Redox-active and DNA-binding coordination complexes of clotrimazole

DNA interactions of anticancer mononuclear Cu²⁺, Co²⁺, Zn²⁺, and Ni²⁺ complexes with the biologically active ligand clotrimazole (clotri) are reported. To fully characterize DNA binding modes for these complexes of the formulae [M(clotri)₂Cl₂]·nH₂O (1-4), [M(clotri)₂Br₂]·nH₂O (5,6), [M(clotri)₃NO₃]NO₃·nH₂O (9), and [M(clotri)₃(NO₃)₂] (10), circular dichroism (CD) and linear dichroism (LD) spectroscopy, UV melting experiments, atomic force microscopy (AFM) and ethidium bromide (EtBr) displacement methods were used. Results indicate mixed electrostatic interactions, possibly through groove binding, that result in accretion and coiling of DNA. Electrochemical studies indicate that the Cu²⁺ complex 9 readily reduces to the reactive-oxygen-species-generating Cu⁺, which oxidatively damages DNA. There is a subtle correlation between logP values, calculated electrostatic potentials, and cytotoxicity of the complexes. The extent of cell-nucleus DNA-metal adduct formation in the HeLa cervix-uterine carcinoma cell line does not necessarily correlate with cytotoxicity, indicating that the nature of DNA lesions may be crucial to activity. This journal is