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The transient species formed by oxidation of three dimers of 5,6-dihydroxyindole (1), a major building block of the natural biopolymer eumelanin, have been investigated. Pulse radiolytic oxidation of 5,5',6,6'-tetrahydroxy-2,4'-biindolyl (3) and 5,5',6,6'-tetrahydroxy-2,7'-biindolyl (4) led to semiquinones absorbing around 450 nm, which decayed with second-order kinetics (2k = 2.8 x 10(9) and 1.4 x 10(9) M-1 s(-1), respectively) to give the corresponding quinones (500-550 nm). 5,5', 6, 6'-Tetrahydroxy-2,2'-biindolyl (2), on the other hand, furnished a semiquinone (lambda(max) = 480 nm) which disproportionated at a comparable rate (2k = 3 x 10(9) M-1 s(-1)) to give a relatively stable quinone (lambda(max) = 570 nm). A quantum mechanical investigation of o-quinone, quinonimine, and quinone methide structures of 2-4 suggested that oxidized 2-4 exist mainly as 2-substituted extended quinone methide tautomers. Finally, an oxidation product of 3 was isolated for the first time and was formulated as the hydroxylated derivative 5 arising conceivably by the addition of water to the quinone methide intermediate predicted by theoretical analysis. Overall, these results suggest that the oxidation chemistry of biindolyls 2-4 differs significantly from that of the parent 1, whereby caution must be exercised before concepts that apply strictly to the mode of coupling of 1 are extended to higher oligomers.

Piceatannol (1) was found to be more effective than caffeic acid, an established antinitrosating agent, in inhibiting N-nitrosation of 2,3-diaminonaphthalene. Product analysis of the reaction mixture of 1 (20 microM) with nitrite ions (80 microM) at pH 3.0 and at 37 degrees C showed conversion to a single major nitration product, (E)-3,3',4,5'-tetrahydroxy-beta-nitrostilbene (2) (68% yield). This would result from an unexpected nitration at the double bond sector via the 4-phenoxyl radical, which was analyzed at the unrestricted DFT level.

Redox imbalance in biological systems is associated with a complex interplay of oxidative pathways leading to more or less extensive degradation and breakdown of important cellular constituents including chiefly lipids, such as polyunsaturated fatty acids (PUFAs), as well as carbohydrates and proteins, among others. PUFA oxidation is a central event in lipid peroxidation and is associated with a chain reaction involving peroxide intermediates. These latter eventually break down to give α,β-unsaturated aldehydes, including 4-hydroxy-2-nonenal (HNE), acrolein, crotonaldehyde, and dialdehydes, such as malondialdehyde, glyoxal and methylglyoxal. Oxidative stressrelated aldehydes (OSRAs) are currently recognized to play a complex and crucial role in the onset and progression of several disease states, including vascular diseases, neurodegeneration and cancer. An important role of aldehydes in lipofuscinogenesis and age-related disorders has also been demonstrated. Besides being the measurable end product of lipid peroxidation and oxidative cell injury, aldehydes can act themselves as amplifiers of damaging events through covalent reaction with cellular targets such as proteins and nucleic acids. HNE, for example, has been implicated in a variety of cytopathological effects associated to oxidative stress and is currently one of the best recognized and most studied cytotoxic products of lipid peroxidation. The ability of glyoxal to cause interstrand DNA crosslinks is another remarkable example for the active role of aldehydes in mediating toxic mechanism in disease states, and the activation of the glyoxalase system to control glyoxal-mediated cell damage is indirect evidence of the impact of these processes on the progression of disease. Several conditions have been associated with an increase in the levels of endogenous aldehydes, including Fanconi anaemia, and the impact of this phenomenon may vary from one disease to the other depending on levels and potential targets involved, as well as the underlying specific pathways of toxicity. Starting from an initial survey of the basic mechanisms of aldehyde generation from lipid peroxidation and other oxidative processes following the onset of redox imbalance, this chapter aims at addressing a number of central issues in oxidative stress-related disorders: 1) what are the mechanisms of OSRAs toxicity in the progression and final outcome of the disease? 2) What are the main targets of OSRAs and what is the role of these interactions in the etiopathogenesis of oxidative stress-related disease states? 3) Can OSRA quantitation yield clues about the advancement and outcome of diseases? Far from being comprehensive, the present survey seeks rather to provide an inspiring and critical perspective of the biomedical relevance of aldehydes as markers of redox imbalance and their potential diagnostic and prognostic value with special reference to Fanconi anaemia and rare cancer-prone diseases

