The intercalation of imidazoacridinones into DNA induces conformational changes in their side chain

Imidazoacridinones (IAs) are a new group of highly active antitumor compoun ds. The intercalation of the IA molecule into DNA is the preliminary step i n the mode of action of these compounds. There are no experimental data abo ut the structure of an intercalation complex formed by imidazoacridinones. Therefore the design of new potentially better compounds of this group shou ld employ the molecular modelling techniques. The results of molecular dynamics simulations performed for four IA analogu es are presented. Each of the compounds was studied in two systems: i) in w ater, and ii) in the intercalation complex with dodecamer duplex d(GCGCGCGC GCGC)(2). Significant differences in the conformation of the side chain in the two environments were observed for all studied IAs. These changes were induced by electrostatic as well as van der Waals interactions between the intercalator and DNA. Moreover, the results showed that the geometry of the intercalation complex depends on: i) the chemical constitution of the side chain, and ii) the substituent in position 8 of the ring system.