Evaluation of the binding mode of a cytotoxic dinuclear nickel complex to two neighboring phosphates of the DNA backbone.

A family of dinuclear complexes based on 2,7-disubstituted 1,8-naphthalenediol-ligands has been designed to bind covalently to two neighboring phosphate diester groups in the backbone of DNA. The dinuclear Cu and Ni complexes bind to DNA resulting in the inhibition of DNA synthesis in PCR experiments and in a cytotoxicity that is stronger for human cancer cells than for human stem cells of the same proliferation rate. These experiments support but cannot prove that the dinuclear complexes bind as intended to two neighboring phosphate ester groups of the DNA backbone. Here, we evaluate the potential binding mode of the cytotoxic dinuclear Ni complex using simple phosphate diester models (dimethyl phosphate and diphenyl phosphate). Depending on the reaction conditions, the phosphate diesters bind to the Ni ions in a bridging or in a terminal coordination mode. The latter occurs by substitution of two coordinated acetates by the phosphate diesters. This reaction has been followed by NMR spectroscopy, which demonstrates that the substitution of acetate by phosphate is thermodynamically strongly favored, while the exchange with excess phosphate is fast on the NMR time scale. The molecular structure of the Ni complex with two coordinated diphenyl phosphates served as a model for the computational evaluation of the binding to the DNA backbone. This combined experimental and computational study suggests a monodentate coordination mode of the DNA phosphate diesters to the Ni ions that is assisted by hydrogen bonds with water ligands.