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ABSTRACT: Ferula communis (L.), a plant belonging to Apiaceae, is widely present in Sardinia, Italy. Currently, interest in F. communis focuses on the presence of two chemotypes in the wild. One chemotype is poisonous to animals, whereas the other chemotype is non-poisonous. Polyphenol oxidase (PPO) has been extracted and partially purified from the two chemotypes of F. communis. The biochemical characterization of the enzymes showed significant differences. In particular, while the two PPOs were not able to use 6- and 7-hydroxycoumarin as substrates, they showed distinct specificity for 6,7- and 7,8-dihydroxycoumarin. Significant differences in the enzyme behavior towards common PPO inhibitors were also observed. In addition, activation energy and activation energy for denaturation were determined, showing significant differences between FP-PPO and FNP-PPO, particularly for denaturation kinetics. The possible roles of the two PPOs in determining differences in composition and toxicity of the two F. communis chemotypes are also discussed.
Phytochemistry 03/2013; · 3.35 Impact Factor
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ABSTRACT: Cynomorium coccineum is an edible, non-photosynthetic plant widespread along the coasts of the Mediterranean Sea. The medicinal properties of Maltese mushroom - one of the oldest vernacular names used to identify this species - have been kept in high regard since ancient times to the present day. We evaluated the antioxidant potential of fresh specimens of C. coccineum picked in Sardinia, Italy. Both aqueous and methanolic extracts were tested by using multiple assay systems (DPPH, FRAP, TEAC, ORAC-PYR). Total phenolics and flavonoids were also determined. Gallic acid and cyanidin 3-O-glucoside were identified as the main constituents and measured. Both extracts showed antioxidant capacities; ORAC-PYR assay gave the highest antioxidant value in both cases. The methanolic extract was further investigated with in vitro biological models of lipid oxidation; it showed a significant activity in preventing cholesterol degradation and exerted protection against Cu2+-mediated degradation of the liposomal unsaturated fatty acids. Results of the present study demonstrate that the extracts of C. coccineum show a significant total antioxidant power and also exert an in vitro protective effect in different bio-assays of oxidative stress. Therefore, Maltese mushroom can be considered a valuable source of antioxidants and phytochemicals useful in the preparation of nutraceuticals and functional foods.
Nutrients 01/2013; 5(1):149-61. · 0.68 Impact Factor
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ABSTRACT: BACKGROUND: Synthetic dyes represent a broad and heterogeneous class of durable pollutants, that are released in large amounts by the textile industry. The ability of two immobilized metalloporphines (structurally emulating the ligninolytic peroxidases) to bleach six chosen dyes (alizarin red S, phenosafranine, xylenol orange, methylene blue, methyl green, and methyl orange) was compared to enzymatic catalysts. To achieve a green and sustainable process, very mild conditions were chosen. RESULTS: IPS/MnTSPP was the most promising biomimetic catalyst as it was able to effectively and quickly bleach all tested dyes. Biomimetic catalysis was fully characterized: maximum activity was centered at neutral pH, in the absence of any organic solvent, using hydrogen peroxide as the oxidant. The immobilized metalloporphine kept a large part of its activity during multi-cycle use; however, well-known redox mediators were not able to increase its catalytic activity. IPS/MnTSPP was also more promising for use in industrial applications than its enzymatic counterparts (lignin peroxidase, laccase, manganese peroxidase, and horseradish peroxidase). CONCLUSIONS: On the whole, the conditions were very mild (standard pressure, room temperature and neutral pH, using no organic solvents, and the most environmental-friendly oxidant) and a significant bleaching and partial mineralization of the dyes was achieved in approximately 1 h. Therefore, the process was consistent with large-scale applications. The biomimetic catalyst also had more promising features than the enzymatic catalysts.
