Tris(benzimidazolyl)amine-Cu(ii) coordination units bridged by carboxylates: structures and DNA-condensing property

Abstract

Multinuclear multibenzimidazole metal complexes frequently exhibit novel structures and properties, and are an example of versatile compounds in bioinorganic chemistry. In this work, first, we synthesized the mononuclear complex [Cu(ntb)(H₂O)]²⁺, 1, by using tris[(benzimidazol-2-yl)methyl]amine (ntb). Then, a library of multicationic ntb-Cu(II) complexes, 2–9, was prepared by replacing the labile water molecule in 1 with multifunctional carboxylates acting as a bridge linker between two or four ntb-Cu(II) units under slightly acidic or alkaline conditions. Their X-ray crystal structures reveal that these complexes contain one, two or four [Cu(ntb)]²⁺ units. The pH media used in preparation can control the coordination patterns of the carboxylates and the overall architecture of the complexes, although the Cu(II) centers in the complexes always maintain a five-coordinated structure regardless of the preparation conditions used. Both intra- and inter-molecular π⋯π interactions involved in the benzimidazoles, as well as extensive hydrogen bonding networks in the complexes were observed to occur in the crystal packing. We selected complexes 1 and the dicarboxylate-bridged 4–7 as potential DNA condensers, as they can be dissolved to the required levels for examining their DNA-binding and -condensing properties in the buffer solutions tested (pH 7.4). For these complexes, the effects of the structural variations, including the number of Cu(II) ions and positive charges, length of linkers, and overall architecture, on the DNA-binding and -condensing properties and cytotoxicity were assessed and compared by biophysical measurements. The results from absorption titration showed that the affinities of the complexes for DNA are dominated by both the electrostatic interaction between them and the π⋯π interactions through the intercalation of the benzimidazolyl groups in the complexes into DNA base pairs. The DNA-condensing ability was observed to be mainly controlled by the numbers of positive charges on the complexes, and less correlated with the carboxylate linkers. Moreover, no direct relationships have been found between the apparent DNA-binding affinity and DNA-condensing ability of the complexes. The ability of DNA condensation triggered by 7b that carries four ntb-Cu(II) units and six positive charges is much stronger than those by the other complexes, but it also exhibits the largest cytotoxicity. This work aids in understanding the structure–activity relationships for metal complexes likely acting as a new type of gene-delivery systems.