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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. [ABSTRACT FROM AUTHOR]

Three new nickel Schiff base complexes were prepared using a two-step procedure that involves initial selective dialkylation of 2,4,6-trihydroxybenzaldehyde, followed by reaction with 1,2-phenylenediamine and nickel(II) acetate. Each of the complexes possessed the same Schiff base core but differed in the identity of the four pendant groups. All complexes were characterised by microanalysis, NMR spectroscopy and ESI mass spectrometry. In addition, two of the complexes were also characterised in the solid state using X-ray crystallography, which confirmed the presence of a square planar geometry around the metal ion. The DNA binding properties of the three nickel complexes with double stranded DNA and a range of G-quadruplex DNA structures were explored using ESI mass spectrometry, CD spectroscopy, UV melting curves, Fluorescence Resonance Energy Transfer (FRET) assays, Fluorescent Indicator Displacement (FID) assays and molecular docking studies. These techniques confirmed the ability of the three nickel complexes to bind to most of the DNA molecules examined, as well as stabilise the latter in several instances. In addition, the results of these investigations provided evidence that pendant groups with morpholine rings generally reduced DNA binding behaviour, whilst pendants featuring piperidine ring systems attached to the Schiff base core by three and not two methylene linkers often showed the greatest extent of binding or DNA stabilisation. [ABSTRACT FROM AUTHOR]

A series of novel isomeric nickel Schiff base complexes, as well as nickel complexes of related ligands having asymmetric structures have been prepared and characterised using microanalysis, 1H and 13C NMR spectroscopy and ESI-MS. The Schiff base ligands were prepared by condensation reactions involving ethylenediamine and different derivatives of benzophenone. The solid-state structures of eight of the complexes were also determined and revealed that each possessed a regular square planar coordination geometry around the metal ion. Many of the new complexes featured at least one, and in many instances two, protonatable pendant groups that enhance aqueous solubility. This enabled the DNA binding properties of the latter complexes to be explored using a variety of instrumental approaches, including ESI-MS, circular dichroism (CD) spectroscopy, FRET melting assays and FID assays, as well as molecular docking studies. The results of experiments performed using ESI-MS suggested that none of the nickel complexes exhibit a high affinity towards either a double stranded DNA (dsDNA) molecule D2, or the parallel unimolecular quadruplex DNA (qDNA) molecule Q1. In contrast, complexes (8) and (12) both gave spectra which reflected a significant level of binding to the parallel tetramolecular qDNA Q4. The results of binding experiments performed using CD spectroscopy suggested that (12) exhibits a significant level of affinity towards most types of DNA, while (4) shows a preference for interacting with parallel, unimolecular qDNA molecules. Complex (4) produced the lowest values of DC50 in FID assays performed using parallel Q1 or Q4, confirming its affinity for these qDNA molecules. The results of FRET melting experiments provided further evidence that (12), along with (8), can interact extensively with anti-parallel unimolecular qDNA. Experiments which monitored the effect of the nickel complexes on the melting temperature of D2 showed that none had a stabilising effect on this dsDNA molecule. [ABSTRACT FROM AUTHOR]

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. The complexes bearing the ethylpiperidine moieties had greater solubility in water, and were therefore suitable for use in DNA binding experiments. ESI mass spectra of solutions containing 4 and the parallel, tetramolecular quadruplex Q4, contained ions attributable to formation of non-covalent complexes. In contrast, no ions from non-covalent complexes were observed when the experiments were repeated using 4 and either a double stranded DNA (dsDNA) molecule (D2), or parallel Q1, a unimolecular quadruplex DNA (qDNA). The ESI-MS binding study also revealed that 14 has a significant ability to form non-covalent complexes with qDNA, but does not interact to the same extent with D2. This is supported by the large changes to the ellipticity of bands observed in the circular dichroism spectra of two different unimolecular qDNA molecules (c-kit1 and Q1), including the latter annealed under conditions designed to induce formation of alternative topologies (antiparallel and hybrid). In Fluorescent Indicator Displacement (FID) assays conducted using the new nickel complexes, 14 gave the lowest values of DC50 for experiments conducted with Q1 and Q4. Furthermore, 14 showed greater stabilisation of an antiparallel qDNA molecule in FRET assays than when the other new complexes were examined. These results highlight the potential of 14 as a lead complex for future structure/DNA binding investigations. This is reinforced by the results obtained from cytotoxicity studies performed using four of the nickel complexes, including 14, and Chinese hamster lung cancer (V79) cells, which gave IC50 values between 4 and 12 μM. These complexes were also shown to have the ability to induce apoptosis in the same cancer cell line. [ABSTRACT FROM AUTHOR]