Redox imbalance in biological systems is associated with a complex interplay of oxidative pathways leading to more or less extensive degradation and breakdown of important cellular constituents including chiefly lipids, such as polyunsaturated fatty acids (PUFAs), as well as carbohydrates and proteins, among others. PUFA oxidation is a central event in lipid peroxidation and is associated with a chain reaction involving peroxide intermediates. These latter eventually break down to give α,β-unsaturated aldehydes, including 4-hydroxy-2-nonenal (HNE), acrolein, crotonaldehyde, and dialdehydes, such as malondialdehyde, glyoxal and methylglyoxal. Oxidative stressrelated aldehydes (OSRAs) are currently recognized to play a complex and crucial role in the onset and progression of several disease states, including vascular diseases, neurodegeneration and cancer. An important role of aldehydes in lipofuscinogenesis and age-related disorders has also been demonstrated. Besides being the measurable end product of lipid peroxidation and oxidative cell injury, aldehydes can act themselves as amplifiers of damaging events through covalent reaction with cellular targets such as proteins and nucleic acids. HNE, for example, has been implicated in a variety of cytopathological effects associated to oxidative stress and is currently one of the best recognized and most studied cytotoxic products of lipid peroxidation. The ability of glyoxal to cause interstrand DNA crosslinks is another remarkable example for the active role of aldehydes in mediating toxic mechanism in disease states, and the activation of the glyoxalase system to control glyoxal-mediated cell damage is indirect evidence of the impact of these processes on the progression of disease. Several conditions have been associated with an increase in the levels of endogenous aldehydes, including Fanconi anaemia, and the impact of this phenomenon may vary from one disease to the other depending on levels and potential targets involved, as well as the underlying specific pathways of toxicity. Starting from an initial survey of the basic mechanisms of aldehyde generation from lipid peroxidation and other oxidative processes following the onset of redox imbalance, this chapter aims at addressing a number of central issues in oxidative stress-related disorders: 1) what are the mechanisms of OSRAs toxicity in the progression and final outcome of the disease? 2) What are the main targets of OSRAs and what is the role of these interactions in the etiopathogenesis of oxidative stress-related disease states? 3) Can OSRA quantitation yield clues about the advancement and outcome of diseases? Far from being comprehensive, the present survey seeks rather to provide an inspiring and critical perspective of the biomedical relevance of aldehydes as markers of redox imbalance and their potential diagnostic and prognostic value with special reference to Fanconi anaemia and rare cancer-prone diseases

Spent coffee grounds (SCG) represent the main by-products of the coffee industry as they are obtained both during instant coffee production and as a result of coffee beverage consumption in restaurants, coffee shops, etc. We report herein the enhancement of a variety of properties of potential technological interest following treatment of SCG by a easy- to-do, scalable purification/activation process that will be presented.1 As an example, 2,2-diphenylpicrylhydrazyl (DPPH) assay indicated a ca. 30-fold higher activity of the activated SCG in comparison with the untreated sample, while a ca. doubled Trolox equivalent value was measured in the ferric reducing/antioxidant power (FRAP) assay (Table 1). A very high efficiency in the nitric oxide (NO) scavenging assay was also observed. A polyethylene (PE) film containing 2% activated SCG (Figure 1) showed improved stability toward thermal and photo-oxidative degradation. The use of this material in functional packaging is currently under investigation. Preliminary data on the binding of heavy metals and adsorption of model organic dyes encourage exploring the potential of activated SCG as an active component of filtering membranes.

