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17 pages, 8071 KiB

Open AccessArticle

Genistein Improves Skin Flap Viability in Rats: A Preliminary In Vivo and In Vitro Investigation

by Lenka Fáber, Ivan Kováč, Petra Mitrengová, Martin Novotný, Lenka Varinská, Tomáš Vasilenko, Martin Kello, Matúš Čoma, Tomáš Kuruc, Klaudia Petrová, Ivana Miláčková, Anika Kuczmannová, Vlasta Peržeľová, Štefánia Mižáková, Erik Dosedla, František Sabol, Ján Luczy, Milan Nagy, Jaroslav Majerník, Martin Koščo, Pavel Mučaji and Peter Gál Show full author list Hide full author list

Molecules 2018, 23(7), 1637; https://doi.org/10.3390/molecules23071637 - 4 Jul 2018

Cited by 8 | Viewed by 4529

Abstract

Selective estrogen receptor modulators (SERMs) have been developed to achieve beneficial effects of estrogens while minimizing their side effects. In this context, we decided to evaluate the protective effect of genistein, a natural SERM, on skin flap viability in rats and in a [...] Read more.

Selective estrogen receptor modulators (SERMs) have been developed to achieve beneficial effects of estrogens while minimizing their side effects. In this context, we decided to evaluate the protective effect of genistein, a natural SERM, on skin flap viability in rats and in a series of in vitro experiments on endothelial cells (migration, proliferation, antioxidant properties, and gene expression profiling following genistein treatment). Our results showed that administration of genistein increased skin flap viability, but importantly, the difference is only significant when treatment is started 3 days prior the flap surgery. Based on our in vitro experiments, it may be hypothesized that the underlying mechanism may rather by mediated by increasing SOD activity and Bcl-2 expression. The gene expression profiling further revealed 9 up-regulated genes (angiogenesis/inflammation promoting: CTGF, CXCL5, IL-6, ITGB3, MMP-14, and VEGF-A; angiogenesis inhibiting: COL18A1, TIMP-2, and TIMP-3). In conclusion, we observed a protective effect of genistein on skin flap viability which could be potentially applied in plastic surgery to women undergoing a reconstructive and/or plastic intervention. Nevertheless, further research is needed to explain the exact underlying mechanism and to find the optimal treatment protocol. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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19 pages, 5352 KiB

Open AccessArticle

¹H-NMR Profiling and Chemometric Analysis of Selected Honeys from South Africa, Zambia, and Slovakia

by Emmanuel O. Olawode, Roman Tandlich and Garth Cambray

Molecules 2018, 23(3), 578; https://doi.org/10.3390/molecules23030578 - 5 Mar 2018

Cited by 25 | Viewed by 7630

Abstract

Honey is the natural sweet substance produced by honeybee from nectar or honeydew, exhibiting several nutritional and health benefits. It contains a complex mixture of compounds in different proportions, with sugars being the main component. The physicochemical characteristics of ten honeys were evaluated; [...] Read more.

Honey is the natural sweet substance produced by honeybee from nectar or honeydew, exhibiting several nutritional and health benefits. It contains a complex mixture of compounds in different proportions, with sugars being the main component. The physicochemical characteristics of ten honeys were evaluated; represented by five, three, and two from South Africa, Slovakia, and Zambia, respectively. The range of values for the pH (3.75–4.38), electrical conductivity (99–659 µS/cm), and moisture content (14.2–17.7%) are within the recommended limits for quality honeys. ¹H-NMR (Nuclear Magnetic Resonance) profiling of the honeys in D₂O was determined, and the data were analysed by chemometrics. This method is fast, reproducible, and sample pre-treatment is not necessary. The ¹H-NMR fingerprints of various chemical shift regions showed similarity or dissimilarity across geographical origins that are useful for identification, detection of adulteration, and quality control. The principal component analysis PCA and partial linear square discriminant analysis PLS-DA of the ¹H-NMR profiles successively categorises the honeys into two chemically related groups. The R² values are higher than the corresponding Q² values for all samples, confirming the reliability of the model. Honeys in the same cluster contain similar metabolites and belong to the same botanic or floral origin. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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15 pages, 14023 KiB

Open AccessArticle

β-Escin Effectively Modulates HUVECs Proliferation and Tube Formation

by Lenka Varinská, Lenka Fáber, Martin Kello, Eva Petrovová, Ľudmila Balážová, Peter Solár, Matúš Čoma, Peter Urdzík, Ján Mojžiš, Emil Švajdlenka, Pavel Mučaji and Peter Gál

Molecules 2018, 23(1), 197; https://doi.org/10.3390/molecules23010197 - 17 Jan 2018

Cited by 20 | Viewed by 5981

Abstract

In the present study we evaluated the anti-angiogenic activities of β-escin (the major active compound of Aesculus hippocastanum L. seeds). Human umbilical-vein endothelial cells (HUVECs) were used as an in vitro model for studying the molecular mechanism underlying the anti-angiogenic effect of β-escin. [...] Read more.

