Next Issue
Previous Issue

E-Mail Alert

Add your e-mail address to receive forthcoming issues of this journal:

Journal Browser

Journal Browser

Table of Contents

Molecules, Volume 22, Issue 4 (April 2017)

  • Issues are regarded as officially published after their release is announced to the table of contents alert mailing list.
  • You may sign up for e-mail alerts to receive table of contents of newly released issues.
  • PDF is the official format for papers published in both, html and pdf forms. To view the papers in pdf format, click on the "PDF Full-text" link, and use the free Adobe Readerexternal link to open them.
Cover Story The figure showed in the cover describes the action of barbatic acid from the lichen Cladia [...] Read more.
View options order results:
result details:
Displaying articles 1-174
Export citation of selected articles as:

Editorial

Jump to: Research, Review, Other

Open AccessEditorial Special Issue: Enzyme Immobilization 2016
Molecules 2017, 22(4), 601; doi:10.3390/molecules22040601
Received: 5 April 2017 / Revised: 6 April 2017 / Accepted: 6 April 2017 / Published: 8 April 2017
PDF Full-text (176 KB) | HTML Full-text | XML Full-text
(This article belongs to the Special Issue Enzyme Immobilization 2016)

Research

Jump to: Editorial, Review, Other

Open AccessArticle Screening, Purification and Characterization of Anionic Antimicrobial Proteins from Foeniculum Vulgare
Molecules 2017, 22(4), 602; doi:10.3390/molecules22040602
Received: 2 March 2017 / Revised: 5 April 2017 / Accepted: 6 April 2017 / Published: 8 April 2017
PDF Full-text (1058 KB) | HTML Full-text | XML Full-text
Abstract
Foeniculum vulgare Mill., commonly called fennel, is a medicinal plant belonging to the Umbelliferae (Apiaceae) family, and is used in traditional medicine. Antibacterial peptides were isolated using sodium phosphate citrate buffer and, for extraction, cetyltrimethyl ammonium bromide (CTAB) buffer with pH 6, have
[...] Read more.
Foeniculum vulgare Mill., commonly called fennel, is a medicinal plant belonging to the Umbelliferae (Apiaceae) family, and is used in traditional medicine. Antibacterial peptides were isolated using sodium phosphate citrate buffer and, for extraction, cetyltrimethyl ammonium bromide (CTAB) buffer with pH 6, have been employed and antimicrobial activity tested against four reference strains. The extracted protein was subjected to 3 kDa dialysis and separation was carried out by DEAE-ion exchange chromatography and further proteins were identified by 2D gel electrophoresis. The results of Foeniculum vulgare elutes obtained from DEAE-ion exchange chromatography were tested for antibacterial activity. Elute 3 shows the highest antibacterial activity on Pseudomonas aeruginosa with a diameter of a zone of inhibition of 16 mm and IC50 value 25.02 (mcg/mL). Based on the findings of the wide usage in treatment of various ailments and day-to-day life, Foeniculum vulgare seeds were used in the present research and have shown promising antibacterial effects, which requires further proteomic research to authenticate the role of the anticipated proteins. Full article
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
Figures

Figure 1

Open AccessFeature PaperArticle Gold Nanoparticles Deposited on Surface Modified Carbon Xerogels as Reusable Catalysts for Cyclohexane C-H Activation in the Presence of CO and Water
Molecules 2017, 22(4), 603; doi:10.3390/molecules22040603
Received: 12 February 2017 / Revised: 31 March 2017 / Accepted: 3 April 2017 / Published: 9 April 2017
PDF Full-text (3225 KB) | HTML Full-text | XML Full-text
Abstract
The use of gold as a promotor of alkane hydrocarboxylation is reported for the first time. Cyclohexane hydrocarboxylation to cyclohexanecarboxylic acid (up to 55% yield) with CO, water, and peroxodisulfate in a water/acetonitrile medium at circa 50 °C has been achieved in the
[...] Read more.
The use of gold as a promotor of alkane hydrocarboxylation is reported for the first time. Cyclohexane hydrocarboxylation to cyclohexanecarboxylic acid (up to 55% yield) with CO, water, and peroxodisulfate in a water/acetonitrile medium at circa 50 °C has been achieved in the presence of gold nanoparticles deposited by a colloidal method on a carbon xerogel in its original form (CX), after oxidation with HNO3 (-ox), or after oxidation with HNO3 and subsequent treatment with NaOH (-ox-Na). Au/CX-ox-Na behaves as re-usable catalyst maintaining its initial activity and selectivity for at least seven consecutive cycles. Green metric values of atom economy or carbon efficiency also attest to the improvement brought by this novel catalytic system to the hydrocarboxylation of cyclohexane. Full article
(This article belongs to the Special Issue Reactions of Hydrocarbons and other C‒H Compounds)
Figures

Open AccessArticle Structural Characterization and Antifungal Studies of Zinc-Doped Hydroxyapatite Coatings
Molecules 2017, 22(4), 604; doi:10.3390/molecules22040604
Received: 6 March 2017 / Revised: 31 March 2017 / Accepted: 7 April 2017 / Published: 9 April 2017
PDF Full-text (16915 KB) | HTML Full-text | XML Full-text
Abstract
The present study is focused on the synthesis, characterization and antifungal evaluation of zinc-doped hydroxyapatite (Zn:HAp) coatings. The Zn:HAp coatings were deposited on a pure Si (Zn:HAp_Si) and Ti (Zn:HAp_Ti) substrate by a sol-gel dip coating method using a zinc-doped hydroxyapatite nanogel. The
[...] Read more.
The present study is focused on the synthesis, characterization and antifungal evaluation of zinc-doped hydroxyapatite (Zn:HAp) coatings. The Zn:HAp coatings were deposited on a pure Si (Zn:HAp_Si) and Ti (Zn:HAp_Ti) substrate by a sol-gel dip coating method using a zinc-doped hydroxyapatite nanogel. The nature of the crystal phase was determined by X-ray diffraction (XRD). The crystalline phase of the prepared Zn:HAp composite was assigned to hexagonal hydroxyapatite in the P63/m space group. The colloidal properties of the resulting Zn:HAp (xZn = 0.1) nanogel were analyzed by Dynamic Light Scattering (DLS) and zeta potential. Scanning Electron Microscopy (SEM) was used to investigate the morphology of the zinc-doped hydroxyapatite (Zn:HAp) nanogel composite and Zn:HAp coatings. The elements Ca, P, O and Zn were found in the Zn:HAp composite. According to the EDX results, the degree of Zn substitution in the structure of Zn:HAp composite was 1.67 wt%. Moreover, the antifungal activity of Zn:HAp_Si and Zn:HAp_Ti against Candida albicans (C. albicans) was evaluated. A decrease in the number of surviving cells was not observed under dark conditions, whereas under daylight and UV light illumination a major decrease in the number of surviving cells was observed. Full article
(This article belongs to the Special Issue Antibacterial Materials and Coatings)
Figures

