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Molecules, Volume 23, Issue 4 (April 2018)

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Cover Story (view full-size image) New hybrids that can be used as sensitive coatings for real-time metal analysis were easily [...] Read more.
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Editorial

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Open AccessFeature PaperEditorial A Serendipitous Journey Leading to My Love of Dendritic Patterns and Chemistry
Molecules 2018, 23(4), 824; https://doi.org/10.3390/molecules23040824
Received: 30 March 2018 / Revised: 1 April 2018 / Accepted: 2 April 2018 / Published: 4 April 2018
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Abstract
As the oldest of four Midwestern boys who were offsprings of an accountant and a housewife, each with less than a formal high school degree, we were blessed to have such parents.[...] Full article
Open AccessEditorial Lewis Pair Polymerization for New Reactivity and Structure in Polymer Synthesis
Molecules 2018, 23(4), 915; https://doi.org/10.3390/molecules23040915
Received: 8 April 2018 / Revised: 9 April 2018 / Accepted: 12 April 2018 / Published: 16 April 2018
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Open AccessFeature PaperEditorial Biomedical Applications of Polylactide (PLA) and Its Copolymers
Molecules 2018, 23(4), 980; https://doi.org/10.3390/molecules23040980
Received: 19 April 2018 / Revised: 21 April 2018 / Accepted: 21 April 2018 / Published: 23 April 2018
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(This article belongs to the Special Issue Biomedical Applications of Polylactide (PLA) and its Copolymers)

Research

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Open AccessArticle Efficient Synthesis and Bioactivity of Novel Triazole Derivatives
Molecules 2018, 23(4), 709; https://doi.org/10.3390/molecules23040709
Received: 25 February 2018 / Revised: 12 March 2018 / Accepted: 15 March 2018 / Published: 21 March 2018
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Abstract
Triazole pesticides are organic nitrogen-containing heterocyclic compounds, which contain 1,2,3-triazole ring. In order to develop potential glucosamine-6-phosphate synthase (GlmS) inhibitor fungicides, forty compounds of triazole derivatives were synthesized in an efficient way, thirty nine of them were new compounds. The structures of all
[...] Read more.
Triazole pesticides are organic nitrogen-containing heterocyclic compounds, which contain 1,2,3-triazole ring. In order to develop potential glucosamine-6-phosphate synthase (GlmS) inhibitor fungicides, forty compounds of triazole derivatives were synthesized in an efficient way, thirty nine of them were new compounds. The structures of all the compounds were confirmed by high resolution mass spectrometer (HRMS), 1H-NMR and 13C-NMR. The fungicidal activities results based on means of mycelium growth rate method indicated that some of the compounds exhibited good fungicidal activities against P. CapasiciLeonian, Sclerotinia sclerotiorum (Lib.) de Bary, Pyricularia oryzae Cav. and Fusarium oxysporum Schl. F.sp. vasinfectum (Atk.) Snyd. & Hans. at the concentration of 50 µg/mL, especially the inhibitory rates of compounds 1-d and 1-f were over 80%. At the same time, the preliminary studies based on the Elson-Morgan method indicated that the compounds exhibited some inhibitory activity toward glucosamine-6-phosphate synthase (GlmS). These compounds will be further studied as potential antifungal lead compounds. The structure-activity relationships (SAR) were discussed in terms of the effects of the substituents on both the benzene and the sugar ring. Full article
(This article belongs to the Section Organic Chemistry)
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Open AccessArticle Synthesis of Benzofuran-2-One Derivatives and Evaluation of Their Antioxidant Capacity by Comparing DPPH Assay and Cyclic Voltammetry
Molecules 2018, 23(4), 710; https://doi.org/10.3390/molecules23040710
Received: 3 March 2018 / Revised: 17 March 2018 / Accepted: 19 March 2018 / Published: 21 March 2018
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Abstract
The present work aimed to synthesise promising antioxidant compounds as a valuable alternative to the currently expensive and easily degradable molecules that are employed as stabilizers in industrial preparation. Taking into account our experience concerning domino Friedel-Crafts/lactonization reactions, we successfully improved and extended
[...] Read more.
The present work aimed to synthesise promising antioxidant compounds as a valuable alternative to the currently expensive and easily degradable molecules that are employed as stabilizers in industrial preparation. Taking into account our experience concerning domino Friedel-Crafts/lactonization reactions, we successfully improved and extended the previously reported methodology toward the synthesis of 3,3-disubstituted-3H-benzofuran-2-one derivatives 920 starting from polyphenols 16 as substrates and either diethylketomalonate (7) or 3,3,3-trifluoromethyl pyruvate (8) as electrophilic counterpart. The antioxidant capacity of the most stable compounds (911 and 1520) was evaluated by both DPPH assay and Cyclic Voltammetry analyses performed in alcoholic media (methanol) as well as in aprotic solvent (acetonitrile). By comparing the recorded experimental data, a remarkable activity can be attributed to few of the tested lactones. Full article
(This article belongs to the Section Medicinal Chemistry)
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Open AccessArticle Theoretical Investigation of the Formation Mechanism of NH3 and HCN during Pyrrole Pyrolysis: The Effect of H2O
Molecules 2018, 23(4), 711; https://doi.org/10.3390/molecules23040711
Received: 26 February 2018 / Revised: 14 March 2018 / Accepted: 19 March 2018 / Published: 21 March 2018
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Abstract
Coal is a major contributor to the global emission of nitrogen oxides (NOx). The NOx formation during coal utilization typically derives from the thermal decomposition of N-containing compounds (e.g., pyrrolic groups). NH3 and HCN are common precursors of NO
[...] Read more.
Coal is a major contributor to the global emission of nitrogen oxides (NOx). The NOx formation during coal utilization typically derives from the thermal decomposition of N-containing compounds (e.g., pyrrolic groups). NH3 and HCN are common precursors of NOx from the decomposition of N-containing compounds. The existence of H2O has significant influences on the pyrrole decomposition and NOx formation. In this study, the effects of H2O on pyrrole pyrolysis to form NOx precursors HCN and NH3 are investigated using the density functional theory (DFT) method. The calculation results indicate that the presence of H2O can lead to the formation of both NH3 and HCN during pyrrole pyrolysis, while only HCN is formed in the absence of H2O. The initial interaction between pyrrole and H2O determines the N products. NH3 will be formed when H2O attacks the C2 position of pyrrole with its hydroxyl group. On the contrary, HCN will be generated instead of NH3 when H2O attacks the C3 position of pyrrole with its hydroxyl group. In addition, the DFT calculations clearly indicate that the formation of NH3 will be promoted by H2O, whereas the formation of HCN is inhibited. Full article
(This article belongs to the Section Theoretical Chemistry)
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Open AccessArticle Digestibility of Bovine Serum Albumin and Peptidomics of the Digests: Effect of Glycation Derived from α-Dicarbonyl Compounds
Molecules 2018, 23(4), 712; https://doi.org/10.3390/molecules23040712
Received: 5 January 2018 / Revised: 2 March 2018 / Accepted: 7 March 2018 / Published: 21 March 2018
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Abstract
α-Dicarbonyl compounds, which are widely generated during sugar fragmentation and oil oxidation, are important precursors of advanced glycation end products (AGEs). In this study, the effect of glycation derived from glyoxal (GO), methylglyoxal (MGO) and diacetyl (DA) on the in vitro digestibility of
[...] Read more.
α-Dicarbonyl compounds, which are widely generated during sugar fragmentation and oil oxidation, are important precursors of advanced glycation end products (AGEs). In this study, the effect of glycation derived from glyoxal (GO), methylglyoxal (MGO) and diacetyl (DA) on the in vitro digestibility of bovine serum albumin (BSA) was investigated. Glycation from α-dicarbonyl compounds reduced digestibility of BSA in both gastric and intestinal stage of digestion according to measurement of degree of hydrolysis. Changes in peptide composition of digests induced by glycation were displayed, showing absence of peptides, occurrence of new peptides and formation of peptide-AGEs, based on the results obtained using liquid chromatography electron-spray-ionization tandem mass spectrometry (LC-ESI-MS/MS). Crosslinked glycation structures derived from DA largely reduced the sensitivity of glycated BSA towards digestive proteases based on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) results. Network structures were found to remain in the digests of glycated samples by transmission electron microscope (TEM), thus the impact of AGEs in unabsorbed digests on the gut flora should be an interest for further studies. Full article
(This article belongs to the Section Analytical Chemistry)
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Open AccessArticle Utilizing a Spiro Core with Acridine- and Phenothiazine-Based New Hole Transporting Materials for Highly Efficient Green Phosphorescent Organic Light-Emitting Diodes
Molecules 2018, 23(4), 713; https://doi.org/10.3390/molecules23040713
Received: 19 February 2018 / Revised: 9 March 2018 / Accepted: 19 March 2018 / Published: 21 March 2018
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Abstract
Two new hole transporting materials, 2,7-bis(9,9-diphenylacridin-10(9H)-yl)-9,9′ spirobi[fluorene] (SP1) and 2,7-di(10H-phenothiazin-10-yl)-9,9′-spirobi[fluorene] (SP2), were designed and synthesized by using the Buchwald–Hartwig coupling reaction with a high yield percentage of over 84%. Both of the materials exhibited high glass transition temperatures of
[...] Read more.
Two new hole transporting materials, 2,7-bis(9,9-diphenylacridin-10(9H)-yl)-9,9′ spirobi[fluorene] (SP1) and 2,7-di(10H-phenothiazin-10-yl)-9,9′-spirobi[fluorene] (SP2), were designed and synthesized by using the Buchwald–Hartwig coupling reaction with a high yield percentage of over 84%. Both of the materials exhibited high glass transition temperatures of over 150 °C. In order to understand the device performances, we have fabricated green phosphorescent organic light-emitting diodes (PhOLEDs) with SP1 and SP2 as hole transporting materials. Both of the materials revealed improved device properties, in particular, the SP2-based device showed excellent power (34.47 lm/W) and current (38.41 cd/A) efficiencies when compare with the 4,4′-bis(N-phenyl-1-naphthylamino)biphenyl (NPB)-based reference device (30.33 lm/W and 32.83 cd/A). The external quantum efficiency (EQE) of SP2 was 13.43%, which was higher than SP1 (13.27%) and the reference material (11.45%) with a similar device structure. The SP2 hole transporting material provides an effective charge transporting path from anode to emission layer, which is explained by the device efficiencies. Full article
(This article belongs to the Special Issue Advances in Spiro Compounds)
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Open AccessArticle Development and Validation of a HPLC-ESI-MS/MS Method for Simultaneous Quantification of Fourteen Alkaloids in Mouse Plasma after Oral Administration of the Extract of Corydalis yanhusuo Tuber: Application to Pharmacokinetic Study
Molecules 2018, 23(4), 714; https://doi.org/10.3390/molecules23040714
Received: 2 March 2018 / Revised: 19 March 2018 / Accepted: 20 March 2018 / Published: 21 March 2018
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Abstract
The tuber of Corydalis yanhusuo is a famous traditional Chinese medicine and found to have potent pharmacological effects, such as antinociceptive, antitumor, antibacterial, anti-inflammatory, and anti-depressive activities. Although there are several methods to be developed for the analysis and detection of the bioactive
[...] Read more.
The tuber of Corydalis yanhusuo is a famous traditional Chinese medicine and found to have potent pharmacological effects, such as antinociceptive, antitumor, antibacterial, anti-inflammatory, and anti-depressive activities. Although there are several methods to be developed for the analysis and detection of the bioactive ingredients’ alkaloids, so far, only few prominent alkaloids could be quantified, and in vitro and in vivo changes of comprehensive alkaloids after oral administration are still little known. In this study, we first developed a simple and sensitive high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) method to quantify the comprehensive alkaloids of extracts of C. yanhusuo in mouse plasma, using nitidine chloride as an internal standard. As results, at least fourteen alkaloids, including an aporphine (oxoglaucine), a protopine (protopine), five tertiary alkaloids (corydaline, tetrahydroberberine, tetrahydropalmatine, tetrahydrocolumbamine, and tetrahydrocoptisine) and seven quaternary alkaloids (columbamine, palmatine, berberine, epiberberine, coptisine, jatrorrhizine, and dehydrocorydaline) could be well quantified simultaneously in mouse plasma. The lower limits of quantification were greater than, or equal to, 0.67 ng/mL, and the average matrix effects ranged from 96.4% to 114.3%. The mean extraction recoveries of quality control samples were over 71.40%, and the precision and accuracy were within the acceptable limits. All the analytes were shown to be stable under different storage conditions. Then the established method was successfully applied to investigate the pharmacokinetics of these alkaloids after oral administration of the extract of Corydalis yanhusuo in mice. To the best of our knowledge, this is the first document to report the comprehensive and simultaneous analyses of alkaloids of C. yanhusuo in mouse plasma. It was efficient and useful for comprehensive pharmacokinetic and metabolomic analyses of these complex alkaloids after drug administration. Full article
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Open AccessArticle Selection and Characterization of Single-Stranded DNA Aptamers Binding Human B-Cell Surface Protein CD20 by Cell-SELEX
Molecules 2018, 23(4), 715; https://doi.org/10.3390/molecules23040715
Received: 4 March 2018 / Revised: 9 March 2018 / Accepted: 12 March 2018 / Published: 21 March 2018
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Abstract
The B-lymphocyte antigen (CD20) is a suitable target for single-stranded (ss) nucleic acid oligomer (aptamers). The aim of study was selection and characterization of a ssDNA aptamer against CD20 using Cell-Systematic Evolution of Ligands by Exponential Enrichment (Cell-SELEX). The cDNA clone of CD20
[...] Read more.
The B-lymphocyte antigen (CD20) is a suitable target for single-stranded (ss) nucleic acid oligomer (aptamers). The aim of study was selection and characterization of a ssDNA aptamer against CD20 using Cell-Systematic Evolution of Ligands by Exponential Enrichment (Cell-SELEX). The cDNA clone of CD20 (pcDNA-CD20) was transfected to human embryonic kidney (HEK293T) cells. Ten rounds of Cell-SELEX was performed on recombinant HEK-CD20 cells. The final eluted ssDNA pool was amplified and ligated in T/A vector for cloning. The plasmids of positive clones were extracted, sequenced and the secondary structures of the aptamers predicted using DNAMAN® software. The sequencing results revealed 10 different types; three of them had the highest thermodynamic stability, named AP-1, AP-2 and AP-3. The AP-1 aptamer was the most thermodynamically stable one (ΔGAP-1 = −10.87 kcal/mol) with the highest binding affinity to CD20 (96.91 ± 4.5 nM). Since, the CD20 is a suitable target for recognition of B-Cell. The selected aptamers could be comparable to antibodies with many advantages. The AP-1, AP-2 and AP-3 could be candidate instead of antibodies for diagnostic and therapeutic applications in immune deficiency, autoimmune diseases, leukemia and lymphoma. Full article
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Open AccessArticle Synthesis of Some Novel Thiadiazole Derivative Compounds and Screening Their Antidepressant-Like Activities
Molecules 2018, 23(4), 716; https://doi.org/10.3390/molecules23040716
Received: 7 February 2018 / Revised: 1 March 2018 / Accepted: 7 March 2018 / Published: 21 March 2018
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Abstract
Novel thiadiazole derivatives were synthesized through the reaction of acetylated 2-aminothiadiazole and piperazine derivatives. The chemical structures of the compounds were clarified by Infrared Spectroscopy (IR), 1H Nuclear Magnetic Resonance Spectroscopy (1H-NMR), 13C Nuclear Magnetic Resonance Spectroscopy (13
[...] Read more.
