Graziella Vecchio

Metal complexes of functionalized cyclodextrins as enzyme models and chiral receptors

Abstract Cyclodextrins (CDs) are cyclic oligomers of α-1,4 linked d -glucopyranose. The main feature of CDs is an hydrophobic cavity which renders these molecules unusual. By appropriate functionalization new systems can be obtained and the features of these molecules can be increased and modulated. Among the various applications the building of molecular receptors and enzyme models by cyclodextrins is a particularly fascinating field. The present review will be a survey of the metal complexing properties of CDs and a report on some recent results of metal complexes formed by functionalized cyclodextrins. The metal ion can assist the host–guest interaction often increasing the properties of CDs to act as chiral receptors. Furthermore it can act as catalytic center in the mimicking of some metallo–enzyme models by functionalized cyclodextrins.

Neuroprotective features of carnosine in oxidative driven diseases.

Carnosine (β-alanyl-L-histidine) is a natural dipeptide widely and abundantly distributed in excitable tissues of several animal tissues. Although its physiological role has not been completely understood yet, many beneficial actions have been attributed to carnosine, such as being an antioxidant, antiglycating and ion-chelating agent, a wound healing promoter and a free-radical scavenger. The role of carnosine in the neuroprotection of oxidative stress-driven disorders has been reviewed. The effects of carnosine have been extensively studied both in vivo and in vitro models of cerebral damages, such as neurodegenerative disorders and hypoxia-ischemia injuries. Beside the classical sacrificial agent, carnosine has been reevaluated as a molecular chaperon and an inducer of antioxidant systems in oxidative stress conditions. Thus, beneficial effects on most of the common biochemical events that characterize neurological disorders make carnosine a very promising molecule among all the endogenous compounds in the treatment and/or prevention of oxidative driven diseases.

Determination of superoxide dismutase-like activity of copper(II) complexes. Relevance of the speciation for the correct interpretation of in vitro O2- scavenger activity.

The superoxide dismutase activity of several copper(II) complexes of linear and cyclic dipeptides has been measured. The results of a classic indirect method (xanthine-xanthine oxidase) have been compared with those obtained by generation of the superoxide radical through 2-(3-benzoylphenyl)propionic acid (ketoprofen) photolysis. A simulation approach, based on the knowledge of the stability constants of the different complex species existing in experimental conditions, has allowed us to obtain the correct speciation and to use these data to calculate the pertinent catalytic constants.

Potentiometric, spectroscopic and antioxidant activity studies of SOD mimics containing carnosine

Stability constant values and bonding details of the copper(II) complexes of the β-cyclodextrin functionalized with the carnosine dipeptide (β-alanyl-L-histidine) at its narrow (CDAH6) or at its wide (CDAH3) rim were determined in aqueous solution. The potentiometric and spectroscopic data (UV-vis, CD and EPR) show that the involvement of a secondary OH group induces drastic differences in the coordination properties of CDAH3, in comparison with those of CDAH6. Direct and indirect assays were carried out showing that the copper(II) complexes with the two cyclodextrin derivatives are SOD-mimics with high catalytic activity. In addition the complex species are scavenger compounds towards ˙OH radicals, giving rise to a particular kind of copper(II) complexes with a combined activity against two toxic radical species, O2˙− and ˙OH. The cyclodextrin moiety contributes to the scavenger activity, without damaging the cellular membranes of neuronal and red blood cells.

Coordination properties of 6-deoxy-6-[1-(2-amino) ethylamino]-β-cyclodextrin and the ability of its copper(II) complex to recognize and separate amino acid enantiomeric pairs

The functionalized cyclodextrin 6-deoxy-6-[1-(2-amino)ethylamino]-β-cyclodextrin was synthesized, and an NMR, EPR, pH-metric, and calorimetric investigation was carried out in aqueous solution in order to ascertain its behaviour towards protonation and copper(II) complex formation. The thermodynamic parameters of the ternary complex formation with alanine, phenylalanine and tryptophan enantiomeric pairs were also determined (25° C andI=0.1 mol dm−3). No thermodynamic enantioselectivity was observed in these systems, while a chiral, though poor, discrimination was observed in LEC: c.d. spectra also show enantiomeric stereoselectivity. The results of the present investigation, compared with previously reported results, suggest the occurence of acis-complex ⇆trans-complex equilibrium in such systems.

8-Hydroxyquinolines in medicinal chemistry: A structural perspective.

