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Human rights bodies formulate highly specific orders to minimize the risk of State non-compliance. However, specificity comes at a cost, reducing State autonomy when local agents implement measures on the ground. This article develops the concept of specificity in human rights reparations and analyses the specificity formulas deployed by the Inter-American Court of Human Rights in structural measures as a form of positive subsidiarity. We employ qualitative data analysis software to process 322 measures of non-repetition ordered by the Inter-American Court through to the end of 2020. This analysis identifies two modes of specificity: process-based, which defines procedures for compliance, and outcome-based, which sets the goals for the State. After coding over 800 segments of text from Court decisions, we outline an exhaustive legal framework with 26 process-based categories and 2 outcome-based forms of specificity. We conclude that outcome-based specificity can help courts balance positive subsidiarity and State autonomy in the design of reparations. [ABSTRACT FROM AUTHOR]

Copper(II) complexes have become a potential alternative to the use of platinum drugs in cancer therapy due to their multi-target mode of action. In this context, we report the syntheses of new mononuclear and dinuclear coordination compounds of this element, 1 and 2, derived from the ligand 5-methylsalicylaldehyde 2-furoyl hydrazone (H2L). All three compounds were structurally and spectroscopically characterized, both in the solid state and in solution. In 1, Cu is coordinated by three donor-atoms from the hydrazonic ligand and one chloride ion. H2L is deprotonated at the phenol oxygen. The dinuclear complex 2 is, on the other hand, a dimeric form of 1 in which the chloride ions of a pair of mononuclear units are lost and phenoxo bridges take their places, double-connecting the metal centres and resulting in a single species with the ligand fully deprotonated. The compounds were fairly stable in aqueous medium at room temperature. An experimental–theoretical combined approach demonstrated that all of them are able to bind human serum albumin (HSA), although at different sites and with diverse stoichiometries and affinities (as concluded by the calculated binding energies). In view of this, and due to the well-known antiproliferative activity of hydrazone-containing copper complexes, we consider the compounds presented in here promising, and believe that they deserve more profound studies regarding the assessment of their potential against tumour cell lines. [ABSTRACT FROM AUTHOR]

Three new copper(II) complexes with the ligands quinuclidine [Cu(C7H13N)2(OH2)Cl]Cl.2H 2O (1), quinine [Cu(C20H23O2N2)(OH 2)2]ClO4 (2), and hydroquinidine [Cu(C20H27O2N2)(OH 2) Cl2]Cl.fraction one-halfH2O (3) have been isolated and characterized. The binding sites were assigned on the basis of vibrational spectroscopy, electron paramagnetic resonance, and thermal analysis results. The possibility of the involvement of the quinuclidinic nitrogen in the coordination was evidenced in complex 1, in which copper(II) is coordinated to two quinuclidine molecules. In the case of quinine-type ligands, if the starting material is deprotonated in both nitrogens, copper(II) coordination occurs through the quinuclidinic nitrogen, as in complex 2. In contrast, if the starting material is protonated in the quinuclidinic nitrogen the binding site is the quinolinic nitrogen, as in complex 3. Therefore, both nitrogens of quinine-type ligands constitute binding sites for copper(II) ions.

In fact, our latest results seem to point to the formation of ternary hydrazone-metal-protein complexes as fundamental species in the prevention of protein oligomerization and redox deactivation of the metal ([37]). Keywords: N -acylhydrazones; cognitive decline; biometals; metallophores; Metal-Protein Attenuating Compounds (MPACs) EN N -acylhydrazones cognitive decline biometals metallophores Metal-Protein Attenuating Compounds (MPACs) 1 6 6 02/18/22 20220216 NES 220216 Introduction The relevance of some endogenous metals, such as the redox-active copper and iron, and the putative neuromodulator zinc, to neurodegeneration is quite well documented in the scientific literature ([1], [2]). On the other hand, Richarson, Kalinowski and co-workers presented novel semicarbazone and hydrazone families of adamantane-containing chelators aiming to target multiple Alzheimer's hallmarks ([19]). [Extracted from the article]

Based on a variety of evidence (photographs, feces, specimens), three previously unsuspected caviomorph rodents are reported from Argentina: (1) a spiny rat (Echimyidae) probably belonging to the genus Phyllomys, in northern Misiones Province near Iguazú National Park; (2) an undetermined octodontid (Octodontidae) in western Chacoan Córdoba Province; and (3) the octodontid Spalacopus (Octodontidae), in high-Andean ranges of San Juan Province. The latter constitutes the first record of the genus for Argentina, and all the three findings highlight the necessity to increase collecting efforts in the country. [ABSTRACT FROM AUTHOR]

