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).
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DNA-binding properties of cytotoxic naphtindolizinedione-carboxamides acting as type II Topoisomerase inhibitors. A combined in silico and experimental study.
Published:
13 November 2020
by MDPI
in The 24th International Electronic Conference on Synthetic Organic Chemistry
session Computational Chemistry
Abstract:
Keywords: anticancer agent; docking calculation; molecular dynamics; spectroscopic methods