DNA-Binding Properties of Cytotoxic Naphtindolizinedione-Carboxamides Acting as Type II Topoisomerase Inhibitors: A Combined In Silico and Experimental Study

Some clinically-used anticancer drugs are DNA intercalators acting as topoisomerase (Topo) IIα poisons in tumor cells highly expressing the enzyme. Synthetic naphtindolizinedione-carboxamides, previously designed as potential antitumor agents and showing relevant cytotoxic activities in vitro, have been now evaluated for their DNA-binding and inhibition of human Topo IIα, in comparison with the drug mitoxantrone. Docking calculation of each synthetic molecule as ligand with the CGCGAATTCGCG oligonucleotide model showed a stable intercalation in the DNA cut inside the enzyme. Moreover, molecular dynamics simulation indicated the stability of each DNA complex by evaluating the H-bonds involved as a function of time. These results are correlated to spectroscopic (binding constants and melting temperature by UV–VIS analysis, circular dichroism) and biological data (cytotoxicity and inhibition of human Topo IIα decatenation assay).