Walnut husks and related washing waters are produced in large scale as a waste product during walnut processing. We recently identified a dihydronaphthalenone compound, known as regiolone, as the main phenolic component of walnut husk washing waters (WHWW). 1 We report now that regiolone inhibits dopa and linoleic acid oxidation mediated by mushroom tyrosinase and soybean lipoxygenase, respectively, in a dose-dependent manner (Figure 1).2 IC50 values of 53 nM (mushroom tyrosinase) and 480 M (soybean lipoxygenase) were determined. Regiolone was found to be more active than known tyrosinase and lipoxygenase inhibitors such as kojic acid and caffeic acid. Model studies aimed at assessing the mechanism of inhibition revealed that regiolone is a poor chelating agent but a strong reductant toward the active metals of tyrosinase and lipoxygenase, namely copper and iron ions. These results open new perspectives in the exploitation of regiolone as a food preservative. Its easy availability by a scalable and low cost extraction from WHWW would warrant efforts along this direction.

Hydroxytyrosol and resveratrol occupy a prominent position among natural polyphenols because of their antioxidant potency and the wide range of biological properties. Several efforts have been directed toward the preparation of novel derivatives of these compounds with improved antioxidant and pharmacological activities. In pursuing a research program on the design and synthesis of novel bioinspired antioxidant agents, we recently became interested in exploring the potential of sulfur/selenium-containing conjugates of natural polyphenols as prototypes of novel multifunctional compounds combining diverse scavenging and inhibitory activities against oxidative stress-inducing species and systems. S/Se-alkyl substituted phenols are efficient scavengers of hydroperoxides and have recently been shown to display efficient chain-breaking activity.1,2 Along this line 5-S-lipoylhydroxytyrosol (1) and its polysulfides 2-4 were prepared by conjugation of hydroxytyrosol with dihydrolipoic acid. 3 Compound 1 exhibited significant activity in the ferric reducing/antioxidant power (FRAP) assay (1.60 Trolox equivalents), while polysulfides 2-4 were more efficient in the DPPH reduction assay (88-93% reduction vs. 68% by Trolox). At 10 M concentration all compounds 1-4 proved to be efficient hydroxyl radical scavengers (56-69% inhibition) in a Fenton reaction assay. When administered to human HepG2 cells, 1-4 proved to be non-toxic and exhibited marked protective effects against reactive oxygen species (ROS) generation (60-84% inhibition at 1 M concentration) and cell damage induced by 400 M tert-butylhydroperoxide. All compounds 1-4 exhibited overall greater antioxidant activity than hydroxytyrosol. Benzo[b]selenophene and diselenide derivatives of resveratrol (5-8) were also prepared and they proved to be more potent than the parent compound in the DPPH assay. The diselenide derivative 8 was also found to act as an efficient glutathione peroxidase mimic in preliminary experiments. The new hydroxytyrosol and resveratrol derivatives represent promising lead structures for the development of innovative antioxidants inspired to natural products.

Aim of this paper is to present a computational revisitation of the main structural and spectroscopic features of quinhydrone, a prototype of complexes built on noncovalent interactions, with a view to proposing an accurate yet computationally convenient approach to the characterization of such kind of complexes. Several methods are compared in terms of energy profiles along selected coordinates, which involve the relative distance and/or orientation of the two aromatic rings. MP2 and DFT calculations agree in indicating that H-bonding and dispersion forces play a more important role than charge transfer in stabilizing quinhydrone. Distance- and orientation-dependent overlap of ? clouds was found by TD-DFT calculations to be a major determinant of quinhydrone visible absorption and color. This journal is © The Royal Society of Chemistry 2014.

In the presence of micromolar peroxides or biometals (Fe(III)???, Cu(II)???, V(V) salts)???, and following a strong acid input, the stable 3-???phenyl-???2H-???1,???4-???benzothiazine is efficiently converted to a green-???blue ??2,???2'-???bi(2H-???1,???4-???benzothiazine) chromophore via dehydrogenative coupling of a 1,???4-???benzothiazinyl radical. The new system is of potential practical interest for colorimetric peroxide and redox biometal detection.

