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).