Open AccessArticle An Efficient One-Pot Protocol for the Synthesis of Substituted 3,4-Dihydropyrimidin-2(1H)-ones Using Metallophthalocyanines (MPcs) as Potent Heterogeneous Catalysts: Synthesis, Characterization, Aggregation and Antimicrobial Activity
Molecules 2017, 22(4), 605; doi:10.3390/molecules22040605
Received: 3 February 2017 / Revised: 15 March 2017 / Accepted: 23 March 2017 / Published: 9 April 2017
PDF Full-text (2289 KB) | HTML Full-text | XML Full-text
Abstract
In this study, novel phthalonitrile 3 and their corresponding metal-free 4 and metallophthalocyanine derivatives 57 bearing 2-isopropenyl-4-methoxy-1-methylbenzene groups were synthesized and characterized. 3,4-Dihydropyrimidinones have been synthesized by a modified Biginelli-type reaction with various metallophthalocyanines 57 as catalysts. Compared to
[...] Read more.
In this study, novel phthalonitrile 3 and their corresponding metal-free 4 and metallophthalocyanine derivatives 57 bearing 2-isopropenyl-4-methoxy-1-methylbenzene groups were synthesized and characterized. 3,4-Dihydropyrimidinones have been synthesized by a modified Biginelli-type reaction with various metallophthalocyanines 57 as catalysts. Compared to the classical Biginielli reaction, the new method has the advantages of good yield and short reaction time. Among the various metallophthalocyanines studied, cobalt (II)-phthalocyanine was found to be most active for this transformation. The newly prepared compounds were characterized using elemental analyses, MS, IR, 1H/13C-NMR and UV-Vis spectroscopy. In addition; the 3,4-dihydropyrimidinones (DHPMs) 812 were investigated for antimicrobial activities and revealed good activity. The minimum inhibitory concentration (MIC) was determined by the microdilution technique in Mueller-Hinton broth. The MICs were recorded after 24 hours of incubation at 37 °C. These results are promising, showing these compounds are biologically active. Full article
(This article belongs to the Special Issue Multicomponent Reaction-Based Synthesis of Bioactive Molecules)
Figures

Figure 1

Open AccessArticle Thermo-Oxidative Stability Evaluation of Bullfrog (Rana catesbeiana Shaw) Oil
Molecules 2017, 22(4), 606; doi:10.3390/molecules22040606
Received: 6 January 2017 / Revised: 2 March 2017 / Accepted: 6 April 2017 / Published: 10 April 2017
PDF Full-text (1653 KB) | HTML Full-text | XML Full-text
Abstract
Bullfrog oil (BO), a natural product obtained from recycling of adipose tissue from the amphibian Rana catesbeiana Shaw, has been recently evaluated as a therapeutic activity ingredient. This work aimed to evaluate the long-term and accelerated thermal oxidative stabilities of this product, which
[...] Read more.
Bullfrog oil (BO), a natural product obtained from recycling of adipose tissue from the amphibian Rana catesbeiana Shaw, has been recently evaluated as a therapeutic activity ingredient. This work aimed to evaluate the long-term and accelerated thermal oxidative stabilities of this product, which is a promising raw material for emulsion technology development. BO was extracted from amphibian adipose tissue at 70 °C with a yield of 60% ± 0.9%. Its main fatty acid compounds were oleic (30.0%) and eicosapentaenoic (17.6%) acids. Using titration techniques, BO showed peroxide, acid, iodine and saponification indices of 1.92 mEq·O2/kg, 2.95 mg·KOH/g oil, 104.2 g I2/100 g oil and 171.2 mg·KOH/g oil, respectively. In order to improve the accelerated oxidative stability of BO, synthetic antioxidants butylhydroxytoluene (BHT) and buthylhydroxyanisole (BHA) were used. The addition of BHT increased the oxidation induction time compared to the pure oil, or the oil containing BHA. From the results, the best oil-antioxidant mixture and concentration to increase the oxidative stability and allow the oil to be a stable raw material for formulation purposes was derived. Full article
Figures

Open AccessArticle Bioassay-Guided Isolation of Anti-Inflammatory Components from the Bulbs of Lilium brownii var. viridulum and Identifying the Underlying Mechanism through Acting on the NF-κB/MAPKs Pathway
Molecules 2017, 22(4), 506; doi:10.3390/molecules22040506
Received: 11 February 2017 / Revised: 17 March 2017 / Accepted: 20 March 2017 / Published: 23 March 2017
PDF Full-text (6049 KB) | HTML Full-text | XML Full-text
Abstract
The bulbs of Lilium brownii var. viridulum (LB) are commonly used as both traditional Chinese medicines and popular functional food for many centuries in China. Previous studies reported that the extract of lily bulbs exhibited anti-inflammatory activity both in vivo and in vitro,
[...] Read more.
The bulbs of Lilium brownii var. viridulum (LB) are commonly used as both traditional Chinese medicines and popular functional food for many centuries in China. Previous studies reported that the extract of lily bulbs exhibited anti-inflammatory activity both in vivo and in vitro, but its active components and associated molecular mechanisms remain elusive. In the present study, using bioassay-guided isolation method, two phenylpropenoid acylglycerols, 1-O-feruloyl-2-O-p-coumaroylglycerol (1) and 1,3-O-diferuloylglycerol (2), were obtained and identified from the chloroform fraction of LB. Both compounds 1 and 2 significantly decreased the production of nitrite oxide (NO) in lipopolysaccharide (LPS)-stimulated mouse macrophage RAW264.7 cells in a dose-dependent manner with half maximal inhibitory concentration (IC50) values of 9.12 ± 0.72 μM and 12.01 ± 1.07 μM, respectively. They also inhibited the production of prostaglandin E2 (PGE2) and several other pro-inflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Furthermore, compounds 1 and 2 downregulated the protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). They also inhibited the nuclear translocation of nuclear factor-κB (NF-κB) p65 subunit and suppressed mitogen-activated protein kinases (MAPKs) pathway. Taken these data together, compounds 1 and 2 exhibited anti-inflammatory activities through acting on the NF-κB and MAPKs pathway. This research provides the first evidence on the major bioactive constituents and related molecular mechanisms of LB as an anti-inflammatory agent. Our findings also advanced the understanding of LB as a traditional herbal medicine for the prevention and treatment of inflammation. Full article
(This article belongs to the Special Issue Natural Products and Chronic Diseases)
Figures

Open AccessArticle New Benzimidazole-1,2,4-Triazole Hybrid Compounds: Synthesis, Anticandidal Activity and Cytotoxicity Evaluation
Molecules 2017, 22(4), 507; doi:10.3390/molecules22040507
Received: 9 February 2017 / Revised: 20 March 2017 / Accepted: 21 March 2017 / Published: 27 March 2017
PDF Full-text (1280 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Owing to the growing need for antifungal agents, we synthesized a new series 2-((5-(4-(5-substituted-1H-benzimidazol-2-yl)phenyl)-4-substituted-4H-1,2,4-triazol-3-yl)thio)-1-(substitutedphenyl)ethan-1-one derivatives, which were tested against Candida species. The synthesized compounds were characterized and elucidated by FT-IR, 1H-NMR, 13C-NMR and HR-MS spectroscopies. The synthesized
[...] Read more.
Owing to the growing need for antifungal agents, we synthesized a new series 2-((5-(4-(5-substituted-1H-benzimidazol-2-yl)phenyl)-4-substituted-4H-1,2,4-triazol-3-yl)thio)-1-(substitutedphenyl)ethan-1-one derivatives, which were tested against Candida species. The synthesized compounds were characterized and elucidated by FT-IR, 1H-NMR, 13C-NMR and HR-MS spectroscopies. The synthesized compounds were screened in vitro anticandidal activity against Candida species by broth microdiluation methods. In vitro cytotoxic effects of the final compounds were determined by MTT assay. Microbiological studies revealed that compounds 5m, 5o, 5r, 5t, 5y, 5ab, and 5ad possess a good antifungal profile. Compounds 5w was the most active derivative and showed comparable antifungal activity to those of reference drugs ketoconazole and fluconazole. Cytotoxicity evaluation of compounds 5m, 5o, 5r, 5w, 5y, 5ab and 5ad showed that compounds 5w and 5ad were the least cytotoxic agents. Effects of these two compounds against ergosterol biosynthesis were observed by LC-MS-MS method, which is based on quantification of ergosterol level in C. albicans. Compounds 5w and 5d inhibited ergosterol biosynthesis concentration dependently. A fluorescence microscopy study was performed to visualize effect of compound 5w against C. albicans at cellular level. It was determined that compound 5w has a membrane damaging effect, which may be related with inhibition of biosynthesis of ergosterol. Full article
(This article belongs to the Section Medicinal Chemistry)
Figures