In the present study we evaluated the anti-angiogenic activities of β-escin (the major active compound of Aesculus hippocastanum L. seeds). Human umbilical-vein endothelial cells (HUVECs) were used as an in vitro model for studying the molecular mechanism underlying the anti-angiogenic effect of β-escin. We investigated the in vitro effects on proliferation, migration, and tube formation of HUVECs and in vivo anti-angiogenic activity was evaluated in a chick chorioallantoic membrane (CAM) angiogenesis assay. Moreover, the effect on gene expressions was determined by the RT2 ProfilerTM human angiogenesis PCR Array. It was found that β-escin exerts inhibitory effect on the basic fibroblast growth factor (bFGF)-induced proliferation, migration and tube formation, as well as CAM angiogenesis in vivo. The inhibition of critical steps of angiogenic process observed with β-escin could be partially explained by suppression of Akt activation in response to bFGF. Moreover, the anti-angiogenic effects of β-escin could also be mediated via inhibition of EFNB2 and FGF-1 gene expressions in endothelial cells. In conclusion, β-escin affects endothelial cells as a negative mediator of angiogenesis in vitro and in vivo and may therefore be considered as a promising candidate for further research elucidating its underlying mechanism of action. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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3972 KiB

Open AccessArticle

Synthesis, Analysis, Cholinesterase-Inhibiting Activity and Molecular Modelling Studies of 3-(Dialkylamino)-2-hydroxypropyl 4-[(Alkoxy-carbonyl)amino]benzoates and Their Quaternary Ammonium Salts

by Tereza Padrtova, Pavlina Marvanova, Klara Odehnalova, Renata Kubinova, Oscar Parravicini, Adriana Garro, Ricardo D. Enriz, Otakar Humpa, Michal Oravec and Petr Mokry

Molecules 2017, 22(12), 2048; https://doi.org/10.3390/molecules22122048 - 23 Nov 2017

Cited by 11 | Viewed by 5399

Abstract

Tertiary amines 3-(dialkylamino)-2-hydroxypropyl 4-[(alkoxycarbonyl)amino]benzoates and their quaternary ammonium salts were synthesized. The final step of synthesis of quaternary ammonium salts was carried out by microwave-assisted synthesis. Software-calculated data provided the background needed to compare fifteen new resulting compounds by their physicochemical properties. The [...] Read more.

Tertiary amines 3-(dialkylamino)-2-hydroxypropyl 4-[(alkoxycarbonyl)amino]benzoates and their quaternary ammonium salts were synthesized. The final step of synthesis of quaternary ammonium salts was carried out by microwave-assisted synthesis. Software-calculated data provided the background needed to compare fifteen new resulting compounds by their physicochemical properties. The acid dissociation constant (pK_a) and lipophilicity index (log P) of tertiary amines were determined; while quaternary ammonium salts were characterized by software-calculated lipophilicity index and surface tension. Biological evaluation aimed at testing acetylcholinesterase and butyrylcholinesterase-inhibiting activity of synthesized compounds. A possible mechanism of action of these compounds was determined by molecular modelling study using combined techniques of docking; molecular dynamics simulations and quantum mechanics calculations. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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4173 KiB

Open AccessArticle

Optimization of Dissolution Compartments in a Biorelevant Dissolution Apparatus Golem v2, Supported by Multivariate Analysis

by Ivan Stupák, Sylvie Pavloková, Jakub Vysloužil, Jiří Dohnal and Martin Čulen

Molecules 2017, 22(12), 2042; https://doi.org/10.3390/molecules22122042 - 23 Nov 2017

Cited by 10 | Viewed by 5500

Abstract

Biorelevant dissolution instruments represent an important tool for pharmaceutical research and development. These instruments are designed to simulate the dissolution of drug formulations in conditions most closely mimicking the gastrointestinal tract. In this work, we focused on the optimization of dissolution compartments/vessels for [...] Read more.

Biorelevant dissolution instruments represent an important tool for pharmaceutical research and development. These instruments are designed to simulate the dissolution of drug formulations in conditions most closely mimicking the gastrointestinal tract. In this work, we focused on the optimization of dissolution compartments/vessels for an updated version of the biorelevant dissolution apparatus—Golem v2. We designed eight compartments of uniform size but different inner geometry. The dissolution performance of the compartments was tested using immediate release caffeine tablets and evaluated by standard statistical methods and principal component analysis. Based on two phases of dissolution testing (using 250 and 100 mL of dissolution medium), we selected two compartment types yielding the highest measurement reproducibility. We also confirmed a statistically ssignificant effect of agitation rate and dissolution volume on the extent of drug dissolved and measurement reproducibility. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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809 KiB

Open AccessArticle

Lipid Peroxidation Process in Meat and Meat Products: A Comparison Study of Malondialdehyde Determination between Modified 2-Thiobarbituric Acid Spectrophotometric Method and Reverse-Phase High-Performance Liquid Chromatography

by Anna Reitznerová, Monika Šuleková, Jozef Nagy, Slavomír Marcinčák, Boris Semjon, Milan Čertík and Tatiana Klempová

Molecules 2017, 22(11), 1988; https://doi.org/10.3390/molecules22111988 - 16 Nov 2017

Cited by 110 | Viewed by 9653

Abstract

The aim of this work was to compare the methods of malondialdehyde detection, as the main secondary product of the lipid peroxidation process, in meat and meat products. Malondialdehyde measurements were performed by two modified methods, the 2-thiobarbituric acid spectrophotometric method and the [...] Read more.

