Sustainable Electropolymerization of Zingerone and Its C2 Symmetric Dimer for Amperometric Biosensor Films.

Polymeric permselective films are frequently used for amperometric biosensors to prevent electroactive interference present in the target matrix. Phenylenediamines are the most commonly used for the deposition of shielding polymeric films against interfering species; however, even phenolic monomers have been utilized in the creation of these films for microsensors and biosensors. The purpose of this paper is to evaluate the performances of electrosynthesized polymers, layered by means of constant potential amperometry (CPA), of naturally occurring compound zingerone (ZING) and its dimer dehydrozingerone (ZING DIM), which was obtained by straight oxidative coupling reaction. The polymers showed interesting shielding characteristics against the main interfering species, such as ascorbic acid (AA): actually, polyZING exhibited an AA shielding aptitude comprised between 77.6 and 99.6%, comparable to that obtained with PPD. Moreover, a marked capability of increased monitoring of hydrogen peroxide (HP), when data were compared with bare metal results, was observed. In particular, polyZING showed increases ranging between 55.6 and 85.6%. In the present work, the molecular structures of the obtained polymers have been theorized and docking analyses were performed to understand their peculiar characteristics better. The structures were docked using the Lamarckian genetic algorithm (LGA). Glutamate biosensors based on those polymers were built, and their performances were compared with biosensors based on PPD, which is the most widespread polymer for the construction of amperometric biosensors.

Antioxidant Activity of Natural Phenols and Derived Hydroxylated Biphenyls.

A comparative in vitro study of the antioxidant potential of natural phenols (zingerone, curcumin, raspberry ketone, magnolol) and their synthesized derivatives was performed. The antioxidant efficiency was evaluated in blood serum obtained from healthy individuals, by means of spectrophotometry, before and after the addition of pro-oxidant tert-butyl hydroperoxide (TBH). Moreover, the antioxidant effect of an equimolar mixture of curcumin and zingerone was investigated. Interpretation of our results reveals that in the blood serum of healthy individuals curcumin (C1), raspberry ketone (RK1), magnolol (M1) and synthesized derivative of zingerone (Z2) demonstrate remarkable antioxidant effects (p < 0.05). However, in the state of TBH-induced excessive oxidative stress natural magnolol and synthesized derivatives C1, Z1 and RK1 show powerful antioxidant activity and thus can be further investigated to obtain information about their metabolic transformations and their potential influence at the cellular level. Results obtained from measurements in an equimolar mixture of zingerone and curcumin indicate synergism (p < 0.05) between the two compounds. This combination is especially successful due to the fast and efficient neutralization of added pro-oxidant TBH. The commercial availability of turmeric and ginger and their frequent combined use in diet suggest ideas for further broader utilization of the beneficial synergistic effect of their phenolic components.

Antamanide Analogs as Potential Inhibitors of Tyrosinase.

The tyrosinase enzyme, which catalyzes the hydroxylation of monophenols and the oxidation of o-diphenols, is typically involved in the synthesis of the dark product melanin starting from the amino acid tyrosine. Contributing to the browning of plant and fruit tissues and to the hyperpigmentation of the skin, leading to melasma or age spots, the research of possible tyrosinase inhibitors has attracted much interest in agri-food, cosmetic, and medicinal industries. In this study, we analyzed the capability of antamanide, a mushroom bioactive cyclic decapeptide, and some of its glycine derivatives, compared to that of pseudostellarin A, a known tyrosinase inhibitor, to hinder tyrosinase activity by using a spectrophotometric method. Additionally, computational docking studies were performed in order to elucidate the interactions occurring with the tyrosinase catalytic site. Our results show that antamanide did not exert any inhibitory activity. On the contrary, the three glycine derivatives AG9, AG6, and AOG9, which differ from each other by the position of a glycine that substitutes phenylalanine in the parent molecule, improving water solubility and flexibility, showed tyrosinase inhibition by spectrophotometric assays. Analytical data were confirmed by computational studies.

Inhibitory Effect of Curcumin-Inspired Derivatives on Tyrosinase Activity and Melanogenesis.

