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.

Nickel, copper, and zinc dinuclear helicates: how do bulky groups influence their architecture?

The ligand design factors that may influence the isolation of metallosupramolecular helicates or mesocates still deserve to be investigated. In this sense, dinuclear nickel(II), copper(II) and zinc(II) compounds were obtained by electrochemical synthesis using a family of five Schiff base ligands, H2Ln (n = 1-5), derived from bisphenylmethane and functionalized with bulky tert-butyl groups in the periphery and ethyl groups in the spacer. Six of the new complexes were characterized by X-ray crystallography, thus demonstrating that the helicate structure is predominant in the solid state. 1H NMR studies were performed for the zinc complexes to analyze if the helical architecture of the metal complexes is retained in solution. These studies reveal that the presence of a tert-butyl group in the ortho position with respect to the OH group is an essential factor identified for the existence of a helicate conformation in solution.

Enemies or Allies? Hormetic and Apparent Non-Dose-Dependent Effects of Natural Bioactive Antioxidants in the Treatment of Inflammation.

This review aims to analyze the emerging number of studies on biological media that describe the unexpected effects of different natural bioactive antioxidants. Hormetic effects, with a biphasic response depending on the dose, or activities that are apparently non-dose-dependent, have been described for compounds such as resveratrol, curcumin, ferulic acid or linoleic acid, among others. The analysis of the reported studies confirms the incidence of these types of effects, which should be taken into account by researchers, discarding initial interpretations of imprecise methodologies or measurements. The incidence of these types of effects should enhance research into the different mechanisms of action, particularly those studied in the field of basic research, that will help us understand the causes of these unusual behaviors, depending on the dose, such as the inactivation of the signaling pathways of the immune defense system. Antioxidative and anti-inflammatory activities in biological media should be addressed in ways that go beyond a mere statistical approach. In this work, some of the research pathways that may explain the understanding of these activities are revised, paying special attention to the ability of the selected bioactive compounds (curcumin, resveratrol, ferulic acid and linoleic acid) to form metal complexes and the activity of these complexes in biological media.

A Dinuclear Copper(II) Complex Electrochemically Obtained via the Endogenous Hydroxylation of a Carbamate Schiff Base Ligand: Synthesis, Structure and Catalase Activity.

In the present work, we report a neutral dinuclear copper(II) complex, [Cu2(L1)(OH)], derived from a new [N,O] donor Schiff base ligand L1 that was formed after the endogenous hydroxylation of an initial carbamate Schiff base H2L coordinated with copper ions in an electrochemical cell. The copper(II) complex has been fully characterized using different techniques, including X-ray diffraction. Direct current (DC) magnetic susceptibility measurements were also performed at variable temperatures, showing evidence of antiferromagnetic behavior. Its catalase-like activity was also tested, demonstrating that this activity is affected by temperature.

Desulfurization of thiosemicarbazones: the role of metal ions and biological implications.

Thiosemicarbazones are biologically active substances whose structural formula is formed by an azomethine, an hydrazine, and a thioamide fragments, to generate a R2C=N-NR-C(=S)-NR2 backbone. These compounds often act as ligands to generate highly stable metal-organic complexes. In certain experimental conditions, however, thiosemicarbazones undergo reactions leading to the cleavage of the chain. Sometimes, the breakage involves desulfurization processes. The present work summarizes the different chemical factors that influence the desulfurization reactions of thiosemicarbazones, such as pH, the presence of oxidant reactants or the establishment of redox processes as those electrochemically induced, the effects of the solvent, the temperature, and the electromagnetic radiation. Many of these reactions require coordination of thiosemicarbazones to metal ions, even those present in the intracellular environment. The nature of the products generated in these reactions, their detection in vivo and in vitro, together with the relevance for the biological activity of these compounds, mainly as antineoplastic agents, is discussed.

Effect of Magnetic Anisotropy on the 1H NMR Paramagnetic Shifts and Relaxation Rates of Small Dysprosium(III) Complexes.

