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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]

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]

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]

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.