Open AccessArticle Computational Identification of Antibody Epitopes on the Dengue Virus NS1 Protein
Molecules 2017, 22(4), 607; doi:10.3390/molecules22040607
Received: 6 November 2016 / Revised: 5 April 2017 / Accepted: 6 April 2017 / Published: 10 April 2017
PDF Full-text (11964 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
We have previously described a method to predict antigenic epitopes on proteins recognized by specific antibodies. Here we have applied this method to identify epitopes on the NS1 proteins of the four Dengue virus serotypes (DENV1–4) that are bound by a small panel
[...] Read more.
We have previously described a method to predict antigenic epitopes on proteins recognized by specific antibodies. Here we have applied this method to identify epitopes on the NS1 proteins of the four Dengue virus serotypes (DENV1–4) that are bound by a small panel of monoclonal antibodies 1H7.4, 1G5.3 and Gus2. Several epitope regions were predicted for these antibodies and these were found to reflect the experimentally observed reactivities. The known binding epitopes on DENV2 for the antibodies 1H7.4 and 1G5.3 were identified, revealing the reasons for the serotype specificity of 1H7.4 and 1G5.3, and the non-selectivity of Gus2. As DENV NS1 is critical for virus replication and a key vaccine candidate, epitope prediction will be valuable in designing appropriate vaccine control strategies. The ability to predict potential epitopes by computational methods significantly reduces the amount of experimental work required to screen peptide libraries for epitope mapping. Full article
(This article belongs to the Special Issue Biomolecular Simulations)
Figures

Figure 1

Open AccessArticle Structure-Activity and Lipophilicity Relationships of Selected Antibacterial Natural Flavones and Flavanones of Chilean Flora
Molecules 2017, 22(4), 608; doi:10.3390/molecules22040608
Received: 7 December 2016 / Revised: 31 March 2017 / Accepted: 5 April 2017 / Published: 10 April 2017
Cited by 1 | PDF Full-text (1386 KB) | HTML Full-text | XML Full-text
Abstract
In this study, we tested eight naturally-occurring flavonoids—three flavanones and five flavones—for their possible antibacterial properties against four Gram-positive and four Gram-negative bacteria. Flavonoids are known for their antimicrobial properties, and due their structural diversity; these plant-derived compounds are a good model to
[...] Read more.
In this study, we tested eight naturally-occurring flavonoids—three flavanones and five flavones—for their possible antibacterial properties against four Gram-positive and four Gram-negative bacteria. Flavonoids are known for their antimicrobial properties, and due their structural diversity; these plant-derived compounds are a good model to study potential novel antibacterial mechanisms. The lipophilicity and the interaction of antibacterial compounds with the cell membrane define the success or failure to access its target. Therefore, through the determination of partition coefficients in a non-polar/aqueous phase, lipophilicity estimation and the quantification of the antibacterial activity of different flavonoids, flavanones, and flavones, a relationship between these parameters was assessed. Active flavonoids presented diffusion coefficients between 9.4 × 10−10 and 12.3 × 10−10 m2/s and lipophilicity range between 2.0 to 3.3. Active flavonoids against Gram-negative bacteria showed a narrower range of lipophilicity values, compared to active flavonoids against Gram-positive bacteria, which showed a wide range of lipophilicity and cell lysis. Galangin was the most active flavonoid, whose structural features are the presence of two hydroxyl groups located strategically on ring A and the absence of polar groups on ring B. Methylation of one hydroxyl group decreases the activity in 3-O-methylgalangin, and methylation of both hydroxyl groups caused inactivation, as shown for 3,7-O-dimethylgalangin. In conclusion, the amphipathic features of flavonoids play a crucial role in the antibacterial activity. In these compounds, hydrophilic and hydrophobic moieties must be present and could be predicted by lipophilicity analysis. Full article
(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products)
Figures

Open AccessArticle Molecularly Imprinted Polymers for Selective Extraction of Oblongifolin C from Garcinia yunnanensis Hu
Molecules 2017, 22(4), 508; doi:10.3390/molecules22040508
Received: 26 January 2017 / Revised: 19 March 2017 / Accepted: 21 March 2017 / Published: 23 March 2017
PDF Full-text (1735 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Molecularly imprinted polymers (MIPs) were synthesized and applied for the selective extraction of oblongifolin C (OC) from fruit extracts of Garcinia yunnanensis Hu. A series of experiments and computational approaches were employed to improve the efficiency of screening for optimal MIP systems in
[...] Read more.
Molecularly imprinted polymers (MIPs) were synthesized and applied for the selective extraction of oblongifolin C (OC) from fruit extracts of Garcinia yunnanensis Hu. A series of experiments and computational approaches were employed to improve the efficiency of screening for optimal MIP systems in the study. The molar ratio (1:4) was eventually chosen based on the comparison of the binding energy of the complexes between the template (OC) and the functional monomers using density functional theory (DFT) at the RI-PBE-D3-gCP/def2-TZVP level of theory. The binding characterization and the molecular recognition mechanism of MIPs were further explained using the molecular modeling method along with NMR and IR spectra data. The reusability of this approach was demonstrated in over 20 batch rebinding experiments. A mass of 140.5 mg of OC (>95% purity) was obtained from the 5 g extracts, with 2 g of MIPs with the best binding properties, through a gradient elution program from 35% to 70% methanol-water solution. At the same time, another structural analog, 46.5 mg of guttiferone K (GK) (>88% purity), was also obtained by the gradient elution procedure. Our results showed that the structural analogs could be separated from the crude extracts by the molecularly imprinted solid-phase extraction (MISPE) using a gradient elution procedure for the first time. Full article
(This article belongs to the Section Natural Products)
Figures

