Crystallographic and molecular mechanics calculations on the anti-tumor drugs N-[(2-dimethylamino)ethyl]-and N-[(2-dimethyl-amino)butyl]-9-aminoacridine-4-carboxamides and their dications: implications for models of DNA-binding.

The molecular structures of the N-(2-dimethylamino)ethyl and N-(2-dimethylamino)butyl derivatives of 9-aminoacridine-4-carboxamide, of current interest as potential anti-cancer agents have been determined by X-ray Crystallography. Both are in the free base form and have an intramolecular-hydrogen bond between N10 of the acridine and the nitrogen atom of the carboxamide substituent. Molecular mechanics calculations have been used to explore the conformational flexibility of this substituent with respect to the chromophore in order to determine the low-energy conformers of both free base and protonated forms. These have revealed flexibility in the system with relatively low energy cost, especially in the physiological condition when the N10 atom is protonated and suggest that a previously published model for the interaction of these compounds with DNA, is energetically feasible. Implications for interactions with DNA have also been examined by computer modelling.