Novel thiadiazole derivatives were synthesized through the reaction of acetylated 2-aminothiadiazole and piperazine derivatives. The chemical structures of the compounds were clarified by Infrared Spectroscopy (IR), 1H Nuclear Magnetic Resonance Spectroscopy (1H-NMR), 13C Nuclear Magnetic Resonance Spectroscopy (13C-NMR) and Electronspray Ionisation Mass Spectroscopy (ESI-MS) spectroscopic methods. Antidepressant-like activities were evaluated by the tail-suspension (TST) and modified forced swimming (MFST) methods. Besides, possible influence of the test compounds on motor activities of the animals were examined by activity cage tests. In the TST, administration of the compounds 2c, 2d, 2e, 2f, 2g and 2h significantly decreased the immobility time of mice regarding the control values. Further, in the MFST, the same compounds reduced the total number of immobility behaviors while increasing swimming performance. However, no change was observed in the total number of climbing behaviors. These data suggested that compounds 2c, 2d, 2e, 2f, 2g and 2h possess notable antidepressant-like activities. Reference drug fluoxetine (10 mg/kg) was also exhibited its antidepressant activity, as expected. No significant difference was seen between the locomotor activity values of the test groups signifying that observed antidepressant-like activities are specific. Theoretical calculation of absorption, distribution, metabolism, excretion (ADME) properties for the obtained compounds were performed and obtained data supported the antidepressant-like potential of these novel thiadiazole derivatives. Full article
(This article belongs to the Section Medicinal Chemistry)
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Open AccessArticle Heterophyllin B Ameliorates Lipopolysaccharide-Induced Inflammation and Oxidative Stress in RAW 264.7 Macrophages by Suppressing the PI3K/Akt Pathways
Molecules 2018, 23(4), 717; https://doi.org/10.3390/molecules23040717
Received: 1 March 2018 / Revised: 17 March 2018 / Accepted: 19 March 2018 / Published: 21 March 2018
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Abstract
Heterophyllin B (HB), an active cyclic peptide, is a compound existing in the ethyl acetate extract of Pseudostellaria heterophylla (Miq.) Pax and exhibited the activity of inhibiting the production of NO and cytokines, such as IL-1β and IL-6, in LPS-stimulated RAW 264.7 macrophages.
[...] Read more.
Heterophyllin B (HB), an active cyclic peptide, is a compound existing in the ethyl acetate extract of Pseudostellaria heterophylla (Miq.) Pax and exhibited the activity of inhibiting the production of NO and cytokines, such as IL-1β and IL-6, in LPS-stimulated RAW 264.7 macrophages. In addition, HB suppressed the production of ROS and the apoptosis induced by LPS in RAW 264.7 macrophages. The underlying mechanism was investigated in the LPS-induced RAW 264.7 cells. The results showed that HB decreased the level of IL-1β and IL-6 expression by qRT-PCR analysis. HB up-regulated the relative ratio of p-AKT/AKT and p-PI3K/PI3K as indicated by western blot analysis. In summary, HB inhibited the LPS-induced inflammation and apoptosis through the PI3K/Akt signaling pathways and represented a potential therapeutic target for treatment of inflammatory diseases. Full article
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Open AccessArticle Amaryllidaceae Alkaloids as Potential Glycogen Synthase Kinase-3β Inhibitors
Molecules 2018, 23(4), 719; https://doi.org/10.3390/molecules23040719
Received: 15 February 2018 / Revised: 19 March 2018 / Accepted: 19 March 2018 / Published: 21 March 2018
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Abstract
Glycogen synthase kinase-3β (GSK-3β) is a multifunctional serine/threonine protein kinase that was originally identified as an enzyme involved in the control of glycogen metabolism. It plays a key role in diverse physiological processes including metabolism, the cell cycle, and gene expression by regulating
[...] Read more.
Glycogen synthase kinase-3β (GSK-3β) is a multifunctional serine/threonine protein kinase that was originally identified as an enzyme involved in the control of glycogen metabolism. It plays a key role in diverse physiological processes including metabolism, the cell cycle, and gene expression by regulating a wide variety of well-known substances like glycogen synthase, tau-protein, and β-catenin. Recent studies have identified GSK-3β as a potential therapeutic target in Alzheimer´s disease, bipolar disorder, stroke, more than 15 types of cancer, and diabetes. GSK-3β is one of the most attractive targets for medicinal chemists in the discovery, design, and synthesis of new selective potent inhibitors. In the current study, twenty-eight Amaryllidaceae alkaloids of various structural types were studied for their potency to inhibit GSK-3β. Promising results have been demonstrated by alkaloids of the homolycorine-{9-O-demethylhomolycorine (IC50 = 30.00 ± 0.71 µM), masonine (IC50 = 27.81 ± 0.01 μM)}, and lycorine-types {caranine (IC50 = 30.75 ± 0.04 μM)}. Full article
(This article belongs to the collection Bioactive Compounds)
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Open AccessArticle New Metabolites Isolated from a Laurencia obtusa Population Collected in Corsica
Molecules 2018, 23(4), 720; https://doi.org/10.3390/molecules23040720
Received: 19 February 2018 / Revised: 12 March 2018 / Accepted: 16 March 2018 / Published: 21 March 2018
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Abstract
The chemical investigation of an ethyl acetate extract (EtOAc) obtained from Laurencia obtusa, collected in Corsica, allowed for the identification of three new compounds (1, 2, and 4) and six known compounds. Compounds 1 to 4 were isolated
[...] Read more.
The chemical investigation of an ethyl acetate extract (EtOAc) obtained from Laurencia obtusa, collected in Corsica, allowed for the identification of three new compounds (1, 2, and 4) and six known compounds. Compounds 1 to 4 were isolated and fully characterized by a detailed spectroscopic analysis. Compounds 1 and 2 are two C15-acetogenins sharing the same ring system: a tetrahydropyran linked by a methylene to a tetrahydrofuran ring. Compound 1 exhibits a bromoallene unit whereas compound 2 possesses an uncommon α-bromo-α,β-unsaturated aldehyde terminal unit. Compound 4 is the first diterpene exhibiting a 19(4 3)abeo-labdane skeleton isolated from a Laurencia species. Isolation of concinndiol (compound 3) together with compound 4 suggests a common biosynthetic origin. Additionally, five known compounds, namely sagonenyne, laurene, α-bromocuparene, microcladallene A, and β-snyderol were identified in chromatographic fractions by NMR analysis using a computerized method that was developed in our laboratory. Full article
(This article belongs to the Section Natural Products Chemistry)
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Open AccessArticle Copper(II) Thiosemicarbazone Complexes and Their Proligands upon UVA Irradiation: An EPR and Spectrophotometric Steady-State Study
Molecules 2018, 23(4), 721; https://doi.org/10.3390/molecules23040721
Received: 27 February 2018 / Revised: 15 March 2018 / Accepted: 19 March 2018 / Published: 21 March 2018
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Abstract
X- and Q-band electron paramagnetic resonance (EPR) spectroscopy was used to characterize polycrystalline Cu(II) complexes that contained sodium 5-sulfonate salicylaldehyde thiosemicarbazones possessing a hydrogen, methyl, ethyl, or phenyl substituent at the terminal nitrogen. The ability of thiosemicarbazone proligands to generate superoxide radical anions
[...] Read more.
X- and Q-band electron paramagnetic resonance (EPR) spectroscopy was used to characterize polycrystalline Cu(II) complexes that contained sodium 5-sulfonate salicylaldehyde thiosemicarbazones possessing a hydrogen, methyl, ethyl, or phenyl substituent at the terminal nitrogen. The ability of thiosemicarbazone proligands to generate superoxide radical anions and hydroxyl radicals upon their exposure to UVA irradiation in aerated aqueous solutions was evidenced by the EPR spin trapping technique. The UVA irradiation of proligands in neutral or alkaline solutions and dimethylsulfoxide (DMSO) caused a significant decrease in the absorption bands of aldimine and phenolic chromophores. Mixing of proligand solutions with the equimolar amount of copper(II) ions resulted in the formation of 1:1 Cu(II)-to-ligand complex, with the EPR and UV-Vis spectra fully compatible with those obtained for the dissolved Cu(II) thiosemicarbazone complexes. The formation of the complexes fully inhibited the photoinduced generation of reactive oxygen species, and only subtle changes were found in the electronic absorption spectra of the complexes in aqueous and DMSO solutions upon UVA steady-state irradiation. The dark redox activity of copper(II) complexes and proligand/Cu(II) aqueous solutions towards hydrogen peroxide which resulted in the generation of hydroxyl radicals, was confirmed by spin trapping experiments. Full article
(This article belongs to the Section Inorganic Chemistry)
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Open AccessFeature PaperArticle Nutraceutical Potential of Phenolics from ′Brava′ and ′Mansa′ Extra-Virgin Olive Oils on the Inhibition of Enzymes Associated to Neurodegenerative Disorders in Comparison with Those of ′Picual′ and ′Cornicabra′
Molecules 2018, 23(4), 722; https://doi.org/10.3390/molecules23040722
Received: 27 February 2018 / Revised: 15 March 2018 / Accepted: 19 March 2018 / Published: 21 March 2018
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Abstract
The increasing interest in the Mediterranean diet is based on the protective effects against several diseases, including neurodegenerative disorders. Polyphenol-rich functional foods have been proposed to be unique supplementary and nutraceutical treatments for these disorders. Extra-virgin olive oils (EVOOs) obtained from ′Brava′ and
[...] Read more.
The increasing interest in the Mediterranean diet is based on the protective effects against several diseases, including neurodegenerative disorders. Polyphenol-rich functional foods have been proposed to be unique supplementary and nutraceutical treatments for these disorders. Extra-virgin olive oils (EVOOs) obtained from ′Brava′ and ′Mansa′, varieties recently identified from Galicia (northwestern Spain), were selected for in vitro screening to evaluate their capacity to inhibit key enzymes involved in Alzheimer′s disease (AD) (acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and 5-lipoxygenase (5-LOX)), major depressive disorder (MDD) and Parkinson′s disease (PD) (monoamine oxidases: hMAO-A and hMAO-B respectively). ′Brava′ oil exhibited the best inhibitory activity against all enzymes, when they are compared to ′Mansa′ oil: BuChE (IC50 = 245 ± 5 and 591 ± 23 mg·mL−1), 5-LOX (IC50 = 45 ± 7 and 106 ± 14 mg·mL−1), hMAO-A (IC50 = 30 ± 1 and 72 ± 10 mg·mL−1) and hMAO-B (IC50 = 191 ± 8 and 208 ± 14 mg·mL−1), respectively. The inhibitory capacity of the phenolic extracts could be associated with the content of secoiridoids, lignans and phenolic acids. Full article
(This article belongs to the Special Issue Nutraceuticals and Their Medicinal Importance)
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Open AccessArticle Food Additive Sodium Benzoate (NaB) Activates NFκB and Induces Apoptosis in HCT116 Cells
Molecules 2018, 23(4), 723; https://doi.org/10.3390/molecules23040723
Received: 17 February 2018 / Revised: 16 March 2018 / Accepted: 19 March 2018 / Published: 22 March 2018
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Abstract
NaB, the metabolite of cinnamon and sodium salt of benzoic acid is a commonly used food and beverage preservative. Various studies have investigated NaB for its effects on different cellular models. However, the effects of NaB on cancer cell viability signaling is substantially
[...] Read more.
NaB, the metabolite of cinnamon and sodium salt of benzoic acid is a commonly used food and beverage preservative. Various studies have investigated NaB for its effects on different cellular models. However, the effects of NaB on cancer cell viability signaling is substantially unknown. In this study, the effects of NaB on viability parameters and NFκB, one of the most important regulators in apoptosis, were examined in HCT116 colon cancer cells. Cell culture, light microscopy, spectrophotometry, flow cytometry, and western blot were used as methods to determine cell viability, caspase-3 activity, NFκB, Bcl-xl, Bim, and PARP proteins, respectively. NaB (6.25 mM–50 mM) treatment inhibited cell viability by inducing apoptosis, which was evident with increased Annexin V-PE staining and caspase-3 activity. NFκB activation accompanied the induction of apoptosis in NaB treated cells. Inhibition of NFκB with BAY 11-7082 did not show a pronounced effect on cell viability but induced a more apoptotic profile, which was confirmed by increased PARP fragmentation and caspase-3 activity. This effect was mostly evident at 50 mM concentration of NaB. Bcl-xl levels were not affected by NaB or BAY 11-7082/NaB treatment; whereas, total Bim increased with NaB treatment. Inhibition of NFκB activity further increased Bim levels. Overall, these results suggest that NaB induces apoptosis and activates NFκB in HCT116 colon cancer cells. Activation of NFκB emerges as target in an attempt to protect cells against apoptosis. Full article
(This article belongs to the Section Chemical Biology)
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Open AccessArticle Development of Phaleria macrocarpa (Scheff.) Boerl Fruits Using Response Surface Methodology Focused on Phenolics, Flavonoids and Antioxidant Properties
Molecules 2018, 23(4), 724; https://doi.org/10.3390/molecules23040724
Received: 29 November 2017 / Revised: 11 February 2018 / Accepted: 13 February 2018 / Published: 22 March 2018
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Abstract
In this study, the optimal conditions for the extraction of antioxidants from the Buah Mahkota Dewa fruit (Phaleria macrocarpa) was determined by using Response Surface Methodology (RSM). The optimisation was applied using a Central Composite Design (CCD) to investigate the effect of
[...] Read more.