Tyrosinase is a well-known copper-containing metalloenzyme typically involved in the synthesis of melanin. Recently, curcumin and several synthetic derivatives have been recognized as tyrosinase inhibitors with interesting anti-melanogenic therapeutic activity. In this study, three curcumin-inspired compounds 1, 6 and 7 were prepared in yields ranging from 60 to 88 % and spectrophotometric, electrochemical, in vitro and in silico analyses were carried out. The viability of PC12 cells, a rat pheochromocytoma derived-cell line, with compounds 1, 6 and 7, showed values around 80% at 5 µM concentration. In cell proliferation assays, compounds 1, 6 and 7 did not show significant toxicity on fibroblasts nor melanoma cells up to 10 µM with viability values over 90%. The inhibition of tyrosinase activity was evaluated both by a UV-Vis spectroscopic method at two different concentrations, 0.2 and 2.0 µM, and by amperometric assay with IC50 for compounds 1, 6 and 7 ranging from 11 to 24 nM. Melanin content assays on human melanoma cells were performed to test the capability of compounds to inhibit melanin biosynthesis. All compounds exerted a decrease in melanin content, with compound 7 being the most effective by showing a melanogenesis inhibition up to four times greater than arbutin at 100 µM. Moreover, the antioxidant activity of the selected inhibitors was evaluated against H2O2 in amperometric experiments, whereby compound 7 was about three times more effective compared to compounds 1 and 6. The tyrosinase X-ray structure of Bacterium megaterium crystal was used to carry out molecular docking studies in the presence of compounds 1, 6 and 7 in comparison with that of kojic acid and arbutin, two conventional tyrosinase inhibitors. Molecular docking of compounds 6 and 7 confirmed the high affinity of these compounds to tyrosinase protein.

Anticancer Activity of Two Novel Hydroxylated Biphenyl Compounds toward Malignant Melanoma Cells.

Melanoma, the deadliest form of skin cancer, is still one of the most difficult cancers to treat despite recent advances in targeted and immune therapies. About 50% of advanced melanoma do not benefit of such therapies, and novel treatments are requested. Curcumin and its analogs have shown good anticancer properties and are being considered for use in combination with or sequence to recent therapies to improve patient outcomes. Our group previously published the synthesis and anticancer activity characterization of a novel curcumin-related compound against melanoma and neuroblastoma cells (D6). Here, two hydroxylated biphenyl compounds-namely, compounds 11 and 12-were selected among a small collection of previously screened C2-symmetric hydroxylated biphenyls structurally related to D6 and curcumin, showing the best antitumor potentiality against melanoma cells (IC50 values of 1.7 ± 0.5 µM for 11 and 2.0 ± 0.7 µM for 12) and no toxicity of normal fibroblasts up to 32 µM. Their antiproliferative activity was deeply characterized on five melanoma cell lines by performing dose-response and clonal growth inhibition assays, which revealed long-lasting and irreversible effects for both compounds. Apoptosis induction was ascertained by the annexin V and TUNEL assays, whereas Western blotting showed caspase activation and PARP cleavage. A cell cycle analysis, following cell treatments with either compound 11 or 12, highlighted an arrest in the G2/M transition. Taking all this evidence together, 11 and 12 were shown to be good candidates as lead compounds to develop new anticancer drugs against malignant melanoma.

Prenylated Trans-Cinnamic Esters and Ethers against Clinical Fusarium spp.: Repositioning of Natural Compounds in Antimicrobial Discovery.