Figure 1

Open AccessArticle Nerolidol and Farnesol Inhibit Some Cytochrome P450 Activities but Did Not Affect Other Xenobiotic-Metabolizing Enzymes in Rat and Human Hepatic Subcellular Fractions
Molecules 2017, 22(4), 509; doi:10.3390/molecules22040509
Received: 10 February 2017 / Revised: 15 March 2017 / Accepted: 20 March 2017 / Published: 24 March 2017
PDF Full-text (589 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Sesquiterpenes, 15-carbon compounds formed from three isoprenoid units, are the main components of plant essential oils. Sesquiterpenes occur in human food, but they are principally taken as components of many folk medicines and dietary supplements. The aim of our study was to test
[...] Read more.
Sesquiterpenes, 15-carbon compounds formed from three isoprenoid units, are the main components of plant essential oils. Sesquiterpenes occur in human food, but they are principally taken as components of many folk medicines and dietary supplements. The aim of our study was to test and compare the potential inhibitory effect of acyclic sesquiterpenes, trans-nerolidol, cis-nerolidol and farnesol, on the activities of the main xenobiotic-metabolizing enzymes in rat and human liver in vitro. Rat and human subcellular fractions, relatively specific substrates, corresponding coenzymes and HPLC, spectrophotometric or spectrofluorometric analysis of product formation were used. The results showed significant inhibition of cytochromes P450 (namely CYP1A, CYP2B and CYP3A subfamilies) activities by all tested sesquiterpenes in rat as well as in human hepatic microsomes. On the other hand, all tested sesquiterpenes did not significantly affect the activities of carbonyl-reducing enzymes and conjugation enzymes. The results indicate that acyclic sesquiterpenes might affect CYP1A, CYP2B and CYP3A mediated metabolism of concurrently administered drugs and other xenobiotics. The possible drug–sesquiterpene interactions should be verified in in vivo experiments. Full article
(This article belongs to the Section Natural Products)
Figures

Figure 1

Open AccessArticle Anti-Inflammatory and Antioxidant Properties of Casein Hydrolysate Produced Using High Hydrostatic Pressure Combined with Proteolytic Enzymes
Molecules 2017, 22(4), 609; doi:10.3390/molecules22040609
Received: 9 March 2017 / Revised: 3 April 2017 / Accepted: 6 April 2017 / Published: 10 April 2017
PDF Full-text (2075 KB) | HTML Full-text | XML Full-text
Abstract
Casein-derived peptides are shown to possess radical scavenging and metal chelating properties. The objective of this study was to evaluate novel anti-inflammatory properties of casein hydrolysates (CH) produced by an eco-friendly process that combines high hydrostatic pressure with enzymatic hydrolysis (HHP-EH). Casein was
[...] Read more.
Casein-derived peptides are shown to possess radical scavenging and metal chelating properties. The objective of this study was to evaluate novel anti-inflammatory properties of casein hydrolysates (CH) produced by an eco-friendly process that combines high hydrostatic pressure with enzymatic hydrolysis (HHP-EH). Casein was hydrolysed by different proteases, including flavourzyme (Fla), savinase (Sav), thermolysin (Ther), trypsin (Try), and elastase (Ela) at 0.1, 50, 100, and 200 MPa pressure levels under various enzyme-to-substrate ratios and incubation times. Casein hydrolysates were evaluated for the degree of hydrolysis (DH), molecular weight distribution patterns, and anti-inflammatory properties in chemical and cellular models. Hydrolysates produced using HHP-EH exhibited higher DH values and proportions of smaller peptides compared to atmospheric pressure-enzymatic hydrolysis (AP-EH). Among five enzymes, Fla-digested HHP-EH-CH (HHP-Fla-CH) showed significantly higher antioxidant properties than AP-Fla-CH. The anti-inflammatory properties of HHP-Fla-CH were also observed by significantly reduced nitric oxide and by the suppression of the synthesis of pro-inflammatory cytokines in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) revealed that 59% of the amino acids of the peptides in HHP-Fla-CH were composed of proline, valine, and leucine, indicating the potential anti-inflammatory properties. In conclusion, the HHP-EH method provides a promising technology to produce bioactive peptides from casein in an eco-friendly process. Full article
(This article belongs to the Special Issue Green Production of Bioactive Natural Products)
Figures

Figure 1

Open AccessArticle Structural Analysis and Immuno-Stimulating Activity of an Acidic Polysaccharide from the Stems of Dendrobium nobile Lindl.
Molecules 2017, 22(4), 611; doi:10.3390/molecules22040611
Received: 16 March 2017 / Revised: 5 April 2017 / Accepted: 5 April 2017 / Published: 10 April 2017
PDF Full-text (1693 KB) | HTML Full-text | XML Full-text
Abstract
Dendrobium nobile Lindl., an epiphytic herb distributed in the Southeast Asia, is used as a tonic and antipyretic herbal medicine in China. In this study, a water-soluble acidic heteropolysaccharide, DNP-W4, containing mannose, glucose, galactose, xylose, rhamnose, and galacturonic acid, in the molar ratios
[...] Read more.
Dendrobium nobile Lindl., an epiphytic herb distributed in the Southeast Asia, is used as a tonic and antipyretic herbal medicine in China. In this study, a water-soluble acidic heteropolysaccharide, DNP-W4, containing mannose, glucose, galactose, xylose, rhamnose, and galacturonic acid, in the molar ratios of 1.0:4.9:2.5:0.5:1.0:0.9, was obtained from the stems of Dendrobium nobile Lindl. Using methylation analysis, partial acid hydrolysis, pectolyase treatment, NMR, and ESI-MS, the structure of DNP-W4 was elucidated. The obtained data indicated that DNP-W4 was a complex heteropolysaccharide and possessed a backbone composed of (1→4)-linked β-d-Glcp, (1→6)-linked β-d-Glcp, and (1→6)-linked β-d-Galp, with substitutes at O-4/6 of Glcp residues and O-3 of Galp. The branches of DNP-W4 were composed of terminal Manp, (1→6)-linked β-d-Manp, (1→3)-linked β-d-Glcp, β-d-Glcp, β-d-Galp, (1→4)-linked α-d-GalAp, (1→2)-linked α-L-Rhap, and Xylp. DNP-W4 had little immunological activities, but its derivatives had immuno-stimulating activities to some extent. Full article
(This article belongs to the Special Issue Natural Polysaccharides)
Figures

Figure 1

Open AccessArticle Silane Modified Diopside for Improved Interfacial Adhesion and Bioactivity of Composite Scaffolds
Molecules 2017, 22(4), 511; doi:10.3390/molecules22040511
Received: 14 February 2017 / Revised: 18 March 2017 / Accepted: 21 March 2017 / Published: 23 March 2017
PDF Full-text (6646 KB) | HTML Full-text | XML Full-text
Abstract
Diopside (DIOP) was introduced into polyetheretherketone/polyglycolicacid (PEEK/PGA) scaffolds fabricated via selective laser sintering to improve bioactivity. The DIOP surface was then modified using a silane coupling agent, 3-glycidoxypropyltrimethoxysilane (KH570), to reinforce interfacial adhesion. The results showed that the tensile properties and thermal stability
[...] Read more.
Diopside (DIOP) was introduced into polyetheretherketone/polyglycolicacid (PEEK/PGA) scaffolds fabricated via selective laser sintering to improve bioactivity. The DIOP surface was then modified using a silane coupling agent, 3-glycidoxypropyltrimethoxysilane (KH570), to reinforce interfacial adhesion. The results showed that the tensile properties and thermal stability of the scaffolds were significantly enhanced. It could be explained that, on the one hand, the hydrophilic group of KH570 formed an organic covalent bond with the hydroxy group on DIOP surface. On the other hand, there existed relatively high compatibility between its hydrophobic group and the biopolymer matrix. Thus, the ameliorated interface interaction led to a homogeneous state of DIOP dispersion in the matrix. More importantly, an in vitro bioactivity study demonstrated that the scaffolds with KH570-modified DIOP (KDIOP) exhibited the capability of forming a layer of apatite. In addition, cell culture experiments revealed that they had good biocompatibility compared to the scaffolds without KDIOP. It indicated that the scaffolds with KDIOP possess potential application in tissue engineering. Full article
Figures