Chemistry Central Journal 12/2012; 6(1):161. · 3.28 Impact Factor
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ABSTRACT: Cynomorium coccineum L. is a non-photosynthetic plant, spread over Mediterranean countries, amply used in traditional medicine. We investigated the composition and effect on intestinal Caco-2 cell viability and lipid profile of fixed oil obtained from dried stems of the plant. Oil isolation has been performed by supercritical fractioned extraction with CO(2). (13)C NMR spectroscopy has been used to study the molecular composition of oil lipids; fatty acid composition was identified using GC and HPLC techniques. The fixed oil was composed mainly by triacylglycerols and derivates. The main fatty acids were 18:1 n-9 (38%), 18:2 n-6 (20%), 16:0 (15%), and 18:3 n-3 (10.8%). The oil showed a significant in vitro inhibitory effect on the growth of colon cancer undifferentiated Caco-2 cells. Moreover, cell viability, lipid composition, and lipid peroxidation were measured in intestinal epithelial cells (differentiated Caco-2 cells) after 24h incubation with fixed oil. The oil did not show a toxic effect on colon epithelial cell viability but induced a significant change in fatty acid composition, with a significant accumulation of the essential fatty acids 18:3 n-3 and 18:2 n-6. The results showed remarkable biological activity of Maltese mushroom oil, and qualify it as a potential resource for food/pharmaceutical applications.
Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 07/2012; 50(10):3799-807. · 2.99 Impact Factor
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ABSTRACT: In this paper, the authors present an effort to increase the applicability domain (AD) by means of retraining models using a database of 701 great dissimilar molecules presenting anti-tyrosinase activity and 728 drugs with other uses. Atom-based linear indices and best subset linear discriminant analysis (LDA) were used to develop individual classification models. Eighteen individual classification-based QSAR models for the tyrosinase inhibitory activity were obtained with global accuracy varying from 88.15-91.60% in the training set and values of Matthews correlation coefficients (C) varying from 0.76-0.82. The external validation set shows globally classifications above 85.99% and 0.72 for C. All individual models were validated and fulfilled by OECD principles. A brief analysis of AD for the training set of 478 compounds and the new active compounds included in the re-training was carried out. Various assembled multiclassifier systems contained eighteen models using different selection criterions were obtained, which provide possibility of select the best strategy for particular problem. The various assembled multiclassifier systems also estimated the potency of active identified compounds. Eighteen validated potency models by OECD principles were used.
International Journal of Chemoinformatics and Chemical Engineering (IJCCE). 07/2012; 2(2):142-144.
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ABSTRACT: Tyrosinase is an oxidoreductase enzyme EC 114181 involved in the two main steps of the biochemical melanin pathway In humans it is also related to the process of freeradical scavenging avoiding UVradiations sideeffects However abnormal overproduction of melanin lead to hyperpigmentation that includes melanoma lentigenes age spots and other skin disorders Therefore the research of novel chemical with inhibitory activity against the enzyme remains as a challenge to scientific community In this chapter we survey the results achieved in the elucidation of new tyrosinase inhibitors by using Quantitative StructureActivity Relationships QSAR and TOMOCOMDCARDD TOpological MOlecular COMputational DesignComputerAided Rational Drug Design approach Later the use of different chemometric machine learning and artificial intelligence techniques for modeling the tyrosinase inhibitory activity is showed Finally it has been shown that the algorithm proposed in this chapter was being used to the ligandbased virtual screening of several inhouse databases and many classes of compounds from both natural and synthetic sources These compounds were found to have potent inhibitory profiles against the enzyme compared to the current reference depigmenting agents kojic acid and Lmimosine
01/2012: pages 298-341;
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ABSTRACT: Backgroundo-Aminophenols have been long recognised as tyrosinase substrates. However their exact mode of interaction with the enzyme's active site is unclear. Properly vic-substituted o-aminophenols could help gain some insight into tyrosinase catalytic mechanism.Methods
