Reactions of model proteins with aurothiomalate, a clinically established gold(I) drug: The comparison with auranofin.

Aurothiomalate (AuTm) is an old, clinically established, antiarthritic gold drug that is currently being reconsidered as a candidate drug for cancer treatment and for other therapeutic indications within a more general drug repositioning program. As the biological effects of gold drugs seem to be mediated, mainly, by their interactions with protein targets we have analyzed here, in detail, the metalation patterns produced by aurothiomalate in a few model proteins. In particular, the reactions of aurothiomalate with the small proteins ribonuclease A, cytochrome c and lysozyme were explored through ESI MS (electrospray ionization mass spectrometry) analysis. Notably, characteristic and rather constant features emerged in the protein metalation patterns induced by AuTm that are markedly distinct from those caused by auranofin; a non-covalent interaction mode is invoked for AuTm binding to the mentioned proteins. The affinity constants of AuTm toward the three mentioned proteins were also initially assessed. The implications of the present findings are discussed.

Experimental and molecular modeling studies of the interaction of the polypyridyl Fe(II) and Fe(III) complexes with DNA and BSA.

Two mononuclear iron complexes, [Fe(tppz)2](PF6)2·H2O (1) and Fe(tppz)Cl3·2CHCl3 (2) where tppz is (2,3,5,6-tetra(2-pyridyl)pyrazine), have been synthesized and characterized by elemental analysis, spectroscopic methods (UV-Vis and IR) and single crystal X-ray structure analysis. The interaction of (1) as the nitrate salt ([Fe(tppz)2](NO3)2) with calf-thymus DNA (CT-DNA) has been monitored by UV-Vis spectroscopy, competitive fluorescence titration, circular dichroism (CD), voltammetric techniques, viscosity measurement, and gel electrophoresis. Gel electrophoresis of DNA with [Fe(tppz)2](NO3)2 demonstrated that the complex also has the ability to cleave supercoiled plasmid DNA. The results have indicated that the complex binds to CT-DNA by three binding modes, viz., electrostatic, groove and partial insertion of the pyridyl rings between the base stacks of double-stranded DNA. Molecular docking of [Fe(tppz)2](NO3)2 with the DNA sequence d(ACCGACGTCGGT)2 suggests the complex fits into the major groove. The water-insoluble complex (2) can catalyze the cleavage of BSA at 40 °C. There are no reports of the catalytic effect of polypyridyl metal complexes on the BSA cleavage. Molecular docking of (2) with BSA suggests that, when the chloro ligands in the axial positions are replaced by water molecules, the BSA can interact with the Fe(III) complex more easily.

DNA binding and DNA cleavage studies of a water soluble cobalt(II) complex containing dinitrogen Schiff base ligand: the effect of metal on the mode of binding.

Binding interaction of a water soluble cobalt(II) complex of a Schiff base, SF, (SF = N,N'-bis{5-[(triphenylphosphonium chloride)-methyl] salicylidine}-o-phenylenediamine) with calf thymus DNA (CT-DNA) has been investigated. The intrinsic binding constant (K(b) = 5 x 10(4) M(-1)) was determined. In comparison with previous study the results indicate that the binding affinity of SF is stronger than its Co(II) complex. Multi-spectroscopic experiments reveal that the binding modes of Co(II) complex in comparison with SF are different; SF may be intercalating between DNA base pairs while its Co(II) complex most likely interact with DNA in an electrostatic binding mode.

DNA binding and gel electrophoresis studies of a copper (II) complex containing mixed aliphatic and aromatic dinitrogen ligands.

The interaction of a novel mixed ligand copper (II) complex, [Cu(N-N)(L)(EtOH)](NO(3))(2) . 2H(2)O, in which N-N indicates 2,9-dimethyl-1,10-phenanthroline and L indicates N,N-dimethyltrimethylenediamine with calf thymus DNA was investigated by absorption, circular dichroism, voltammetric, and viscosimetric techniques. The absorption spectra of the complex with calf thymus DNA showed a marked hypochromism in the pi --> pi* and metal to ligand charge transfer (MLCT) transitions, with no obvious red shift attributed to a partial intercalation. The intrinsic binding constant (K(b)) was determined as 2 x 10(5) M(-1). There was slight to appreciable changes in the relative viscosity of DNA, which is consistent with enhanced hydrophobic interaction of the methyl-substituted phen ring and partial intercalation mode of binding. Electrochemical studies showed a decrease in the peak current, which is ascribed to the strong binding between Cu (II) complex and DNA. The fluorescence spectral characteristics showed that the Cu (II) complex is able to displace the methylene blue bound to DNA, but not as complete as intercalative molecules. It is remarkable that this mixed ligand complex, in contrast to [Cu(2,9-dmp)(2)](+) (2,9-dmp = 2,9-dimethyl-1,10-phenanthroline), which fails to cleave DNA, has ability to cleave the supercoiled plasmid DNA.

In vitro study of DNA interaction with a water-soluble dinitrogen schiff base.

The present study investigates the binding interaction between a water-soluble Schiff base, N,N'-bis{5-[(triphenylphosphonium chloride)-methyl]salicylidine}-o-phenylenediamine (SF), and calf thymus DNA (CT-DNA) using emission, absorption, circular dichroism, and viscosity studies. In fluorimetric studies, the dynamic enhancement constant (K(D)) and bimolecular enhancement constant (K(B)) were calculated at different temperatures and demonstrated that fluorescence enhancement is not initiated by a dynamic process, but instead by a static process that involves complex DNA formation in the ground state. Further, the enthalpy and entropy of the reaction between SF and CT-DNA showed that the reaction is exothermic and enthalpy-favored (DeltaH = -153.51 kJ mol(-1); DeltaS = -427.67 J mol(-1) K). In addition, detectable changes in the circular dichroism spectrum of CT-DNA in the presence of SF indicated deep conformational changes in the DNA double helix following interaction with SF. Further, the Schiff base at different concentrations is able to perform cleavage of pUC18 plasmid DNA. All these results prove that SF interacts with CT-DNA via an intercalative mode of binding.