Figure 1

Open AccessArticle Design and Synthesis of Novel Pyrazole-Substituted Different Nitrogenous Heterocyclic Ring Systems as Potential Anti-Inflammatory Agents
Molecules 2017, 22(4), 512; doi:10.3390/molecules22040512
Received: 24 January 2017 / Revised: 1 March 2017 / Accepted: 2 March 2017 / Published: 24 March 2017
PDF Full-text (1990 KB) | HTML Full-text | XML Full-text
Abstract
With the aim of developing novel anti-inflammatory scaffolds, a new series of pyrazole-substituted various nitrogenous heterocyclic ring systems at C-4 position were synthesized through different chemical reactions and validated by means of spectral and elemental data. The new obtained compounds were investigated for
[...] Read more.
With the aim of developing novel anti-inflammatory scaffolds, a new series of pyrazole-substituted various nitrogenous heterocyclic ring systems at C-4 position were synthesized through different chemical reactions and validated by means of spectral and elemental data. The new obtained compounds were investigated for their anti-inflammatory activity using the carrageenan-induced paw edema standard technique and revealed that, compound 6b showed increased potency with % inhibition of edema 85.23 ± 1.92 and 85.78 ± 0.99, respectively, higher than the standard reference drugs indomethacin and celebrex (72.99% and 83.76%). Molecular modeling studies were initiated herein to validate the attained pharmacological data and provide understandable evidence for the observed anti-inflammatory behavior. Full article
(This article belongs to the Section Medicinal Chemistry)
Figures

Figure 1

Open AccessArticle c-Jun Contributes to Transcriptional Control of GNA12 Expression in Prostate Cancer Cells
Molecules 2017, 22(4), 612; doi:10.3390/molecules22040612
Received: 3 March 2017 / Revised: 30 March 2017 / Accepted: 5 April 2017 / Published: 10 April 2017
PDF Full-text (1644 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Abstract: GNA12 is the α subunit of a heterotrimeric G protein that possesses oncogenic potential. Activated GNA12 also promotes prostate and breast cancer cell invasion in vitro and in vivo, and its expression is up-regulated in many tumors, particularly metastatic tissues. In
[...] Read more.
Abstract: GNA12 is the α subunit of a heterotrimeric G protein that possesses oncogenic potential. Activated GNA12 also promotes prostate and breast cancer cell invasion in vitro and in vivo, and its expression is up-regulated in many tumors, particularly metastatic tissues. In this study, we explored the control of expression of GNA12 in prostate cancer cells. Initial studies on LnCAP (low metastatic potential, containing low levels of GNA12) and PC3 (high metastatic potential, containing high GNA12 levels) cells revealed that GNA12 mRNA levels correlated with protein levels, suggesting control at the transcriptional level. To identify potential factors controlling GNA12 transcription, we cloned the upstream 5′ regulatory region of the human GNA12 gene and examined its activity using reporter assays. Deletion analysis revealed the highest level of promoter activity in a 784 bp region, and subsequent in silico analysis indicated the presence of transcription factor binding sites for C/EBP (CCAAT/enhancer binding protein), CREB1 (cAMP-response-element-binding protein 1), and c-Jun in this minimal element for transcriptional control. A small interfering RNA (siRNA) knockdown approach revealed that silencing of c-Jun expression significantly reduced GNA12 5′ regulatory region reporter activity. In addition, chromatin immunoprecipitation assays confirmed that c-Jun binds to the GNA12 5′ regulatory region in PC3 cells. Silencing of c-Jun expression reduced mRNA and protein levels of GNA12, but not the closely-related GNA13, in prostate cancer cells. Understanding the mechanisms by which GNA12 expression is controlled may aid in the development of therapies that target key elements responsible for GNA12-mediated tumor progression. Full article
(This article belongs to the Special Issue G-protein Coupled Receptor Structure and Function)
Figures

Figure 1

Open AccessArticle Synthesis of Pyrrolo[1,2-a]pyrimidine Enantiomers via Domino Ring-Closure followed by Retro Diels-Alder Protocol
Molecules 2017, 22(4), 613; doi:10.3390/molecules22040613
Received: 10 March 2017 / Revised: 4 April 2017 / Accepted: 6 April 2017 / Published: 13 April 2017
PDF Full-text (1910 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
From 2-aminonorbornene hydroxamic acids, a simple and efficient method for the preparation of pyrrolo[1,2-a]pyrimidine enantiomers is reported. The synthesis is based on domino ring-closure followed by microwave-induced retro Diels-Alder (RDA) protocols, where the chirality of the desired products is transferred from
[...] Read more.
From 2-aminonorbornene hydroxamic acids, a simple and efficient method for the preparation of pyrrolo[1,2-a]pyrimidine enantiomers is reported. The synthesis is based on domino ring-closure followed by microwave-induced retro Diels-Alder (RDA) protocols, where the chirality of the desired products is transferred from norbornene derivatives. The stereochemistry of the synthesized compounds was proven by X-ray crystallography. The absolute configuration of the product is determined by the configuration of the starting amino hydroxamic acid. Full article
(This article belongs to the Special Issue Asymmetric Synthesis 2017)
Figures

Open AccessArticle Isolation, Characterization and Antiproliferative Activity of New Metabolites from the South African Endemic Red Algal Species Laurencia alfredensis
Molecules 2017, 22(4), 513; doi:10.3390/molecules22040513
Received: 27 February 2017 / Revised: 21 March 2017 / Accepted: 21 March 2017 / Published: 23 March 2017
PDF Full-text (1773 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The marine red algae of the genus Laurencia have been widely studied for their structurally diverse and biologically active secondary metabolites. We report here the natural product investigation of the organic extract of a newly identified South African endemic species, Laurencia alfredensis.
[...] Read more.
The marine red algae of the genus Laurencia have been widely studied for their structurally diverse and biologically active secondary metabolites. We report here the natural product investigation of the organic extract of a newly identified South African endemic species, Laurencia alfredensis. A sequence of column chromatography, preparative TLC and normal phase HPLC resulted in the isolation of eleven compounds comprising three labdane-type diterpenes (13), four polyether triterpenes (47), three cholestane-type ecdysteroids (810) and a glycolipid (11). Compounds 13, 58 and 10 have not previously been reported, while compound 9 is reported here for the first time from a natural source and the known compound 11 isolated for the first time from the genus Laurencia. The structural elucidation and the relative configuration assignments of the compounds were accomplished by extensive use of 1D- and 2D-NMR, HR-ESI-MS, UV and IR spectroscopic techniques, while the absolute configuration of compound 1 was determined by single-crystal X-ray diffraction analysis. All compounds were evaluated against the MDA-MB-231 breast and HeLa cervical cancer cell lines. Compound 2 exhibited low micromolar antiproliferative activity (IC50 = 9.3 µM) against the triple negative breast carcinoma and compound 7 was similarly active (IC50 = 8.8 µM) against the cervical cancer cell line. Full article
(This article belongs to the Special Issue Natural Product: A Continuing Source of Novel Drug Leads)
Figures

