Nature-inspired antioxidants and redox- active organic systems for biomedical research and applications.

The imitation of Nature’s chemical principles and logics has emerged as a competitive strategy for the design and implementation of functional molecular systems and biomaterials for innovative technological and biomedical applications. A unique source of inspiration in this context is offered by phenols, polyphenols and especially catechols, in view of their various biological roles. In this frame, the present project addressed structure-property-function relationships in synthetic eumelanin and polydopamine by a biomimetic chemistry and modeling approach and in particular: a) the elucidation of the main structural components of polydopamine and their role in wet adhesion and film-forming properties; b) preparation of model eumelanins at high degree of regioregularity and comparative evaluation of their chromophoric and antioxidant properties; c) design and implementation of novel fluorescence turn-on systems for sensing applications or alternative mussel-inspired systems for technological applications; d) preparation and characterization (NMR, mass spectrometry, UV-visible and EPR spectroscopy, particle and film morphology, antioxidant properties) of novel adhesive polymers based on control of monomer structure, functional groups and deposition conditions. Main outcomes can be summarized as follows: 1) PDA film deposition: a) requires high dopamine concentrations (>1 mM); b) is not attributable to cyclized 5,6-dihydroxyindole (DHI) intermediates produced by dopamine autoxidation; c) is accelerated by equimolar amounts of periodate causing fast conversion to the o-quinone; d) is enhanced by the addition of hexamethylenediamine (HMDA) and other long chain aliphatic diamines even at low dopamine concentrations (<1 mM). 2) A pH-sensitive fluorescent thin film was obtained by optimization of the strongly fluorogenic reaction between dopamine and resorcinols. This fluorogenic reaction is efficient and may be exploited for the sensing of volatile amine. 3) Enzymatic oxidation of tyramine proved a practical procedure for surface functionalization and coating at neutral pH and at much lower substrate concentration compared to standard autoxidative PDA coating protocols. 4) Eumelanin precursors, 5,6-dihydroxyindoles, can form adhesive films under dip coating conditions in the presence of HMDA. 5) Synthetic eumelanin pigments prepared from biosynthetic precursors, DHICA and its methyl ester, are of particular interest due to their strong antioxidant properties and the intense absorption in the UVB/UVA region. Research work on related topics has also been carried out showing that: - Gelatin-based hydrogels are able of incorporating and releasing under controlled conditions DHICA and MeDHICA. Chemical assays confirmed the antioxidant power of the indoles incorporated into the gelatin network; - New 1,4-benzothiazine based chromophores prepared from 3-substituted 1,4-benzothiazines show a peculiar acidichromic behaviour hinting to their exploitation as pH sensors or related applications; - Melanins feature a reversible redox behavior as evidenced by electrochemistry-based reverse engineering methods exchanging electrons with various reductants and oxidants, including drugs and neurotoxicants; - Biomimetic phenolic polymers exhibit correlations between the electron-transfer or hydrogen atom transfer capacity and EPR indices of π-electron spin delocalization highlighting specific structural determinants of the antioxidant activity; - 3-hydroxytyrosol and even more its 5-S-Lipoyl conjugate are able to counteract Hg-induced cytotoxicity in human erythrocytes. Sulfated derivatives of tyrosol polymers proved to be highly efficient as antioxidants and as anticoagulant agents in in vitro assays. Overall, these results fulfil the main objectives of the PhD project and expand the current repertoire of functional nature-inspired materials and systems.