Eight vic-substituted o-aminophenols belonging to two isomeric series were systematically evaluated as tyrosinase substrates and/or activators and/or inhibitors, by means of spectrophotometric techniques and HPLC-MS analysis. Some relevant kinetic parameters have also been obtained.ResultsFour o-aminophenolic compounds derived from 3-hydroxyorthanilic acid (2-amino-3-hydroxybenzenesulfonic acid) and their four counterparts derived from the isomeric 2-hydroxymetanilic acid (3-amino-2-hydroxybenzenesulfonic acid) were synthesised and tested as putative substrates for mushroom tyrosinase. While the hydroxyorthanilic derivatives were quite inactive as both substrates and inhibitors, the hydroxymetanilic compounds on the contrary all acted as substrates for the enzyme, which oxidised them to the corresponding phenoxazinone derivatives.General significanceBased on the available structures of the active sites of tyrosinases, the different affinities of the four metanilic derivatives for the enzyme, and their oxidation rates, we propose a new hypothesis regarding the interaction between o-aminophenols and the active site of tyrosinase that is in agreement with the obtained experimental results.Graphical abstractView high quality image (54K)Highlights► Two series of vic-substituted o-aminophenols were tested as tyrosinase substrates. ► Only hydroxymetanilic compounds were oxidised by the enzyme. ► A rationale for enzyme/substrate interaction in catalytic cycle was proposed.
Biochimica et Biophysica Acta (BBA) - General Subjects 05/2011; 1810(8):799-807. · 5.00 Impact Factor
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ABSTRACT: The present work is devoted to the development and application of a multi-agent Quantitative Structure-Activity Relationship (QSAR) classification system for tyrosinase inhibitor identification, in which the individual QSAR outputs are the inputs of a fusion approach based on the voting mechanism. The individual models are based on TOMOCOMD-CARDD (TOpological Molecular COMputational Design-Computer Aided Rational Drug Design) atom-based bilinear descriptors and Linear Discriminant Analysis (LDA) on a novel enlarged, balanced database of 1,429 compounds within 701 greatly dissimilar molecules presenting anti-tyrosinase activity. A total of 21 adequate models are obtained taking into account the requirements of the Organization for Economic Cooperation and Development (OECD) principles for QSAR validation and present global accuracies (Q) above 84.50 and 79.27% in the training and test sets, respectively. The resulted fusion system is used for the in silico identification of synthesized coumarin derivatives as novel tyrosinase inhibitors. The 7-hydroxycoumarin (compound C07) shows potent activity for the inhibition of monophenolase activity of mushroom tyrosinase giving a value of inhibition percentage close to 100% in vitro assays, by means of spectrophotometric analysis. The current report could help to shed some clues in the identification of new chemicals that inhibit tyrosinase enzyme, for entering in the pipeline of drug discovery development.
Molecular Diversity 05/2011; 15(2):507-20. · 3.15 Impact Factor
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ABSTRACT: A number of vanilloids have been tested as tyrosinase inhibitors using Ligand-Based Virtual Screening (LBVS) driven by QSAR (Quantitative Structure-Activity Relationship) models as the multi-agent classification system. A total of 81 models were used to screen this family. Then, a preliminary cluster analysis of the selected chemicals was carried out based on their bioactivity to detect possible similar substructural features among these compounds and the active database used in the QSAR model construction. The compounds identified were tested in vitro to corroborate the results obtained in silico. Among them, two chemicals, isovanillin (K(M) (app) = 1.08 mM) near to kojic acid (reference drug) in one cluster and isovanillyl alcohol (K(M) (app) = 0.88 mM) at the same distance as hydroquinone (reference drug) in another cluster showed inhibitory activity against tyrosinase. The algorithm proposed here could result in a suitable approach for faster and more effective identification of hit and/or lead compounds with tyrosinase inhibitory activity, helping to shorten the long pipeline in the research of novel depigmenting agents to treat skin disorders. Copyright © 2010 John Wiley & Sons, Ltd.