Onychomycosis is a common nail infection mainly caused by species belonging to the F. oxysporum, F. solani, and F. fujikuroi species complexes. The aim of this study was to evaluate the in vitro susceptibility of six representative strains of clinically relevant Fusarium spp. toward a set of natural-occurring hydroxycinnamic acids and their derivatives with the purpose to develop naturally occurring products in order to cope with emerging resistance phenomena. By introducing a prenylated chain at one of the hydroxy groups of trans-cinnamic acids 1-3, ten prenylated derivatives (coded 4-13) were preliminarily investigated in solid Fusarium minimal medium (FMM). Minimal inhibitory concentration (MIC) and lethal dose 50 (LD50) values were then determined in liquid FMM for the most active selected antifungal p-coumaric acid 3,3'-dimethyl allyl ester 13, in comparison with the conventional fungicides terbinafine (TRB) and amphotericin B (AmB), through the quantification of the fungal growth. Significant growth inhibition was observed for prenylated derivatives 4-13, evidencing ester 13 as the most active. This compound presented MIC and LD50 values (62-250 µM and 7.8-125 µM, respectively) comparable to those determined for TRB and AmB in the majority of the tested pathogenic strains. The position and size of the prenylated chain and the presence of a free phenol OH group appear crucial for the antifungal activity. This work represents the first report on the activity of prenylated cinnamic esters and ethers against clinical Fusarium spp. and opens new avenues in the development of alternative antifungal compounds based on a drug repositioning strategy.

Association between olfactory sensitivity and behavioral responses of Drosophila suzukii to naturally occurring volatile compounds.

Drosophila suzukii Matsumura (Diptera: Drosophilidae) is an invasive, destructive crop pest that originated in South East Asia. D. suzukii recently invaded Western countries and is threatening both European and American fruit industries. It is extremely attracted to otherwise undamaged, ripening fruits, unlike most other Drosophila species that attack only decaying or rotten fruits. Recent studies on different insect species showed that several naturally occurring compounds of easy market availability showing deterrent action may be used to supplement mass catches with food traps. Based on these considerations, the aim of the present work was to test the effects of some natural compounds (alone or in the mixture) on the olfactory system of the D. suzukii and the behavioral responses evoked. We measured by electroantennogram (EAG) recordings, the olfactory sensitivity of antennae to increasing concentrations of eugenol, vanillin, menthol, cis-jasmone; eugenol + vanillin, +menthol, +cis-jasmone; vanillin + menthol, +cis-jasmone. In addition, the behavioral responses to the same compounds and mixtures were evaluated. Our electrophysiological results show a dose-response relationship between the EAG amplitudes and the increasing concentrations of the olfactory compound. The behavioral results show that the number of laid eggs is significantly different between the standard diet and the standard diet + natural compound. These results underline a specificity in the olfactory sensitivity and in the ovipositing behavior of D. suzukii females; also, they could be valuable for the identification of key chemicals aimed at the future development of strategies in the management and control of this harmful insect for crops.

Synthesis and Studies of the Inhibitory Effect of Hydroxylated Phenylpropanoids and Biphenols Derivatives on Tyrosinase and Laccase Enzymes.

The impaired activity of tyrosinase and laccase can provoke serious concerns in the life cycles of mammals, insects and microorganisms. Investigation of inhibitors of these two enzymes may lead to the discovery of whitening agents, medicinal products, anti-browning substances and compounds for controlling harmful insects and bacteria. A small collection of novel reversible tyrosinase and laccase inhibitors with a phenylpropanoid and hydroxylated biphenyl core was prepared using naturally occurring compounds and their activity was measured by spectrophotometric and electrochemical assays. Biosensors based on tyrosinase and laccase enzymes were constructed and used to detect the type of protein-ligand interaction and half maximal inhibitory concentration (IC50). Most of the inhibitors showed an IC50 in a range of 20-423 nM for tyrosinase and 23-2619 nM for laccase. Due to the safety concerns of conventional tyrosinase and laccase inhibitors, the viability of the new compounds was assayed on PC12 cells, four of which showed a viability of roughly 80% at 40 µM. In silico studies on the crystal structure of laccase enzyme identified a hydroxylated biphenyl bearing a prenylated chain as the lead structure, which activated strong and effective interactions at the active site of the enzyme. These data were confirmed by in vivo experiments performed on the insect model Tenebrio molitur.

A Long-Distance RF-Powered Sensor Node with Adaptive Power Management for IoT Applications.