Two different series of nickel Schiff base complexes were prepared as part of a study aimed at discovering new compounds with high affinity and selectivity for quadruplex DNA (qDNA). The new complexes were prepared by modification of a literature method for synthesising N,N'-bis-(4-((1-(2-ethyl)piperidine)-oxy)salicylidene) phenylenediaminenickel(II) (complex (1)). For Series 1 complexes, the phenylenediamine head group of the literature complex was replaced with ethylenediamine, phenanthrenediamine, R,R- and S,S-diaminocyclohexane. These complexes, as well as an asymmetric molecule featuring a naphthalene moiety on one side and a single ethyl piperidinyl salicylidene group on the other, were prepared in order to examine the effect of varying the number and position of aromatic groups on DNA binding. Series 2 complexes were isomers of those in Series 1, in which pendant ethyl piperidine groups were located at different positions. All new complexes were characterised by 1D and 2D NMR spectroscopic methods alongside microanalysis and ESI-MS. In addition, the solid state structures of eight new complexes were determined using single crystal X-ray diffraction methods. N,N'-Bis-(4-((1-(2-ethyl)piperidine)oxy)-salicylidine)diaminophenanthrenenickel(II) (9), was shown by ESI-MS, CD spectroscopy and UV melting studies to exhibit a greater affinity towards, and ability to stabilise, dsDNA than all other complexes in the first series. ESI-MS revealed (9) to have a strong tendency to form a 1 : 1 complex with the tetramolecular, parallel qDNA molecule Q4, however it exhibited low affinity towards the parallel unimolecular qDNA molecule Q1. The enantiomeric complexes (5) and (7), featuring R,R- and S,S-diaminocyclohexane moieties, respectively, showed similar binding profiles towards all DNA molecules investigated, whereas the asymmetric complex (11), exhibited very low DNA affinity in all cases. Series 2 complexes showed very similar DNA affinity and selectivity to their isomeric counterparts in Series 1. For example, (14) and (15), both of which contain a phenylenediamine head group, showed higher affinity towards D2, Q1 and Q4, than any of the other Series 2 complexes. In addition, complex (21), which contains a meso-1,2-diphenylethylenediamine moiety, interacted strongly with Q4, but not D2 or Q1. This observation was very similar to that made previously for the isomeric complex (3). [ABSTRACT FROM AUTHOR]

As part of a program of preparing metal complexes which exhibit unique affinities towards different DNA structures, we have synthesised the novel Schiff base complex N,N′-bis-4-(hydroxysalicylidine)meso-diphenylethylenediaminenickel(ii) (4), via the reaction of meso-1,2-diphenylethylenediamine and 2,4-dihydroxybenzaldehyde. This compound was subsequently reacted with 1-(2-chloroethyl)piperidine or 1-(2-chloropropyl)piperidine, to afford the alkylated complexes N,N′-bis-(4-((1-(2-ethyl)piperidine)oxy)salicylidine)meso-1,2-diphenylethylenediaminenickel(ii) (5) and N,N′-bis-(4-((1-(3-propyl)piperidine)oxy)-salicylidine)meso-1,2-diphenylethylenediaminenickel(ii) (6), respectively. These complexes were characterised by microanalysis and X-ray crystallography in the solid state, and in solution by 1H and 13C NMR spectroscopy. Electrospray ionisation mass spectrometry (ESI-MS) was used to confirm the identity of (5) and (6). The affinities of (5) and (6) towards a discrete 16 mer duplex DNA molecule, and examples of both tetramolecular and unimolecular DNA quadruplexes, was explored using a variety of techniques. In addition, the affinity of two other complexes (2) and (3), towards the same DNA molecules was examined. Complexes (2) and (3) were prepared by methods analogous to those which afforded (5) and (6), however 1,2-phenylenediamine was used instead of meso-1,2-diphenylethylenediamine in the initial step of the synthetic procedure. The results of ESI-MS and DNA melting temperature measurements suggest that (5) and (6) exhibit a lower affinity than (2) and (3) towards the 16 mer duplex DNA molecule, while circular dichroism (CD) spectroscopy suggested that none of the four complexes had a major effect on the conformation of the nucleic acid. In contrast, ESI-MS and CD spectroscopy suggested that both (5) and (6) show significant binding to a tetramolecular DNA quadruplex. The results of ESI-MS and Fluorescence Resonance Energy Transfer (FRET) assays indicated that (5) and (6) did not bind as tightly to a unimolecular DNA quadruplex, although both complexes had a major effect on the CD spectrum of the latter. These results highlight that the presence of the meso-1,2-diphenylethylenediamine moiety in metal complexes of this type may provide a general method for instilling selectivity for some DNA quadruplexes over dsDNA. [ABSTRACT FROM AUTHOR]

