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

Abstract

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) complexes in addition to their cytotoxicity, DNA-binding, DNA cleavage ability and inhibition of topoisomerase IIα 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 topoisomerase IIα, however, this property of the complexes with low stability is most probably linked to the liberated free copper(II).

Keywords: Cytotoxicity; DNA binding; Solution stability; Structure-property relationship; Topoisomerase inhibition.