In this study, the optimal conditions for the extraction of antioxidants from the Buah Mahkota Dewa fruit (Phaleria macrocarpa) was determined by using Response Surface Methodology (RSM). The optimisation was applied using a Central Composite Design (CCD) to investigate the effect of three independent variables, namely extraction temperature (°C), extraction time (minutes) and extraction solvent to-feed ratio (% v/v) on four responses: free radical scavenging activity (DPPH), ferric ion reducing power assay (FRAP), total phenolic content (TPC) and total flavonoid content (TFC). The optimal conditions for the antioxidants extraction were found to be 64 °C extraction temperature, 66 min extraction time and 75% v/v solvent to-feed ratio giving the highest percentage yields of DPPH, FRAP, TPC and TFC of 86.85%, 7.47%, 292.86 mg/g and 3.22 mg/g, respectively. Moreover, the data were subjected to Response Surface Methodology (RSM) and the results showed that the polynomial equations for all models were significant, did not show lack of fit, and presented adjusted determination coefficients (R2) above 99%, proving that the yield of phenolic, flavonoid and antioxidants activities obtained experimentally were close to the predicted values and the suitability of the model employed in RSM to optimise the extraction conditions. Hence, in this study, the fruit from P. macrocarpa could be considered to have strong antioxidant ability and can be used in various cosmeceutical or medicinal applications. Full article
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Open AccessArticle New Findings in Prunus padus L. Fruits as a Source of Natural Compounds: Characterization of Metabolite Profiles and Preliminary Evaluation of Antioxidant Activity
Molecules 2018, 23(4), 725; https://doi.org/10.3390/molecules23040725
Received: 23 February 2018 / Revised: 14 March 2018 / Accepted: 21 March 2018 / Published: 22 March 2018
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Abstract
European bird cherry (Prunus padus L.) has been known since the Middle Ages for its medical/food use and high health-promoting value. This study aimed to assess the potential of these fruits as a source of bioactive compounds through the characterization of its
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European bird cherry (Prunus padus L.) has been known since the Middle Ages for its medical/food use and high health-promoting value. This study aimed to assess the potential of these fruits as a source of bioactive compounds through the characterization of its physicochemical traits, nutraceutical properties, phytochemical composition via HPLC fingerprint, and antioxidant capacity. Fully ripened fruits of Prunus padus L. (Colorata cv) were collected in mid-July 2017 in Chieri, north-western Italy. The TPC (194.22 ± 32.83 mgGAE/100 gFW) and TAC (147.42 ± 0.58 mgC3G/100 gFW) values were obtained from the analyzed extracts. The most important phytochemical class was organic acids (48.62 ± 2.31%), followed by polyphenols (35.34 ± 1.80%), monoterpenes (9.36 ± 0.64%), and vitamin C (6.68 ± 0.22%). In this research the most important flavonols selected as marker were quercitrin (16.37 ± 3.51 mg/100 gFW) and quercetin (11.86 ± 2.36 mg/100 gFW). Data were reported based on fresh weight. Moreover, fresh fruits showed a mean antioxidant activity value of 17.78 ± 0.84 mmol Fe2+·kg−1. Even though the seeds and leaves contain cyanogenic glycosides, this study showed that these fruits could be a natural source of bioactive compounds with high antioxidant properties, due to the contents of organic and phenolic acids, catechins, and a synergetic effect of vitamin C and flavonoids. Full article
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Open AccessArticle Reparative Effects of Astaxanthin-Hyaluronan Nanoaggregates against Retrorsine-CCl4-Induced Liver Fibrosis and Necrosis
Molecules 2018, 23(4), 726; https://doi.org/10.3390/molecules23040726
Received: 6 March 2018 / Revised: 20 March 2018 / Accepted: 21 March 2018 / Published: 22 March 2018
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Abstract
Astaxanthin (Asta), a xanthophyll carotenoid, has been reported to be a strong antioxidative agent and has anti-inflammatory, antitumor and free radical-scavenging activities. However, inadequate stability and water solubility results in its low bioavailability. This study incorporated Asta into hydrophilic hyaluronan nanoparticles (HAn) to
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Astaxanthin (Asta), a xanthophyll carotenoid, has been reported to be a strong antioxidative agent and has anti-inflammatory, antitumor and free radical-scavenging activities. However, inadequate stability and water solubility results in its low bioavailability. This study incorporated Asta into hydrophilic hyaluronan nanoparticles (HAn) to produce Asta-HAn aggregates (AHAna) using an electrostatic field system and investigated the restorative effects of AHAna on retrorsine-CCl4-induced liver fibrosis in rats in vivo. Transmission electron microscopy (TEM) revealed that the prepared HAn were approximately 15 ± 2.1 nm in diameter and after the incorporation of Asta into HAn, the size increased to 210–500 nm. The incorporation efficiency of Asta was approximately 93% and approximately 54% of Asta was released after incubation for 18 h. Significant reductions in alanine aminotransferase and aspartate aminotransferase levels were observed after the rats were intraperitoneally injected with AHAna. Histopathological findings revealed the greatest reduction in hepatic fibrosis and hepatocyte necrosis in the rats after 2 weeks of intraperitoneal injection with AHAna, which is consistent with the data acquired from serum biochemical analysis. The restorative effects on liver damage displayed by AHAna in vivo demonstrated that Asta aggregated through HAn incorporation exerts therapeutic effects on liver fibrosis and necrosis. Full article
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Open AccessArticle Heterogeneity of Circulating Tumor Cells in Neoadjuvant Chemotherapy of Breast Cancer
Molecules 2018, 23(4), 727; https://doi.org/10.3390/molecules23040727
Received: 16 January 2018 / Revised: 14 March 2018 / Accepted: 18 March 2018 / Published: 22 March 2018
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Abstract
The biological properties of circulating tumor cells (CTCs), and their dynamics during neoadjuvant chemotherapy are important, both for disease progression prediction and therapeutic target determination, with the aim of preventing disease progression. The aim of our study was to estimate of different CTC
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The biological properties of circulating tumor cells (CTCs), and their dynamics during neoadjuvant chemotherapy are important, both for disease progression prediction and therapeutic target determination, with the aim of preventing disease progression. The aim of our study was to estimate of different CTC subsets in breast cancer during the NACT (neoadjuvant chemotherapy). The prospective study includes 27 patients with invasive breast cancer, T2-4N0-3M0, aged 32 to 60 years. Venous heparinized blood samples, taken before and after biopsy, after each courses of chemotherapy (on days 3–7), and before surgical intervention, served as the material for this study. Different subsets of circulating tumor cells were determined on the basis of the expression of EpCAM, CD45, CD44, CD24, and N-Cadherin using flow cytometry. As the result of this study, it has been observed that significant changes in the quantity of the different subsets of circulating tumor cells in patients’ blood were observed after carrying out the 3rd course of NACT. NACT causes significant changes in the quantity of six CTC subsets, with various combinations of stemness and epithelial-mesenchymal transition (EMT) properties. Full article
(This article belongs to the Special Issue Molecular Imaging and Treatment Monitoring of Cancer)
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Open AccessArticle Simultaneous Screening of Major Flame Retardants and Plasticizers in Polymer Materials Using Pyrolyzer/Thermal Desorption Gas Chromatography Mass Spectrometry (Py/TD–GC–MS)
Molecules 2018, 23(4), 728; https://doi.org/10.3390/molecules23040728
Received: 8 February 2018 / Revised: 14 March 2018 / Accepted: 20 March 2018 / Published: 22 March 2018
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Abstract
This study was conducted with the aim of achieving the simultaneous screening of various additives in polymer materials by utilizing a solvent-free pyrolyzer/thermal desorption gas chromatography mass spectrometry (Py/TD-GC–MS) method. As a first step to achieve this goal, simultaneous screening has been examined
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This study was conducted with the aim of achieving the simultaneous screening of various additives in polymer materials by utilizing a solvent-free pyrolyzer/thermal desorption gas chromatography mass spectrometry (Py/TD-GC–MS) method. As a first step to achieve this goal, simultaneous screening has been examined by selecting major substances representing plasticizers and flame retardants, such as short chain chlorinated paraffins (SCCPs), decabromodiphenyl ether (DecaBDE), hexabromocyclododecane (HBCDD), and di(2-ethylhexyl) phthalate (DEHP). A quantitative MS analysis was performed to check for the peak areas and sensitivities. Since Py/TD-GC–MS is fraught with the risk of thermal degradation of the sample, temperatures during the analytical process were finely tuned for securing reliable results. The instrumental sensitivity was confirmed by the S/N ratio on each component. The detection limits of all components were less than 50 mg/kg, which are sufficiently lower than the regulatory criteria. With regard to reproducibility, a relative standard deviation (RSD) of about 5% was confirmed by employing a spike recovery test on a polystyrene polymer solution containing mixed standard solution (ca. 1000 mg/kg). In conclusion, the results obtained in this study indicate that Py/TD-GC–MS is applicable for the screening of major flame retardants and plasticizers in real samples with sufficient reproducibility at regulatory levels. Full article
(This article belongs to the Special Issue Functional Molecular Materials)
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Open AccessArticle Effects of Limited Hydrolysis and High-Pressure Homogenization on Functional Properties of Oyster Protein Isolates
Molecules 2018, 23(4), 729; https://doi.org/10.3390/molecules23040729
Received: 4 March 2018 / Revised: 16 March 2018 / Accepted: 21 March 2018 / Published: 22 March 2018
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Abstract
In this study, the effects of limited hydrolysis and/or high-pressure homogenization (HPH) treatment in acid conditions on the functional properties of oyster protein isolates (OPI) were studied. Protein solubility, surface hydrophobicity, particle size distribution, zeta potential, foaming, and emulsifying properties were evaluated. The
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In this study, the effects of limited hydrolysis and/or high-pressure homogenization (HPH) treatment in acid conditions on the functional properties of oyster protein isolates (OPI) were studied. Protein solubility, surface hydrophobicity, particle size distribution, zeta potential, foaming, and emulsifying properties were evaluated. The results showed that acid treatment led to the dissociation and unfolding of OPI. Subsequent treatment such as limited proteolysis, HPH, and their combination remarkably improved the functional properties of OPI. Acid treatment produced flexible aggregates, as well as reduced particle size and solubility. On the contrary, limited hydrolysis increased the solubility of OPI. Furthermore, HPH enhanced the effectiveness of the above treatments. The emulsifying and foaming properties of acid- or hydrolysis-treated OPI significantly improved. In conclusion, a combination of acid treatment, limited proteolysis, and HPH improved the functional properties of OPI. The improvements in the functional properties of OPI could potentiate the use of oyster protein and its hydrolysates in the food industry. Full article
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Open AccessArticle Effects of Ultrasound Assisted Extraction in Conjugation with Aid of Actinidin on the Molecular and Physicochemical Properties of Bovine Hide Gelatin
Molecules 2018, 23(4), 730; https://doi.org/10.3390/molecules23040730
Received: 25 December 2017 / Revised: 10 February 2018 / Accepted: 12 February 2018 / Published: 22 March 2018
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Abstract
Actinidin was used to pretreat the bovine hide and ultrasonic wave (53 kHz and 500 W) was used for the time durations of 2, 4 and 6 h at 60 °C to extract gelatin samples (UA2, UA4 and UA6, respectively). Control (UAC) gelatin
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Actinidin was used to pretreat the bovine hide and ultrasonic wave (53 kHz and 500 W) was used for the time durations of 2, 4 and 6 h at 60 °C to extract gelatin samples (UA2, UA4 and UA6, respectively). Control (UAC) gelatin was extracted using ultrasound for 6 h at 60 °C without enzyme pretreatment. There was significant (p < 0.05) increase in gelatin yield as the time duration of ultrasound treatment increased with UA6 giving the highest yield of 19.65%. Gel strength and viscosity of UAC and UA6 extracted gelatin samples were 627.53 and 502.16 g and 16.33 and 15.60 mPa.s, respectively. Longer duration of ultrasound treatment increased amino acids content of the extracted gelatin and UAC exhibited the highest content of amino acids. Progressive degradation of polypeptide chains was observed in the protein pattern of the extracted gelatin as the time duration of ultrasound extraction increased. Fourier transform infrared (FTIR) spectroscopy depicted loss of molecular order and degradation in UA6. Scanning electron microscopy (SEM) revealed protein aggregation and network formation in the gelatin samples with increasing time of ultrasound treatment. The study indicated that ultrasound assisted gelatin extraction using actinidin exhibited high yield with good quality gelatin. Full article
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Open AccessArticle Synthesis and Physicochemical Evaluation of Entecavir-Fatty Acid Conjugates in Reducing Food Effect on Intestinal Absorption
Molecules 2018, 23(4), 731; https://doi.org/10.3390/molecules23040731
Received: 5 February 2018 / Revised: 15 March 2018 / Accepted: 20 March 2018 / Published: 22 March 2018
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Abstract
The oral bioavailability of entecavir (EV), an anti-viral agent commonly prescribed to treat hepatitis B infections, is drastically reduced under a post-prandial state. This is primarily due to its low permeability in the gastrointestinal tract. To reduce the food effect on the intestinal
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The oral bioavailability of entecavir (EV), an anti-viral agent commonly prescribed to treat hepatitis B infections, is drastically reduced under a post-prandial state. This is primarily due to its low permeability in the gastrointestinal tract. To reduce the food effect on the intestinal absorption of the nucleotide analogue, four lipidic prodrugs were synthesized via the esterification of the primary alcohol of EV with fatty acids (hexanoic acid, octanoic acid, decanoic acid, and dodecanoic acid). EV-3-dodecanoate (or EV-C12) exhibited high solubility in a fed state simulated intestinal fluid (78.8 μg/mL), with the acceptable calculated logP value (3.62) and the lowest hydrolysis rate (22.5% for 12 h in simulated gastric fluid, pH 1.2). Therefore, it was chosen as a candidate to improve intestinal absorption of EV, especially under a fed state condition. Physical characterization using scanning electron microscopy, a differential scanning calorimeter, and X-ray powder diffraction revealed that EV-C12 had a rectangular-shaped crystalline form, with a melting point of about 170 °C. In a release test in biorelevant media, such as fasted and fed state-simulated intestinal and/or gastric fluid, more than 90% of the prodrug was released within 2 h in all media tested. These data suggest that this lipidic prodrug might have the potential to alleviate the negative food effect on the intestinal absorption of EV with increased therapeutic efficacy and patient compliance. Full article
(This article belongs to the Section Medicinal Chemistry)
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Open AccessArticle Functional Characterization of the Saccharomyces cerevisiae Equilibrative Nucleoside Transporter 1 (ScENT1)
Molecules 2018, 23(4), 732; https://doi.org/10.3390/molecules23040732
Received: 3 December 2017 / Revised: 7 March 2018 / Accepted: 14 March 2018 / Published: 22 March 2018
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Abstract
Equilibrative nucleoside transporters (ENTs) are polytopic membrane transporters responsible for the translocation of nucleosides, nucleobases—to a lesser extent—and nucleoside analog therapeutics across cellular membranes. ENTs function in a diffusion controlled bidirectional manner and are thought to utilize an alternating access transport mechanism. However,
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Equilibrative nucleoside transporters (ENTs) are polytopic membrane transporters responsible for the translocation of nucleosides, nucleobases—to a lesser extent—and nucleoside analog therapeutics across cellular membranes. ENTs function in a diffusion controlled bidirectional manner and are thought to utilize an alternating access transport mechanism. However, a detailed understanding of ENT function at the molecular level has remained elusive. ScENT1 (formerly known as Function Unknown Now 26 or FUN26) is the only known ENT ortholog endogenously expressed in S. cerevisiae, and a proteoliposome assay system was used to study homogenously overexpressed and purified ScENT1 (wildtype relative to L390A and F249I mutants). L390 and F249 are highly conserved residues and were found to alter transporter function. L390A produced a reduction of mean transport activity while F249I increased mean substrate translocation relative to wildtype protein. However, both mutations resulted in transport of UTP—a novel gain of function for any ENT. These residues were then mapped onto an ab initio model of FUN26 which suggests they function in substrate translocation (L390) or cytoplasmic gating (F249). Furthermore, wildtype, L390A, and F249I were found to be sensitive to the presence of alcohols. Ethanol attenuated ScENT1-mediated transport of uridine by ~50%. These findings further demonstrate functional similarities between ScENT1 and human ENT isoforms and support identification of FUN26 as ScENT1, the first ENT isoform in S. cerevisiae. Full article