The aim of this work was to compare the methods of malondialdehyde detection, as the main secondary product of the lipid peroxidation process, in meat and meat products. Malondialdehyde measurements were performed by two modified methods, the 2-thiobarbituric acid spectrophotometric method and the reverse-phase high-performance liquid chromatography in raw, mechanically-deboned chicken meat and in manufactured frankfurters. The malondialdehyde concentrations measured by the 2-thiobarbituric acid spectrophotometric method were found to be overestimated by more than 25% in raw meat and more than 27% in frankfurters in comparison to the results of reverse-phase high-performance liquid chromatography (p < 0.05). The achieved results showed that the presented modified reverse-phase high-performance liquid chromatography method was more applicable and more accurate for the quantification of malondialdehyde in samples of meat and meat products. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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2475 KiB

Open AccessArticle

Larix decidua Bark as a Source of Phytoconstituents: An LC-MS Study

by Valeria Baldan, Stefania Sut, Marta Faggian, Elena Dalla Gassa, Sara Ferrari, Gabriele De Nadai, Stefano Francescato, Gianni Baratto and Stefano Dall’Acqua

Molecules 2017, 22(11), 1974; https://doi.org/10.3390/molecules22111974 - 15 Nov 2017

Cited by 20 | Viewed by 5050

Abstract

Larix decidua bark is a waste of the timber industry and is widely diffused in Northern Italy. This material can be considered a good source of antioxidants and phytoconstituents with possible use in cosmetic or nutraceutical products. In this study, simple extraction of [...] Read more.

Larix decidua bark is a waste of the timber industry and is widely diffused in Northern Italy. This material can be considered a good source of antioxidants and phytoconstituents with possible use in cosmetic or nutraceutical products. In this study, simple extraction of larch bark was performed using mixtures of ethanol/water. Furthermore, the phytochemical composition of larch bark extract was studied using LC-MSⁿ methods and the main constituents were identified as flavonoids, spiro-polyphenols, and procyanidins. To confirm the identification by LC-MS semi-preparative HPLC was performed in order to isolate the main constituents and verify the structures by ¹H-NMR. Antioxidant properties were studied using an in vitro approach combining DPPH assay and LC-MS in order to establish different roles of the various classes of phytochemicasl of the extract. DPPH activity of some of the isolated compounds was also assessed. The overall results indicate this waste material as a good source of antioxidant compounds, mainly procyanidins, whichresulted the most active constituents in the DPPH assay. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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522 KiB

Open AccessArticle

Capillary Electrophoresis Hyphenated with Mass Spectrometry for Determination of Inflammatory Bowel Disease Drugs in Clinical Urine Samples

by Katarína Maráková, Juraj Piešťanský, Zuzana Zelinková and Peter Mikuš

Molecules 2017, 22(11), 1973; https://doi.org/10.3390/molecules22111973 - 15 Nov 2017

Cited by 12 | Viewed by 4415

Abstract

Azathioprine is the main thiopurine drug used in the treatment of immune-based inflammations of gastrointestinal tract. For the purpose of therapy control and optimization, effective and reliable analytical methods for a rapid drug monitoring in biological fluids are essential. Here, we developed a [...] Read more.

Azathioprine is the main thiopurine drug used in the treatment of immune-based inflammations of gastrointestinal tract. For the purpose of therapy control and optimization, effective and reliable analytical methods for a rapid drug monitoring in biological fluids are essential. Here, we developed a separation method based on the capillary electrophoresis (CE) hyphenated with tandem mass spectrometry (MS/MS) for the simultaneous determination of azathioprine and its selected metabolites (6-thioguanine, 6-mercaptopurine, and 6-methylmercaptopurine) as well as other co-medicated drugs (mesalazine, prednisone, and allopurinol). The optimized CE-MS/MS conditions provided a very efficient and stable system for the separation and sensitive detection of these drugs in human urine matrices. The developed method was successfully applied for the assay of the targeted drugs and their selected metabolites in urine samples collected from patients suffering from inflammatory bowel disease (IBD) and receiving azathioprine therapy. The developed CE-MS/MS method, due to its reliability, short analysis time, production of complex clinical profiles, and favorable performance parameters, evaluated according to FDA guidelines for bioanalytical method validation, is proposed for routine clinical laboratories to optimize thiopurine therapy, estimate enzymatic activity, and control patient compliance with medication and co-medication. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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3443 KiB

Open AccessArticle

Proline-Based Carbamates as Cholinesterase Inhibitors

by Hana Pizova, Marketa Havelkova, Pavel Bobal, Sarka Stepankova, Tereza Kauerova, Andrzej Bak, Peter Kollar, Violetta Kozik, Michal Oravec, Ales Imramovsky and Josef Jampilek

Molecules 2017, 22(11), 1969; https://doi.org/10.3390/molecules22111969 - 14 Nov 2017

Cited by 17 | Viewed by 5136

Abstract

Series of twenty-five benzyl (2S)-2-(arylcarbamoyl)pyrrolidine-1-carboxylates was prepared and completely characterized. All the compounds were tested for their in vitro ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the selectivity of compounds to individual cholinesterases was determined. Screening of the cytotoxicity [...] Read more.

