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.

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.

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.

Selective Metal-Assisted Assembly of Mesocates or Helicates with Tristhiosemicarbazone Ligands.

The effect of the ligand and/or metal-related factors on the formation of tristhiosemicarbazone metallosupramolecular complexes has been studied in this work. The crystal structures of zinc(II) and lead(II) tristhiosemicarbazone mesocates and a hydrolyzed cadmium(II) helicate let us better rationalize some factors involved in the selective formation of helicates or mesocates.

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.

"The Golden Method": Electrochemical Synthesis Is an Efficient Route to Gold Complexes.

Gold compounds to be obtained by the direct electrochemical oxidation of a noble metal are reported. This achievement provides an alternative procedure to obtaining neutral gold compounds with potential medical or catalytic applications.

Alkali-metal-ion-directed self-assembly of redox-active manganese(III) supramolecular boxes.

The ability to organize functional molecules into higher dimensional arrays with well-defined spatial relationships between the components is one of the major goals in supramolecular chemistry. We report here a new route for the preparation of supramolecular boxes, incorporating two types of metal ions: (i) alkali-metal ions, which induce the supramolecular architecture and essentially play a structural role in the final compounds; (ii) manganese(III) ions, which are redox-active systems and give functionality to the new cages. Our results evidence that the size of the cavity inside the box can be tuned depending on the alkali metal used, a characteristic that gives this new family of compounds the potential to act selectively against different substrates. These compounds behave as active catalysts for disproportionation of H2O2 or for water photolysis, but they catalyze neither catecholase reaction nor peroxidase action upon using bulky organic substrates.

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.

Cluster helicates: promising functional materials.

Cluster helicates are a new type of supramolecular architecture that consists of a metal cluster wrapped around by ligands arranged in a helical mode. This class of compounds combines the unique properties of metal clusters with the sophisticated chiral arrangement found in helicates. Therefore, these architectures show promising applications in the development of advanced materials with specific electronic, magnetic, optical, catalytic and biological properties. This review delves into a few pioneering studies on cluster helicates and their applications as nanomagnetic, nanoelectric and catalyst materials. Furthermore, it emphasises the necessity for further exploration in this area and the fields related to the functional applications that cluster helicates can bring to the future of materials science.

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.

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.

Manganese-Schiff base complexes as catalysts for water photolysis.

Four manganese(III)-Schiff base complexes (1-4) of formula [MnL(n)(H(2)O)(2)](2)(ClO(4))(2)·mH(2)O (n = 1-4; m = 0, 1) have been prepared. The multidentate H(2)L(n) Schiff base ligands consist of 3R,5R-substituted N,N'-bis(salicylidene)-1,2-diimino-2,2-dimethylethane, where R = OEt, OMe, Br or Cl. The complexes have been thoroughly characterized by elemental analysis, mass spectrometry, magnetic susceptibility measurements, IR, UV, paramagnetic (1)H NMR and EPR spectroscopies. Other properties, including redox studies and molar conductivity measurements, have also been assessed. The crystal structure of 1 was solved by X-ray diffraction, which revealed the dimeric nature of the compound through µ-aqua bridges. The ability of these complexes to split water has been studied by water photolysis experiments, with the oxygen evolution measured in aqueous media in the presence of a hydrogen acceptor (p-benzoquinone), the reduction of which was followed by UV-spectroscopy. The discussion of the photolytic behaviour includes advances in the knowledge of the structural motifs and the chemical activity of this type of complex, as revealed by the development of several characterization techniques in the last decade. Parallel-mode Mn(III) EPR shows that complexes 1-4 not only mimic reactivity but also share some structural characteristics from partially assembled natural OEC clusters.

Endogenous arene hydroxylation promoted by copper(I) cluster helicates.

A novel neutral triple-stranded hexanuclear copper(I) cluster helicate [Cu(I)(6)L(3)]·2CH(3)CN derived from a thiosemicarbazone ligand could be synthesized and crystallographically characterized. The MALDI mass spectrum of this complex suggests that the tetranuclear copper(I) cluster helicate [Cu(I)(4)L(2)] is also present in solution. These copper(I) cluster helicates are capable, in the presence of O(2), of hydroxylating the arene linker of their supporting ligand strands. The resulting dinuclear complex [Cu(II)(2)L'(OH)] is formed by two copper(II) centers, a new ligand arising from the hydroxylation reaction, and one hydroxide group. The magnetic investigation of this compound shows a strong antiferromagnetic coupling between the two Cu(II) centers. The kinetic studies for the hydroxylation process show values of ΔH(≠)=-70 kJ mol(-1), similar to those mediated by the tyrosinase enzymes.

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.

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.

Unprecedent isolation of a mixture of conformational and linkage isomers in a thiosemicarbazone cobalt mesocate.

A cobalt(II) thiosemicarbazonate mesocate has been structurally characterized as an unexpected mixture of conformational and linkage isomers. Moreover, we have shown that the absence of a nitrogen atom in the spacer of the helicand ligand H(2)L(a), enables the assembly of an achiral mesohelical complex in the case of Co(II) ions.

Novel peroxidase mimics: mu-Aqua manganese-Schiff base dimers.

The interaction of manganese(II) carboxylate salts [Mn(O(2)CR)(2), where R=ethane, pentane] with H(2)L(1) [N,N'-bis(3-methoxy-2-hydroxybenzaldehyde)-1,2-phenylenediamine] and H(2)L(2) [N,N'-bis(3-ethoxy-2-hydroxybenzaldehyde)-1,2-phenylenediamine] was studied. MnL(1)(O(2)CEt)(H(2)O) (1), MnL(1)(O(2)CPe(n))(H(2)O) (2), MnL(2)(O(2)CEt)(H(2)O)(2) (3) and MnL(2)(O(2)CPe(n))(H(2)O)(2) (4) were isolated and thoroughly characterised by elemental analysis, FAB mass spectrometry, infrared and (1)H NMR spectroscopy, magnetic susceptibility measurements, molar conductivities, and cyclic and normal pulse voltammetry. Compounds 1 and 2 were crystallographically characterised revealing a tetragonally elongated octahedral geometry for the manganese coordination sphere and also a dimeric nature through mu-aqua bridges. Complexes 1-4 behave as efficient peroxidase mimics in the presence of the water-soluble trap ABTS, probably due to their ease to coordinate the substrate molecule. A correlation between rhombicity of the complexes and peroxidase activity has also been established.

An unusual assembled Pb(ii) meso-helicate that shows the inert pair effect.

A dinuclear Pb(ii) mesocate has been prepared with an unprecedented four-coordinated kernel in which the Pb(ii) lone pair is stereochemically active. This is the first time that this effect has been observed in a supramolecular Pb(ii) helicate or meso-helicate.