Figure 1

Open AccessArticle Bergamot Essential Oil Attenuates Anxiety-Like Behaviour in Rats
Molecules 2017, 22(4), 614; doi:10.3390/molecules22040614
Received: 15 March 2017 / Revised: 7 April 2017 / Accepted: 9 April 2017 / Published: 11 April 2017
PDF Full-text (5185 KB) | HTML Full-text | XML Full-text
Abstract
Preclinical studies have recently highlighted that bergamot essential oil (BEO) is endowed with remarkable neurobiolological effects. BEO can affect synaptic transmission, modulate electroencephalographic activity and it showed neuroprotective and analgesic properties. The phytocomplex, along with other essential oils, is also widely used in
[...] Read more.
Preclinical studies have recently highlighted that bergamot essential oil (BEO) is endowed with remarkable neurobiolological effects. BEO can affect synaptic transmission, modulate electroencephalographic activity and it showed neuroprotective and analgesic properties. The phytocomplex, along with other essential oils, is also widely used in aromatherapy to minimize symptoms of stress-induced anxiety and mild mood disorders. However, only limited preclinical evidences are actually available. This study examined the anxiolytic/sedative-like effects of BEO using an open field task (OFT), an elevated plus-maze task (EPM), and a forced swimming task (FST) in rats. This study further compared behavioural effects of BEO to those of the benzodiazepine diazepam. Analysis of data suggests that BEO induces anxiolytic-like/relaxant effects in animal behavioural tasks not superimposable to those of the DZP. The present observations provide further insight to the pharmacological profile of BEO and support its rational use in aromatherapy. Full article
(This article belongs to the Special Issue Essential Oils: Chemistry and Bioactivity)
Figures

Figure 1

Open AccessArticle Anti-Melanogenic Properties of Greek Plants. A Novel Depigmenting Agent from Morus alba Wood
Molecules 2017, 22(4), 514; doi:10.3390/molecules22040514
Received: 12 February 2017 / Revised: 10 March 2017 / Accepted: 12 March 2017 / Published: 23 March 2017
PDF Full-text (2107 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In therapeutic interventions associated with melanin hyperpigmentation, tyrosinase is regarded as a target enzyme as it catalyzes the rate-limiting steps in mammalian melanogenesis. Since many known agents have been proven to be toxic, there has been increasing impetus to identify alternative tyrosinase inhibitors,
[...] Read more.
In therapeutic interventions associated with melanin hyperpigmentation, tyrosinase is regarded as a target enzyme as it catalyzes the rate-limiting steps in mammalian melanogenesis. Since many known agents have been proven to be toxic, there has been increasing impetus to identify alternative tyrosinase inhibitors, especially from natural sources. In this study, we investigated 900 extracts from Greek plants for potential tyrosinase inhibitive properties. Among the five most potent extracts, the methanol extract of Morus alba wood (MAM) demonstrated a significant reduction in intracellular tyrosinase and melanin content in B16F10 melanoma cells. Bioassay-guided isolation led to the acquisition of twelve compounds: oxyresveratrol (1), kuwanon C (2), mulberroside A (3), resorcinol (4), dihydrooxyresveratol (5), trans-dihydromorin (6), 2,4,3′-trihydroxydihydrostilbene (7), kuwanon H (8), 2,4-dihydroxybenzaldehyde (9), morusin (10), moracin M (11) and kuwanon G (12). Among these, 2,4,3′-trihydroxydihydrostilbene (7) is isolated for the first time from Morus alba and constitutes a novel potent tyrosinase inhibitor (IC50 0.8 ± 0.15). We report here for the first time dihydrooxyresveratrol (5) as a potent natural tyrosinase inhibitor (IC50 0.3 ± 0.05). Computational docking analysis indicated the binding modes of six tyrosinase inhibitors with the aminoacids of the active centre of tyrosinase. Finally, we found both MAM extract and compounds 1, 6 and 7 to significantly suppress in vivo melanogenesis during zebrafish embryogenesis. Full article
(This article belongs to the collection Bioactive Compounds)
Figures

Figure 1

Open AccessArticle Phenolic Compounds from the Rhizomes of Smilax china L. and Their Anti-Inflammatory Activity
Molecules 2017, 22(4), 515; doi:10.3390/molecules22040515
Received: 20 February 2017 / Revised: 17 March 2017 / Accepted: 18 March 2017 / Published: 3 April 2017
PDF Full-text (736 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
A new triflavanoid, kandelin B-5 (1), was isolated from the rhizomes of Smilax china L., together with six known phenylpropanoid substituted flavan-3-ols (27), nine flavonoids (816), two stilbenoids (17, 18),
[...] Read more.
A new triflavanoid, kandelin B-5 (1), was isolated from the rhizomes of Smilax china L., together with six known phenylpropanoid substituted flavan-3-ols (27), nine flavonoids (816), two stilbenoids (17, 18), and two other compounds (19, 20). The structure of compound 1 was determined on the basis of 1D, 2D NMR and HR-ESI-MS data, as well as chemical method. Compounds 25, 812, 15, 17, and 19 were evaluated for anti-inflammatory activity. Only compounds 10, 15 and 17 showed slightly IL-1β expression inhibitory activities on LPS induced THP-1 cells, with inhibition rate of 15.8%, 37.3%, and 35.8%, respectively, at concentration of 50 μg/mL. Full article
(This article belongs to the collection Bioactive Compounds)
Figures

Open AccessArticle Synthesis of Novel Saccharin Derivatives
Molecules 2017, 22(4), 516; doi:10.3390/molecules22040516
Received: 3 March 2017 / Revised: 20 March 2017 / Accepted: 20 March 2017 / Published: 23 March 2017
PDF Full-text (1456 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The synthesis of saccharin (1,2-benzisothiazol-3-one-1,1-dioxide) derivatives substituted on the benzene ring has seen limited development despite the longevity of this compound’s use as an artificial sweetener. This type of saccharin derivative would however present attractive properties for the development of new bioactive, drug-like
[...] Read more.
The synthesis of saccharin (1,2-benzisothiazol-3-one-1,1-dioxide) derivatives substituted on the benzene ring has seen limited development despite the longevity of this compound’s use as an artificial sweetener. This type of saccharin derivative would however present attractive properties for the development of new bioactive, drug-like small molecule compounds. Here we report the derivatisation of the benzene ring of saccharin using Cu(I)-catalyzed azide alkyne cycloaddition (CuAAC) to synthesise a diverse library of novel saccharin-1,2,3-triazole conjugates. All library compounds retain the capability for interactions with biomolecules via the unmodified sulfonamide and lactam groups of the parent saccharin core heterocycle. The compounds also encompass alternate orientations of the 1,2,3-triazole heterocycle, thus further adding diversity to the potential hydrogen bonding interactions of these compounds with biomolecules of therapeutic interest. Our findings demonstrate that specifically functionalized derivatives of saccharin may be prepared from either saccharin azide or saccharin alkyne building blocks in high yield using CuAAC. Full article
(This article belongs to the Special Issue Women in Organic Chemistry)
Figures