Series of twenty-five benzyl (2S)-2-(arylcarbamoyl)pyrrolidine-1-carboxylates was prepared and completely characterized. All the compounds were tested for their in vitro ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the selectivity of compounds to individual cholinesterases was determined. Screening of the cytotoxicity of all the compounds was performed using a human monocytic leukaemia THP-1 cell line, and the compounds demonstrated insignificant toxicity. All the compounds showed rather moderate inhibitory effect against AChE; benzyl (2S)-2-[(2-chlorophenyl)carbamoyl]pyrrolidine-1-carboxylate (IC₅₀ = 46.35 μM) was the most potent agent. On the other hand, benzyl (2S)-2-[(4-bromophenyl)-] and benzyl (2S)-2-[(2-bromophenyl)carbamoyl]pyrrolidine-1-carboxylates expressed anti-BChE activity (IC₅₀ = 28.21 and 27.38 μM, respectively) comparable with that of rivastigmine. The ortho-brominated compound as well as benzyl (2S)-2-[(2-hydroxyphenyl)carbamoyl]pyrrolidine-1-carboxylate demonstrated greater selectivity to BChE. The in silico characterization of the structure–inhibitory potency for the set of proline-based carbamates considering electronic, steric and lipophilic properties was provided using comparative molecular surface analysis (CoMSA) and principal component analysis (PCA). Moreover, the systematic space inspection with splitting data into the training/test subset was performed to monitor the statistical estimators performance in the effort to map the probability-guided pharmacophore pattern. The comprehensive screening of the AChE/BChE profile revealed potentially relevant structural and physicochemical features that might be essential for mapping of the carbamates inhibition efficiency indicating qualitative variations exerted on the reaction site by the substituent in the 3′-/4′-position of the phenyl ring. In addition, the investigation was completed by a molecular docking study of recombinant human AChE. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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1350 KiB

Open AccessArticle

Design, Synthesis and Anticancer Evaluation of Fangchinoline Derivatives

by Yazhou Liu, Bin Xia, Junjie Lan, Shengcao Hu, Lan Huang, Chao Chen, Xueyi Zeng, Huayong Lou, Changhu Lin and Weidong Pan

Molecules 2017, 22(11), 1923; https://doi.org/10.3390/molecules22111923 - 8 Nov 2017

Cited by 14 | Viewed by 4505

Abstract

Twenty fangchinoline derivatives were synthesized from the natural product fangchinoline, and their anticancer activities on human breast cancer MDA-MB-231 cell line, human prostate cancer PC3 cell line, human melanoma WM9 cell line and human leukaemia HEL and K562 cell lines were evaluated. The [...] Read more.

Twenty fangchinoline derivatives were synthesized from the natural product fangchinoline, and their anticancer activities on human breast cancer MDA-MB-231 cell line, human prostate cancer PC3 cell line, human melanoma WM9 cell line and human leukaemia HEL and K562 cell lines were evaluated. The biological result showed that those derivatives exhibited potent activities on inhibiting cancer cell growth, and the structure-activity relationships were investigated. Among them, compound 4g, which was protected by benzoyl group in 7-phenolic position and nitrified in 14-position, showed impressive inhibition on all 5 cancer cell lines, especially WM9 cell line, with an IC₅₀ value of 1.07 µM. Further mechanistic studies demonstrated that compound 4g may induce cancer cell death by apoptotic means. These research results suggested that compound 4g could be a lead for the further development toward an anticancer agent against human melanoma WM9 in the future. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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804 KiB

Open AccessArticle

Natural Deep Eutectic Solvents (NADES) to Enhance Berberine Absorption: An In Vivo Pharmacokinetic Study

by Stefania Sut, Marta Faggian, Valeria Baldan, Gabriele Poloniato, Ignazio Castagliuolo, Iztok Grabnar, Beatrice Perissutti, Paola Brun, Filippo Maggi, Dario Voinovich, Gregorio Peron and Stefano Dall’Acqua

Molecules 2017, 22(11), 1921; https://doi.org/10.3390/molecules22111921 - 8 Nov 2017

Cited by 93 | Viewed by 9890

Abstract

In the present study results related to the in vivo administration of Natural Deep Eutectic Solvents (NADES)-solubilized berberine are reported for the first time. NADES are mixtures of small natural compounds having a melting point significantly lower than that of any individual component. [...] Read more.

In the present study results related to the in vivo administration of Natural Deep Eutectic Solvents (NADES)-solubilized berberine are reported for the first time. NADES are mixtures of small natural compounds having a melting point significantly lower than that of any individual component. Such solvents have gained much attention of the scientific community in the green chemistry area, being considered useful alternatives to common organic solvents. NADES can be used also as administration vehicles, and this can be attractive for nutraceutical products when eutectics are formed with food grade ingredients. In this work, different NADES were prepared using mainly food grade constituents and were tested as solvents for the alkaloid berberine. Three selected NADES/berberine solutions and an aqueous suspension were orally administered to mice with in dose of 50 mg/Kg. Blood levels of berberine were measured by a LC-MS/MS method. The pharmacokinetic analysis revealed a 2–20 fold increase in blood concentration of NADES/berberine with significant changes in pharmacokinetic profile. Natural Deep Eutectic Solvents may thus be considered attractive solubilizing agents and may also play a role in the increase of absorption of poorly bioavailable natural products such as berberine. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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256 KiB

Open AccessArticle

Chokeberry Pomace as a Determinant of Antioxidant Parameters Assayed in Blood and Liver Tissue of Polish Merino and Wrzosówka Lambs

by Paulina Lipińska, Atanas G. Atanasov, Marek Palka and Artur Jóźwik

Molecules 2017, 22(11), 1461; https://doi.org/10.3390/molecules22111461 - 7 Nov 2017

Cited by 17 | Viewed by 4342

Abstract

Despite being a plant by-product, chokeberry pomace is believed to exert some therapeutic effects because it is one of the richest sources of highly bioavailable non-enzymatic antioxidants. The aim of this study was to determine the functionality of bioactive compounds present in the [...] Read more.