Drug Testing and Analysis 03/2011; 3(3):176-81. · 2.54 Impact Factor
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ABSTRACT: Cluster analysis (CA), Linear and Quadratic Discriminant Analysis (L(Q)DA), Binary Logistic Regression (BLR) and Classification Tree (CT) are applied on two datasets for description of tyrosinase inhibitory activity from molecular structures. The first set included 701 tyrosinase inhibitors (TI) that are used for performance of inhibitory and non-inhibitory activity and the second one is for potency estimation of active compounds. 2D TOMOCOMD-CARDD atom-based quadratic indices are computed as molecular descriptors. CA is used to “rational” design of training (TS) and prediction set (PS) but it shows of not being adequate as classification technique. On the first data, the overall accuracies (Q) are 91.42%, 92.35% 91.88%, 91.79% for TS, and 91.04%, 92.43%, 88.24%, 89.36% for PS in LDA, QDA BLR and CT-based model, respectively, while the corresponding values obtained on the second one are 89.95%, 90.70%, 90.20%, 89.20% for TS and 83.71%, 84.44%, 82.96%, 82.22% for PS. A comparative analysis of used statistical techniques is held out taking into consideration generated posterior probability, accuracy, required assumptions and the form of predictor variables used. On the two datasets, results depicted by Receiver Operating Characteristic (ROC) curves together with Multiple Comparison Procedures (MCP) show that QDA has in general the best behavior as classification algorithm. The results suggest that it will be possible to produce a better description of tyrosinase activity applying the statistical techniques presented in this report, which could increase the practicality of the in silico data mining for the discovery of novel TIs.
Chemometrics and Intelligent Laboratory Systems 12/2010; 104(2):249–259. · 1.92 Impact Factor
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ABSTRACT: In this report, we show the results of quantitative structure-activity relationship (QSAR) studies of tyrosinase inhibitory activity, by using the bond-based quadratic indices as molecular descriptors (MDs) and linear discriminant analysis (LDA), to generate discriminant functions to predict the anti-tyrosinase activity. The best two models [Eqs (6) and (12)] out of the total 12 QSAR models developed here show accuracies of 93.51% and 91.21%, as well as high Matthews correlation coefficients (C) of 0.86 and 0.82, respectively, in the training set. The validation external series depicts values of 90.00% and 89.44% for these best two equations (6) and (12), respectively. Afterwards, a second external prediction data are used to perform a virtual screening of compounds reported in the literature as active (tyrosinase inhibitors). In a final step, a series of lignans is analysed using the in silico-developed models, and in vitro corroboration of the activity is carried out. An issue of great importance to remark here is that all compounds present greater inhibition values than Kojic acid (standard tyrosinase inhibitor: IC₅₀ = 16.67 μm). The current obtained results could be used as a framework to increase the speed, in the biosilico discovery of leads for the treatment of skin disorders.
Chemical Biology & Drug Design 10/2010; 76(6):538-45. · 2.28 Impact Factor
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Valeria Marina Nurchi,
Guido Crisponi,
Joanna Izabela Lachowicz,
Sergio Murgia,
Tiziana Pivetta,
Maurizio Remelli, Antonio Rescigno,
Juan Niclós-Gutíerrez,
Josefa María González-Pérez,
Alicia Domínguez-Martín,
Alfonso Castiñeiras,
Zbigniew Szewczuk
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ABSTRACT: With the aim to design new chelators for the clinical treatment of different diseases involving the trivalent metal ions Fe(III) and Al(III), we present the equilibria of kojic acid and its derivative 6-[5-hydroxy-2-hydroxymethyl-pyran-4-one]-5-hydroxy-2-hydroxymethyl-pyran-4-one with these two metal ions. Potentiometric and spectrophotometric techniques for iron, and potentiometry and (1)H NMR for aluminum were used, supported by X-ray, electrospray ionization-mass spectrometry (ESI-MS), calorimetry and quantum chemical calculations. In this work, evidence is given on the formation of MeL, MeL(2), and MeL(3) complexes of both metal ions with kojic acid, confirmed by the X-ray structure of the FeL(3) complex, and of variously protonated Me(2)L(2) and MeL(2) complexes of 6-[5-hydroxy-2-hydroxymethyl-pyran-4-one]-5-hydroxy-2-hydroxymethyl-pyran-4-one. The extremely good pFe value for this second ligand gives confidence to, and opens perspectives for, the search of new kojic acid derivatives.
