The influence of N-dialkyl and other cationic substituents on DNA intercalation and genotoxicity.

DNA intercalation by small chemical molecules can result in frameshift mutagenesis and chromosomal breakage. With evidence mounting that broadly diverse structures are capable of intercalating between DNA base pairs, it becomes important to better define those structural features that enhance intercalation strength and those that confer genotoxicity particularly among those intercalators that do not have the classical planar tricyclic fused ring structure. A chemical substituent that is present on many pharmaceutical and other biologically active molecules is the N-dialkyl group. In the present study, we investigate if and how the presence of an aromatic N-dialkyl or other cationic group affects the genotoxicity and DNA intercalation ability of 26 selected acridines, phenothiazines, benzophenones, triphenylethylenes and other classes of molecules. The data were obtained from the literature, from experiments using a cell-based DNA intercalation assay, and from modeling studies using a three-dimensional computational DNA docking program. It is demonstrated that cationic substitution can enhance both genotoxicity and electrostatic interactions within a chemical/DNA intercalation complex.