Despite being a plant by-product, chokeberry pomace is believed to exert some therapeutic effects because it is one of the richest sources of highly bioavailable non-enzymatic antioxidants. The aim of this study was to determine the functionality of bioactive compounds present in the Aronia melanocarpa pomace (chokeberry) based on enzymatic and non-enzymatic parameters related to the active defence of liver and blood against the effects of oxidative stress. The experiment was conducted with 48 lambs of two breeds—Polish Merino and Wrzosówka. Experimental groups were administered the basic feed with the addition of 150 g or 300 g of black chokeberry pomace per each kg of the complete feed. The activities of antioxidative enzymes (superoxide dismutase, glutathione peroxidase), peptides (glutathione, glutathione disulfide), and a lipid peroxidation indicator (malondialdehyde), as well as the capacity of non-enzymatic antioxidants were investigated. The results proved a strong effect of bioactive compounds contained in the black chokeberry pomace on the estimated parameters. The inclusion of chokeberry pomace in feed mixtures brought many benefits linked with the antioxidative protection. Parameters responsible for the oxidative status were significantly modified despite the commonly-held view about a limited possibility of transferring phenolic compounds to the organs. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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Open AccessArticle

Ferulaldehyde Improves the Effect of Methotrexate in Experimental Arthritis

by Lukáš Slovák, Karol Švík, Danica Mihalová, Jaroslav Tóth, Szilvia Czigle, Ľudmila Pašková, František Bilka and Katarína Bauerová

Molecules 2017, 22(11), 1911; https://doi.org/10.3390/molecules22111911 - 6 Nov 2017

Cited by 12 | Viewed by 4367

Abstract

Methotrexate (MTX) is still the gold standard for treatment of rheumatoid arthritis (RA). The therapeutic efficacy of low-dose of MTX can be increased by its combination with a natural substance, ferulaldehyde (FRA). The aim of this study was to evaluate the effect FRA [...] Read more.

Methotrexate (MTX) is still the gold standard for treatment of rheumatoid arthritis (RA). The therapeutic efficacy of low-dose of MTX can be increased by its combination with a natural substance, ferulaldehyde (FRA). The aim of this study was to evaluate the effect FRA and MTX administered alone or in combination in adjuvant arthritis. The disease was induced to Lewis male rats by intradermal injection, which contains a suspension of heat-inactivated Mycobacterium butyricum in incomplete Freund’s adjuvant. The experiment of 28 days included: healthy animals, arthritic animals, arthritic animals with administration of FRA at the oral daily dose of 15 mg/kg, arthritic animals with administration of MTX at the oral dose of 0.3 mg/kg twice a week, and arthritic animals administered with FRA and MTX. FRA in monotherapy decreased significantly only the level of interleukin-1β (IL-1β) and matrix metalloproteinase-9 in plasma. Combination of FRA and low-dose MTX was more effective than MTX alone when comparing body weight, hind paw volume, arthritic score, plasmatic levels of IL-1β, activity of γ-glutamyl transferase, and relative mRNA expression of IL-1β in the spleen. Therefore, the combination treatment was the most effective. The obtained results are interesting for future possible innovative therapy of patients with RA. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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Open AccessArticle

HPLC Analysis and Biochemical Characterization of LOX from Eschscholtzia californica Cham.

by Renáta Kollárová, Ivana Holková, Drahomíra Rauová, Barbora Bálintová, Peter Mikuš and Marek Obložinský

Molecules 2017, 22(11), 1899; https://doi.org/10.3390/molecules22111899 - 4 Nov 2017

Cited by 4 | Viewed by 4982

Abstract

Background: Plant lipoxygenases (LOXs, EC 1.13.11.12) are involved in lipid degradation, regulation of growth and development, senescence, and defence reactions. LOX represents the starting enzyme of the octadecanoid pathway. The aim of the work was to purify LOX from California poppy (Eschscholtzia [...] Read more.

Background: Plant lipoxygenases (LOXs, EC 1.13.11.12) are involved in lipid degradation, regulation of growth and development, senescence, and defence reactions. LOX represents the starting enzyme of the octadecanoid pathway. The aim of the work was to purify LOX from California poppy (Eschscholtzia californica Cham.), to determine its biochemical properties and to identify and quantify the products of LOX reaction with unsaturated fatty acids. Methods: LOX from California poppy seedlings was purified by hydrophobic chromatography (Phenyl-Sepharose CL-4B) and by ion-exchange chromatography (Q-Sepharose). The isolated LOX was incubated with linoleic acid used as a substrate. The HPLC experiments were performed with the Agilent Technologies 1050 series HPLC system. For the preparative separation of a mixture of hydroxy fatty acids from the sample matrix, the RP-HPLC method was used (column 120-5 Nucleosil C18). Then, the NP-HPLC analysis (separation, identification, and determination) of hydroxy fatty acid isomers was carried out on a Zorbax Rx-SIL column. Results: The purified LOX indicates the presence of a nontraditional plant enzyme with dual positional specificity (a ratio of 9- and 13-hydroperoxide products 1:1), a relative molecular mass of 85 kDa, a pH optimum of 6.5, an increasing activity stimulation by CaCl₂ till 2 mM, and a high substrate reactivity to linoleic acid with kinetic values of K_M 2.6 mM and V_max 3.14 μM/min/mg. Conclusions: For the first time, the LOX from California poppy seedlings was partially purified and the biochemical properties of the enzyme were analyzed. A dual positional specificity of the LOX found from California poppy seedlings is in agreement with the results obtained for LOXs isolated from other Papaveraceaes. A 1:1 ratio of 9-/13-HODE is attractive for the simultaneous investigation of both biotic stress responses (indicated by the 9-HODE marker) and the biosynthesis of jasmonic acid and jasmonates (indicated by the 13-HODE marker). Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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Open AccessArticle