Open AccessArticle Anti-Inflammatory, Antioxidant and Crystallographic Studies of N-Palmitoyl-ethanol Amine (PEA) Derivatives
Molecules 2017, 22(4), 616; doi:10.3390/molecules22040616
Received: 10 January 2017 / Revised: 3 April 2017 / Accepted: 5 April 2017 / Published: 11 April 2017
PDF Full-text (4884 KB) | HTML Full-text | XML Full-text
Abstract
N-Palmitoyl-ethanolamine (PEA) is an anti-inflammatory component of egg yolk that is usually employed for the prevention of respiratory apparatus virus infection and then frequently used for its efficient anti-inflammatory and analgesic effects in experimental models of visceral, neuropathic, and inflammatory diseases. Nevertheless,
[...] Read more.
N-Palmitoyl-ethanolamine (PEA) is an anti-inflammatory component of egg yolk that is usually employed for the prevention of respiratory apparatus virus infection and then frequently used for its efficient anti-inflammatory and analgesic effects in experimental models of visceral, neuropathic, and inflammatory diseases. Nevertheless, data of its use in animal or human therapy are still scarce and further studies are needed. Herein, we report the biological evaluation of a small library of N-palmitoyl-ethanolamine analogues or derivatives, characterized by a protected acid function (either as palmitoyl amides or hexadecyl esters), useful to decrease their hydrolysis rate in vitro and prolong their biological activity. Two of these compounds—namely phenyl-carbamic acid hexadecyl ester (4) and 2-methyl-pentadecanoic acid (4-nitro-phenyl)-amide (5)—have shown good anti-inflammatory and antioxidant properties, without affecting the viability of J774A.1 macrophages. Finally, crystals suitable for X-ray analysis of compound 4 have been obtained, and its solved crystal structure is here reported. Our outcomes may be helpful for a rational drug design based on new PEA analogues/derivatives with improved biological properties. Full article
(This article belongs to the Section Medicinal Chemistry)
Figures

Open AccessArticle Synthesis and Cytotoxicity of N-Substituted Dibenzo[a,j]xanthene-3,11-dicarboxamide Derivatives
Molecules 2017, 22(4), 517; doi:10.3390/molecules22040517
Received: 22 February 2017 / Revised: 16 March 2017 / Accepted: 21 March 2017 / Published: 23 March 2017
PDF Full-text (806 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In order to study the structure-activity relationships of xanthene derivatives, four series of N-substituted 14-aryl-14H-dibenzo[a,j]xanthene-3,11-dicarboxamide derivatives were synthesized. The structures of all compounds were identified by 1H-NMR, HR-MS and IR spectra, in which compounds 6a–h
[...] Read more.
In order to study the structure-activity relationships of xanthene derivatives, four series of N-substituted 14-aryl-14H-dibenzo[a,j]xanthene-3,11-dicarboxamide derivatives were synthesized. The structures of all compounds were identified by 1H-NMR, HR-MS and IR spectra, in which compounds 6a–h were further identified by 13C-NMR spectra. The in vitro antitumor activity of the synthesized compounds was tested by MTT assay. Most of them displayed strong inhibitory activity on human hepatocellular carcinoma cell lines (SK-HEP-1, HepG2 and SMMC-7721 cells) and acute promyelocytic leukemia NB4 cells. Compounds 6c6e exhibited significant inhibitory activity against NB4 cells with IC50 values of 0.52 μM and 0.76 μM, respectively, much lower than 5.31 μM of the positive control As2O3. Full article
(This article belongs to the Section Organic Synthesis)
Figures

Figure 1

Open AccessArticle A Study of Intramolecular Hydrogen Bonding in Levoglucosan Derivatives
Molecules 2017, 22(4), 518; doi:10.3390/molecules22040518
Received: 30 January 2017 / Revised: 9 March 2017 / Accepted: 21 March 2017 / Published: 24 March 2017
PDF Full-text (3509 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Organofluorine is a weak hydrogen-bond (HB) acceptor. Bernet et al. have demonstrated its capability to perturb OH···O intramolecular hydrogen bonds (IMHBs), using conformationally rigid carbohydrate scaffolds including levoglucosan derivatives. These investigations are supplemented here by experimental and theoretical studies involving six new levoglucosan
[...] Read more.
Organofluorine is a weak hydrogen-bond (HB) acceptor. Bernet et al. have demonstrated its capability to perturb OH···O intramolecular hydrogen bonds (IMHBs), using conformationally rigid carbohydrate scaffolds including levoglucosan derivatives. These investigations are supplemented here by experimental and theoretical studies involving six new levoglucosan derivatives, and complement the findings of Bernet et al. However, it is shown that conformational analysis is instrumental in interpreting the experimental data, due to the occurrence of non-intramolecular hydrogen-bonded populations which, although minor, cannot be neglected and appears surprisingly significant. The DFT conformational analysis, together with the computation of NMR parameters (coupling constants and chemical shifts) and wavefunction analyses (AIM, NBO), provides a full picture. Thus, for all compounds, the most stabilized structures show the OH groups in a conformation allowing IMHB with O5 and O6, when possible. Furthermore, the combined approach points out the occurrence of various IMHBs and the effect of the chemical modulations on their features. Thus, two-center or three-center IMHB interactions are observed in these compounds, depending on the presence or absence of additional HB acceptors, such as methoxy or fluorine. Full article
(This article belongs to the Special Issue Intramolecular Hydrogen Bonding 2017)
Figures

Open AccessArticle Effects of Schiff Base Formation and Aldol Condensation on the Determination of Aldehydes in Rice Wine Using GC-MS
Molecules 2017, 22(4), 618; doi:10.3390/molecules22040618
Received: 10 March 2017 / Revised: 6 April 2017 / Accepted: 10 April 2017 / Published: 11 April 2017
PDF Full-text (334 KB) | HTML Full-text | XML Full-text
Abstract
The Schiff base reaction and aldol condensation that occur during sample preparation can lead to the reduction of aldehyde content in the analysis of traditional Korean rice wine, makgeolli. The contents of aldehydes were decreased, whereas those of hydroxy carbonyl compounds were
[...] Read more.
The Schiff base reaction and aldol condensation that occur during sample preparation can lead to the reduction of aldehyde content in the analysis of traditional Korean rice wine, makgeolli. The contents of aldehydes were decreased, whereas those of hydroxy carbonyl compounds were increased by increasing the pH. In the presence of added amino acids, the levels of aldehydes in makgeolli were reduced as the amount of the amino acid alanine increased. Also, the contents of hydroxyl carbonyl compounds were reduced by alanine addition as compared to the control. Therefore, the determination of aldehydes can be affected by pH and the amount of amino acids, which can vary during fermentation and storage of alcoholic beverages because pH and amino acids affect Schiff base formation and aldol condensation. Full article
Figures