Although normal aging presents an accumulation of copper and iron in the brain, this becomes more relevant in neurodegeneration. α-Synuclein (α-Syn) misfolding has long been linked with the development of Parkinson's disease (PD). Copper binding promotes aggregation of α-Syn, as well as generalized oxidative stress. In this sense, the use of therapies that target metal dyshomeostasis has been in focus in the past years. Metal–Protein Attenuating Compounds (MPACs) are moderate chelators that aim at disrupting specific, abnormal metal–protein interactions. Our research group has now established that N-acylhydrazones compose a set of truly encouraging MPACs for the bioinorganic management of metal-enhanced aggregopathies. In the present work, a novel ligand, namely 1-methyl-1H-imidazole-2-carboxaldehyde isonicotinoyl hydrazone (X1INH), is reported. We describe solution studies on the interaction and affinity of this compound for copper(II) ions showing that a fine tuning of metal-affinity was achieved. A series of in vitro biophysical NMR experiments were performed in order to assess the X1INH ability to compete with α-Syn monomers for the binding of both copper(I) and copper(II) ions, which are central in PD pathology. A preference for copper(I) has been observed. X1INH is less toxic to human neuroglioma (H4) cells in comparison to structure-related compounds. Finally, we show that treatment with X1INH results in a higher number of smaller, less compact inclusions in a well-established model of α-Syn aggregation. Thus, X1INH constitutes a promising MPAC for the treatment of Parkinson's disease. [ABSTRACT FROM AUTHOR]

An analytical method for the determination of 8-hydroxyquinoline-2-carboxaldehyde isonicotinoyl hydrazone (INHHQ) is reported for the first time. The electrochemical method involving INHHQ was performed at a glassy carbon (GC) electrode modified with multiwalled carbon nanotubes (MWCNTs). The GC-MWCNTs promoted a significantly large enhancement in the Faradaic current employing square wave voltammetry (SWV) to determine INHHQ in the fortified extracts of the brain from Wistar rats. In addition, the MWCNTs increased the active electrode area, produced an electro-catalytic effect and provided significantly faster electron transfer. The quantification of INHHQ was made by the use of a supporting electrolyte consisting of Britton-Robinson (BR) buffer at a concentration of 0.02 mol L−1 and a pH of 11.0 in 0.25 mol L−1 KCl. The quantitative assay using square wave voltammetry was achieved by the serial addition of a standard into the electrochemical cell containing the sample. The limit of detection (LOD) for the protocol was equal to 0.25 µg mL−1 (0.85 µmol L−1). A procedure involving thin-layer chromatography (TLC) was employed in order to improve the selectivity required to determine INHHQ. The recoveries of the analyte in brain tissue from Wistar rats were statistically comparable to the values obtained by a high-performance liquid chromatography (HPLC) protocol. [ABSTRACT FROM AUTHOR]

Misfolded prion protein (PrPSc) is known for its role in fatal neurodegenerative conditions, such as Creutzfeldt–Jakob disease. PrP fragments and their mutants represent important tools in the investigation of the neurotoxic mechanisms and in the evaluation of new compounds that can interfere with the processes involved in neuronal death. Metal-catalyzed oxidation of PrP has been implicated as a trigger for the conformational changes in protein structure, which, in turn, lead to misfolding. Targeting redox-active biometals copper and iron is relevant in the context of protection against the oxidation of biomolecules and the generation of oxidative stress, observed in several conditions and considered an event that might promote sporadic prion diseases as well as other neurodegenerative disorders. In this context, ortho-pyridine aroylhydrazones are of interest, as they can act as moderate tridentate ligands towards divalent metal ions such as copper(II). In the present work, we explore the potentiality of this chemical class as peptide protecting agents against the deleterious metal-catalyzed oxidation in the M112A mutant fragment of human PrP, which mimics relevant structural features that may play an important role in the neurotoxicity observed in prion pathologies. The compounds inhere studied, especially HPCFur, showed an improved stability in aqueous solution compared to our patented lead hydrazone INHHQ, displaying a very interesting protective effect toward the oxidation of methionine and histidine, processes that are related to both physiological and pathological aging. [ABSTRACT FROM AUTHOR]