A Rapid and Simple TLC-Densitometric Method for Assay of Clobetasol Propionate in Topical Solution

by Malgorzata Dolowy, Violetta Kozik, Andrzej Bak, Josef Jampilek, Krzysztof Barbusinski, Maciej Thomas and Alina Pyka-Pajak

Molecules 2017, 22(11), 1888; https://doi.org/10.3390/molecules22111888 - 3 Nov 2017

Cited by 8 | Viewed by 5301

Abstract

A rapid, simple to use and low-cost thin-layer chromatographic procedure in normal phase system with densitometric detection at 246 nm was carefully validated according to the International Conference on Harmonisation (ICH) guidelines for assay of clobetasol propionate in topical solution containing clobetasol propionate [...] Read more.

A rapid, simple to use and low-cost thin-layer chromatographic procedure in normal phase system with densitometric detection at 246 nm was carefully validated according to the International Conference on Harmonisation (ICH) guidelines for assay of clobetasol propionate in topical solution containing clobetasol propionate in quantity 0.50 mg/mL. The adopted thin-layer chromatographic (TLC)-densitometric procedure could effectively separate clobetasol propionate from its related compound, namely clobetasol. It is linear for clobetasol propionate in the range of 0.188 ÷ 5 µg/spot. The limit of detection (LOD) and limit of quantification (LOQ) value is 0.061 and 0.186 µg/spot, respectively. Accuracy of proposed procedure was evaluated by recovery test. The mean recovery of studied clobetasol propionate ranges from 98.7 to 101.0%. The coefficient of variation (CV, %) obtained during intra-day and inter-day studies, which was less than 2% (0.40 ÷ 1.17%), confirms the precision of described method. The assay value of clobetasol propionate is consistent with the pharmacopoeial requirements. In conclusion, it can be suitable as a simple and economic procedure for routine quality control laboratories of clobetasol propionate in topical solution. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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Open AccessArticle

Ureidopyrazine Derivatives: Synthesis and Biological Evaluation as Anti-Infectives and Abiotic Elicitors

by Ghada Bouz, Martin Juhás, Pavlína Niklová, Ondřej Janďourek, Pavla Paterová, Jiří Janoušek, Lenka Tůmová, Zuzana Kovalíková, Petr Kastner, Martin Doležal and Jan Zitko

Molecules 2017, 22(10), 1797; https://doi.org/10.3390/molecules22101797 - 23 Oct 2017

Cited by 7 | Viewed by 4979

Abstract

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) has become a frequently deadly infection due to increasing antimicrobial resistance. This serious issue has driven efforts worldwide to discover new drugs effective against Mtb. One research area is the synthesis and evaluation [...] Read more.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) has become a frequently deadly infection due to increasing antimicrobial resistance. This serious issue has driven efforts worldwide to discover new drugs effective against Mtb. One research area is the synthesis and evaluation of pyrazinamide derivatives as potential anti-TB drugs. In this paper we report the synthesis and biological evaluations of a series of ureidopyrazines. Compounds were synthesized by reacting alkyl/aryl isocyanates with aminopyrazine or with propyl 5-aminopyrazine-2-carboxylate. Reactions were performed in pressurized vials using a CEM Discover microwave reactor with a focused field. Purity and chemical structures of products were assessed, and the final compounds were tested in vitro for their antimycobacterial, antibacterial, and antifungal activities. Propyl 5-(3-phenylureido)pyrazine-2-carboxylate (compound 4, MIC_Mtb = 1.56 μg/mL, 5.19 μM) and propyl 5-(3-(4-methoxyphenyl)ureido)pyrazine-2-carboxylate (compound 6, MIC_Mtb = 6.25 μg/mL, 18.91 μM) had high antimycobacterial activity against Mtb H37Rv with no in vitro cytotoxicity on HepG2 cell line. Therefore 4 and 6 are suitable for further structural modifications that might improve their biological activity and physicochemical properties. Based on the structural similarity to 1-(2-chloropyridin-4-yl)-3-phenylurea, a known plant growth regulator, two selected compounds were evaluated for similar activity as abiotic elicitors. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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8082 KiB

Open AccessArticle

Silver Nanoparticles Stabilised by Cationic Gemini Surfactants with Variable Spacer Length

by Martin Pisárčik, Josef Jampílek, Miloš Lukáč, Renáta Horáková, Ferdinand Devínsky, Marián Bukovský, Michal Kalina, Jakub Tkacz and Tomáš Opravil

Molecules 2017, 22(10), 1794; https://doi.org/10.3390/molecules22101794 - 23 Oct 2017

Cited by 36 | Viewed by 7737

Abstract

The present study is focused on the synthesis and investigation of the physicochemical and biological properties of silver nanoparticles stabilized with a series of cationic gemini surfactants having a polymethylene spacer of variable length. UV-VIS spectroscopy, dynamic light scattering, scanning electron microscopy and [...] Read more.