We present a detailed analysis of the 1H NMR chemical shifts and transverse relaxation rates of three small Dy(III) complexes having different symmetries (C3, D2 or C2). The complexes show sizeable emission in the visible region due to 4F9/2 → 6HJ transitions (J = 15/2 to 11/2). Additionally, NIR emission is observed at ca. 850 (4F9/2 → 6H7/2), 930 (4F9/2 → 6H5/2), 1010 (4F9/2 → 6F9/2), and 1175 nm (4F9/2 → 6F7/2). Emission quantum yields of 1-2% were determined in aqueous solutions. The emission lifetimes indicate that no water molecules are present in the inner coordination sphere of Dy(III), which in the case of [Dy(CB-TE2PA)]+ was confirmed through the X-ray crystal structure. The 1H NMR paramagnetic shifts induced by Dy(III) were found to be dominated by the pseudocontact mechanism, though, for some protons, contact shifts are not negligible. The analysis of the pseudocontact shifts provided the magnetic susceptibility tensors of the three complexes, which were also investigated using CASSCF calculations. The transverse 1H relaxation data follow a good linear correlation with 1/r6, where r is the distance between the Dy(III) ion and the observed proton. This indicates that magnetic anisotropy is not significantly affecting the relaxation of 1H nuclei in the family of complexes investigated here.

Schiff Bases Functionalized with T-Butyl Groups as Adequate Ligands to Extended Assembly of Cu(II) Helicates.

The study of the inherent factors that influence the isolation of one type of metallosupramolecular architecture over another is one of the main objectives in the field of Metallosupramolecular Chemistry. In this work, we report two new neutral copper(II) helicates, [Cu2(L1)2]·4CH3CN and [Cu2(L2)2]·CH3CN, obtained by means of an electrochemical methodology and derived from two Schiff-based strands functionalized with ortho and para-t-butyl groups on the aromatic surface. These small modifications let us explore the relationship between the ligand design and the structure of the extended metallosupramolecular architecture. The magnetic properties of the Cu(II) helicates were explored by Electron Paramagnetic Resonance (EPR) spectroscopy and Direct Current (DC) magnetic susceptibility measurements.

Exploring the Biological Properties of Zn(II) Bisthiosemicarbazone Helicates.

The design of artificial helicoidal molecules derived from metal ions with biological properties is one of the objectives within metallosupramolecular chemistry. Herein, we report three zinc helicates derived from a family of bisthiosemicarbazone ligands with different terminal groups, Zn2(LMe)2∙2H2O 1, Zn2(LPh)2∙2H2O 2 and Zn2(LPhNO2)23, obtained by an electrochemical methodology. These helicates have been fully characterized by different techniques, including X-ray diffraction. Biological studies of the zinc(II) helicates such as toxicity assays with erythrocytes and interaction studies with proteins and oligonucleotides were performed, demonstrating in all cases low toxicity and an absence of covalent interaction with the proteins and oligonucleotides. The in vitro cytotoxicity of the helicates was tested against MCF-7 (human breast carcinoma), A2780 (human ovarian carcinoma cells), NCI-H460 (human lung carcinoma cells) and MRC-5 (normal human lung fibroblasts), comparing the IC50 values with cisplatin. We will try to demonstrate if the terminal substituent of the ligand precursor exerts any effect in toxicity or in the antitumor activity of the zinc helicates.

Hydrolysis of a carbamate triggered by coordination of metal ions.

The mechanism of carbamate activation promoted by different metal ions has been explored in this work. The reaction of the carbamate ligand H2L with chloride metal salts (M = Ni, Cu, Zn, Cd) leads to the coordination of the metal ions to the ligand, causing hydrolysis of the systems. This self-immolation process results in mononuclear dihydrazone complexes, carbon dioxide and the release of alcohol species from the pendant groups of the carbamate ligand. The conditions under which this process occurs have been studied in detail.