We present a self-sustained battery-less multi-sensor platform with RF harvesting capability down to -17 dBm and implementing a standard DASH7 wireless communication interface. The node operates at distances up to 17 m from a 2 W UHF carrier. RF power transfer allows operation when common energy scavenging sources (e.g., sun, heat, etc.) are not available, while the DASH7 communication protocol makes it fully compatible with a standard IoT infrastructure. An optimized energy-harvesting module has been designed, including a rectifying antenna (rectenna) and an integrated nano-power DC/DC converter performing maximum-power-point-tracking (MPPT). A nonlinear/electromagnetic co-design procedure is adopted to design the rectenna, which is optimized to operate at ultra-low power levels. An ultra-low power microcontroller controls on-board sensors and wireless protocol, to adapt the power consumption to the available detected power by changing wake-up policies. As a result, adaptive behavior can be observed in the designed platform, to the extent that the transmission data rate is dynamically determined by RF power. Among the novel features of the system, we highlight the use of nano-power energy harvesting, the implementation of specific hardware/software wake-up policies, optimized algorithms for best sampling rate implementation, and adaptive behavior by the node based on the power received.

Protein expression changes induced in a malignant melanoma cell line by the curcumin analogue compound D6.

BACKGROUND: We have previously demonstrated that the hydroxylated biphenyl compound D6 (3E,3'E)-4,4'-(5,5',6,6'-tetramethoxy-[1,1'-biphenyl]-3,3'-diyl)bis(but-3-en-2-one), a structural analogue of curcumin, exerts a strong antitumor activity on melanoma cells both in vitro and in vivo. Although the mechanism of action of D6 is yet to be clarified, this compound is thought to inhibit cancer cell growth by arresting the cell cycle in G2/M phase, and to induce apoptosis through the mitochondrial intrinsic pathway. To investigate the changes in protein expression induced by exposure of melanoma cells to D6, a differential proteomic study was carried out on D6-treated and untreated primary melanoma LB24Dagi cells. METHODS: Proteins were fractionated by SDS-PAGE and subjected to in gel digestion. The peptide mixtures were analyzed by liquid chromatography coupled with tandem mass spectrometry. Proteins were identified and quantified using database search and spectral counting. Proteomic data were finally uploaded into the Ingenuity Pathway Analysis software to find significantly modulated networks and pathways. RESULTS: Analysis of the differentially expressed protein profiles revealed the activation of a strong cellular stress response, with overexpression of several HSPs and stimulation of ubiquitin-proteasome pathways. These were accompanied by a decrease of protein synthesis, evidenced by downregulation of proteins involved in mRNA processing and translation. These findings are consistent with our previous results on gene expression profiling in melanoma cells treated with D6. CONCLUSIONS: Our findings confirm that the curcumin analogue D6 triggers a strong stress response in melanoma cells, turning down majority of cell functions and finally driving cells to apoptosis.

Electropolymerized phenol derivatives as permselective polymers for biosensor applications.

Amperometric biosensors are often coated with a polymeric permselective film to avoid electroactive interference by reducing agents present in the target medium. Phenylenediamine and phenol monomers are commonly used to form these permselective films in the design of microsensors and biosensors. This paper aims to evaluate the permselectivity, stability and lifetime of polymers electrosynthesized using either constant potential amperometry (CPA) or cyclic voltammetry (CV) from naturally occurring phenylpropanoids in monomeric and dimeric forms (eugenol, isoeugenol, dehydrodieugenol and magnolol). Sensors were characterized by scanning electron microscopy and permselectivity analysis. Magnolol formed an electro-deposited polymer with a more defined three-dimensional texture in comparison with the other films. The phenol-derived films showed different permselectivity towards H2O2 over ascorbic acid and dopamine, likely to be related to the thickness and compactness of the polymer. The CV-derived films had a better permselectivity compared to the CPA-corresponding polymers. Based on these results, the permselectivity, stability and lifetime of a biosensor for glucose were studied when a magnolol coating was electro-deposited. The structural principles governing the permselectivity of the magnolol-derived film are suggested to be mainly related to the conformational flexibility of this monomer. Newly designed biosensors, coated with electropolymerized natural phenol derivatives, may represent promising analytical devices for different application fields.

4-Substituted-2-Methoxyphenol: Suitable Building Block to Prepare New Bioactive Natural-like Hydroxylated Biphenyls.