(This article belongs to the Special Issue Nucleoside and Nucleotide Analogues)
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Open AccessFeature PaperArticle Theoretical Insights into the Solvent Polarity Effect on the Quality of Self-Assembled N-Octadecanethiol Monolayers on Cu (111) Surfaces
Molecules 2018, 23(4), 733; https://doi.org/10.3390/molecules23040733
Received: 9 February 2018 / Revised: 14 March 2018 / Accepted: 21 March 2018 / Published: 22 March 2018
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Abstract
The effect of solvent polarity on the quality of self-assembled n-octadecanethiol (C18SH) on Cu surfaces was systematically analyzed using first-principles calculations. The results indicate that the adsorption energy for C18SH on a Cu surface is −3.37 eV, which
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The effect of solvent polarity on the quality of self-assembled n-octadecanethiol (C18SH) on Cu surfaces was systematically analyzed using first-principles calculations. The results indicate that the adsorption energy for C18SH on a Cu surface is −3.37 eV, which is higher than the adsorption energies of the solvent molecules. The higher adsorption energy of dissociated C18SH makes the monolayer self-assembly easier on a Cu (111) surface through competitive adsorption. Furthermore, the adsorption energy per unit area for C18SH decreases from −3.24 eV·Å−2 to −3.37 eV·Å−2 in solvents with an increased dielectric constant of 1 to 78.54. Detailed energy analysis reveals that the electrostatic energy gradually increases, while the kinetic energy decreases with increasing dielectric constant. The increased electrostatic energies are mainly attributable to the disappearance of electrostatic interactions on the sulfur end of C18SH. The decreased kinetic energy is mainly due to the generated push force in the polar solvent, which limits the mobility of C18SH. A molecular dynamics simulation also confirms that the -CH3 site has a great interaction with CH3(CH2)4CH3 molecules and a weak interaction with CH3CH2OH molecules. The different types of interactions help to explain why the surface coverage of C18SH on Cu in a high-polarity ethanol solution is significantly larger than that in a low-polarity n-hexane solution at the stabilized stage. Full article
(This article belongs to the Section Physical Chemistry)
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Open AccessArticle A Metabolomics Approach Uncovers Differences between Traditional and Commercial Dairy Products in Buryatia (Russian Federation)
Molecules 2018, 23(4), 735; https://doi.org/10.3390/molecules23040735
Received: 8 February 2018 / Revised: 20 March 2018 / Accepted: 21 March 2018 / Published: 22 March 2018
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Abstract
Commercially available and traditional dairy products differ in terms of their manufacturing processes. In this study, commercially available and traditionally fermented cheese, yogurt, and milk beverages were analyzed and compared. The metabolomic technique of ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry (UPLC-Q-TOF) in
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Commercially available and traditional dairy products differ in terms of their manufacturing processes. In this study, commercially available and traditionally fermented cheese, yogurt, and milk beverages were analyzed and compared. The metabolomic technique of ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry (UPLC-Q-TOF) in the MSE mode was used in combination with statistical methods, including univariate analysis and chemometric analysis, to determine the differences in metabolite profiles between commercially and traditionally fermented dairy products. The experimental results were analyzed statistically and showed that traditional and commercial dairy products were well differentiated in both positive and negative ion modes, with significant differences observed between the samples. After screening for metabolite differences, we detected differences between traditional milk beverages and yogurt and their commercial counterparts in terms of the levels of compounds such as l-lysine, l-methionine, l-citrulline, l-proline, l-serine, l-valine and l-homocysteine, and of short peptides such as Asp-Arg, Gly-Arg, His-Pro, Pro-Asn. The greatest difference between commercially available and traditional cheese was in the short peptide composition, as commercially available and traditional cheese is rich in short peptides. Full article
(This article belongs to the Section Metabolites)
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Open AccessArticle Facilitating Anti-Cancer Combinatorial Drug Discovery by Targeting Epistatic Disease Genes
Molecules 2018, 23(4), 736; https://doi.org/10.3390/molecules23040736
Received: 25 January 2018 / Revised: 15 March 2018 / Accepted: 20 March 2018 / Published: 23 March 2018
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Abstract
Due to synergistic effects, combinatorial drugs are widely used for treating complex diseases. However, combining drugs and making them synergetic remains a challenge. Genetic disease genes are considered a promising source of drug targets with important implications for navigating the drug space. Most
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Due to synergistic effects, combinatorial drugs are widely used for treating complex diseases. However, combining drugs and making them synergetic remains a challenge. Genetic disease genes are considered a promising source of drug targets with important implications for navigating the drug space. Most diseases are not caused by a single pathogenic factor, but by multiple disease genes, in particular, interacting disease genes. Thus, it is reasonable to consider that targeting epistatic disease genes may enhance the therapeutic effects of combinatorial drugs. In this study, synthetic lethality gene pairs of tumors, similar to epistatic disease genes, were first targeted by combinatorial drugs, resulting in the enrichment of the combinatorial drugs with cancer treatment, which verified our hypothesis. Then, conventional epistasis detection software was used to identify epistatic disease genes from the genome wide association studies (GWAS) dataset. Furthermore, combinatorial drugs were predicted by targeting these epistatic disease genes, and five combinations were proven to have synergistic anti-cancer effects on MCF-7 cells through cell cytotoxicity assay. Combined with the three-dimensional (3D) genome-based method, the epistatic disease genes were filtered and were more closely related to disease. By targeting the filtered gene pairs, the efficiency of combinatorial drug discovery has been further improved. Full article
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Open AccessArticle The Melatonin Signaling Pathway in a Long-Term Memory In Vitro Study
Molecules 2018, 23(4), 737; https://doi.org/10.3390/molecules23040737
Received: 30 January 2018 / Revised: 15 March 2018 / Accepted: 20 March 2018 / Published: 23 March 2018
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Abstract
The activation of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) via phosphorylation in the hippocampus is an important signaling mechanism for enhancing memory processing. Although melatonin is known to increase CREB expression in various animal models, the signaling mechanism between melatonin and
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The activation of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) via phosphorylation in the hippocampus is an important signaling mechanism for enhancing memory processing. Although melatonin is known to increase CREB expression in various animal models, the signaling mechanism between melatonin and CREB has been unknown in vitro. Thus, we confirmed the signaling pathway between the melatonin receptor 1 (MT1) and CREB using melatonin in HT-22 cells. Melatonin increased MT1 and gradually induced signals associated with long-term memory processing through phosphorylation of Raf, ERK, p90RSK, CREB, and BDNF expression. We also confirmed that the calcium, JNK, and AKT pathways were not involved in this signaling pathway by melatonin in HT-22 cells. Furthermore, we investigated whether melatonin regulated the expressions of CREB-BDNF associated with long-term memory processing in aged HT-22 cells. In conclusion, melatonin mediated the MT1-ERK-p90RSK-CREB-BDNF signaling pathway in the in vitro long-term memory processing model and increased the levels of p-CREB and BDNF expression in melatonin-treated cells compared to untreated HT-22 cells in the cellular aged state. Therefore, this paper suggests that melatonin induces CREB signaling pathways associated with long-term memory processing in vitro. Full article
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Open AccessFeature PaperArticle Encapsulation of Curcumin-Loaded Liposomes for Colonic Drug Delivery in a pH-Responsive Polymer Cluster Using a pH-Driven and Organic Solvent-Free Process
Molecules 2018, 23(4), 739; https://doi.org/10.3390/molecules23040739
Received: 6 February 2018 / Revised: 9 March 2018 / Accepted: 21 March 2018 / Published: 23 March 2018
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Abstract
The present study aimed to develop and optimize liposome formulation for the colonic delivery of biologically active compounds. A strategy to facilitate such targeting is to formulate liposomes with a polymer coating sensitive to the pH shifts in the gastrointestinal tract. To this
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The present study aimed to develop and optimize liposome formulation for the colonic delivery of biologically active compounds. A strategy to facilitate such targeting is to formulate liposomes with a polymer coating sensitive to the pH shifts in the gastrointestinal tract. To this end, liposomes encapsulating curcumin—chosen as the biologically active compound model—and coated with the pH-responsive polymer Eudragit S100 were prepared and characterized. Curcumin was encapsulated into small unilamellar vesicles (SUVs) by the micelle-to-vesicle transition method (MVT) in a simple and organic solvent-free way. Curcumin-loaded liposomes were coated with Eudragit S100 by a fast and easily scalable pH-driven method. The prepared liposomes were evaluated for size, surface morphology, entrapment efficiency, stability, in vitro drug release, and curcumin antioxidant activity. In particular, curcumin-loaded liposomes displayed size lower than 100 nm, encapsulation efficiency of 98%, high stability at both 4 °C and 25 °C, high in vitro antioxidant activity, and a cumulative release that was completed within 200 min. A good Eudragit S100 coating which did not alter the properties of the curcumin-loaded liposomes was obtained. The present work therefore provides a fast and solvent-free method to prepare pH-responsive polymer-coated liposomes for the colonic delivery of biologically active compounds. Full article
(This article belongs to the Special Issue Chemical Transformation of Renewable Material for Green Chemistry)
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Open AccessArticle Design, Synthesis, and SAR of Novel 2-Glycinamide Cyclohexyl Sulfonamide Derivatives against Botrytis cinerea
Molecules 2018, 23(4), 740; https://doi.org/10.3390/molecules23040740
Received: 6 February 2018 / Revised: 14 March 2018 / Accepted: 19 March 2018 / Published: 23 March 2018
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Abstract
N-(2-trifluoromethyl-4-chlorophenyl)-2-oxocyclohexyl sulfonamide (chesulfamide) is in the limelight as a novel fungicide, and has fungicidal activity against Botrytis cinerea. For exploring more novel structures, 33 new compounds were synthesized by N-alkylation and acid–amine coupling reactions with chesulfamide as the core moiety,
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N-(2-trifluoromethyl-4-chlorophenyl)-2-oxocyclohexyl sulfonamide (chesulfamide) is in the limelight as a novel fungicide, and has fungicidal activity against Botrytis cinerea. For exploring more novel structures, 33 new compounds were synthesized by N-alkylation and acid–amine coupling reactions with chesulfamide as the core moiety, and their structures were characterized and established by 1H-NMR, 13C-NMR, MS, and elemental analysis. The structure of (1R,2S)-2-(2-(N-(4-chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2-trifluoromethylphenyl) acetamide (II-19) was defined by X-ray single crystal diffraction. The in vivo and in vitro fungicidal activities against B. cinerea were evaluated. The bioassay results of mycelial growth demonstrated that most compounds exhibited excellent inhibitory activity against B. cinerea at 50 μg mL−1, and 7 compounds showed lower EC50 values than boscalid (EC50 = 4.46 μg mL−1) against B. cinerea (CY-09). In cucumber pot experiment, the inhibitory rates of four compounds (II-4, II-5, II-12, and II-13) against B. cinerea were 90.48, 93.45, 92.86, and 91.07, which were better than cyprodinil (88.69%), the best performing of all controls. In tomato pot experiment, the control efficacy of two analogs (II-8 and II-15) were 87.98 and 87.97% at 200 μg mL−1, which were significantly higher than boscalid (78.10%). Most compounds have an excellent fungicidal effect on B. cinerea, with potential as a lead compound for developing new pesticides. Full article
(This article belongs to the Section Medicinal Chemistry)
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Open AccessArticle Effects of Lysozyme on the Activity of Ionic of Fluoroquinolone Species
Molecules 2018, 23(4), 741; https://doi.org/10.3390/molecules23040741
Received: 3 February 2018 / Revised: 16 March 2018 / Accepted: 21 March 2018 / Published: 23 March 2018
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Abstract
Fluoroquinolones (FQs) constitute an important class of biologically active broad-spectrum antibacterial drugs that are which are in contact with many biological fluids under different acidity conditions. We studied the reactivity of ciprofloxacin (Cpx) and levofloxacin (Lev) and their interaction with lysozyme (Lyz) at
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Fluoroquinolones (FQs) constitute an important class of biologically active broad-spectrum antibacterial drugs that are which are in contact with many biological fluids under different acidity conditions. We studied the reactivity of ciprofloxacin (Cpx) and levofloxacin (Lev) and their interaction with lysozyme (Lyz) at different pH values, using UV-visible absorption, fluorescence, infrared spectroscopies supported by DFT calculation and docking. In addition, by antimicrobial assays, the biological consequences of the interaction were evaluated. DFT calculation predicted that the FQ cationic species present at acid pH have lower stabilization energies, with an electric charge rearrangement because of their interactions with solvent molecules. NBO and frontier orbital calculations evidenced the role of two charged centers, NH2+ and COO, for interactions by electronic delocalization effects. Both FQs bind to Lyz via a static quenching with a higher interaction in neutral medium. The interaction induces a structural rearrangement in β-sheet content while in basic pH a protective effect against the denaturation of Lyz was inferred. The analysis of thermodynamic parameters and docking showed that hydrophobic, electrostatic forces and hydrogen bond are the responsible of Cpx-Lyz and Lev-Lyz associations. Antimicrobial assays evidenced an antagonist effect of Lyz in acid medium while in neutral medium the FQs’ activities were not modified by Lyz. Full article
(This article belongs to the Section Physical Chemistry)
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Open AccessArticle Identification, Characterization, and Expression Analysis of a FMRFamide-Like Peptide Gene in the Common Chinese Cuttlefish (Sepiella japonica)
Molecules 2018, 23(4), 742; https://doi.org/10.3390/molecules23040742
Received: 12 January 2018 / Revised: 17 March 2018 / Accepted: 20 March 2018 / Published: 23 March 2018
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Abstract
The peptide FMRFamide is one of the well-known peptides involved in multiple physiological processes in the phylum Mollusca. In this study, a FMRFamide gene (GenBank accession No. KJ933411) was identified in a cuttlefish species called Sepiella japonica and was designated as SjFMRFamide. The
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The peptide FMRFamide is one of the well-known peptides involved in multiple physiological processes in the phylum Mollusca. In this study, a FMRFamide gene (GenBank accession No. KJ933411) was identified in a cuttlefish species called Sepiella japonica and was designated as SjFMRFamide. The total length of the SjFMRFamide sequence was found to be 1880 bp while the open reading frame contained 996 bp encoding a protein of 331 amino acid residues with a predicted isoelectric point (pI) and molecular weight (MW) of 9.18 and 38.8 kDa along with a 333 bp 5′-untranslated region (UTR) and 551 bp 3′-UTR. The deduced SjFMRFamide precursor protein contains one signal peptide and expresses four kinds FMRFamide-related peptides including a single copy of FLRFamide, ALSGDAFLRFamide, and FIRFamide and multiple copies of FMRFamide. Results of phylogenetic relation analysis strongly indicated that the sequence of this gene shares high identity with the genes of known FMRFamides. Spatial expression analysis indicated the highest mRNA expression of SjFMRFamide in the brain of male and female cuttlefishes among the eight tissues analyzed. An in situ hybridization assay of the brain indicated that SjFMRFamide was transcribed in several functional lobes, which suggests that it might be related to many physiological regulatory mechanisms. This is the first study describing FMRFamide in S. japonica and the results may contribute to future studies of neuropeptide evolution or may prove useful for the development of aquaculture methods for this cuttlefish species. Full article
