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Reactive oxygen species (ROS) are harmful species produced during metabolic processes, such as photosynthesis and respiration, of living organism. In both case, the substrate (oxygen/water) undergoes several multi electronic reaction, during which some electrons can “escape” from the catalytic cycle and produce ROS, such as superoxide radical anion, hydrogen peroxide, hydroxyl radical and other derivatives. These species are really dangerous, since they are able to oxidize almost all cellular components. Indeed they can damage lipids, proteins, DNA, affecting cellular functions till cell death. Under oxidative stress condition, accumulation of damage due to ROS has been supposed to play a role in several pathologies, and in particular in age-related ones, such as Alzheimer’s disease (AD). This disease is characterized by an accumulation of neurotoxic senile plaques, mainly made of short peptide monomers, that tend to aggregate into fibrils, called amyloid β peptide (Aβ). Although the mechanism involved in the production of these peptides is still unknown, some hypothesis suggest that ROS are produced within the fibrils and are responsible for further Aβ production. Nature has developed different catalytic strategies to limit ROS production, and the most important is the enzymatic pathway: superoxide dismutases (SOD) and catalase (CAT) enzymes are able to dismutate, respectively, superoxide and hydrogen peroxide. Nevertheless, in case of unpaired ROS production it is of huge interest to find new artificial systems that are able to help natural enzymes in their task. In this thesis, four different classes of synthetic enzymes (synzymes) that mimic natural anti ROS systems have been investigated: I. Isostructural mononuclear manganese complexes, with general formula [Mn(L)X2], characterized by a pentadentate ligand L, containing different heteroatoms (N, O or S) have been used for the dismutation of hydrogen peroxide and superoxide anion. Their activity, also depending on heteroatoms, and stability were studied, first in organic solvents to have a comparison with literature similar compounds, then in aqueous solution, where only few compounds were known to work. The sulfur-containing complex [Mn(L)(OTf)2] was found to exhibit high dual SOD/CAT-like activity with excellent stability, when used in the presence of a base. II. Isostructural dinuclear manganese complexes, with general formula [Mn2L2X], were widely studied as artificial catalases. A comparison with other dimanganese complexes, in terms of Michealis-Menten parameter, KM and kcat, was performed. Superoxide dismutase activity was also evaluated, demonstrating the unique dual SOD/CAT behavior of [Mn2L2X] with respect to other dinuclear complexes. Finally, the ligands were modified with mitochondriotropic functionalities. In particular, two fluorescent rhodamine derivatives and a triphenylphosphonium salt, were taken into account. III. Some multimetallic manganese oxoclusters, containing 6-13 manganese atoms, were synthetized during a Short Term Scientific Mission in Dublin, in the group of Prof. Wolfgang Schmitt. The catalase-like activity of these compounds was tested for the first time. Their H2O2 dismutation capability was thus demonstrated and their stability in aqueous environment was checked. Preliminary test as SOD mimics were also performed. IV. In the end, a completely inorganic compound, a polyoxometalate (POM) substituted with four ruthenium atoms, with formula [Ru4O4(OH)2(H2O)4(γ-SiW10O36)2]10-, able to dismutate hydrogen peroxide was studied. Its activity in different biological buffers and media was initially optimized. Its capability of interaction with Aβ peptides, coupled with its catalase activity, were exploited to control these two major events involved in Alzheimer’s disease. Preliminary test on neuronal cells were then performed (with Dr.ssa de Bartolo (ITM-CNR, Rende, CS)), confirming the interesting properties of the compound in vitro and finding a very low toxicity. Finally, encapsulation of POM was achieved in order to enables delivery and targeting in cells, using polymeric multilayer biocompatible microcapsules in which POM is deposited. The presence of POM and its catalytic activity were confirmed and analyzed.

The coupling of a polycationic Mn(III)-porphyrin, with a dinuclear Mn2(II,II)L2 core (HL = 2-{[[di(2-pyridyl)methyl](methyl)amino]methyl}phenol), results in a dual Superoxide Dismutase (SOD) and Catalase (CAT) functional analogue, Mn2L2Pn+, enabling a detoxification cascade of the superoxide anion and hydrogen peroxide into benign H2O and O2. The SOD/CAT artificial manifolds, joined in one asset, exhibit a peak catalytic performance under physiological conditions, with log kcat(O2• –) ≥ 7 and kcat(H2O2)/KM = 1890. The dual-enzyme (dizyme) concept allows for a built-in self-protection against the irreversible bleaching of the porphyrin unit (>75% protection), readily induced by H2O2 (200 μM, 20 equiv, in buffer solution, pH 7.8). We show herein that incubation of the photosynthetic green algae, Chlamydomonas reinhardtii, with the synthetic dizyme (as low as 0.1 μM), prevents H2O2 accumulation under high-light illumination conditions, thus providing antioxidant surveillance and photoprotection.