A New Class of Quadruplex DNA-Binding Nickel Schiff Base Complexes

We have prepared six new nickel Schiff base complexes via reactions of substituted benzophenones with different diamines in the presence of nickel(II). These new complexes were then reacted with 1-(2-choroethyl)piperidine to afford a further six novel nickel(II) Schiff base complexes bearing pendant ethylpiperidine groups. Each new complex was characterised by microanalysis, 1H and 13C NMR spectroscopy and Electrospray Ionisation-Mass Spectrometry (ESI-MS). Nine of the complexes were also characterised in the solid state using X-ray crystallography. The complexes bearing the ethylpiperidine moieties had greater solubility in water, and were therefore suitable for use in DNA binding experiments to evaluate the effects on DNA affinity of changing the diamine moiety or the number of pendant groups. Initial DNA binding experiments were conducted using ESI-MS, and involved a double stranded DNA molecule (D2), as well as unimolecular and tetramolecular quadruplex DNA molecules (Q1 and Q4, respectively). The latter were annealed under conditions to afford a parallel G-quadruplex topology. Additional DNA binding experiments were conducted using circular dichroism (CD) spectroscopy and the same three DNA molecules, as well as parallel c-kit1, and Q1 annealed to produce antiparallel and hybrid topologies. The DNA binding properties of the nickel complexes were also examined by DNA melting experiments, Fluorescence Resonance Energy Transfer (FRET) assays and Fluorescent Indicator Displacement (FID) assays. These experiments showed that altering the diamine used to prepare the nickel complex typically had little effect on DNA binding properties. In contrast, changing the number of pendant groups appended to the Schiff base core had, in some cases, significant effects. Four of the nickel complexes containing pendant groups were examined for cytotoxicity towards Chinese hamster lung cancer (V79) cells, and gave IC50 values in the range 4 – 12 μM. In addition, each of the complexes were shown to have the ability to induce apoptosis in the same cancer cell line.