A small collection of eugenol- and curcumin-analog hydroxylated biphenyls was prepared by straightforward methods starting from natural 4-substituted-2-methoxyphenols and their antitumoral activity was evaluated in vitro. Two curcumin-biphenyl derivatives showed interesting growth inhibitory activities on different malignant melanoma cell lines with IC50 ranging from 13 to 1 µM. Preliminary molecular modeling studies were carried out to evaluate conformations and dihedral angles suitable for antiproliferative activity in hydroxylated biphenyls bearing a side aliphatic chain.

Antioxidant potential of curcumin-related compounds studied by chemiluminescence kinetics, chain-breaking efficiencies, scavenging activity (ORAC) and DFT calculations.

This study compares the ability to scavenge different peroxyl radicals and to act as chain-breaking antioxidants of monomers related to curcumin (1): dehydrozingerone (2), zingerone (3), (2Z,5E)-ethyl 2-hydroxy-6-(4-hydroxy-3-methoxyphenyl)-4-oxohexa-2,5-dienoate (4), ferulic acid (5) and their corresponding C 2-symmetric dimers 6-9. Four models were applied: model 1 - chemiluminescence (CL) of a hydrocarbon substrate used for determination of the rate constants (k A) of the reactions of the antioxidants with peroxyl radicals; model 2 - lipid autoxidation (lipidAO) used for assessing the chain-breaking antioxidant efficiency and reactivity; model 3 - oxygen radical absorbance capacity (ORAC), which yields the activity against peroxyl radicals generated by an azoinitiator; model 4 - density functional theory (DFT) calculations at UB3LYP/6-31+G(d,p) level, applied to explain the structure-activity relationship. Dimers showed 2-2.5-fold higher values of k A than their monomers. Model 2 gives information about the effects of the side chains and revealed much higher antioxidant activity for monomers and dimers with α,ß-unsaturated side chains. Curcumin and 6 in fact are dimers of the same monomer 2. We conclude that the type of linkage between the two "halves" by which the molecule is made up does not exert influence on the antioxidant efficiency and reactivity of these two dimers. The dimers and the monomers demonstrated higher activity than Trolox (10) in aqueous medium (model 3). A comparison of the studied compounds with DL-α-tocopherol (11), Trolox and curcumin is made. All dimers are characterized through lower bond dissociation enthalpies (BDEs) than their monomers (model 4), which qualitatively supports the experimental results.

Neuroprotective Effects of the Nutraceutical Dehydrozingerone and Its C2-Symmetric Dimer in a Drosophila Model of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons responsible for unintended or uncontrollable movements. Mutations in the leucine-rich repeat kinase 2 locus contribute to genetic forms of PD. The fruit fly Drosophila melanogaster carrying this mutation (LRRK2-Dm) is an in vivo model of PD that develops motor impairment and stands for an eligible non-mammalian paradigm to test novel therapeutic approaches. Dehydrozingerone (DHZ) is a natural phenolic compound isolated from ginger and presents anti-inflammatory, antioxidant and neuroprotective properties, making it a potential therapeutic target for PD. We administered DHZ and its C2-symmetric dimer (DHZ-DIM) at 0.5 and 1 mM for 14 and 21 days in the LRRK2-Dm, with the aim of assessing changes in rescuing motor behavior, brain dopaminergic neurons, mitochondria and synapses (T-bars). The shorter treatment with both molecules revealed efficacy at the higher dose, improving climbing behavior with a prevention of dopaminergic neuronal demise. After 21 days, a recovery of the motor disability, dopaminergic neuron loss, mitochondrial damage and T-bars failure was observed with the DHZ-DIM. Our data indicate that the DHZ-DIM exerts a more potent neuroprotective effect with respect to the monomer in LRRK2-Dm, prompting further investigation of these compounds in rodent models of PD.

Molecular changes induced by the curcumin analogue D6 in human melanoma cells.