Two Synthetic Approaches to Coinage Metal(I) Mesocates: Electrochemical versus Chemical Synthesis.

We report two different approaches to isolate neutral and cationic mesocate-type metallosupramolecular architectures derived from coinage monovalent ions. For this purpose, we use a thiocarbohydrazone ligand, H2L (1), conveniently tuned with bulky phosphine groups to stabilize the MI ions and prevent ligand crossing to achieve the selective formation of mesocates. The neutral complexes [Cu2(HL)2] (2), [Ag2(HL)2] (3), and [Au2(HL)2] (4) were prepared by an electrochemical method, while the cationic complexes [Cu2(H2L)2](PF6)2 (5), [Cu2(H2L)2](BF4)2 (6), [Ag2(H2L)2](PF6)2 (7), [Ag4(HL)2](NO3)2 (8), and [Au2(H2L)2]Cl2 (9) were obtained by using a metal salt as the precursor. All of the complexes are neutral or cationic dinuclear mesocates, except the silver nitrate derivative, which exhibits a tetranuclear cluster mesocate architecture. The crystal structures of the neutral and cationic copper(I), silver(I), and gold(I) complexes allow us to analyze the influence of synthetic methodology or the counterion role on both the micro- and macrostructures of the mesocates.

Comparative study of the antitumoral activity of phosphine-thiosemicarbazone gold(I) complexes obtained by different methodologies.

A series of phosphino-thiosemicarbazone gold(I) dinuclear complexes obtained by two different synthetic procedures have been prepared. All the compounds have been spectroscopically characterized including single crystal X ray diffraction analysis in some of cases. [Au2(HL1)Cl2] (1), [Au2(HL2)2]Cl2 (2) and [Au2(HL3)2]Cl2 (3) have been prepared by chemical synthesis using a gold(III) salt as precursor; while [Au2(L1)2] (4), [Au2(L2)2]∙2CH3CN (5) and [Au2(L3)2] (6) have been isolated from an electrochemical synthesis (HLn = 2-[2-(diphenylphosphanyl)-benzylidene]-N-R-thiosemicarbazone; HL1: R = methyl, HL2: R = methoxyphenyl, HL3: R = nitrophenyl). The in vitro cytotoxic activity of these gold(I) complexes was tested against some human tumor cell lines: HeLa 229 (cervical epithelial carcinoma), MCF-7 (ovarian adenocarcinoma), NCI-H460 (non-small-cell lung cancer) and MRC5 (normal human lung fibroblast), and the IC50 values compared with those of cisplatin. The neutral methyl-substituted complexes 1 and 4 and methoxyphenyl 5 displayed significant cytotoxic activities in all investigated cancer cell lines, being 1 and 4 the most effective. The ability of complexes 1 and 4 to induce cell death by apoptosis in Hela 229 was also investigated by fluorescence microscopy using the apoptotic DNA fragmentation as marker. These results indicated that the inhibition of cell proliferation is mainly due to an apoptotic process. In order to obtain more information about the mechanism of action of these metallocompounds, the interactions of complexes 1 and 4 with the thioredoxin reductase (TrxR) enzyme were analyzed. Both complexes exhibited a strong inhibition of the thioredoxin reductase activity.

Effect of the Metal Ion on the Enantioselectivity and Linkage Isomerization of Thiosemicarbazone Helicates.

The effect of the metal ion and ligand design on the enantioselectivity and linkage isomerization of neutral cobalt and zinc bisthiosemicarbazone metallohelicates has been investigated in this work. The electrochemical synthesis has afforded the enantioselective formation of chirally pure cobalt helicates, and the ΛΛ isomer of a single enantiomer has been crystallized as only product for the cobalt methyl-substituted thiosemicarbazone helicate. Interestingly linkage isomers have been formed from zinc ethyl-substituted thiosemicarbazone helicate enantiomers for the first time. The co-existence of these isomers has been evaluated from the point of view of both experimental results and computational calculations.