Effect of substituents on the ability of nickel Schiff base complexes with four pendant groups to bind to G-quadruplexes

Abstract

The synthesis of eleven new nickel Schiff base complexes each bearing four pendant groups is reported. The structures of the complexes differ in the identity of the pendant groups and/or diamine moiety. All complexes were characterised by microanalysis, Nuclear Magnetic Resonance (NMR) spectroscopy and Electrospray Ionisation Mass Spectrometry (ESI-MS), while the solid-state structures of two of the molecules were also determined using X-ray crystallographic methods. The DNA binding properties of the nickel complexes with double stranded DNA and a range of G-quadruplex DNA structures was explored using different spectroscopic methods as well as computational techniques. Results from ESI-MS experiments and Fluorescent Indicator Displacement (FID) assays were consistent with each other and indicated that varying the diamine moiety had less influence on DNA affinity than changing the pendant groups. These conclusions were also generally supported by results obtained from UV melting experiments and Fluorescence Resonance Energy Transfer (FRET) assays. The cytotoxicity of selected examples of the new complexes, and close analogues reported recently, towards V79 Chinese hamster lung cancer cells and THP-1 human leukemia cells was measured. All were found to display modest cytotoxicity, with flow cytometry experiments suggesting an apoptotic pathway was the most likely mechanism of cell death.