Aging is a natural process characterized by several biological changes. In this context, oxidative stress appears as a key factor that leads cells and organisms to severe dysfunctions and diseases. To cope with reactive oxygen species and oxidative-related damage, there has been increased use of superoxide dismutase (SOD)/catalase (CAT) biomimetic compounds. Recently, we have shown that three metal-based compounds {[Fe(HPClNOL)Cl2]NO3, [Cu(HPClNOL)(CH3CN)](ClO4)2 and Mn(HPClNOL)(Cl)2}, harboring in vitro SOD and/or CAT activities, were critical for protection of yeast cells against oxidative stress. In this work, treating Saccharomyces cerevisiae with these SOD/CAT mimics (25.0 mM/1 h), we highlight the pivotal role of these compounds to extend the life span of yeast during chronological aging. Evaluating lipid and protein oxidation of aged cells, it becomes evident that these mimics extend the life expectancy of yeast mainly due to the reduction in oxidative stress biomarkers. In addition, the treatment of yeast cells with these mimics regulated the amounts of lipid droplet occurrence, consistent with the requirement and protection of lipids for cell integrity during aging. Concerning SOD/CAT mimics uptake, using inductively coupled plasma mass spectrometry, we add new evidence that these complexes, besides being bioabsorbed by S. cerevisiae cells, can also affect metal homeostasis. Finally, our work presents a new application for these SOD/CAT mimics, which demonstrate a great potential to be employed as antiaging agents. Taken together, these promising results prompt future studies concerning the relevance of administration of these molecules against the emerging aging-related diseases such as Parkinson's, Alzheimer's and Huntington's. [ABSTRACT FROM AUTHOR]

The catalytic mechanism that involves the cleavage of the phosphate diester model BDNPP(bis(2,4-dinitrophenyl) phosphate) catalyzed through a dinuclear copper complex is investigated in the current study. The metal complex was originally designed to catalyze catechol oxidation, and it showed an interesting catalytic promiscuity case in biomimetic systems. The current study investigates two different reaction mechanisms through quantum mechanics calculations in the gas phase, and it also includes the solvent effect through PCM (polarizable continuum model) single-point calculations using water as solvent. Two mechanisms are presented in order to fully describe the phosphate diester hydrolysis. Mechanism 1 is of the SN2 type, which involves the direct attack of the μ-OH bridge between the two copper(II) ions toward the phosphorus center, whereas mechanism 2 is the process in which hydrolysis takes place through proton transfer between the oxygen atom in the bridging hydroxo ligand and the other oxygen atom in the phosphate model. Actually, the present theoretical study shows two possible reaction paths in mechanism 1. Its first reaction path (p1) involves a proton transfer that occurs immediately after the hydrolytic cleavage, so that the proton transfer is the rate-determining step, which is followed by the entry of two water molecules. Its second reaction path (p2) consists of the entry of two water molecules right after the hydrolytic cleavage, but with no proton transfer; thus, hydrolytic cleavage is the rate-limiting step. The most likely catalytic path occurs in mechanism 1, following the second reaction path (p2), since it involves the lowest free energy activation barrier (ΔG⧧ = 23.7 kcal mol-1, in aqueous solution). A kinetic analysis showed that the experimental kobs value of 1.7 10-5 s-1 agrees with the calculated value k1 = 2.6 ? 10-5 s-1; the concerted mechanism is kinetically favorable. The KIE (kinetic isotope effect) analysis applied to the second reaction path (p2) in mechanism 1 was also taken into account to assess the changes that take place inTS1-i (transition state of mechanism 1) and to perfectly characterize the mechanism described herein. [ABSTRACT FROM AUTHOR]

The crystal structures of the new complexes [Cu(HL1)(OH2)(ClO4)]ClO4·2H2O (1) and [Zn2(HL2)(L2)]ClO4(2), derived from two related, phenol-based compartmental ligands, are described. Compound2constitutes the first report of a complex obtained fromH2L2. The metal compounds are structurally different;2is a dimer in which all the heteroatoms of the ligand take part in coordination, while1is mononuclear containing a pair ofcis-oriented ligands that complete an “open” coordination sphere, in which the aldehyde group ofHL1is not involved. The protonation status of the central phenol groups ofHL1andH2L2are also dissimilar between the complexes. Infrared vibrational analyses of both complexes, as well as their respective ligands, were performed to connect the observed spectral features with the structural properties of the solids. While some distinctive bands shifted upon complexation, it was not possible to confirm involvement of the aromatic aldehyde group in coordination by this technique.1H NMR experiments involving2suggest that its particular protonation status is maintained upon dissolution in d6-DMSO. [ABSTRACT FROM AUTHOR]