The present study is focused on the synthesis and investigation of the physicochemical and biological properties of silver nanoparticles stabilized with a series of cationic gemini surfactants having a polymethylene spacer of variable length. UV-VIS spectroscopy, dynamic light scattering, scanning electron microscopy and zeta potential measurements were applied to provide physicochemical characterization of the silver nanoparticles. The mean size values of the nanoparticles were found to be in the 50 to 115 nm range. From the nanoparticle size distributions and scanning electron microscopy images it results that a population of small nanoparticles with the size of several nanometers was confirmed if the nanoparticles were stabilized with gemini molecules with either a short methylene spacer (two or four −CH₂− groups) or a long spacer (12 −CH₂− groups). The average zeta potential value for silver nanoparticles stabilized with gemini molecules is roughly independent of gemini surfactant spacer length and is approx. +58 mV. An interaction model between silver nanoparticles and gemini molecules which reflects the gained experimental data, is suggested. Microbicidal activity determinations revealed that the silver nanoparticles stabilized with gemini surfactants are more efficient against Gram-negative bacteria and yeasts, which has a direct relation to the interaction mechanism of nanoparticles with the bacterial cell membrane and its structural composition. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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Caustic Ingestion in the Elderly: Influence of Age on Clinical Outcome

by Blazena Caganova, Tatiana Foltanova, Erik Puchon, Elena Ondriasova, Silvia Plackova, Tomas Fazekas and Magdalena Kuzelova

Molecules 2017, 22(10), 1726; https://doi.org/10.3390/molecules22101726 - 14 Oct 2017

Cited by 7 | Viewed by 6115

Abstract

Caustic poisonings are still associated with many fatalities. Studies focusing on the elderly are rare. The purpose of the present study was to compare the clinical outcomes of caustic ingestion injury in elderly and non-elderly adults with regard to gender, intent of exposure, [...] Read more.

Caustic poisonings are still associated with many fatalities. Studies focusing on the elderly are rare. The purpose of the present study was to compare the clinical outcomes of caustic ingestion injury in elderly and non-elderly adults with regard to gender, intent of exposure, substance ingested, severity of mucosal injury, complications, and mortality. Caustic substance exposures reported to the National Toxicological Information Centre in Slovakia during 1998–2015 were reviewed retrospectively. The patients were divided into two groups: the non-elderly (<60 years) and elderly adults (≥60 years). The mortality rate in the elderly was significantly higher (elderly 23.0% vs. non-elderly 11.3%; p = 0.041). The risk of fatal outcome in the elderly was increased by acid ingestion (OR = 7.822; p = 0.002), particularly hydrochloric acid (OR = 5.714, p = 0.006). The incidence of respiratory complications was almost two times higher in the elderly was 31.1% vs. 17.4% for the non-elderly (p = 0.037). Respiratory complications significantly correlated with an increased mortality rate (p = 0.001) in the elderly whereas there was no association between GI complications and mortality in the elderly (p = 0.480). Elderly patients with respiratory complications had the poorest clinical outcomes. The highest risk of complications and fatalities was observed in patients after hydrochloric acid ingestion. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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Open AccessArticle

Halogenated 1-Hydroxynaphthalene-2-Carboxanilides Affecting Photosynthetic Electron Transport in Photosystem II

by Tomas Gonec, Jiri Kos, Matus Pesko, Jana Dohanosova, Michal Oravec, Tibor Liptaj, Katarina Kralova and Josef Jampilek

Molecules 2017, 22(10), 1709; https://doi.org/10.3390/molecules22101709 - 12 Oct 2017

Cited by 20 | Viewed by 4064

Abstract

Series of seventeen new multihalogenated 1-hydroxynaphthalene-2-carboxanilides was prepared and characterized. All the compounds were tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. 1-Hydroxy-N-phenylnaphthalene-2-carboxamides substituted in the anilide part by [...] Read more.

Series of seventeen new multihalogenated 1-hydroxynaphthalene-2-carboxanilides was prepared and characterized. All the compounds were tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. 1-Hydroxy-N-phenylnaphthalene-2-carboxamides substituted in the anilide part by 3,5-dichloro-, 4-bromo-3-chloro-, 2,5-dibromo- and 3,4,5-trichloro atoms were the most potent PET inhibitors (IC₅₀ = 5.2, 6.7, 7.6 and 8.0 µM, respectively). The inhibitory activity of these compounds depends on the position and the type of halogen substituents, i.e., on lipophilicity and electronic properties of individual substituents of the anilide part of the molecule. Interactions of the studied compounds with chlorophyll a and aromatic amino acids present in pigment-protein complexes mainly in PS II were documented by fluorescence spectroscopy. The section between P₆₈₀ and plastoquinone Q_B in the PET chain occurring on the acceptor side of PS II can be suggested as the site of action of the compounds. The structure-activity relationships are discussed. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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Two-Dimensional Capillary Electrophoresis with On-Line Sample Preparation and Cyclodextrin Separation Environment for Direct Determination of Serotonin in Human Urine

by Juraj Piešťanský, Katarína Maráková and Peter Mikuš

Molecules 2017, 22(10), 1668; https://doi.org/10.3390/molecules22101668 - 7 Oct 2017

Cited by 15 | Viewed by 4923

Abstract

An advanced two-dimensional capillary electrophoresis method, based on on-line combination of capillary isotachophoresis and capillary zone electrophoresis with cyclodextrin additive in background electrolyte, was developed for effective determination of serotonin in human urine. Hydrodynamically closed separation system and large bore capillaries (300–800 µm) [...] Read more.