(This article belongs to the Section Molecular Diversity)
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Open AccessArticle Potential of Cellulose Functionalized with Carboxylic Acid as Biosorbent for the Removal of Cationic Dyes in Aqueous Solution
Molecules 2018, 23(4), 743; https://doi.org/10.3390/molecules23040743
Received: 27 February 2018 / Revised: 16 March 2018 / Accepted: 21 March 2018 / Published: 23 March 2018
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Abstract
In the last decade, adsorption has been used to minimize the pollution caused by dyes, which represents a serious environmental problem. In this context, this work reports the preparation of phthalic anhydride-modified cellulose (PhCel), through the reaction of cellulose (Cel) with phthalic anhydride
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In the last decade, adsorption has been used to minimize the pollution caused by dyes, which represents a serious environmental problem. In this context, this work reports the preparation of phthalic anhydride-modified cellulose (PhCel), through the reaction of cellulose (Cel) with phthalic anhydride (Ph). The efficiency of the reaction was observed by elemental analysis, Fourier Transform Infrared (FTIR) spectroscopy, X-ray diffraction (XRD) and thermogravimetry/derivative thermogravimetry (TG/DTG). The adsorbent matrix (Cel and PhCel) was used in the removal of crystal violet (CV) and methylene blue (MB) dyes in aqueous medium. In the kinetic study, the experimental data obtained had the best fit to the pseudo-first-order model. In general, the isotherms obtained at different temperatures had a best fit to the model proposed by Langmuir, and the CV and MB adsorption process in adsorbent matrixes can be favored strictly by hydrogen bonds and/or electrostatic interactions for Cel and electrostatic interactions for PhCel. Full article
(This article belongs to the Special Issue Cellulose Chemical Modifications—Towards Sustainable Materials)
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Open AccessFeature PaperArticle Investigating the Interaction of Ascorbic Acid with Anthocyanins and Pyranoanthocyanins
Molecules 2018, 23(4), 744; https://doi.org/10.3390/molecules23040744
Received: 27 February 2018 / Revised: 18 March 2018 / Accepted: 21 March 2018 / Published: 23 March 2018
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Abstract
Juices colored by anthocyanins experience color loss related to fortification with ascorbic acid (AA), thought to be the result of condensation at Carbon-4 of anthocyanins. To further understand this mechanism, pyranoanthocyanins, having a fourth-ring covalently occupying Carbon-4, were synthesized to compare its reactivity
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Juices colored by anthocyanins experience color loss related to fortification with ascorbic acid (AA), thought to be the result of condensation at Carbon-4 of anthocyanins. To further understand this mechanism, pyranoanthocyanins, having a fourth-ring covalently occupying Carbon-4, were synthesized to compare its reactivity with AA against that of anthocyanins. Pyranoanthocyanins were synthesized by combining chokeberry anthocyanins with pyruvic acid. AA (250–1000 mg/L) was added to either chokeberry extract, cyanidin-3-galactoside, or 5-Carboxypyranocyanidin-3-galactoside. Samples were stored in the dark for 5 days at 25 °C and spectra (380–700 nm), color (CIE-L*c*h*), and composition changes (HPLC-MS/MS) were monitored. Extensive bleaching occurred for cyanidin-3-galactoside and chokeberry colored solutions, with a decrease in half-lives from 22.8 to 0.3 days for Cyanidin-3-galactoside when 1000 mg/L AA was added. 5-Carboxypyranocyanidin-3-galactoside solution better maintained color with limited loss in absorbance, due to the formation of colored degradation products (λvis-max = 477 to 487 nm), and half-life decrease from 40.8 to 2.7 days, an 8–13-fold improvement compared to anthocyanins. This suggested alternative sites of reactivity with AA. Carbon-4 may be the preferred site for AA-pigment interactions, but it was not the only location. With Carbon-4 blocked, 5-Carboxypyranocyanidin-3-galactoside reacted with AA to form new pigments and reduce bleaching. Full article
(This article belongs to the Special Issue Advances in Anthocyanin Research 2018)
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Open AccessArticle PER, a Circadian Clock Component, Mediates the Suppression of MMP-1 Expression in HaCaT Keratinocytes by cAMP
Molecules 2018, 23(4), 745; https://doi.org/10.3390/molecules23040745
Received: 14 February 2018 / Revised: 9 March 2018 / Accepted: 19 March 2018 / Published: 23 March 2018
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Abstract
Skin circadian clock system responds to daily changes, thereby regulating skin functions. Exposure of the skin to UV irradiation induces the expression of matrix metalloproteinase-1 (MMP-1) and causes DNA damage. It has been reported both DNA repair and DNA replication are regulated by
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Skin circadian clock system responds to daily changes, thereby regulating skin functions. Exposure of the skin to UV irradiation induces the expression of matrix metalloproteinase-1 (MMP-1) and causes DNA damage. It has been reported both DNA repair and DNA replication are regulated by the circadian clock in mouse skin. However, the molecular link between circadian clock and MMP-1 has little been investigated. We found PERIOD protein, a morning clock component, represses the expression of MMP-1 in human keratinocytes by using a PER-knockdown strategy. Treatment with siPer3 alleviated the suppression of MMP-1 expression induced by forskolin. Results revealed PER3 suppresses the expression of MMP-1 via cAMP signaling pathway. Additionally, we screened for an activator of PER that could repress the expression of MMP-1 using HaCaT cell line containing PER promoter-luciferase reporter gene. Results showed Lespedeza capitate extract (LCE) increased PER promoter activity. LCE inhibited the expression of MMP-1 and its effect of LCE was abolished in knockdown of PER2 or PER3, demonstrating LCE can repress the expression of MMP-1 through PER. Since circadian clock component PER can regulate MMP-1 expression, it might be a new molecular mechanism to develop therapeutics to alleviate skin aging and skin cancer. Full article
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Open AccessArticle Synthesis, Characterization, and Antifungal Activity of Novel Benzo[4,5]imidazo[1,2-d][1,2,4]triazine Derivatives
Molecules 2018, 23(4), 746; https://doi.org/10.3390/molecules23040746
Received: 7 March 2018 / Revised: 19 March 2018 / Accepted: 21 March 2018 / Published: 23 March 2018
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Abstract
A series of novel fused heterocyclic compounds bearing benzo[4,5]imidazo[1,2-d][1,2,4]triazine 4a4w were designed and conveniently synthesized via the intermediates 2-(halogenated alkyl)-1H-benzo[d]imidazoles 2a, 2b, and 2-((1-(substituted phenyl)hydrazinyl)alkyl)-1H-benzo[d]imidazoles 3a3g.
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A series of novel fused heterocyclic compounds bearing benzo[4,5]imidazo[1,2-d][1,2,4]triazine 4a4w were designed and conveniently synthesized via the intermediates 2-(halogenated alkyl)-1H-benzo[d]imidazoles 2a, 2b, and 2-((1-(substituted phenyl)hydrazinyl)alkyl)-1H-benzo[d]imidazoles 3a3g. The structures of all target compounds were characterized by FT-IR, 1H NMR, 13C NMR, and EI-MS, of which, the structure of compound 4n was further determined by the single crystal X-ray diffraction. The crystal structure of 4n was crystallized in the triclinic crystal system, space group P 1 ¯ with a = 9.033 (6) Å, b = 10.136 (7) Å, c = 10.396 (7) Å, α = 118.323 (7)°, β = 91.750 (8)°, γ = 104.198 (7)°, Z = 2, V = 800.2 (9) Å3; total R indices: R1 = 0.0475, wR2 = 0.1284. The antifungal activity of title compounds 4a4w in vitro against the phytopathogenic fungi Botrytis cinerea (B. cinerea), Rhizoctonia solani (R. solani) and Colletotrichum capsici (C. capsici) were evaluated, the bioassay results demonstrated that most of the title compounds exhibited obvious fungicidal activities at 50 μg/mL. This work indicated that benzo[4,5]imidazo[1,2-d][1,2,4]triazine derivatives could be considered as a new leading structure in searching for novel agricultural fungicides. Full article
(This article belongs to the Section Molecular Diversity)
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Open AccessArticle Design, Synthesis, and Biological Evaluation of Axitinib Derivatives
Molecules 2018, 23(4), 747; https://doi.org/10.3390/molecules23040747
Received: 27 February 2018 / Revised: 20 March 2018 / Accepted: 21 March 2018 / Published: 23 March 2018
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Abstract
Axitinib is an approved kinase inhibitor for the therapy of advanced metastatic renal cell carcinoma (RCC). It prevents angiogenesis, cellular adhesion, and induces apoptosis of cancer cells. Here, nine axitinib derivatives were designed by replacing the C=C moiety with the N=N group, and
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Axitinib is an approved kinase inhibitor for the therapy of advanced metastatic renal cell carcinoma (RCC). It prevents angiogenesis, cellular adhesion, and induces apoptosis of cancer cells. Here, nine axitinib derivatives were designed by replacing the C=C moiety with the N=N group, and the substituted benzene or pyrrole analogs were considered to replace the pyridine ring. Biological activity results showed that most of nascent derivatives exhibited favorable VEGFR-2 kinase inhibitory activities, and TM6, 7, 9, and 11 behaved more potent anti-proliferative activities than axitinib. This novel series of compounds shows a potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role. Full article
(This article belongs to the Section Medicinal Chemistry)
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Open AccessArticle Expression of Pinellia pedatisecta Lectin Gene in Transgenic Wheat Enhances Resistance to Wheat Aphids
Molecules 2018, 23(4), 748; https://doi.org/10.3390/molecules23040748
Received: 11 February 2018 / Revised: 18 March 2018 / Accepted: 22 March 2018 / Published: 24 March 2018
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Abstract
Wheat aphids are major pests during the seed filling stage of wheat. Plant lectins are toxic to sap-sucking pests such as wheat aphids. In this study, Pinellia pedatisecta agglutinin (ppa), a gene encoding mannose binding lectin, was cloned, and it shared
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Wheat aphids are major pests during the seed filling stage of wheat. Plant lectins are toxic to sap-sucking pests such as wheat aphids. In this study, Pinellia pedatisecta agglutinin (ppa), a gene encoding mannose binding lectin, was cloned, and it shared 92.69% nucleotide similarity and 94% amino acid similarity with Pinellia ternata agglutinin (pta). The ppa gene, driven by the constitutive and phloem-specific ribulose bisphosphate carboxylase small subunit gene (rbcs) promoter in pBAC-rbcs-ppa expression vector, was transferred into the wheat cultivar Baofeng104 (BF104) by particle bombardment transformation. Fifty-four T0 transgenic plants were generated. The inheritance and expression of the ppa gene were confirmed by PCR and RT-PCR analysis respectively, and seven homozygous transgenic lines were obtained. An aphid bioassay on detached leaf segments revealed that seven ppa transgenic wheat lines had lower aphid growth rates and higher inhibition rates than BF104. Furthermore, two-year aphid bioassays in isolated fields showed that aphid numbers per tiller of transgenic lines were significantly decreased, compared with wild type BF104. Therefore, ppa could be a strong biotechnological candidate to produce aphid-resistant wheat. Full article
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Open AccessArticle Molecular Mechanisms of Melatonin Protection from Gastric Mucosal Apoptotic Injury in Experimental Burns
Molecules 2018, 23(4), 749; https://doi.org/10.3390/molecules23040749
Received: 22 February 2018 / Revised: 20 March 2018 / Accepted: 21 March 2018 / Published: 24 March 2018
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Abstract
Melatonin, a basic secretory pineal gland product, is a nontoxic, multifunctional molecule. It has antioxidant and anti-apoptotic activities and protects tissues from injury. The objective of the present study was to determine the molecular mechanism of melatonin anti-apoptotic effect on gastric injury in
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Melatonin, a basic secretory pineal gland product, is a nontoxic, multifunctional molecule. It has antioxidant and anti-apoptotic activities and protects tissues from injury. The objective of the present study was to determine the molecular mechanism of melatonin anti-apoptotic effect on gastric injury in a rat burn model. We hypothesized that melatonin gastric protection may be related to the activation of transcription erythroid 2-related factor 2 (Nrf2). Using a 30% total body surface area (TBSA) rat burn model, melatonin (10 mg/kg, i.p.) was injected immediately and 12 h after thermal skin injury. Via light immunohistochemistry, we determined the tissue level of 4-hydroxy-2-nonenal (4-HNE) as a marker of lipid peroxidation, Bcl-2 and Bax as apoptosis-related proteins, and Nrf2. Results are presented as medians (interquartile range (IQR)). Thermal trauma in burned animals, compared with the controls, increased the expression of pro-apoptotic Bax protein (1.37 (0.94–1.47)), decreased anti-apoptotic Bcl-2 protein (1.16 (1.06–1.23), p < 0.001) in epithelial cells, and elevated Bax/Bcl-2 ratios (p < 0.05). Tissue 4-HNE and Nrf2 levels were increased following severe burns (1.55 (0.98–1.61) and 1.16 (1.01–1.25), p < 0.05, respectively). Melatonin significantly decreased 4-HNE (0.87 (0.74–0.96), p < 0.01) and upregulated Nrf2 (1.55 (1.52–1.65), p < 0.001) levels. It also augmented Bax (1.68 (1.5–1.8), p < 0.001) and Bcl-2 expressions (1.96 (1.89–2.01), p < 0.0001), but reduced Bax/Bcl-2 ratios (p < 0.05). Our results suggest that experimental thermal trauma induces oxidative gastric mucosal injury. Melatonin manifests a gastroprotective effect through Nrf2 activation, lipid peroxidation attenuation, and Bax/Bcl-2 ratio modification as well. Full article
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Open AccessFeature PaperArticle Economy of Catalyst Synthesis—Convenient Access to Libraries of Di- and Tetranaphtho Azepinium Compounds
Molecules 2018, 23(4), 750; https://doi.org/10.3390/molecules23040750
Received: 22 February 2018 / Revised: 14 March 2018 / Accepted: 20 March 2018 / Published: 24 March 2018
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Abstract
Efficient optimization procedures in chiral catalysis are usually linked to a straightforward strategy to access groups of structurally similar catalysts required for fine-tuning. The ease of building up such ligand libraries can be increased when the structure-modifying step (introduction of a substituent) is
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Efficient optimization procedures in chiral catalysis are usually linked to a straightforward strategy to access groups of structurally similar catalysts required for fine-tuning. The ease of building up such ligand libraries can be increased when the structure-modifying step (introduction of a substituent) is done at a later stage of the synthesis. This is demonstrated for the extended family of di- and tetranaphtho azepinium compounds, widely used as chiral phase transfer catalysts (PTC). Using 2,6-diiodo-4,5-dihydro-3H-dinaphtho[2,1-c:1′,2′-e]azepine and 4,8-diiodo-6,7-dihydro-5H-dibenzo[c,e]azepine, respectively, as key intermediates, 18 spiro-azepinium compounds were synthesized in a total yield of 25–42% over 6–7 steps from 1,1′-binaphthyl-2,2′-dicarboxylic acid or diphenic acid, respectively. The replacement of iodo groups with aryl substituents was performed as the last or the penultimate step of the synthesis. Full article
(This article belongs to the Special Issue Enantioselective Catalysis)
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Open AccessArticle Multifunctional Fischer Aminocarbene Complexes as Hole or Electron Transporting Layers in Organic Solar Cells
Molecules 2018, 23(4), 751; https://doi.org/10.3390/molecules23040751
Received: 6 February 2018 / Revised: 7 March 2018 / Accepted: 21 March 2018 / Published: 24 March 2018
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Abstract
A new series of Fischer carbenes have been synthetized and examined as hole-transporting or electron-transporting layers (HTLs or ETLs) in the fabrication of organic solar cells (OSCs). The synthesis of three Fischer aminocarbene complexes with the general formula [Cr(CO)5{C(NHCH2)Ar}]
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A new series of Fischer carbenes have been synthetized and examined as hole-transporting or electron-transporting layers (HTLs or ETLs) in the fabrication of organic solar cells (OSCs). The synthesis of three Fischer aminocarbene complexes with the general formula [Cr(CO)5{C(NHCH2)Ar}] (Ar = 2-pyridyl (3a), 3-pyridyl (3b) and 4-pyridyl (3c)) is reported. The molecular structure of complex 3b has been confirmed by X-ray analysis. In order to study the possible applications of the three Fischer aminocarbenes in OSCs, thin films of these complexes were prepared using a vacuum deposition process. These organometallic films were chemically and morphologically characterized by IR spectroscopy, SEM, AFM and XRD. According to the IR and Tauc analysis, the vacuum deposition process generates thin films free of impurities with an activation energy of 4.0, 2.7 and 2.1 eV for 3a, 3b y 3c, respectively. The UV-vis spectra of the amorphous aminocarbene films show that they are practically transparent to the visible radiation of the electromagnetic spectrum. This is due to the fact that their absorption is located mainly in the ultraviolet range. Two OSCs with bulk-heterojunction configuration were manufactured in order to prove the use of the aminocarbenes as ETL o HTL. The aminocarbene [Cr(CO)5{C(NHCH2) 4-pyridyl}] (3c) proved to be suitable as ETL with a fill factor (FF) of 0.23 and a short circuit current density (JSC) of 1.037 mA/cm2. Full article
