Cytoxicity of 1-alkylperhydroazepine N-oxides and quantitative structure-activity relationships

A new class of nonaromatic amine oxides was tested for cytotoxic activity. The main aim of the present investigation was to screen a series of 1-alkylperhydroazepine N-oxides for in vitro cytotoxicity and to find out whether there is a quantitative structure-activity correlation (QSAR) between cytotoxic effect and structure (as a structural parameter the number of carbon atoms m in the alkyl chain was used). Cytotoxicity was determined here by inhibition of incorporation of [ 14C]adenine into nucleic acid or [ 14C]valine into proteins in Ehrlich ascites carcinoma (EAC) cells. On the basis of primary screening, one of the most active compounds, namely 1-tetradecylperhydroazepine N-oxide (TPNO), was chosen for further biochemical study. The drug inhibited the incorporation rate of [ 14C] labeled precursors (adenine, thymidine, uridine, valine) into appropriate macromolecules of Ehrlich cells. The extent of inhibition was dependent on both time and drug concentration. The lengthening of the alkyl chain in 1-alkylperhydroazepine N-oxides positively affected their cytotoxic activity in EAC cells. For these compounds the optimal m value is 12–14.