Catechol oxidases (COs) are plant enzymes that belong to the oxidoreductases class. They contain a dinuclear copper center in their active site. In this article, we have investigated the dicopper(II) model complex [Cu2(μ-OH)(C21H33ON6)]2+ (Complex-A) under a computational perspective, using the DFT method, since this approach has been very useful in the treatment of bimetallic copper systems. The structural and spectroscopic study of Complex-A as well as the structural analysis of the BDNPP/Complex-A (Complex-B) adduct have been carried out. The calculated parameters for Complex-A are in good accordance with the experimental X-ray data. Some remarkable points can be observed from the calculated UV–vis relative excitations. The Complex-B computed structure verifies its identity as a key intermediate species in the BDNPP hydrolysis mechanism. The CuII···CuII calculated distance in Complex-B (3.026 Å) is shorter than the calculated for Complex-A (3.080 Å); one copper atom is bonded to the oxygen of phosphate [Cu (2)···O64–P] at 2.511 Å. These arguments clearly suggest a monodentate interaction and lead to a new mechanism involving terminal substrate coordination and subsequent intramolecular nucleophilic attack by a bridging hydroxide. Such a hypothesis is completely new in terms of homobimetallic copper systems, and may have important implications regarding the chemistry of several biological dinuclear catalytic sites. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010 [ABSTRACT FROM AUTHOR]

Presented in this Communication are the structure, physicochemical properties, and catalytic promiscuity of a new dinuclear CuII(μ-OH)CuII complex containing a novel N,O-donor symmetric dinucleating ligand. [ABSTRACT FROM AUTHOR]

The title compound (H2 L), C27H28N4O2, is an asymmetric binucleating ligand with well defined soft (N3O-donor) and hard (NO2-donor) sides. H2 L was designed as a ligand for the preparation of heterodinuclear mixed-valence MIII/ M′II complexes which are models for heterobimetallic active sites of enzymes, principally calcineurin. The mol­ecular structure of H2 L shows a spatial pre-organization of the donor groups for coordination. This conformation is stabilized by bifurcated intra- and inter­molecular O—H⋯N hydrogen bonds involving both phenol groups. The inter­molecular hydrogen bonds link mol­ecules of H2 L into chains running parallel to the crystallographic c axis. [ABSTRACT FROM AUTHOR]

Highlights: [•] Titanate nanotubes (TTNT) were modified with 3-aminopropyltriethoxysilane (APTES). [•] Effects of TTNT sodium content and solvent on APTES grafting efficiency were studied. [•] Aqueous ethanol was a more efficient reaction medium for functionalization of TTNT. [•] Within aqueous ethanol TTNT with low sodium content were more efficiently grafted. [•] Grafting of APTES on TTNT surface occurs through Ti–O–Si primary chemical bonding. [ABSTRACT FROM AUTHOR]

Copper(II) complexes have become a potential alternative to the use of platinum drugs in cancer therapy due to their multi-target mode of action. In this context, we report the syntheses of new mononuclear and dinuclear coordination compounds of this element, 1 and 2, derived from the ligand 5-methylsalicylaldehyde 2-furoyl hydrazone (H2L). All three compounds were structurally and spectroscopically characterized, both in the solid state and in solution. In 1, Cu is coordinated by three donor-atoms from the hydrazonic ligand and one chloride ion. H2L is deprotonated at the phenol oxygen. The dinuclear complex 2 is, on the other hand, a dimeric form of 1 in which the chloride ions of a pair of mononuclear units are lost and phenoxo bridges take their places, double-connecting the metal centres and resulting in a single species with the ligand fully deprotonated. The compounds were fairly stable in aqueous medium at room temperature. An experimental-theoretical combined approach demonstrated that all of them are able to bind human serum albumin (HSA), although at different sites and with diverse stoichiometries and affinities (as concluded by the calculated binding energies). In view of this, and due to the well-known antiproliferative activity of hydrazone-containing copper complexes, we consider the compounds presented in here promising, and believe that they deserve more profound studies regarding the assessment of their potential against tumour cell lines.