(This article belongs to the Special Issue Functional Molecular Materials)
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Open AccessArticle Rhamnellosides A and B, ω-Phenylpentaene Fatty Acid Amide Diglycosides from the Fruits of Rhamnella franguloides
Molecules 2018, 23(4), 752; https://doi.org/10.3390/molecules23040752
Received: 2 March 2018 / Revised: 20 March 2018 / Accepted: 23 March 2018 / Published: 24 March 2018
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Abstract
Two new ω-phenylpentaene fatty acid amide diglycosides, rhamnellosides A (1) and B (2), were isolated from the fruits of Rhamnella franguloides (Rhamnaceae). These compounds were prioritized using LC-MS/MS molecular networking dereplication based on our previous discovery of 2-acetoxy-ω-phenylpentaene fatty
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Two new ω-phenylpentaene fatty acid amide diglycosides, rhamnellosides A (1) and B (2), were isolated from the fruits of Rhamnella franguloides (Rhamnaceae). These compounds were prioritized using LC-MS/MS molecular networking dereplication based on our previous discovery of 2-acetoxy-ω-phenylpentaene fatty acid triglycosides berchemiosides A−C from a phylogenetically related species, Berchemia berchemiifolia. The structures of the isolated compounds were elucidated by spectroscopic analyses in combination with chemical derivatization. The pentaene groups of 1 and 2 were found to have (6E, 8E, 10Z, 12Z, 14E)-geometry, which is the same as that found in berchemioside A. Full article
(This article belongs to the Section Natural Products Chemistry)
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Open AccessArticle Physicochemical Characterization and Antioxidant Activity of Humic Acids Isolated from Peat of Various Origins
Molecules 2018, 23(4), 753; https://doi.org/10.3390/molecules23040753
Received: 5 March 2018 / Revised: 20 March 2018 / Accepted: 22 March 2018 / Published: 24 March 2018
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Abstract
Although humic acids (HAs) from peat exhibit various therapeutic properties, there is little information available concerning their physicochemical and antioxidant properties. To address this issue, nine different types of peat, including oligotrophic, mesotrophic, and minerotrophic peat samples, were used for isolation of HA
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Although humic acids (HAs) from peat exhibit various therapeutic properties, there is little information available concerning their physicochemical and antioxidant properties. To address this issue, nine different types of peat, including oligotrophic, mesotrophic, and minerotrophic peat samples, were used for isolation of HA fractions by basic (HAb) and pyrophosphate (HAp) extractions. Physical parameters of the HAs were analyzed by UV-Vis, fluorescent, infrared (IR), and electron paramagnetic resonance (EPR) spectroscopy. Average Mr of the fractions ranged from 17.2 to 39.7 kDa, while their humification index (HIX) varied from 0.49 to 1.21. HAp fractions had a higher content of aromatic structures compared to HAb fractions. Moreover, HAp fractions had a significantly higher content of phenolic OH groups (3.6 ± 0.5 mmol/g) versus HAb (3.1 ± 0.5 mmol/g). All HA fractions exhibited antioxidant activity in radical scavenging and electrochemical assays, and their EPR signal had a single line with g = 2.0035, which is consistent with semiquinone type radicals. Furthermore, the HIX was found to be important in determining the number of semiquinone-type free radicals in the HA structures. Overall, these data provide a molecular basis to explain at least part of the beneficial therapeutic properties of peat-derived HAs. Full article
(This article belongs to the Special Issue The Antioxidant Capacities of Natural Products)
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Open AccessCommunication Effect of Double Bond Position on 2-Phenyl-benzofuran Antioxidants: A Comparative Study of Moracin C and Iso-Moracin C
Molecules 2018, 23(4), 754; https://doi.org/10.3390/molecules23040754
Received: 9 February 2018 / Revised: 16 March 2018 / Accepted: 22 March 2018 / Published: 24 March 2018
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Abstract
Two 2-phenyl-benzofurans, moracin C {2-[3′,5′-dihydroxy-4′-(3-methlbut-2-enyl)phenyl]-6-hydroxybenzofuran} and its isomer iso-moracin C{2-[3′,5′-dihydroxy-4′-(3-methlbut-1-enyl)phenyl]-6-hydroxybenzofuran}, were comparatively studied using redox-related antioxidant assays and non-redox antioxidant assays. Moracin C always resulted in higher IC50 values than iso-moracin C in the redox-related antioxidant assays, including •O2
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Two 2-phenyl-benzofurans, moracin C {2-[3′,5′-dihydroxy-4′-(3-methlbut-2-enyl)phenyl]-6-hydroxybenzofuran} and its isomer iso-moracin C{2-[3′,5′-dihydroxy-4′-(3-methlbut-1-enyl)phenyl]-6-hydroxybenzofuran}, were comparatively studied using redox-related antioxidant assays and non-redox antioxidant assays. Moracin C always resulted in higher IC50 values than iso-moracin C in the redox-related antioxidant assays, including •O2-inhibition, Cu2+-reducing power, DPPH•-inhibition, and ABTS+•-inhibition assays. In the non-redox antioxidant assay, moracin C and iso-moracin C underwent similar radical-adduct-formation (RAF), evidenced by the peaks at m/z 704 and m/z 618 in HPLC-MS spectra. In conclusion, both moracin C and iso-moracin C can act as 2-phenyl-benzofuran antioxidants; their antioxidant mechanisms may include redox-related ET and H+-transfer, and non-redox RAF. A double bond at the conjugation position can enhance the redox-related antioxidant potential, but hardly affects the RAF potential. Full article
(This article belongs to the Special Issue The Antioxidant Capacities of Natural Products)
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Open AccessArticle Co2 and Co3 Mixed Cluster Secondary Building Unit Approach toward a Three-Dimensional Metal-Organic Framework with Permanent Porosity
Molecules 2018, 23(4), 755; https://doi.org/10.3390/molecules23040755
Received: 28 February 2018 / Revised: 19 March 2018 / Accepted: 22 March 2018 / Published: 25 March 2018
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Abstract
Large and permanent porosity is the primary concern when designing metal-organic frameworks (MOFs) for specific applications, such as catalysis and drug delivery. In this article, we report a MOF Co11(BTB)6(NO3)4(DEF)2(H2O)14
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Large and permanent porosity is the primary concern when designing metal-organic frameworks (MOFs) for specific applications, such as catalysis and drug delivery. In this article, we report a MOF Co11(BTB)6(NO3)4(DEF)2(H2O)14 (1, H3BTB = 1,3,5-tris(4-carboxyphenyl)benzene; DEF = N,N-diethylformamide) via a mixed cluster secondary building unit (SBU) approach. MOF 1 is sustained by a rare combination of a linear trinuclear Co3 and two types of dinuclear Co2 SBUs in a 1:2:2 ratio. These SBUs are bridged by BTB ligands to yield a three-dimensional (3D) non-interpenetrated MOF as a result of the less effective packing due to the geometrically contrasting SBUs. The guest-free framework of 1 has an estimated density of 0.469 g cm−3 and exhibits a potential solvent accessible void of 69.6% of the total cell volume. The activated sample of 1 exhibits an estimated Brunauer-Emmett-Teller (BET) surface area of 155 m2 g−1 and is capable of CO2 uptake of 58.61 cm3 g−1 (2.63 mmol g−1, 11.6 wt % at standard temperature and pressure) in a reversible manner at 195 K, showcasing its permanent porosity. Full article
(This article belongs to the Special Issue Functional Molecular Materials)
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Open AccessArticle Synthesis and Evaluation of the Anticonvulsant Activities of 4-(2-(Alkylthio)benzo[d]oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-ones
Molecules 2018, 23(4), 756; https://doi.org/10.3390/molecules23040756
Received: 1 March 2018 / Revised: 22 March 2018 / Accepted: 23 March 2018 / Published: 25 March 2018
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Abstract
In this study, a novel series of 4-(2-(alkylthio)benzo[d]oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-ones (4am) was designed and synthesized. The anticonvulsant activities of these compounds were evaluated by using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models in
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In this study, a novel series of 4-(2-(alkylthio)benzo[d]oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-ones (4am) was designed and synthesized. The anticonvulsant activities of these compounds were evaluated by using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models in mice. The neurotoxicity of these compounds was evaluated using the rotarod neurotoxicity test. The majority of compounds showed anti-MES activities at 100 or 300 mg/kg. Compound 4g was considered to be the most promising, based on its potency against MES- and PTZ-induced seizures with ED50 values of 23.7 and 18.9 mg/kg, respectively. The TD50 value of 4g was 284.0 mg/kg, which resulted in a higher protective index (PI = TD50/ED50) value than that of carbamazepine and valproate. In an ELISA test, compound 4g significantly increased the γ-aminobutyric acid (GABA) content in mouse brain. In addition, pretreatment with thiosemicarbazide (an inhibitor of the GABA synthesizing enzyme) significantly decreased the activity of 4g in the MES model, which suggests that the mechanism through which compound 4g elicits its anticonvulsive action is at least in part through increasing the GABA level in the brain. Full article
(This article belongs to the Section Medicinal Chemistry)
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Open AccessArticle Long-Time Relaxation of Stress-Induced Birefringence of Microcrystalline Alkali Halide Crystals
Molecules 2018, 23(4), 757; https://doi.org/10.3390/molecules23040757
Received: 26 February 2018 / Revised: 18 March 2018 / Accepted: 21 March 2018 / Published: 25 March 2018
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Abstract
Alkali halide single crystals are most commonly used as the diluent matrix in the tablet method or disk technique for spectroscopic measurements. However, stress-induced birefringence (SIB) of alkali halides as well as intrinsic birefringence manifest during the disk formation process. Thus, the true
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Alkali halide single crystals are most commonly used as the diluent matrix in the tablet method or disk technique for spectroscopic measurements. However, stress-induced birefringence (SIB) of alkali halides as well as intrinsic birefringence manifest during the disk formation process. Thus, the true chiroptical measurement is disturbed by optical anisotropies (OA) containing SIB and intrinsic birefringence, except in the case of optical homogeneity. SIB is generally larger than intrinsic birefringence and has a value of several thousand millidegrees in the ultraviolet-visible wavelength range, although this varies with disk type. Here, to investigate the SIB origin, alkali halide crystals were examined using polarized light, X-ray diffraction, Fourier-transform infrared, and electron backscattering diffraction spectroscopic measurements. It was found that, after stress release, the SIB exhibited nonlinear long-time relaxation, which roughly converged within several hours, with the only time-invariant intrinsic birefringence remaining being due to OA. This behavior was strongly related to an increase in the quasi-amorphous domain and the generation of an air gap between the crystallite boundaries and their pellets. Further, a straightforward correlation was found between amorphization and an increase in the disk water content caused by deliquescence. Thus, the OA of alkali halide single crystals was found to have two different origins yielding intrinsic birefringence and SIB. Full article
(This article belongs to the Special Issue Recent Advances in Chiroptical Spectroscopy)
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Open AccessArticle UHPLC-MS/MS Quantification Combined with Chemometrics for Comparative Analysis of Different Batches of Raw, Wine-Processed, and Salt-Processed Radix Achyranthis Bidentatae
Molecules 2018, 23(4), 758; https://doi.org/10.3390/molecules23040758
Received: 2 February 2018 / Revised: 5 March 2018 / Accepted: 22 March 2018 / Published: 26 March 2018
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Abstract
An accurate and reliable method using ultra-high performance liquid chromatography combined with triple quadrupole tandem mass spectrometry (UHPLC–MS/MS) was established for simultaneous quantification of five major bioactive analytes in raw, wine-processed, and salt-processed Radix Achyranthis bidentatae (RAB). The results showed that this method
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An accurate and reliable method using ultra-high performance liquid chromatography combined with triple quadrupole tandem mass spectrometry (UHPLC–MS/MS) was established for simultaneous quantification of five major bioactive analytes in raw, wine-processed, and salt-processed Radix Achyranthis bidentatae (RAB). The results showed that this method exhibited desirable sensitivity, precision, stability, and repeatability. The overall intra-day and inter-day variations (RSD) were in the range of 1.57–2.46 and 1.51–3.00%, respectively. The overall recoveries were 98.58–101.48% with a relative standard deviation (RSD) of 0.01–1.86%. In addition, the developed approach was applied to 21 batches of raw, wine-processed, and salt-processed samples of RAB. Hierarchical clustering analysis (HCA), principal component analysis (PCA), heat map, and boxplot analysis were performed to evaluate the quality of raw, wine-processed, and salt-processed RAB collected from different regions. The chemometrics combined with the quantitative analysis based on UHPLC–MS/MS results indicated that the content of five analytes increased significantly in processed RAB compared to raw RAB. Full article
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Open AccessArticle Intraconversion of Polar Ginsenosides, Their Transformation into Less-Polar Ginsenosides, and Ginsenoside Acetylation in Ginseng Flowers upon Baking and Steaming
Molecules 2018, 23(4), 759; https://doi.org/10.3390/molecules23040759
Received: 25 February 2018 / Revised: 17 March 2018 / Accepted: 20 March 2018 / Published: 26 March 2018
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Abstract
Heating is a traditional method used in ginseng root processing, however, there aren’t reports on differences resulting from baking and steaming. Moreover, ginseng flowers, with 5.06 times more total saponins than ginseng root, are not fully taken advantage of for their ginsenosides. Transformation
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Heating is a traditional method used in ginseng root processing, however, there aren’t reports on differences resulting from baking and steaming. Moreover, ginseng flowers, with 5.06 times more total saponins than ginseng root, are not fully taken advantage of for their ginsenosides. Transformation mechanisms of ginsenosides in ginseng flowers upon baking and steaming were thus explored. HPLC using authentic standards of 20 ginsenosides and UPLC-QTOF-MS/MS were used to quantify and identify ginsenosides, respectively, in ginseng flowers baked or steamed at different temperatures and durations. Results show that baking and steaming caused a 3.2-fold increase in ginsenoside species existed in unheated ginseng flowers (20/64 ginsenosides) and transformation of a certain amount of polar ginsenosides into numerous less polar ginsenosides. Among the 20 ginsenosides with standards, polar ginsenosides were abundant in ginseng flowers baked or steamed at lower temperatures, whereas less polar ginsenosides occurred and were enriched at higher temperatures. Furthermore, the two types of heating treatments could generate mostly similar ginsenosides, but steaming was much efficient than baking in transforming polar- into less polar ginsenosides, with steaming at 120 °C being comparably equivalent to baking at 150 °C. Moreover, both the two heating methods triggered ginsenoside acetylation and thus caused formation of 16 acetylginsenosides. Finally, a new transformation mechanism concerning acetyl-ginsenosides formation was proposed. Full article
(This article belongs to the collection Bioactive Compounds)
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Open AccessFeature PaperArticle Zn(OAc)2-Catalyzing Ring-Opening Polymerization of N-Carboxyanhydrides for the Synthesis of Well-Defined Polypeptides
Molecules 2018, 23(4), 760; https://doi.org/10.3390/molecules23040760
Received: 13 March 2018 / Revised: 23 March 2018 / Accepted: 23 March 2018 / Published: 26 March 2018
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Abstract
Despite notable progress, the fabrication of well-defined polypeptides via controlled ring-opening polymerization (ROP) of α-amino acid N-carboxyanhydrides (NCAs) using convenient catalysts under mild conditions in a relatively short polymerization time is still challenging. Herein, an easily obtained catalyst system composed of zinc