Journal of inorganic biochemistry 02/2010; 104(5):560-9. · 3.25 Impact Factor
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ABSTRACT: In this review an overview of the application of computational approaches is given. Specifically, the uses of Quantitative Structure-Activity Relationship (QSAR) methods for in silico identification of new families of compounds as novel tyrosinase inhibitors are revised. Assembling, validation of models through prediction series, and virtual screening of external data sets are also shown, to prove the accuracy of the QSAR models obtained with the TOMOCOMD-CARDD (TOpological MOlecular COMputational Design-Computer-Aided Rational Drug Design) software and Linear Discriminant Analysis (LDA) as statistical technique. Together with this, a database is collected for these QSAR studies, and could be considered a useful tool in future QSAR modeling of tyrosinase activity and for scientists that work in the field of this enzyme and its inhibitors. Finally, a translation to real world applications is shown by the use of QSAR models in the identification and posterior in-vitro evaluation of different families of compounds. Several different classes of compounds from various sources (natural and synthetic) were identified. Between them, we can find tetraketones, cycloartanes, ethylsteroids, lignans, dicoumarins and vanilloid derivatives. Finally, some considerations are discussed in order to improve the identification of novel drug-like compounds based on the use of QSAR-Ligand-Based Virtual Screening (LBVS).
Current pharmaceutical design 01/2010; 16(24):2601-24. · 4.41 Impact Factor
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ABSTRACT: Laccases are members of the blue copper oxidases family found in nature. They commonly oxidise a wide range of phenol and aniline derivatives, which in turn are involved in oxidative coupling reactions. Yet, laccases remain rarely described as biocatalysts in organic synthesis. This paper describes the chemical preparation of original sulfonated aminophenol substrates and their enzyme-mediated dimerisation into phenoxazine chromophores that feature tuneable water solubility as a function of the sulfonyl substituent. The scope and limitations of the biocatalysed synthetic process are outlined. Kinetic data were collected to evaluate the influence of physicochemical parameters. The structure of the novel phenoxazine dyes ("head-to-head" or "head-to-tail" dimer) was assessed by NMR spectroscopic analysis. Two crystalline compounds were analysed by X-ray diffraction. Such laccase-mediated synthesis (a green chemistry process) was proven to be more efficient than the chemical oxidation of o-aminophenols with silver oxide.
Chemistry 08/2009; 15(33):8283-95. · 5.93 Impact Factor
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ABSTRACT: The enzymatic, selective hydrogenation of cinnamaldehyde to cinnamyl alcohol is reported here. Yeast alcohol dehydrogenase was used in a substrate-coupled process with cofactor recycling. Both 100% selectivity and aldehyde conversion were achieved within 3 h. The reaction took place under very mild conditions, in the absence of toxic organic solvent. The overall process proved inexpensive and deserves further optimization studies in order to evaluate industrial applications.
