Understanding the Factors That Influence the Antioxidant Activity of Manganosalen Complexes with Neuroprotective Effects.

Manganosalen complexes are a class of catalytic antioxidants with beneficial effects against different neurological disorders according to various in vitro and in vivo studies. The interest in the factors that determine their antioxidant activity is based on the fact that they are key to achieving more efficient models. In this work, we report a set of new manganosalen complexes, thoroughly characterized in the solid state and in solution by different techniques. The chelating Schiff base ligands used were prepared from condensation of different substituted hydroxybenzaldehydes with 1,2-diaminoethane and 1,3-diaminopropane. The antioxidant activity of the new models was tested through superoxide dismutase and catalase probes in conjunction with the studies about their neuroprotective effects in human SH-SY5Y neuroblastoma cells in an oxidative stress model. The ability to scavenge excess reactive oxygen species (ROS) varied depending on the manganosalen models, which also yielded different improvements in cell survival. An assessment of the different factors that affect the oxidant activity for these complexes, and others previously reported, revealed the major influence of the structural factors versus the redox properties of the manganosalen complexes.

Neuroprotective effects of fluorophore-labelled manganese complexes: Determination of ROS production, mitochondrial membrane potential and confocal fluorescence microscopy studies in neuroblastoma cells.

In this work, four manganese(II) complexes derived from the ligands H2L1-H2L4, that incorporate dansyl or tosyl fluorescent dyes, have been investigated in term of their antioxidant properties. Two of the manganese(II) complexes have been newly prepared using the asymmetric half-salen ligand H2L2 and the thiosemicarbazone ligand H2L3. The four organic strands and the manganese complexes have been characterized by different analytical and spectroscopic techniques. The study of the antioxidant behaviour of these two new complexes and other two fluorophore-labelled analogues was tested in SH-SY5Y neuroblastoma cells. These four model complexes 1-4 were found to protect cells from oxidative damage in this human neuronal model, by reducing the release of reactive oxygen species. Complexes 1-4 significantly improved cell survival, with levels between 79.1 ± 0.8% and 130.9 ± 4.1%. Moreover, complexes 3 and 4 were able to restore the mitochondrial membrane potential at 1 µM, with 4 reaching levels higher than 85%, similar to the percentages obtained by the positive control agent cyclosporin A. The incorporation of the fluorescent label in the complexes allowed the study of their ability to enter the human neuroblastoma cells by confocal microscopy.

Combined Effect of Caspase-Dependent and Caspase-Independent Apoptosis in the Anticancer Activity of Gold Complexes with Phosphine and Benzimidazole Derivatives.

Since the potential anticancer activity of auranofin was discovered, gold compounds have attracted interest with a view to developing anticancer agents that follow cytotoxic mechanisms other than cisplatin. Two benzimidazole gold(I) derivatives containing triphenylphosphine (Au(pben)(PPh3)) (1) or triethylphosphine (Au(pben)(PEt3)) (2) were prepared and characterized by standard techniques. X-ray crystal structures for 1 and 2 were solved. The cytotoxicity of 1 and 2 was tested in human neuroblastoma SH-SY5Y cells. Cells were incubated with compounds for 24 h with concentrations ranging from 10 µM to 1 nM, and the half-maximal inhibitory concentration (IC50) was determined. 1 and 2 showed an IC50 of 2.7 and 1.6 µM, respectively. In order to better understand the type of cell death induced by compounds, neuroblastoma cells were stained with Annexin-FITC and propidium iodide. The fluorescence analysis revealed that compounds were inducing apoptosis; however, pre-treatment with the caspase inhibitor Z-VAD did not reduce cell death. Analysis of compound effects on caspase-3 activity and reactive oxygen species (ROS) production in SH-SY5Y cells revealed an antiproliferative ability mediated through oxidative stress and both caspase-dependent and caspase-independent mechanisms.

Pursuing the Elixir of Life: In Vivo Antioxidative Effects of Manganosalen Complexes.

Manganosalen complexes are coordination compounds that possess a chelating salen-type ligand, a class of bis-Schiff bases obtained by condensation of salicylaldehyde and a diamine. They may act as catalytic antioxidants mimicking both the structure and the reactivity of the native antioxidant enzymes active site. Thus, manganosalen complexes have been shown to exhibit superoxide dismutase, catalase, and glutathione peroxidase activities, and they could potentially facilitate the scavenging of excess reactive oxygen species (ROS), thereby restoring the redox balance in damaged cells and organs. Initial catalytic studies compared the potency of these compounds as antioxidants in terms of rate constants of the chemical reactivity against ROS, giving catalytic values approaching and even exceeding that of the native antioxidative enzymes. Although most of these catalytic studies lack of biological relevance, subsequent in vitro studies have confirmed the efficiency of many manganosalen complexes in oxidative stress models. These synthetic catalytic scavengers, cheaper than natural antioxidants, have accordingly attracted intensive attention for the therapy of ROS-mediated injuries. The aim of this review is to focus on in vivo studies performed on manganosalen complexes and their activity on the treatment of several pathological disorders associated with oxidative damage. These disorders, ranging from the prevention of fetal malformations to the extension of lifespan, include neurodegenerative, inflammatory, and cardiovascular diseases; tissue injury; and other damages related to the liver, kidney, or lungs.

Salen­manganese complexes for controlling ROS damage: Neuroprotective effects, antioxidant activity and kinetic studies.

A new manganese(III) complex [MnL1(DCA)(H2O)](H2O),1 [H2L1 is the chelating ligand N,N'-bis(2-hydroxy-3-methoxybenzylidene)-1,2-diaminopropane, and DCA is dicyanamide], has been prepared and characterized by different analytical and spectroscopic techniques. The tetragonally elongated octahedral geometry for the manganese coordination sphere was revealed by X-ray diffraction studies for 1. The antioxidant behavior of this complex and other manganese(III)-salen type complexes was tested through superoxide dismutase and catalase probes, and through the study of their neuroprotective effects in SH-SY5Y neuroblastoma cells. In this human neuronal model, these model complexes were found to improve cell survival in an oxidative stress model. During studies aimed to getting a better understanding of the kinetics of the processes involved in this antioxidant behavior, an important effect on the solvent in the kinetics of reaction of the complexes with H2O2 was revealed that suggests a change in the mechanism of reaction of the complexes. The kinetic data in methanol and buffered aqueous solutions correlate well with the results of the test of catalase activity, thus showing that the rate determining step in the catalytic cycle corresponds to the initial reaction of the complexes with H2O2.