investigation of structure activity relationships for aryl nitrenium stability and mutagenicity for amino polyaromatic hydrocarbons

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Virginia Tech

Amino polyaromatic hydrocarbons (amino PAHs) and nitro polyaromatic hydrocarbons (nitro PAHs), two highly mutagenic classes of compounds, are proposed to be metabolized to an electrophilic aryl nitrenium ion which attacks DNA and forms DNA adducts. A structure-activity relationship was investigated between aryl nitrenium ion stability and mutagenic activity. Arylnitrenium stability for seventeen amino PAHs was measured using electron ionization mass spectrometry. The ratio of [M-1]⁺/M⁺ intensities was used as an indicator of nitrenium ion stability. These values were then compared to mutagenicity data from the Ames Salmonella assay. Physical descriptors of isomer classification (based on ring size and shape) and isomer position of substitution were used in the statistical analysis.

A strong correlation between mutagenicity, isomer classification, and stability was found (r²= 0.899 and p<0.001). This finding agrees with reported literature that the compound's physical features of ring size and position of substitution affect mutagenicity. A high correlation of r² = 0.955 was found between mutagenicity, isomer classification, and stability for three sets of isomers: 1- and 2-aminoanthracene, 1- and 2-aminonaphthalene, and 1- and 2-aminofluorene. The nitrenium ion formed from the 2 position was found to be less stable and more mutagenic than the 1 position. This finding agrees with correlations found between mutagenicity and LUMO (Lowest Unoccupied Molecular Orbital) calculations of the electrophilicity of the nitrenium ion. These results indicate that the less stable the nitrenium ion within an isomer pair, the more mutagenic the amino PAH.