Quantitative structure-activity relationships of mutagenic aromatic and heteroaromatic azides and amines

Photolysis of arylazides with long-wavelength UV light in an aqueous medium produces short-lived reactive species that bind to DNA and induce mutations in Salmonella typhimurium TA98. Nitrenes are known reactive products of azide photolysis, so that the DNA-binding and mutagenic species is either a nitrene or nitrene derivative. In the present study we presupposed that the nitrenium ion is the key intermediate. The electronic properties of 19 nitrenium ions with different chemical structures were calculated by the semi-empirical method AM1 and the resulting values plotted against the logarithm of the mutagenicity (log MUT) by means of linear regression analysis. Log MUT correlates with the stability of the nitrenium ion, the energy level of the LUMO and the charges on the exocyclic nitrogen with r = -0.804, 0.865 and -0.874 respectively. Thus, the mutagenicity of the azides is directly proportional to the stability of the nitrenium ions and inversely proportional to the electrophilicity of the exocyclic nitrogen. Furthermore, the mutagenicity of the azides correlates with the mutagenicity of the corresponding arylamines with r = 0.91 (n = 13). These correlations support the key role of the nitrenium ions and demonstrate the value of their electronic structure for the prediction of the mutagenicity of arylazides and arylamines.