Topoisomerase II inhibition activity of new square planar Ni(II) complexes containing N-substituted thiosemicarbazones: Synthesis, spectroscopy, X-ray crystallography and electrochemical characterization

New Ni(II) thiosemicarbazone complexes containing triphenylphosphine namely [Ni(Sal-mtsc)(PPh₃)](2) and [Ni(Nap-mtsc)(PPh₃)] (3) (where Sal-mtsc = salicylaldehyde-N(4)-methylthiosemicarbazone and Nap-mtsc = 2-hydroxy-1-naphthaldehyde-N(4)-methylthiosemicarbazone) have been synthesised and characterized by elemental analysis, IR, electronic and ¹H NMR spectroscopy. The crystal structures of the complexes have been determined by single crystal X-ray diffraction technique. In all the complexes the thiosemicarbazone ligand coordinated to nickel through ONS mode. The electrochemical behavior of the complexes has been investigated by using cyclic voltammetry in acetonitrile. The new complexes were subjected to test their DNA topoisomerase II inhibition efficiency. The complex [Ni(Nap-mtsc)(PPh₃)] (3) showed 95% inhibition. The observed inhibition activity was found to be more potent than the activity of conventional standard Nalidixic acid.     

Double-strand DNA cleavage induced by oxindole-Schiff base copper(II) complexes with potential antitumor activity

Some oxindole-Schiff base copper(II) complexes have already shown potential antitumor activity towards different cells, inducing apoptosis in a process modulated by the ligand, and having nuclei and mitochondria as main targets. Here, three novel copper(II) complexes with analogous ligands were isolated and characterized by spectroscopic techniques, having their reactivity compared to the so far most active complex in this class. Cytotoxicity experiments carried out toward human neuroblastoma SH-SY5Y cells confirmed its pro-apoptosis property. DNA cleavage studies were then performed in the presence of these complexes, in order to verify the influence of ligand structural features in its nuclease activity. All of them were able to cause double-strand DNA scissions, giving rise to nicked circular Form II and linear Form III species, in the presence of hydrogen peroxide. Additionally, DNA Form II was also detected in the absence of peroxide when the most active complex, [Cu(isaepy)₂]²⁺ 1, was used. In an effort to better elucidate their interactions with DNA, solutions of the different complexes titrated with DNA had their absorption spectra monitored. An absorbance hyperchromism observed at 260 nm pointed to the intercalation of these complexes into the DNA structure. Further, investigations of 2-deoxy-d-ribose (DR) oxidation catalyzed by each of those complexes, using 2-thiobarbituric acid reactive species (TBARS) method, and detection of reactive oxygen species (ROS) formation by spin-trapping EPR, suggested that their mechanism of action in performing efficiently DNA cleavage occurs preferentially, but not only by oxidative pathways.     

Physicochemical study of floranol, its copper(II) and iron(III) complexes, and their inhibitory effect on LDL oxidation

The antioxidant activity of floranol (3,5,7,2'-tetrahydroxy-6-methoxy-8-prenylflavanone), a new flavonoid isolated from the roots of Dioclea grandiflora, was evaluated by the inhibition of human low-density lipoprotein (LDL) oxidation. Floranol increased its oxidation lag-phase significantly in a dose-dependent manner. As the antioxidant mechanism may involve metal coordination, we have undertaken a detailed study of floranol interactions with Cu(II) and Fe(III) by combination of UV-visible (UV-Vis) and mass spectrometries and cyclic voltammetry. The acidity constants of the ligand as well as the stability constants of the metal complexes were calculated. The pKa values of 6.58, 11.97 and 13.87 were determined and the following acidity order is proposed 7-OH>5-OH>2'-OH. The best fit between experimental and calculated spectra was obtained assuming the formation of two Cu(II) complexes: [CuL] logbeta=19.34+/-0.05 and [CuL(2)](2-) logbeta=26.4+/-0.10 and three Fe(III) complexes: [FeL(3)](3-) logbeta=44.72+/-0.09, [FeL(2)](-) logbeta=35.32+/-0.08 and [FeL](+) logbeta=19.51+/-0.04. In addition, copper and iron reduction is less favorable in the presence of floranol. These results indicate that floranol can efficiently bind Cu(II) and Fe(III) ions thus preventing their effect on LDL oxidation.     

Binding of oxindole-Schiff base copper(II) complexes to DNA and its modulation by the ligand

Previous studies on copper(II) complexes with oxindole-Schiff base ligands have shown their potential antitumor activity towards different cells, inducing apoptosis through a preferential attack to DNA and/or mitochondria. Herein, we better characterize the interactions between some of these copper(II) complexes and DNA. Investigations on its binding ability to DNA were carried out by fluorescence measurements in competitive experiments with ethidium bromide, using plasmidial or calf-thymus DNA. These results indicated an efficient binding process similar to that observed with copper(II)-phenanthroline species, [Cu(o-phen)₂]²⁺, with binding constants in the range 3 to 9 × 10² M^− 1. DNA cleavage experiments in the presence and absence of distamycin, a recognized binder of DNA, indicated that this binding probably occurs at major or minor groove, leading to double-strand DNA cleavage, and being modulated by the imine ligand. Corroborating these data, discrete changes in EPR spectra of the studied complexes were observed in the presence of DNA, while more remarkable changes were observed in the presence of nucleotides (AMP, GMP, CMP or UMP). Additional evidence for preferential coordination of the copper centers to the bases guanine or cytosine was obtained from titrations of these complexes with each nucleotide, monitored by absorption spectral changes. Therefore, the obtained data point out to their action as groove binders to DNA bases, rather than as intercalators or covalent cross-linkers. Further investigations by SDS PAGE using ³²P-ATP or ³²P-oligonucleotides attested that no hydrolysis of phosphate linkage in DNA or RNA occurs, in the presence of such complexes, confirming their main oxidative mechanism of action.     

Binding and photocleavage of DNA by mixed ligand Co(III) and Ni(II) complexes of thiophene[2, 3-b] quinoline and phenanthrolie/bipyridine

In order to systematically perform an experimental and theoretical study on DNA binding and photocleavage properties of transition metal complexes of the type [M(L)₂(L₁)](PF₆)_n · xH₂O (where M = Co(III) or Ni(II), L = 1,10-phenanthroline or 2.2′ bipryidine, L₁ = Thiophene [2,3-b] quinoline (qt), n = 3 or 2 and x = 5 or 2) have been synthesized and characterized by elemental analysis, IR, ¹H NMR, UV and magnetic susceptibility data. The DNA-binding properties of these complexes have been investigated with UV-Vis, viscosity measurements, thermal denaturation and cyclic voltametric studies. It is experimentally found that all the complexes are bound to DNA via intercalation in the order [Co(bpy)₂(qt)](PF₆)₃ > [Co(phen)₂(qt)](PF₆)₃ > [Ni(phen)₂(qt)](PF₆)₂ > [Ni(bpy)₂(qt)](PF₆)₂. The photocleavage studies with pUC19 DNA shows that all these complexes promoted the conversion of SC form to NC form in absence of ‘inhibitors’.