The coordination modes of (thio)semicarbazone copper(II) complexes strongly modulate the solution chemical properties and mechanism of anticancer activity

Thiosemicarbazones are promising candidates for anticancer therapy and their mechanism of action is often linked to their metal chelating ability. In this study, five (thio)semicarbazones with different donor sets (NNS, NNO, ONS, ONO) were selected and their behaviour in aqueous solution, the stability of their copper(II) com-plexes in addition to their cytotoxicity, DNA-binding, DNA cleavage ability and inhibition of topoisomerase II alpha were investigated and compared. We aimed to reveal relationships between the structural variations, the significantly different physico-chemical properties, solution speciation and biological activity. The cytotoxicity of the ligands did not show correlation with the solubility, lipophilicity and permeability; and the decreased activity of the oxygen donor containing compounds was explained by their stronger preference towards chelation of iron (III) over iron(II). Meanwhile, among the copper complexes the most lipophilic species with the highest stability and membrane permeability exhibited the highest cytotoxicity. The studied copper(II) complexes interact with DNA, and reaction with glutathione led to heavy DNA cleavage in the case of the highly stable complexes which could be reduced in a reversible reaction with moderate rate. All the tested copper complexes inhibited topo-isomerase II alpha, however, this property of the complexes with low stability is most probably linked to the liberated free copper(II).

Automated summary

This study investigates the behavior of five (thio)semicarbazones with different donor sets in aqueous solution, the stability of their copper(II) complexes, and their interaction with DNA and topoisomerase II alpha. The results show that the cytotoxicity of the ligands is not correlated with their solubility, lipophilicity, or permeability, while the most lipophilic and stable copper complexes exhibit the highest cytotoxicity.