Bioscience Biotechnology and Biochemistry 06/2009; 73(5):1224-6. · 1.28 Impact Factor
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ABSTRACT: Recently, an interesting debate arose about the nature (substrate versus inhibitor) of esculetin, a coumarin derivative, for mushroom polyphenol oxidase (PPO). The present study examined the behavior of PPOs preparations from fungal and plant origin towards esculetin as a substrate. Both enzymes were able to oxidize esculetin though at a slow rate. A higher sensitivity was reached when the assay was performed in the presence of 3-methyl-2-benzothiazolinone hydrazone (MBTH) even with a lower amount of PPO. These observations unambiguously confirmed that esculetin has to be considered a substrate for mushroom polyphenol oxidase. The oxidation of esculetin was also demonstrated for the first time by a fungal laccase. This should be taken into account because some mushroom PPO preparations could exert contaminant laccase activity. In addition, a PPO preparation from Ferula communis was demonstrated to use esculetin as a substrate. Umbelliferone, the monophenolic precursor of esculetin along the phenylpropanoid pathway, behaved as a competitive inhibitor for the monophenolase activity of mushroom PPO with a K(i) value=0.014 mM. This is worth a mention because only a few couples of mono- and corresponding o-diphenol show such opposite behavior towards PPO. A possible role of PPO in the esculetin fate along biosynthesis pathway of coumarin derivatives is also discussed.
Biological & Pharmaceutical Bulletin 01/2009; 31(12):2187-93. · 1.66 Impact Factor
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ABSTRACT: Two-dimensional atom- and bond-based TOMOCOMD-CARDD descriptors and linear discriminant analysis (LDA) are used in this report to perform a quantitative structure-activity relationship (QSAR) study of tyrosinase-inhibitory activity. A database of inhibitors of the enzyme is collected for this study, within 246 highly dissimilar molecules presenting antityrosinase activity. In total, 7 discriminant functions are obtained by using the whole set of atom- and bond-based 2D indices. All the LDA-based QSAR models show accuracies above 90% in the training set and values of the Matthews correlation coefficient (C) varying from 0.85 to 0.90. The external validation set shows globally good classifications between 89% and 91% and C values ranging from 0.75 to 0.81. Finally, QSAR models are used in the selection/identification of the 20 new dicoumarins subset to search for tyrosinase inhibitory activity. Theoretical and experimental results show good correspondence between one another. It is important to remark that most compounds in this series exhibit a more potent inhibitory activity against the mushroom tyrosinase enzyme than the reference compound, Kojic acid (IC(50) = 16.67 muM), resulting in a novel nucleus base (lead) with antityrosinase activity, and this could serve as a starting point for the drug discovery of novel tyrosinase inhibitor lead compounds. ( Journal of Biomolecular Screening 2008:1014-1024).
Journal of Biomolecular Screening 12/2008; 13(10):1014-24. · 2.05 Impact Factor
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ABSTRACT: Several Mediterranean shrubs, both autochthonous and naturalized, have been traditionally used as food, flavouring and/or spicing agents, and as phytopharmaceuticals. The interest around 'natural' and 'biological' products is steadily increasing in developed countries. Therefore, it seems reasonable to screen some shrubs with regard to the actual information about their content of phytochemicals, in relation to both real and putative beneficial properties, and with particular concern to their 'antioxidant' power. Moreover, striking molecules from the examined shrubs are compared according to their occurrence in the various genera. Also, their structures and structure/activity relationship are discussed in the light of possible practical application.
Natural Product Research 06/2008; 22(8):689-708. · 1.01 Impact Factor
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02/2008;
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ABSTRACT: The volatile oil of the bark of Cinnamomum zeylanicum was extracted by means of supercritical CO2 fluid extraction in different conditions of pressure and temperature. Its chemical composition was characterized by GC-MS analysis. Nineteen compounds, which in the supercritical extract represented >95% of the oil, were identified. (E)-Cinnamaldehyde (77.1%), (E)-beta-caryophyllene (6.0%), alpha-terpineol (4.4%), and eugenol (3.0%) were found to be the major constituents. The SFE oil of cinnamon was screened for its biological activity about the formation of melanin in vitro. The extract showed antityrosinase activity and was able to reduce the formation of insoluble flakes of melanin from tyrosine. The oil also delayed the browning effect in apple homogenate. (E)-Cinnamaldehyde and eugenol were found to be mainly responsible of this inhibition effect.
Journal of Agricultural and Food Chemistry 12/2007; 55(24):10022-7. · 2.82 Impact Factor