BACKGROUND: In a previous report, we described the in vitro and in vivo antiproliferative and proapoptotic activity of a hydroxylated biphenyl (D6), a structural analogue of curcumin, on malignant melanoma and neuroblastoma tumours. In this paper, we investigated the molecular changes induced by such a compound, underlying cell growth arrest and apoptosis in melanoma cells. RESULTS: To shed light on the mechanisms of action of D6, we firstly demonstrated its quick cellular uptake and subsequent block of cell cycle in G2/M phase transition. A gene expression profile analysis of D6-treated melanoma cells and fibroblasts was then carried out on high density microarrays, to assess gene expression changes induced by this compound. The expression profile study evidenced both an induction of stress response pathways and a modulation of cell growth regulation mechanisms. In particular, our data suggest that the antiproliferative and proapoptotic activities of D6 in melanoma could be partially driven by up-regulation of the p53 signalling pathways as well as by down-regulation of the PI3K/Akt and NF-kB pathways. Modulation of gene expression due to D6 treatment was verified by western blot analysis for single proteins of interest, confirming the results from the gene expression profile analysis. CONCLUSIONS: Our findings contribute to the understanding of the mechanisms of action of D6, through a comprehensive description of the molecular changes induced by this compound at the gene expression level, in agreement with the previously reported anti-tumour effects on melanoma cells.

Small molecules interacting with α-synuclein: antiaggregating and cytoprotective properties.

Curcumin, a dietary polyphenol, has shown a potential to act on the symptoms of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, as a consequence of its antioxidant, anti-inflammatory and anti-protein aggregation properties. Unfortunately, curcumin undergoes rapid degradation at physiological pH into ferulic acid, vanillin and dehydrozingerone, making it an unlikely drug candidate. Here, we evaluated the ability of some curcumin by-products: dehydrozingerone (1), its O-methyl derivative (2), zingerone (3), and their biphenyl analogues (4-6) to interact with α-synuclein (AS), using CD and fluorescence spectroscopy. In addition, the antioxidant properties and the cytoprotective effects in rat pheochromocytoma (PC12) cells prior to intoxication with H2O2, MPP+ and MnCl2 were examined while the Congo red assay was used to evaluate the ability of these compounds to prevent aggregation of AS. We found that the biphenyl zingerone analogue (6) interacts with high affinity with AS and also displays the best antioxidant properties while the biphenyl analogues of dehydrozingerone (4) and of O-methyl-dehydrozingerone (5) are able to partially inhibit the aggregation process of AS, suggesting the potential role of a hydroxylated biphenyl scaffold in the design of AS aggregation inhibitors.

Natural and natural-like polyphenol compounds: in vitro antioxidant activity and potential for therapeutic application.

Introduction: Phenols are a large family of natural and synthetic compounds with known antioxidant activity. The aim of this study was to perform in vitro screening of natural and natural-like phenol monomers and their C2-symmetric dimers (hydroxylated biphenyls) in order to identify those representatives whose pharmacophores have the strongest antioxidant and the lowest prooxidant activity. Material and methods: Antioxidative properties of 36 compounds (monomers and their C2-symmetric dimers) were evaluated in vitro. Different (red/ox) assays were used to measure their total oxidative potential (TOP), their total antioxidative capacity (TAC), the pro-oxidative-antioxidant balance (PAB) and total SH-group content (SHG) in a biologically relevant environment. The Pro-oxidative Score, Antioxidative Score and the Oxy Score were also calculated. Trolox, a water soluble analogue of α-tocopherol, was used as a positive control. Results: In an assay consisting of pooled human serum, 6 of the 36 compounds showed significant antioxidant activity (compounds 6, 7, 12, 13, 26, and 27), whereas 4 showed extremely weak antioxidant activity (compounds 2, 29, 30, and 31). Within the 36 compounds comprising zingerone, dehydrozingerone, aurone, chalcone, and magnolol derivatives, in both monomeric and dimeric forms, the 2 compounds that indicated the highest antioxidant activity were dehydrozingerone derivatives (compounds 6 and 12). Trolox's activity was found between the strong and weak antioxidant compounds analysed in our study. Conclusions: In this study selected dehydrozingerones were identified as good candidates for in-depth testing of their biological behaviour and for possible precursors for synthesis of novel polyphenolic molecules with potential therapeutic applications.

