Cytotoxic 3,6-bis((imidazolidinone)imino)acridines: Synthesis, DNA binding and molecular modeling

Synthesis, DNA binding and fragmentation, topoisomerase inhibition, antitumor activity, and modeling of novel 3,6-bis((1-alkyl-5-oxo-imidazolidin-2-yliden)imino)acridine hydrochlorides 6a–6e are reported. New acridine derivatives bearing two symmetrical imidazolidinone rings, 3,6-bis((1-alkyl-5-oxo-imidazolidin-2-yliden)imino)acridine hydrochlorides 6a–6e (alkyl=ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl), have been prepared and their interactions with calf thymus DNA and selected cell lines were studied. The DNA-binding of 6a–6e to ctDNA was examined by UV–vis, fluorescence, and CD spectroscopy. The binding constants determined by UV–vis spectroscopy were found in the range 1.9×105–7.1×105M−1. An electrophoretic separation proved that ligands 6a–6e inhibited topoisomerase I in 40μM concentration although only those with longer alkyl chains were able to penetrate the membranes and efficiently suppress the cell proliferation. The highest activity in cytotoxic tests was found for 3,6-bis((1-n-hexyl-5-oxo-imidazolidin-2-yliden)imino)acridine hydrochloride (6e) with IC50=2.12μM (HL 60) and 5.28μM (L1210) after 72h incubation. Molecular dynamics simulations and calculations of solvent-accessible surface areas (SASAs) were used to explore the intercalation mechanism. MD simulations favor stacking between adjacent C:G base pairs from the minor groove side. MD and SASAs calculations indicate that the decrease of K with alkyl extension is due to negative entropic change upon binding.