8-Hydroxyquinolines are heterocyclic compounds characterized by a moderate metal-binding affinity. The interest in 8-hydroxyquinolines has grown exponentially in the last two decades as they are privileged structures for the design of new drug candidates that exert a host of biological effects on various targets. The study of biological activities such as neuroprotection, anticancer, antibacterial, antifungal activity has been further promoted by the synthetic versatility of 8-hydroxyquinoline, which allows the generation of a large number of derivatives. These include numerous multifunctional analogues having the metal-binding motif of 8-hydroxyquinoline. In this review, we have summarized 8-hydroxyquinolines, 8-hydroxyquinoline-like compounds, 8-hydroxyquinoline-loaded nanoparticle systems with respect to their biological activities, interaction with metal ions and mechanisms of action.

Administration of carnosine in the treatment of acute spinal cord injury.

L-Carnosine is an endogenously synthesized dipeptide composed of beta-alanine and L-histidine. It acts as a free radical scavenger and possesses antioxidant properties. L-Carnosine reduces proinflammatory and profibrotic cytokines such as transforming growth factor-beta (TGF-beta), interleukin (IL)-1, and tumor necrosis factor (TNF)-alpha in different experimental settings. In the present study, we investigated the efficacy of L and D-carnosine on the animal model of spinal cord injury (SCI). The spinal cord was exposed via a four-level T5-T8 laminectomy and SCI was produced by extradural compression of the spinal cord at level T6-T7 using an aneurysm clip with a closing force of 24 g. Treatment with D-carnosine (150 mg/kg administered i.p., 1 h and 6h, after SCI), but not L-carnosine significantly decreased (a) the degree of spinal cord inflammation and tissue injury (histological score), (b) neutrophil infiltration (myeloperoxidase activity), (c) nitrotyrosine formation, inducible NO synthase (iNOS) and Hsp70 expression, (d) proinflammatory cytokines, and (e) apoptosis (TUNEL staining, Fas ligand, Bax, and Bcl-2 expression). Furthermore, D-carnosine (150 mg/kg administered i.p., 1 h and 6 h, after SCI) significantly ameliorated the loss of limb function (evaluated by motor recovery score). Taken together, our results demonstrate the strong difference between L-carnosine and D-carnosine. The result strongly suggests that D-carnosine treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma.

Gluconjugates of 8-hydroxyquinolines as potential anti-cancer prodrugs

8-Hydroxyquinolines are systems of great interest in the field of inorganic and bioinorganic chemistry. They are metal-binding compounds and are known to exhibit a variety of biological activities, such as antibacterial and anticancer activities. Among these systems, clioquinol has been the focus of a renewed interest in recent years. In this scenario, we synthesized and characterized the new clioquinol glucoconjugate, 5-chloro-7-iodo-8-quinolinyl-β-D-glucopyranoside in order to compare this system to that of clioquinol. We also synthesized, 8-quinolinyl-β-D-glucopyranoside, an 8-hydroxyquinoline glucoconjugate. The reason for the development of glucoconjugates is the glucose avidity, and the over-expression of glucose transporters in cancer cells. Here we demonstrate that glycoconjugates are cleaved in vitro by β-glucosidase and these systems exhibit antiproliferative activity against different tumor cell lines in the presence of copper(II) ions.

New Cyclodextrin‐Bearing 8‐Hydroxyquinoline Ligands as Multifunctional Molecules

Recent investigations have rekindled interest in 8-hydroxyquinolines as therapeutic agents for cancer, Alzheimers disease, and other neurodegenerative disorders. Three new β-cyclodextrin conjugates of 8-hydroxyquinolines and their copper(II) and zinc(II) complexes have been synthesized and characterized spectroscopically. In addition to improving aqueous solubility, due to the presence of the cyclodextrin moiety, the hybrid systems have interesting characteristics including antioxidant activity, and their copper(II) complexes are efficient superoxide dismutase (SOD) mimics. The ligands and their copper(II) complexes show low cytotoxicity, attributed to the presence of the cyclodextrin moiety. These compounds have potential as therapeutic agents in diseases related both to metal dyshomeostasis and oxidative stress.

Inhibition of photohemolysis by copper(II) complexes with Sod-like activity

Red blood cell lysis photosensitized by Ketoprofen, 2-(3-benzoxyphenyl)propionic acid (KPF), was investigated in the presence of some copper(II) complexes with linear and cyclic dipeptides as well as functionalized beta-cyclodextrins with SOD-like activity with the aim of ascertaining their protective activity towards the photoinduced cell damage. The comparison between the decrease of photolytic activity caused by these complexes and their superoxide dismutase activity showed an appreciable correlation. The correct determination of species existing in experimental conditions was obtained through a simulation approach based on the knowledge of the stability constants of the complexes.