An advanced two-dimensional capillary electrophoresis method, based on on-line combination of capillary isotachophoresis and capillary zone electrophoresis with cyclodextrin additive in background electrolyte, was developed for effective determination of serotonin in human urine. Hydrodynamically closed separation system and large bore capillaries (300–800 µm) were chosen for the possibility to enhance the sample load capacity, and, by that, to decrease limit of detection. Isotachophoresis served for the sample preseparation, defined elimination of sample matrix constituents (sample clean up), and preconcentration of the analyte. Cyclodextrin separation environment enhanced separation selectivity of capillary zone electrophoresis. In this way, serotonin could be successfully separated from the rest of the sample matrix constituents migrating in capillary zone electrophoresis step so that human urine could be directly (i.e., without any external sample preparation) injected into the analyzer. The proposed method was successfully validated, showing favorable parameters of sensitivity (limit of detection for serotonin was 2.32 ng·mL⁻¹), linearity (regression coefficient higher than 0.99), precision (repeatability of the migration time and peak area were in the range of 0.02–1.17% and 5.25–7.88%, respectively), and recovery (ranging in the interval of 90.0–93.6%). The developed method was applied for the assay of the human urine samples obtained from healthy volunteers. The determined concentrations of serotonin in such samples were in the range of 12.4–491.2 ng·mL⁻¹ that was in good agreement with literature data. This advanced method represents a highly effective, reliable, and low-cost alternative for the routine determination of serotonin as a biomarker in human urine. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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Review

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How Signaling Molecules Regulate Tumor Microenvironment: Parallels to Wound Repair

by Peter Gál, Lenka Varinská, Lenka Fáber, Štepán Novák, Pavol Szabo, Petra Mitrengová, Andrej Mirossay, Pavel Mučaji and Karel Smetana

Molecules 2017, 22(11), 1818; https://doi.org/10.3390/molecules22111818 - 26 Oct 2017

Cited by 47 | Viewed by 7996

Abstract

It is now suggested that the inhibition of biological programs that are associated with the tumor microenvironment may be critical to the diagnostics, prevention and treatment of cancer. On the other hand, a suitable wound microenvironment would accelerate tissue repair and prevent extensive [...] Read more.

It is now suggested that the inhibition of biological programs that are associated with the tumor microenvironment may be critical to the diagnostics, prevention and treatment of cancer. On the other hand, a suitable wound microenvironment would accelerate tissue repair and prevent extensive scar formation. In the present review paper, we define key signaling molecules (growth factors, cytokines, chemokines, and galectins) involved in the formation of the tumor microenvironment that decrease overall survival and increase drug resistance in cancer suffering patients. Additional attention will also be given to show whether targeted modulation of these regulators promote tissue regeneration and wound management. Whole-genome transcriptome profiling, in vitro and animal experiments revealed that interleukin 6, interleukin 8, chemokine (C-X-C motif) ligand 1, galectin-1, and selected proteins of the extracellular matrix (e.g., fibronectin) do have similar regulation during wound healing and tumor growth. Published data demonstrate remarkable similarities between the tumor and wound microenvironments. Therefore, tailor made manipulation of cancer stroma can have important therapeutic consequences. Moreover, better understanding of cancer cell-stroma interaction can help to improve wound healing by supporting granulation tissue formation and process of reepithelization of extensive and chronic wounds as well as prevention of hypertrophic scars and formation of keloids. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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Open AccessConference Report

The Forty-Sixth Euro Congress on Drug Synthesis and Analysis: Snapshot ^†

by Pavel Mucaji, Atanas G. Atanasov, Andrzej Bak, Violetta Kozik, Karolina Sieron, Mark Olsen, Weidong Pan, Yazhou Liu, Shengchao Hu, Junjie Lan, Norbert Haider, Robert Musiol, Jan Vanco, Marc Diederich, Seungwon Ji, Jan Zitko, Dongdong Wang, Danica Agbaba, Katarina Nikolic, Slavica Oljacic, Jelica Vucicevic, Daniela Jezova, Anna Tsantili-Kakoulidou, Fotios Tsopelas, Constantinos Giaginis, Teresa Kowalska, Mieczyslaw Sajewicz, Jerzy Silberring, Przemyslaw Mielczarek, Marek Smoluch, Izabela Jendrzejewska, Jaroslaw Polanski and Josef Jampilek Show full author list Hide full author list

Molecules 2017, 22(11), 1848; https://doi.org/10.3390/molecules22111848 - 28 Oct 2017

Cited by 5 | Viewed by 6660

Abstract

The 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017) was arranged within the celebration of the 65th Anniversary of the Faculty of Pharmacy at Comenius University in Bratislava, Slovakia from 5–8 September 2017 to get together specialists in medicinal chemistry, organic synthesis, pharmaceutical [...] Read more.

The 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017) was arranged within the celebration of the 65th Anniversary of the Faculty of Pharmacy at Comenius University in Bratislava, Slovakia from 5–8 September 2017 to get together specialists in medicinal chemistry, organic synthesis, pharmaceutical analysis, screening of bioactive compounds, pharmacology and drug formulations; promote the exchange of scientific results, methods and ideas; and encourage cooperation between researchers from all over the world. The topic of the conference, “Drug Synthesis and Analysis,” meant that the symposium welcomed all pharmacists and/or researchers (chemists, analysts, biologists) and students interested in scientific work dealing with investigations of biologically active compounds as potential drugs. The authors of this manuscript were plenary speakers and other participants of the symposium and members of their research teams. The following summary highlights the major points/topics of the meeting. Full article

(This article belongs to the Special Issue Selected Papers from the 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017))

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