The synthesis and characterisation of complexes of the hexaamine cage ligand facial-1,5,9,13,20-pentamethyl-3,7,11,15,18,22-hexaazabicyclo[7.7.7]tricosane (fac-(Me)5-D3 htricosaneN6) with Zn(II), Cd(II) and Hg(II) is reported. Single crystal X-ray structural analyses of the Cd(II) and Hg(II) complexes reveal that the coordination spheres of both cations have an unusual trigonal prismatic stereochemistry organised by the ligand substituents and cavity size. This is unprecedented for hexaamine complexes of these metal ions, and in stark contrast to the distorted octahedral stereochemistry found previously for the analogous Zn(II) complex. An X-ray structural analysis of single crystals of the diprotonated ligand [fac-(Me)5-D3htricosaneN6 - 2H](CF3SO3)2 shows that it also prefers to adopt a trigonal prismatic structure. The 13C NMR spectra of the metal complexes indicate that their structures are preserved at 20 °C in solution. However, heating the Zn(II) complex to ~130 °C appears to convert it to the trigonal prismatic form. In contrast cooling the trigonal prismatic Hg(II) complex to -80 °C does not convert it to the octahedral structure. The results are also compared to the structures of various other transition metal ion complexes of the same or similar ligands. This comparison yields overall an appreciation of the factors that determine the final structures of complexes formed with such tricosaneN6 ligands. [ABSTRACT FROM AUTHOR]

A novel bioelectrode system has been prepared in which an enzyme and a conducting polymer hydrogel are combined in a nanostructured scaffold. The latter consists of fibres of carbon NanoWeb, grown by chemical vapour deposition onto reticulated vitreous carbon (RVC). The catalytic currents produced by this new bioelectrode system are significantly larger than those obtained using conventional electrodes. [ABSTRACT FROM AUTHOR]

ESI mass spectrometry was used to assess the ability of metal complexes to inhibit binding of a transcription factor to a DNA molecule containing its recognition sequence. [ABSTRACT FROM AUTHOR]

The cytotoxicity of the metallointercalators, [Pt(5,6-dimethyl-1,10-phenanthroline)(trans-1R,2R-diaminocyclohexane)](2+) ([56MERR]) and [Pt(5,6-dimethyl-1,10-phenanthroline)(trans-1S,2S-diaminocyclohexane)](2+) ([56MESS]), towards A549 human lung cancer cells was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The IC(50) value obtained following exposure of A549 cells to [56MESS] for 4 h was approximately three times smaller than that obtained when [56MERR] was administered under the same conditions, indicating that the former complex displayed greater cytotoxicity. Both IC(50) values were greater than that obtained after exposure of A549 cells to cisplatin, demonstrating that the latter compound was the most cytotoxic of the three examined. Microprobe synchrotron radiation X-ray fluorescence (SR-XRF) analyses of metallointercalator-treated A549 cells showed that platinum became localised in DNA-rich regions of the nucleus. In contrast, when the same cells were treated with cisplatin the metal became distributed throughout the cell. Determination of the maximum concentration of platinum present inside the cells using graphite furnace atomic absorption spectrophotometry (GFAAS) of platinum-treated cells suggested that there was greater uptake of [56MERR] compared to [56MESS] by the A549 cells, and that platinum uptake did not account for the greater toxicity of [56MESS], as assessed by the MTT assay. Electrospray ionization mass spectrometric (ESI-MS) and circular dichroism (CD) spectroscopic studies of solutions containing either [56MERR] or [56MESS], and a duplex hexadecamer molecule, showed the two metallointercalators displayed very similar affinity towards the nucleic acid. Overall these results indicate that the difference in cytotoxicity of the two platinum metallointercalators is probably the result of variations in their interactions with other cellular components.