Synthesis of Hydroxylated Biphenyl Derivatives Bearing an α,ß-Unsaturated Ketone as a Lead Structure for the Development of Drug Candidates against Malignant Melanoma.

A small collection of C2 -symmetric hydroxylated biphenyl derivatives featuring an α,ß-unsaturated ketone as a lead structure was prepared, and the capacity of these compounds to act as antiproliferative agents against four human malignant melanoma cell lines was assayed. The prodrug approach was applied in order to improve the delivery of compounds into the cell by modulation of the phenolic hydroxy protecting group. The hydroxylated biphenyl structure bearing an α,ß-unsaturated ketone and a phenolic-O-prenylated chain was found to facilitate the delivery of the molecule and interactions with biological targets. Four compounds showed antiproliferative activity resulting in IC50 values in the range of 1.2 to 2.8 µM.

Antioxidant properties of novel curcumin analogues: A combined experimental and computational study.

The multi-target activity of curcumin makes it a promising pharmacological lead for structural modifications focused on the preparation of new better therapeutics with improved bioavailability. A possible modification is to "decompose" the parent curcumin structure into constituent units and to build up curcumin analogues with biphenyl structural moiety. The antioxidant properties of the so-called "monomers" (m1-m3) and "dimers" (d1-d3) are studied experimentally and computationally. Their protective effects as chain-breaking antioxidants are investigated for the individual compounds and in binary/ternary compositions with α-tocopherol (TOH) and ascorbyl palmitate (AscPH). All monomers manifest significant synergism up to 70% in mixtures with TOH. Synergistic effects are found for the ternary compositions of monomeric analogues upon addition to the binary mixture of standard antioxidants (TOH + AscPH). Dimers with biphenyl skeleton manifest a lower potential in compositions under lipid oxidation conditions. DFT computations provide a detailed insight into the structure and antiradical properties of the curcumin analogues and standard antioxidants. PRACTICAL APPLICATIONS: Bioactive compounds in the diet play a crucial role in the prevention of numerous diseases in whose pathogenesis oxidative stress is well known to be involved. Therefore, enhancement of the antioxidant status of the biological target is often helpful. Two of the monomers studied are considered leading agents in the treatment or prophylaxis of smooth muscle disorders and are useful in the maintenance of the normal gut function- as a calmative for the gut and to ease upset stomach. We hypothesized that the presence of a biphenyl scaffold in the parent molecular structure can enhance the biological activity. Equimolar mixtures of TOH with studied compounds have potential application in food chemistry and medicine. A composition comprising the active agent and additional components (strong conventional antioxidants) may be administered in foodstuffs, as a food supplement, beverage supplement, or as a pharmaceutical composition.

Natural Chain-Breaking Antioxidants and Their Synthetic Analogs as Modulators of Oxidative Stress.

Oxidative stress is associated with the increased production of reactive oxygen species or with a significant decrease in the effectiveness of antioxidant enzymes and nonenzymatic defense. The penetration of oxygen and free radicals in the hydrophobic interior of biological membranes initiates radical disintegration of the hydrocarbon "tails" of the lipids. This process is known as "lipid peroxidation", and the accumulation of the oxidation products as peroxides and the aldehydes and acids derived from them are often used as a measure of oxidative stress levels. In total, 40 phenolic antioxidants were selected for a comparative study and analysis of their chain-breaking antioxidant activity, and thus as modulators of oxidative stress. This included natural and natural-like ortho-methoxy and ortho-hydroxy phenols, nine of them newly synthesized. Applied experimental and theoretical methods (bulk lipid autoxidation, chemiluminescence, in silico methods such as density functional theory (DFT) and quantitative structure-activity relationship ((Q)SAR) modeling) were used to clarify their structure-activity relationship. Kinetics of non-inhibited and inhibited lipid oxidation in close connection with inhibitor transformation under oxidative stress is considered. Special attention has been paid to chemical reactions resulting in the initiation of free radicals, a key stage of oxidative stress. Effects of substituents in the side chains and in the phenolic ring of hydroxylated phenols and biphenols, and the concentration were discussed.