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Despite notable progress, the fabrication of well-defined polypeptides via controlled ring-opening polymerization (ROP) of α-amino acid N-carboxyanhydrides (NCAs) using convenient catalysts under mild conditions in a relatively short polymerization time is still challenging. Herein, an easily obtained catalyst system composed of zinc acetate and aniline was explored to mediate the fast ROP of γ-benzyl-l-glutamate-N-carboxyanhydride (BLG-NCA) monomer, to produce poly(γ-benzyl-l-glutamates) (PBLGs) with controllable molecular weights and narrow dispersity. Considering the excellent cooperative action of zinc acetate and a broad scope of aniline derivatives with different functional groups to control ROP of BLG-NCA, this method may offer a useful platform enabling the rapid generation of end-functionalized PBLG and block copolymers for numerous biomedical applications. Full article
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Open AccessArticle Synthesis, Molecular Docking Studies, In Vitro Antimicrobial and Antifungal Activities of Novel Dipeptide Derivatives Based on N-(2-(2-Hydrazinyl-2-oxoethylamino)-2-oxoethyl)-Nicotinamide
Molecules 2018, 23(4), 761; https://doi.org/10.3390/molecules23040761
Received: 16 January 2018 / Revised: 14 March 2018 / Accepted: 20 March 2018 / Published: 27 March 2018
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Abstract
A series of linear dipeptide derivatives (410) were prepared and evaluated as antimicrobial agents via the synthesis of N-(2-(2-hydrazinyl-2-oxoethylamino)-2-oxoethyl) nicotinamide (4). Compound 4 was reacted with 4-chlorobenzaldehyde or 4-hydroxybenzaldehyde, to give the hydrazones 5 and 6
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A series of linear dipeptide derivatives (410) were prepared and evaluated as antimicrobial agents via the synthesis of N-(2-(2-hydrazinyl-2-oxoethylamino)-2-oxoethyl) nicotinamide (4). Compound 4 was reacted with 4-chlorobenzaldehyde or 4-hydroxybenzaldehyde, to give the hydrazones 5 and 6, respectively. On the other hand, Compound 4 was coupled with phenylisocyanate or methylisothiocyanate to give Compounds 7 and 8, respectively. The latter compounds (7 and 8) were coupled with chloroacetic acid to give oxazolidine (9) and thiazolidine (10), respectively. The newly synthesized dipeptide compounds were confirmed by means of their spectral data. The antimicrobial activity of the newly synthesized compounds 410 was evaluated by agar well diffusion, and they showed good activity. Compounds 4, 5, and 9 gave the most promising activity in this study. Most of the tested compounds possessed MIC values ranging from 50 to 500 µg/mL. Furthermore, docking studies were carried out on enoyl reductase from E. coli and cytochrome P450 14 α-sterol demethylase (Cyp51) from Candida albicans active sites. The MolDock scores of the seven tested compounds ranged between −117 and −171 and between −107 and −179, respectively. Full article
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Open AccessArticle Synthesis of Polyheterocyclic Pyrrolo[3,4-b]pyridin-5-ones via a One-Pot (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization/SN2) Process. A Suitable Alternative towards Novel Aza-Analogues of Falipamil
Molecules 2018, 23(4), 763; https://doi.org/10.3390/molecules23040763
Received: 20 February 2018 / Revised: 16 March 2018 / Accepted: 23 March 2018 / Published: 27 March 2018
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Abstract
We describe the one-pot synthesis of twenty polyheterocyclic pyrrolo[3,4-b]pyridin-5-ones via a cascade process (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization) in 20 to 95% overall yields, as well as four pharmacologically promising analogues via an improved cascade process (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization/SN2):
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We describe the one-pot synthesis of twenty polyheterocyclic pyrrolo[3,4-b]pyridin-5-ones via a cascade process (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization) in 20 to 95% overall yields, as well as four pharmacologically promising analogues via an improved cascade process (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization/SN2): two piperazine-linked pyrrolo[3,4-b]pyridin-5-ones in 33 and 34%, and a couple of Falipamil aza-analogues in 30 and 35% overall yields. It is worth highlighting the good substrate scope found, because final products are furnished with alkyl, aryl, and heterocyclic substituents. The use of chain-ring tautomerizable isocyanides (as key reagents for the Ugi-type three component reaction) allowed for a rapid and efficient assembly of the polysubstituted oxindoles, which were used in situ toward the complex products, conferring features like robustness, sustainability, and the one-pot approach to this synthetic methodology. Full article
(This article belongs to the Section Organic Chemistry)
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Open AccessArticle A Visible Light-Driven Minisci-Type Reaction with N-Hydroxyphthalimide Esters
Molecules 2018, 23(4), 764; https://doi.org/10.3390/molecules23040764
Received: 9 March 2018 / Revised: 21 March 2018 / Accepted: 22 March 2018 / Published: 27 March 2018
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Abstract
A visible light-promoted protocol for the redox-neutral coupling of N-hydroxyphthalimide esters with different N-heterocyclic compounds is described. The reaction proceeds through an alkyl radical intermediate generated by reductive decarboxylation of N-hydroxyphthalimide esters. In contrast to the original Minisci protocol, polyalkylation
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A visible light-promoted protocol for the redox-neutral coupling of N-hydroxyphthalimide esters with different N-heterocyclic compounds is described. The reaction proceeds through an alkyl radical intermediate generated by reductive decarboxylation of N-hydroxyphthalimide esters. In contrast to the original Minisci protocol, polyalkylation can largely be avoided. Mechanistic investigations revealed a radical chain mechanism which in some cases can proceed even if no photocatalyst is added. This valuable and functional group-tolerant reaction produces substituted heterocycles in moderate to excellent yield. The use of inexpensive starting materials and LEDs as the light source are key features of this C–C bond formation. Full article
(This article belongs to the Special Issue Radical Chemistry)
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Open AccessArticle Performance of Different Immobilized Lipases in the Syntheses of Short- and Long-Chain Carboxylic Acid Esters by Esterification Reactions in Organic Media
Molecules 2018, 23(4), 766; https://doi.org/10.3390/molecules23040766
Received: 23 February 2018 / Revised: 19 March 2018 / Accepted: 24 March 2018 / Published: 27 March 2018
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Abstract
Short-chain alkyl esters and sugar esters are widely used in the food, pharmaceutical and cosmetic industries due to their flavor and emulsifying characteristics, respectively. Both compounds can be synthesized via biocatalysis using lipases. This work aims to compare the performance of commercial lipases
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Short-chain alkyl esters and sugar esters are widely used in the food, pharmaceutical and cosmetic industries due to their flavor and emulsifying characteristics, respectively. Both compounds can be synthesized via biocatalysis using lipases. This work aims to compare the performance of commercial lipases covalently attached to dry acrylic beads functionalized with oxirane groups (lipases from Candida antarctica type B—IMMCALB-T2-350, Pseudomonas fluorescens—IMMAPF-T2-150, and Thermomyces lanuginosus—IMMTLL-T2-150) and a home-made biocatalyst (lipase from Pseudomonas fluorescens adsorbed onto silica coated with octyl groups, named PFL-octyl-silica) in the syntheses of short- and long-chain carboxylic acid esters. Esters with flavor properties were synthetized by esterification of acetic and butyl acids with several alcohols (e.g., ethanol, 1-butanol, 1-hexanol, and isoamyl alcohol), and sugar esters were synthetized by esterification of oleic and lauric acids with fructose and lactose. All biocatalysts showed similar performance in the syntheses of short-chain alkyl esters, with conversions ranging from 88.9 to 98.4%. However, in the syntheses of sugar esters the performance of PFL-octyl-silica was almost always lower than the commercial IMMCALB-T2-350, whose conversion was up to 96% in the synthesis of fructose oleate. Both biocatalysts showed high operational stability in organic media, thus having great potential for biotransformations. Full article
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Open AccessArticle Computational Simulation Studies on the Binding Selectivity of 1-(1H-Benzimidazol-5-yl)-5-aminopyrazoles in Complexes with FGFR1 and FGFR4
Molecules 2018, 23(4), 767; https://doi.org/10.3390/molecules23040767
Received: 26 February 2018 / Revised: 12 March 2018 / Accepted: 20 March 2018 / Published: 27 March 2018
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Abstract
Fibroblast growth factor receptor 1 (FGFR1) has become a potential target for the treatment of cancer. Designing FGFR1-selective inhibitors remains fundamental to the development of anti-cancer drugs because of highly sequential homology among FGFR subtypes. In present work, four inhibitors were examined with
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Fibroblast growth factor receptor 1 (FGFR1) has become a potential target for the treatment of cancer. Designing FGFR1-selective inhibitors remains fundamental to the development of anti-cancer drugs because of highly sequential homology among FGFR subtypes. In present work, four inhibitors were examined with intermolecular interaction patterns with FGFR1 and FGFR4, respectively, for the exploration of binding mechanisms by applying a combined approach of computational techniques, including flexible docking, binding site analyses, electronic structure computations, molecular dynamic simulations, and binding free energy predictions. Molecular simulation-predicted binding conformations and pharmacophoric features of these molecules in the active pocket of either FGFR1 or FGFR4. MMPB(GB)SA-calculated binding free energies were accordant with the ordering of their tested potency values. Furthermore, in silico mutations of two residues (FGFR1: Tyr563 and Ser565) were also performed to check their impact on ligand binding by applying MD simulations and binding free energy calculations. The present studies may provide a structural understanding of the FGFR1-selective mechanism. The viewpoints from computational simulations would be valuable guidelines for the development of novel FGFR1-selective inhibitors. Full article
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Open AccessCommunication E-p-Methoxycinnamoyl-α-l-rhamnopyranosyl Ester, a Phenylpropanoid Isolated from Scrophularia buergeriana, Increases Nuclear Factor Erythroid-Derived 2-Related Factor 2 Stability by Inhibiting Ubiquitination in Human Keratinocytes
Molecules 2018, 23(4), 768; https://doi.org/10.3390/molecules23040768
Received: 13 March 2018 / Revised: 24 March 2018 / Accepted: 25 March 2018 / Published: 27 March 2018
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Abstract
The nuclear factor erythroid-derived 2-related factor 2 (Nrf2) is a key regulator of gene expression during oxidative stress and drug detoxification. Thus, identifying Nrf2 activators to protect from possible cell damage is necessary. In this study, we investigated whether E-p-methoxycinnamoyl-α-l
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The nuclear factor erythroid-derived 2-related factor 2 (Nrf2) is a key regulator of gene expression during oxidative stress and drug detoxification. Thus, identifying Nrf2 activators to protect from possible cell damage is necessary. In this study, we investigated whether E-p-methoxycinnamoyl-α-l-rhamnopyranosyl ester (MCR), a phenylpropanoid isolated from Scrophularia buergeriana, can activate Nrf2 signaling in human keratinocytes (HaCaT). First, we determined the dose- and time-dependent effects of MCR on the expression and activity of Nrf2. The antioxidant response element-luciferase reporter assay and western blot analysis results showed that MCR markedly induced Nrf2 activity and its protein expression, respectively. Further, MCR increased both the mRNA and protein levels of heme-oxygenase-1, one of the Nrf2 target genes, in the cells. Interestingly, we found that Nrf2 stability was remarkably enhanced by MCR. Furthermore, ubiquitin-dependent proteasomal degradation of Nrf2 was significantly reduced by MCR. Thus, MCR might afford skin protection by enhancing Nrf2 stability or by blocking its proteasomal degradation. Full article
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Open AccessArticle Charge-Controlled Synthetic Hyaluronan-Based Cell Matrices
Molecules 2018, 23(4), 769; https://doi.org/10.3390/molecules23040769
Received: 21 February 2018 / Revised: 22 March 2018 / Accepted: 23 March 2018 / Published: 27 March 2018
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Abstract
The extracellular matrix (ECM) represents a highly charged and hydrated network in which different cells in vertebrate tissues are embedded. Hydrogels as minimal ECM mimetics with a controlled chemistry offer the opportunity to vary material properties by varying the negative network charge. In
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The extracellular matrix (ECM) represents a highly charged and hydrated network in which different cells in vertebrate tissues are embedded. Hydrogels as minimal ECM mimetics with a controlled chemistry offer the opportunity to vary material properties by varying the negative network charge. In this paper, a synthetic biology model of the ECM based on natural and highly negatively charged polyelectrolyte hyaluronic acid (HA) is characterized with specific emphasis on its charge-related bioactivity. Therefore, the thiol-Michael addition click reaction is used to produce HA hydrogels with defined network structure and charge density. The presented hydrogels show enzymatic degradability and cell attachment. These properties depend on both covalent and electrostatic interactions within the hydrogel network. Furthermore, no unspecific or specific attachment of proteins to the presented hydrogels is observed. In addition, these fundamental insights into charge-related ECM behavior and the influence of electrostatic properties could also lead to innovations in existing biomedical products. Full article
(This article belongs to the Special Issue Hyaluronic Acid and its Derivatives for Biomedical Applications)
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Open AccessArticle A New Lignanamide from the Root of Lycium yunnanense Kuang and Its Antioxidant Activity
Molecules 2018, 23(4), 770; https://doi.org/10.3390/molecules23040770
Received: 7 March 2018 / Revised: 21 March 2018 / Accepted: 23 March 2018 / Published: 27 March 2018
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Abstract
A new lignanamide (1), lyciumamide K, together with four known analogues (25), was isolated from the root of Lycium yunnanense Kuang. Based on HR-ESI-MS, NMR spectral data and quantum chemistry ECD calculations, the structure of this new
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A new lignanamide (1), lyciumamide K, together with four known analogues (25), was isolated from the root of Lycium yunnanense Kuang. Based on HR-ESI-MS, NMR spectral data and quantum chemistry ECD calculations, the structure of this new compound was confirmed, including its absolute configuration. Evaluation of the antioxidant activity of compounds 15 in the oxygen radical absorption capacity (ORAC) assay showed that they all exhibited significant antioxidant activities. Particularly, compound 1 showed the best activity with ORAC values (U/mol) of 7.90 ± 0.52. Thus, the new lignanamide may be a good source of bioavtive and protective compounds. Full article
(This article belongs to the Section Natural Products Chemistry)
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Open AccessArticle Stereoselective Syntheses and Application of Chiral Bi- and Tridentate Ligands Derived from (+)-Sabinol
Molecules 2018, 23(4), 771; https://doi.org/10.3390/molecules23040771
Received: 13 February 2018 / Revised: 21 March 2018 / Accepted: 22 March 2018 / Published: 27 March 2018
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Abstract
A library of bidentate diols, as well as tridentate triols and aminodiols, derived from (+)-sabinol, was synthesized in a stereoselective manner. Sabinol was transformed into allylic trichloroacetamide via Overman rearrangement of the corresponding trichloroacetimidate. After changing the protecting group to Boc, the enamine
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A library of bidentate diols, as well as tridentate triols and aminodiols, derived from (+)-sabinol, was synthesized in a stereoselective manner. Sabinol was transformed into allylic trichloroacetamide via Overman rearrangement of the corresponding trichloroacetimidate. After changing the protecting group to Boc, the enamine was subjected to stereospecific dihydroxylation with OsO4/NMO, resulting in the (1R,2R,3R,5R)-aminodiol diastereomer. The obtained primary aminodiol was transformed to a secondary analogue. The ring closure of the N-benzyl-substituted aminodiol with formaldehyde was investigated and regioselective formation of the spiro-oxazolidine ring was observed. Hydroboration or dihydroxylation of sabinol or its benzyl ether with OsO4/NMO resulted in the formation of sabinane-based diols and triols following a highly stereospecific reaction. Treatment of sabinol with m-CPBA afforded O-benzoyl triol as a diastereoisomer of the directly dihydroxylated product, instead of the expected epoxy alcohol. The resulting aminodiols, diol, and triols were applied as chiral catalysts in the reaction of diethylzinc and benzaldehyde from moderate to good selectivity. Full article
(This article belongs to the Special Issue Enantioselective Catalysis)
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Open AccessArticle In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantum
Molecules 2018, 23(4), 772; https://doi.org/10.3390/molecules23040772
Received: 4 March 2018 / Revised: 21 March 2018 / Accepted: 26 March 2018 / Published: 27 March 2018
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Abstract
There is an urgent need for the discovery of new antileishmanial drugs with a new mechanism of action. Type 2 NADH dehydrogenase from Leishmania infantum (LiNDH2) is an enzyme of the parasite’s respiratory system, which catalyzes the electron transfer from NADH
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There is an urgent need for the discovery of new antileishmanial drugs with a new mechanism of action. Type 2 NADH dehydrogenase from Leishmania infantum (LiNDH2) is an enzyme of the parasite’s respiratory system, which catalyzes the electron transfer from NADH to ubiquinone without coupled proton pumping. In previous studies of the related NADH: ubiquinone oxidoreductase crystal structure from Saccharomyces cerevisiae, two ubiquinone-binding sites (UQI and UQII) were identified and shown to play an important role in the NDH-2-catalyzed oxidoreduction reaction. Based on the available structural data, we developed a three-dimensional structural model of LiNDH2 using homology detection methods and performed an in silico virtual screening campaign to search for potential inhibitors targeting the LiNDH2 ubiquinone-binding site 1—UQI. Selected compounds displaying favorable properties in the computational screening experiments were assayed for inhibitory activity in the structurally similar recombinant NDH-2 from S. aureus and leishmanicidal activity was determined in the wild-type axenic amastigotes and promastigotes of L. infantum. The identified compound, a substituted 6-methoxy-quinalidine, showed promising nanomolar leishmanicidal activity on wild-type axenic promastigotes and amastigotes of L. infantum and the potential for further development. Full article
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Open AccessArticle Lentinoids A–D, New Natural Products Isolated from Lentinus strigellus
Molecules 2018, 23(4), 773; https://doi.org/10.3390/molecules23040773
Received: 26 February 2018 / Revised: 18 March 2018 / Accepted: 23 March 2018 / Published: 28 March 2018
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Abstract
Four novel lentinoids (14), along with the known compounds striguellone A (5), isopanepoxydone (6) and panepoxydone (7), were isolated as part of our studies on Lentinus strigellus. The structures of 1
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Four novel lentinoids (14), along with the known compounds striguellone A (5), isopanepoxydone (6) and panepoxydone (7), were isolated as part of our studies on Lentinus strigellus. The structures of 14 have been established by 1D- and 2D-NMR and MS analysis. Compounds (13) and (57) were tested against Listeria monocytogenes, Enterococcus faecalis, Pseudomonas aeruginosa and Klebsiella pneumoniae. These compounds showed inhibition diameters ranging from 7.5–9.5 mm, however, when the minimum inhibitory concentration (MIC) was determined, only compound 1 showed a significant activity of 200 μg/mL. Intermediates for the biosynthesis of the oxygenated cyclohexenyl derivatives isolated from lentinoid fungi (genera Lentinus and Panus) are proposed. Full article
(This article belongs to the Section Natural Products Chemistry)
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Open AccessArticle In Vitro Anti-Toxoplasma gondii and Antimicrobial Activity of Amides Derived from Cinnamic Acid
Molecules 2018, 23(4), 774; https://doi.org/10.3390/molecules23040774
Received: 1 March 2018 / Revised: 19 March 2018 / Accepted: 23 March 2018 / Published: 28 March 2018
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Abstract
Most cinnamic acids, their esters, amides, aldehydes, and alcohols present several therapeutic actions through anti-inflammatory, antitumor, and inhibitory activity against a great variety of microorganisms. In this work, eight amines derived from cinnamic acid were synthesized and tested against host cells infected with
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Most cinnamic acids, their esters, amides, aldehydes, and alcohols present several therapeutic actions through anti-inflammatory, antitumor, and inhibitory activity against a great variety of microorganisms. In this work, eight amines derived from cinnamic acid were synthesized and tested against host cells infected with Toxoplasma gondii and the bacteria Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermidis, and three strains of Staphylococcus aureus. Compounds 3 and 4 showed the best result against intracellular T. gondii, presenting antiparasitic activity at low concentrations (0.38 and 0.77 mM). The antibacterial activity of these compounds was also evaluated by the agar microdilution method, and amides 2 and 5 had a minimum inhibitory concentration of 250 µg mL−1 against two strains of S. aureus (ATCC 25923 and bovine strain LSA 88). These also showed synergistic action along with a variety of antibiotics, demonstrating that amines derived from cinnamic acid have potential as pharmacological agents. Full article
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Open AccessFeature PaperArticle PEG 400/Cerium Ammonium Nitrate Combined with Microwave-Assisted Synthesis for Rapid Access to Beta-Amino Ketones. An Easy-to-Use Protocol for Discovering New Hit Compounds
Molecules 2018, 23(4), 775; https://doi.org/10.3390/molecules23040775
Received: 2 March 2018 / Revised: 22 March 2018 / Accepted: 26 March 2018 / Published: 28 March 2018
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Abstract
Compound libraries are important requirement in target-based drug discovery. In the present work, a small focused compound library based on β-aminoketone scaffold has been prepared combining microwave-assisted organic synthesis (MAOS) with polymer-assisted solution phase synthesis (PASPS) and replacing reaction workup standard purification procedures
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Compound libraries are important requirement in target-based drug discovery. In the present work, a small focused compound library based on β-aminoketone scaffold has been prepared combining microwave-assisted organic synthesis (MAOS) with polymer-assisted solution phase synthesis (PASPS) and replacing reaction workup standard purification procedures with solid phase extraction (SPE). Specifically, the effects of solvent, such as dioxane, dimethylformamide (DMF), polyethylene glycol 400 (PEG 400), temperature, irradiation time, stoichiometric ratio of reagents, and catalysts (HCl, acetic acid, cerium ammonium nitrate (CAN)) were investigated to maximize both conversion and yield. The optimized protocol generally afforded the desired products in satisfying yields and purities. The designed library is a part of our current research on sigma 1 receptor modulators, a valuable tool for the identification of novel potential hit compounds. Full article
(This article belongs to the Section Medicinal Chemistry)
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Open AccessArticle Synthesis and Antiproliferative Activity of Minor Hops Prenylflavonoids and New Insights on Prenyl Group Cyclization
Molecules 2018, 23(4), 776; https://doi.org/10.3390/molecules23040776
Received: 7 March 2018 / Revised: 22 March 2018 / Accepted: 27 March 2018 / Published: 28 March 2018
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Abstract
Synthesis of minor prenylflavonoids found in hops and their non-natural derivatives were performed. The antiproliferative activity of the obtained compounds against some human cancer cell lines was investigated. Using xanthohumol isolated from spent hops as a lead compound, a series of minor hop
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Synthesis of minor prenylflavonoids found in hops and their non-natural derivatives were performed. The antiproliferative activity of the obtained compounds against some human cancer cell lines was investigated. Using xanthohumol isolated from spent hops as a lead compound, a series of minor hop prenylflavonoids and synthetic derivatives were obtained by isomerization, cyclisation, oxidative-cyclisation, oxidation, reduction and demethylation reactions. Three human cancer cell lines—breast (MCF-7), prostate (PC-3) and colon (HT-29)—were used in antiproliferative assays, with cisplatin as a control compound. Five minor hop prenyl flavonoids and nine non-natural derivatives of xanthohumol have been synthetized. Syntheses of xanthohumol K, its dihydro- and tetrahydro-derivatives and 1″,2″,α,β-tetrahydroxanthohumol C were described for the first time. All of the minor hops prenyl flavonoids exhibited strong to moderate antiproliferative activity in vitro. The minor hops flavonoids xanthohumol C and 1″,2″-dihydroxanthohumol K and non-natural 2,3-dehydroisoxanthohumol exhibited the activity comparable to cisplatin. Results described in the article suggest that flavonoids containing chromane- and chromene-like moieties, especially chalcones, are potent antiproliferative agents. The developed new efficient, regioselective cyclisation reaction of the xanthohumol prenyl group to 1″,2″-dihydroxantohumol K may be used in the synthesis of other compounds with the chromane moiety. Full article
(This article belongs to the Special Issue Chalcone: A Privileged Structure in Medicinal Chemistry)
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Open AccessArticle Synthesis of Novel Amino Acid–Fipronil Conjugates and Study on Their Phloem Loading Mechanism
Molecules 2018, 23(4), 778; https://doi.org/10.3390/molecules23040778
Received: 8 February 2018 / Revised: 15 March 2018 / Accepted: 21 March 2018 / Published: 28 March 2018
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Abstract
To develop a new pesticide with phloem mobility, a series of new amino acid–fipronil conjugates were designed and synthesized based on derivatization at the 3-position of the pyrazole ring of fipronil. Experiments using a Ricinus communis seedling system showed that all tested conjugates
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To develop a new pesticide with phloem mobility, a series of new amino acid–fipronil conjugates were designed and synthesized based on derivatization at the 3-position of the pyrazole ring of fipronil. Experiments using a Ricinus communis seedling system showed that all tested conjugates were phloem mobile except for the isoleucine–fipronil conjugate, and that the serine–fipronil conjugate (4g) exhibited the highest concentration in phloem sap (52.00 ± 5.80 μM). According to prediction with log Cf values and uptake experiments with Xenopus oocytes, the phloem loading process of conjugate 4g involved both passive diffusion and an active carrier system (RcANT15). In particular, compared with for a previously reported glycinergic–fipronil conjugate (GlyF), passive diffusion played a more important role for conjugate 4g in the enhancement of phloem mobility. This study suggests that associating a nutrient at a different position of an existing pesticide structure could still be effective in obtaining phloem-mobile derivatives, but the distinct physicochemical properties of resultant conjugates may lead to different phloem loading mechanisms. Full article
(This article belongs to the Section Chemical Biology)
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Open AccessArticle Sensory Characteristics of Various Concentrations of Phenolic Compounds Potentially Associated with Smoked Aroma in Foods
Molecules 2018, 23(4), 780; https://doi.org/10.3390/molecules23040780
Received: 14 February 2018 / Revised: 14 March 2018 / Accepted: 24 March 2018 / Published: 28 March 2018
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Abstract
This research describes the sensory odor characteristics of 19 phenolic compounds (11 phenol derivatives, six guaiacol derivatives, and two syringol derivatives) that have been associated with smoked aroma in previous literature. Seven concentrations varying from 1 to 100,000 ppm of each chemical were
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This research describes the sensory odor characteristics of 19 phenolic compounds (11 phenol derivatives, six guaiacol derivatives, and two syringol derivatives) that have been associated with smoked aroma in previous literature. Seven concentrations varying from 1 to 100,000 ppm of each chemical were examined. A highly trained descriptive panel used a recently published lexicon for smoky aroma and flavor and found that smoked aroma compounds have many different attributes that make up smokiness. Musty/dusty, musty/earthy, pungent, acid, smoky, woody, burnt, ashy, cedar, creosote or petroleum-like collectively imparted smoked aroma. Most of the phenolic compounds were described as having smoky characteristics at low concentrations, generally at 1 and 10 ppm, except 3,4-dimethylphenol at 5000 ppm. 2,6-Dimethylphenol was not associated with smoky characteristics. This research is the first to evaluate a set of phenolic compounds for their sensory characteristics using a professionally developed set of sensory attributes. Full article
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Open AccessArticle Ectopic Overexpression of a Novel R2R3-MYB, NtMYB2 from Chinese Narcissus Represses Anthocyanin Biosynthesis in Tobacco
Molecules 2018, 23(4), 781; https://doi.org/10.3390/molecules23040781
Received: 5 March 2018 / Revised: 21 March 2018 / Accepted: 23 March 2018 / Published: 28 March 2018
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Abstract
R2R3 MYB transcription factors play key functions in the regulation of secondary metabolites. In the present study, a R2R3 MYB transcriptional factor NtMYB2 was identified from Chinese narcissus (Narcissus tazetta L. var. Chinensis Roem) and functionally characterized. NtMYB2 belongs to subgroup 4
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R2R3 MYB transcription factors play key functions in the regulation of secondary metabolites. In the present study, a R2R3 MYB transcriptional factor NtMYB2 was identified from Chinese narcissus (Narcissus tazetta L. var. Chinensis Roem) and functionally characterized. NtMYB2 belongs to subgroup 4 of the R2R3 MYB transcription factor family that are related to repressor MYBs involved in the regulation of anthocyanin and flavonoids. Transient expression confirmed that NtMYB2 strongly reduced the red pigmentation induced by MYB- anthocyanin activators in agro-infiltrated tobacco leaves. Ectopic expression of NtMYB2 in tobacco significantly reduced the pigmentation and altered the floral phenotypes in transgenic tobacco flowers. Gene expression analysis suggested that NtMYB2 repressed the transcript levels of structural genes involved in anthocyanin biosynthesis pathway, especially the UFGT gene. NtMYB2 gene is expressed in all examined narcissus tissues; the levels of transcription in petals and corona is higher than other tissues and the transcription level at the bud stage was highest. These results show that NtMYB2 is involved in the regulation of anthocyanin biosynthesis pathway and may act as a repressor by down regulating the transcripts of key enzyme genes in Chinese narcissus. Full article
(This article belongs to the Section Molecular Diversity)
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Open AccessCommunication Catalytic Annulation of Epoxides with Heterocumulenes by the Indium-Tin System
Molecules 2018, 23(4), 782; https://doi.org/10.3390/molecules23040782
Received: 15 March 2018 / Revised: 27 March 2018 / Accepted: 28 March 2018 / Published: 28 March 2018
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Abstract
In the synthesis of five-membered heterocycles by the annulation of epoxides with heterocumulenes such as carbon dioxide and isocyanates, we developed the indium-tin catalytic system and synthesized various cyclic adducts including novel types products under mild reaction conditions. Full article
(This article belongs to the Special Issue Indium in Organic Synthesis)
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Open AccessArticle Computational Modeling of In Vitro Swelling of Mitochondria: A Biophysical Approach
Molecules 2018, 23(4), 783; https://doi.org/10.3390/molecules23040783
Received: 22 February 2018 / Revised: 12 March 2018 / Accepted: 27 March 2018 / Published: 28 March 2018
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Abstract
Swelling of mitochondria plays an important role in the pathogenesis of human diseases by stimulating mitochondria-mediated cell death through apoptosis, necrosis, and autophagy. Changes in the permeability of the inner mitochondrial membrane (IMM) of ions and other substances induce an increase in the
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Swelling of mitochondria plays an important role in the pathogenesis of human diseases by stimulating mitochondria-mediated cell death through apoptosis, necrosis, and autophagy. Changes in the permeability of the inner mitochondrial membrane (IMM) of ions and other substances induce an increase in the colloid osmotic pressure, leading to matrix swelling. Modeling of mitochondrial swelling is important for simulation and prediction of in vivo events in the cell during oxidative and energy stress. In the present study, we developed a computational model that describes the mechanism of mitochondrial swelling based on osmosis, the rigidity of the IMM, and dynamics of ionic/neutral species. The model describes a new biophysical approach to swelling dynamics, where osmotic pressure created in the matrix is compensated for by the rigidity of the IMM, i.e., osmotic pressure induces membrane deformation, which compensates for the osmotic pressure effect. Thus, the effect is linear and reversible at small membrane deformations, allowing the membrane to restore its normal form. On the other hand, the membrane rigidity drops to zero at large deformations, and the swelling becomes irreversible. As a result, an increased number of dysfunctional mitochondria can activate mitophagy and initiate cell death. Numerical modeling analysis produced results that reasonably describe the experimental data reported earlier. Full article
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