Comparative studies of oxindolimine-metal complexes as inhibitors of human DNA topoisomerase IB

Copper(II) and zinc(II) complexes with oxindolimine ligands, obtained by a condensation reaction between isatin (1H-indole-2,3-dione) and 2-(2-aminoethyl)pyridine, have been previously shown to activate apoptosis very efficiently in different cancer cell lines. Here, we show that these compounds inhibit human DNA topoisomerase IB (Topo I) activity, and this characteristic may be implicated in its pro-apoptotic and potential antitumor properties. The studied metal complexes prevent DNA relaxation and cleavage reaction, whilst they do not have any effect on the religation process. The protein inhibition occurs in two different ways since the copper compound does not permit the enzyme-DNA complex formation, while the zinc analogue permits this complex formation but inhibits the catalytic cleavage reaction. Other related copper and zinc complexes, one with an asymmetric imine ligand derived from isatin, 1,3-diaminopropane, and salicyladehyde, and another one previously reported, derived from isatin and 1,3-diaminopropane, had their corresponding inhibition results towards Topo I compared. These data demonstrated that such complexes can act as good catalytic inhibitors of Topo I, in a process modulated by the ligand features and the nature of the metal ion. Computational studies complemented and supported experimental data, showing three different characteristics of the metal complexes that influence its interaction and consequent inhibition of Topo I. The ligand planarity when bound to the protein increases the occurring interactions in different binding sites, the total charge of the complex modulates the preferential region of interaction, and the copper(II) complexes are expected to be more efficient inhibitors compared to analogous zinc(II), as verified experimentally. Copper(II) and zinc(II) complexes with oxindolimine ligands inhibit topoisomerase IB activity by two different mechanisms, showing that the metal ion nature as well as the ligand features are crucial in modulating the interaction of such complexes with the enzyme. [Display omitted] •Oxindolimine-metal complexes efficiently inhibit Topoisomerase IB enzyme.•Copper compound does not permit the formation of enzyme-DNA complex.•In contrast, zinc analogue inhibits catalytic cleavage reaction.•Ligand planarity increases interaction occurring in different sites of the protein.•Metal complex charge modulates preferential region of interaction.