Most of the biological and application-oriented studies of synthetic melanins have so far been performed on commercial materials or on dopa melanins with low DHICA content, although it is well known that DHICA is a key constituent of human pigments. Recently, it has been reported that DHICA melanin exhibits potent hydroxyl radical-scavenging properties in the Fenton reaction, whereas DHI melanin does not (Jiang et al., Free Radic. Biol. Med. 2010, 48, 1144–1151). We show now that synthetic DHICA melanin is a highly efficient antioxidant compared to other synthetic eumelanins, proving to be a more efficient scavenger than DHI or dopa melanin in the 1,1-diphenyl- 2-picrylhydrazyl (DPPH), 2,2′-azinobis(3-ethylbenzothiazoline-6- sulfonic acid) (ABTS), and nitric oxide (NO) scavenging assays. Analysis of the optical, paramagnetic and morphological properties of DHICA melanin revealed features far different from those of DHI and dopa melanins. These can be accounted for by prevalent intermolecular interactions compensating for conformationally-hindered p-electron delocalization across the polymer backbone. Thus the somewhat counterintuitive conclusion is that the efficient antioxidant properties of DHICA melanin would be primarily determined by non-planar structures with monomer-like behavior and weak aggregating interactions. Formation of weak aggregates may account moreover for a greater accessibility of free radicals to DHICA compared to compact p- stacked DHI and dopa melanins. These results offer the first chemical explanation as to why Nature selected DHICA to confer (photo)protective properties to skin melanins, a fundamental conundrum of human pigmentation, and provide unprecedented insights to orient the design and to engineer eumelanins with superior antioxidant properties for diverse applications.

New trends in material science and nanotechnologies have spurred growing interest in eumelanins black insoluble biopolymers derived by tyrosinase-catalysed oxidation of tyrosine via 5,6-dihydroxyindole (DHI) and its 2-carboxylic acid (DHICA). Efficient antioxidant and photoprotective actions, associated with peculiar optoelectronic properties, are recognised as prominent functions of eumelanin macromolecules within the human and mammalian pigmentary system, making them unique candidates for the realisation of innovative bio-inspired functional soft materials, with structure-based physicalchemical properties. An unprecedented breakthrough into the mechanism of synthetic eumelanin buildup has derived from a detailed investigation of the oxidative polymerization of DHI and its N-methyl derivative (NMDHI) by linear and reflectron matrix-assisted laser/desorption ionization mass spectrometry. Regular collections of oligomers of increasing masses, spanning the entire m/z ranges up to 5000 Da (>30-mer) and 8000?Da (> 50-mer) for the two building blocks, respectively, were disclosed. It is the first time that the in vitro polymerisation of dihydroxyindoles to form synthetic eumelanins is explored up to its high mass limits, giving at the same time information on the polymerisation mode, whether it follows a stepwise pattern (being this the conclusion in our case) or a staking sequencing of small-sized entities. It also highlighted the influence of the N-methyl substituent on the polymerization process; this opens the way to the production of N-functionalized, synthetic eumelanin-inspired soft materials, for possible future technological applications.

The prospects of developing improved models of eumelanin biopolymers and/or novel bioinspired functional materials/scaffolds for application in organoelectronics have incited increasing efforts toward the rational design and synthesis of 5,6-dihydroxyindole (DHI)-based -electron systems with tailored structural and electronic properties.1-3 A valuable entry to this goal has derived from the exploitation of alkynyl chemistry for the assembly of novel oligomers4,5 and the realization of -extended systems

A review focuses on the pigments derived biogenetically from tyrosine and produced intracellularly within specialized cells. Melanin pigments, eumelanins and pheomelanins, can be described today as collections of mol. species with different chem. structures and properties, thus encompassing diverse degrees of chem. heterogeneity. This mol. heterogeneity can be ascribed to a no. of factors, including the range of different monomer units; the different mdes of inter-unit coupling; differences in mol. wt.; the redox state; and the extent and mode of aggregation