Leone, Linda (2020) Artificial metalloenzymes active in oxidation chemistry. [Tesi di dottorato]

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Bioinorganic chemists tackled the challenge to unravel the mechanisms that allow the protein matrix to modulate the catalytic activity of metal-containing cofactors through the development of artificial systems. In this perspective, heme-proteins represent a significant source of inspiration: researchers have attempted for decades to develop efficient and selective metalloporphyrin-based catalysts. Significant advance has been achieved in the design and engineering of protein scaffolds to host metallo-porphyrins and to modulate their reactivity. Peptide-based architectures of different sizes have been exploited for the construction of catalytic systems. Among them, synthetic porphyrin-peptide conjugates known as “Mimochromes” represent an important class of artificial heme-enzymes. Their structure consists of two α-helical peptides covalently linked to a metalloporphyrin core, resulting into a helix-heme-helix sandwich. Their simple scaffold has been optimized to reproduce the functional properties of peroxidases. Mimochrome VI*a (MC6*a), in its FeIII complex, recently emerged as the best artificial peroxidase known so far, overcoming the catalytic efficiency of horseradish peroxidase (HRP) in ABTS oxidation. Moreover, the cobalt derivative (Co-MC6*a) behaves as a very promising catalyst in hydrogen evolution reactions. These recent achievements prompted us to further evaluate the versatility of the MC6*a scaffold towards metal replacement, by swapping iron to manganese. The primary aim of this PhD project was to expand the scope of transformations accessible by MC6*a complexes in oxidation chemistry. Taking into account the catalytic promiscuity of iron and manganese porphyrins towards diverse oxidative transformations, the analysis of the spectroscopic, redox and catalytic properties of Fe- and Mn-MC6*a has been performed. Compared to other peptide-porphyrin conjugates with a fully solvent-exposed distal site, both Fe- and Mn-MC6*a display an increased ability to promote the deprotonation of metal-bound water and hydrogen peroxide. This property allows MC6*a complexes to reach their highest activity towards H2O2 at lower pH values, approaching those of the natural counterparts. Both Fe- and Mn-MC6*a demonstrated to be efficient and robust catalysts in the H2O2-mediated sulfoxidation of thioethers, being among the most active artificial heme-enzymes studied for this reaction. The two catalysts displayed divergent behaviours towards the oxidation of indole. Notably, Mn-MC6*a displays higher chemo-selectivity compared to Fe-MC6*a, but also surpasses most of heme-enzymes examined to the same end. Mn-MC6*a represents one of the most proficient catalysts for indole oxidation, mainly due to the possibility of controlling the formation of different oxidation products with high selectivity. Among them, the formation and isolation of the highly reactive 3-oxindolenine is very important, because it could represent a useful synthon in organic synthesis. Overall, the results of this PhD thesis pave the way for the application of mimochromes to synthetic chemistry. These catalysts fill the middle ground between small-molecule and biological catalysts, since they own a minimal structure that enables substrate promiscuity and a designed peptide scaffold that modulates the reactivity of the metal ion.

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