Electrospray ionisation mass spectrometry, absorption spectrophotometry and circular dichroism spectroscopy were used to investigate the binding of a series of nickel complexes with the general formula [Ni(phen)2L]2+ (L = phen, dpq, dpqC and dppz) to a double stranded DNA hexadecamer. In addition, the binding of the complexes to pUC9 negatively supercoiled plasmid DNA was examined using gel electrophoresis, and their ability to inhibit DNA transcription was measured. Each of the above techniques showed that DNA binding strengthened as the size of the unique ligand L was increased. Comparison of the above results with those obtained previously, and presented here for the first time for the analogous series of ruthenium complexes [Ru(phen)2L]2+, showed that changing the metal ion from nickel to ruthenium consistently resulted in significant increases in DNA binding affinity.

Electrospray ionisation mass spectrometry (ESI-MS) and circular dichroism (CD) spectroscopy were used to compare the binding of mononuclear nickel, ruthenium and platinum complexes to double stranded DNA (dsDNA) and quadruplex DNA (qDNA). CD studies provided evidence for the binding of intact complexes of all three metal ions to qDNA. ESI mass spectra of solutions containing platinum or ruthenium complexes and qDNA showed evidence for the formation of non-covalent complexes consisting of intact metal molecules bound to DNA. However, the corresponding spectra of solutions containing nickel complexes principally contained ions consisting of fragments of the initial nickel molecule bound to qDNA. In contrast ESI mass spectra of solutions containing nickel, ruthenium or platinum complexes and dsDNA only showed the presence of ions attributable to intact metal molecules bound to DNA. The fragmentation observed in mass spectral studies of solutions containing nickel complexes and qDNA is attributable to the lower thermodynamic stability of the former metal complexes relative to those containing platinum or ruthenium, as well as the slightly harsher instrumental conditions required to obtain spectra of qDNA. This conclusion is supported by the results of tandem mass spectral studies, which showed that ions consisting of intact nickel complexes bound to qDNA readily undergo fragmentation by loss of one of the ligands initially bound to the metal. The ESI-MS results also demonstrate that the binding affinity of each of the platinum and ruthenium complexes towards qDNA is significantly less than that towards dsDNA.

The crystal structure of the bicyclic hexaamine complex [Cu(fac-Me5-tricosane-N6)](ClO4)2.H2O (fac-Me5-tricosane-N6 = facial-1,5,9,13,20-pentamethyl-3,7,11,15,18,22-hexaazabicyclo[7.7.7]tricosane) at 100 K defines an apparently tetragonally compressed octahedral geometry, which is attributed to a combination of dynamic interconversion and static disorder between two tetragonally elongated structures sharing a common short axis. This structure is fluxional at 60 K and above as shown by EPR spectroscopy. Aqueous cyclic voltammetry reveals that a remarkably stable Cu(I) form of the complex is stabilised by the encapsulating nature of the expanded cage ligand.

Electrospray ionisation mass spectrometry was used to investigate reactions between six ruthenium compounds and three different non self-complementary duplex oligonucleotides containing 16 base pairs. Each of the compounds studied formed non-covalent complexes containing between one and five ruthenium molecules bound to DNA. Competition experiments involving duplex 16mers and pairs of ruthenium compounds were used to determine the order of relative binding affinities of the metal compounds. Other competition experiments involving ruthenium compounds, and the organic DNA binding agents daunomycin and distamycin, provided information about the sites and modes of DNA binding of the ruthenium compounds.

ESI mass spectra show that up to five ruthenium molecules can bind non-covalently to double stranded 16mer DNA, and provide information on the relative affinity and DNA sequence selectivity of different ruthenium complexes.