Figure 1

Open AccessArticle (R)-(−)-Aloesaponol III 8-Methyl Ether from Eremurus persicus: A Novel Compound against Leishmaniosis
Molecules 2017, 22(4), 519; doi:10.3390/molecules22040519
Received: 15 February 2017 / Revised: 14 March 2017 / Accepted: 20 March 2017 / Published: 24 March 2017
PDF Full-text (3045 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Leishmaniosis is a neglected tropical disease which affects several millions of people worldwide. The current drug therapies are expensive and often lack efficacy, mainly due to the development of parasite resistance. Hence, there is an urgent need for new drugs effective against Leishmania
[...] Read more.
Leishmaniosis is a neglected tropical disease which affects several millions of people worldwide. The current drug therapies are expensive and often lack efficacy, mainly due to the development of parasite resistance. Hence, there is an urgent need for new drugs effective against Leishmania infections. As a part of our ongoing study on the phytochemical characterization and biological investigation of plants used in the traditional medicine of western and central Asia, in the present study, we focused on Eremurus persicus root extract in order to evaluate its potential in the treatment of leishmaniosis. As a result of our study, aloesaponol III 8-methyl ether (ASME) was isolated for the first time from Eremurus persicus root extract, its chemical structure elucidated by means of IR and NMR experiments and the (R) configuration assigned by optical activity measurements: chiroptical aspects were investigated with vibrational circular dichroism (VCD) and electronic circular dichroism (ECD) spectroscopies and DFT (density functional theory) quantum mechanical calculations. Concerning biological investigations, our results clearly proved that (R)-ASME inhibits Leishmania infantum promastigotes viability (IC50 73 µg/mL), inducing morphological alterations and mitochondrial potential deregulation. Moreover, it is not toxic on macrophages at the concentration tested, thus representing a promising molecule against Leishmania infections. Full article
(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)
Figures

Figure 1

Open AccessArticle Degradation of Methyl 2-Aminobenzoate (Methyl Anthranilate) by H2O2/UV: Effect of Inorganic Anions and Derived Radicals
Molecules 2017, 22(4), 619; doi:10.3390/molecules22040619
Received: 24 February 2017 / Revised: 3 April 2017 / Accepted: 6 April 2017 / Published: 12 April 2017
PDF Full-text (3836 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
This study shows that methyl 2-aminobenzoate (also known as methyl anthranilate, hereafter MA) undergoes direct photolysis under UVC and UVB irradiation and that its photodegradation is further accelerated in the presence of H2O2. Hydrogen peroxide acts as a source
[...] Read more.
This study shows that methyl 2-aminobenzoate (also known as methyl anthranilate, hereafter MA) undergoes direct photolysis under UVC and UVB irradiation and that its photodegradation is further accelerated in the presence of H2O2. Hydrogen peroxide acts as a source of hydroxyl radicals (·OH) under photochemical conditions and yields MA hydroxyderivatives. The trend of MA photodegradation rate vs. H2O2 concentration reaches a plateau because of the combined effects of H2O2 absorption saturation and ·OH scavenging by H2O2. The addition of chloride ions causes scavenging of ·OH, yielding Cl2· as the most likely reactive species, and it increases the MA photodegradation rate at high H2O2 concentration values. The reaction between Cl2· and MA, which has second-order rate constant k C l 2 + M A = (4.0 ± 0.3) × 108 M−1·s−1 (determined by laser flash photolysis), appears to be more selective than the ·OH process in the presence of H2O2, because Cl2· undergoes more limited scavenging by H2O2 compared to ·OH. While the addition of carbonate causes ·OH scavenging to produce CO3· ( k C O 3 + M A = (3.1 ± 0.2) × 108 M−1·s−1), carbonate considerably inhibits the photodegradation of MA. A possible explanation is that the elevated pH values of the carbonate solutions make H2O2 to partially occur as HO2, which reacts very quickly with either ·OH or CO3· to produce O2·. The superoxide anion could reduce partially oxidised MA back to the initial substrate, with consequent inhibition of MA photodegradation. Fast MA photodegradation is also observed in the presence of persulphate/UV, which yields SO4· that reacts effectively with MA ( k S O 4 + M A = (5.6 ± 0.4) × 109 M−1·s−1). Irradiated H2O2 is effective in photodegrading MA, but the resulting MA hydroxyderivatives are predicted to be about as toxic as the parent compound for aquatic organisms (most notably, fish and crustaceans). Full article
(This article belongs to the Special Issue Photon-involving Purification of Water and Air)
Figures

Figure 1

Open AccessArticle Uncaria tomentosa Leaves Decoction Modulates Differently ROS Production in Cancer and Normal Cells, and Effects Cisplatin Cytotoxicity
Molecules 2017, 22(4), 620; doi:10.3390/molecules22040620
Received: 20 February 2017 / Revised: 7 April 2017 / Accepted: 8 April 2017 / Published: 12 April 2017
PDF Full-text (5717 KB) | HTML Full-text | XML Full-text
Abstract
Uncaria tomentosa is a woody vine with a long history of use in traditional Peruvian medicine and nowadays supplements containing this vine as ingredient are available. Immunomodulating, anti-inflammatory and anticancer properties of Uncaria tomentosa have been suggested and attributed mainly to the presence
[...] Read more.
Uncaria tomentosa is a woody vine with a long history of use in traditional Peruvian medicine and nowadays supplements containing this vine as ingredient are available. Immunomodulating, anti-inflammatory and anticancer properties of Uncaria tomentosa have been suggested and attributed mainly to the presence of tetracyclic or pentacyclic oxindole alkaloids. However, the synergic action of different compounds occurring in extracts and modulation of redox processes may significantly influence the anticancer activity of Uncaria tomentosa. The aim of the present study was to investigate for the first time the cytotoxic effects of the tetracyclic alkaloids free aqueous extract (decoction) of dried Uncaria tomentosa leaf blades in normal and cancer cells, and to assess the effect of the tested extract on cisplatin (CDDP) cytotoxicity. Tested Uncaria tomentosa extract was not cytotoxic for NHDF cells, but demonstrated cytotoxic effect against HepG2 cells. The extract increased ROS production in HepG2 cells, which resulted in decreased GSH level, leading to apoptosis of these cells through activation of caspase-3 and caspase-7. A reduction of NF-κB active form was observed in cancer cells. In normal cells the extract did not affect ROS production, GSH level and NF-κB activity, and maintained cell viability. HepG2 cells incubation with Uncaria tomentosa decoction and simultaneously with CDDP resulted in an increase in CDPP cytotoxic activity against HepG2, while under the same conditions Uncaria tomentosa prevents NHDF cell viability reduction due to CDDP. The results indicate that Uncaria tomentosa leaves decoction modulates differently cancer and normal cells oxidative metabolism and, enhanced cytotoxicity of CDDP against cancer cells and at the same time increased normal healthy cells resistance to cisplatin. Further studies are needed to confirm our observations and to describe underlying molecular mechanism, and the potential usefulness of Uncaria tomentosa decoction in adjuvant therapy for cancer. Full article
(This article belongs to the Section Natural Products)
Figures

Open AccessCommunication Revision of the Structure of Acremine P from a Marine-Derived Strain of Acremonium persicinum
Molecules 2017, 22(4), 521; doi:10.3390/molecules22040521
Received: 28 February 2017 / Revised: 23 March 2017 / Accepted: 23 March 2017 / Published: 24 March 2017
PDF Full-text (1147 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract The previously published structure of the fungal metabolite acremine P is revised by re-evaluation of chemical shift values and NOESY data, and by DFT calculations. Full article
(This article belongs to the Special Issue Women in Organic Chemistry)
Figures

Chart 1

Open AccessArticle Essential Oils of Hyptis pectinata Chemotypes: Isolation, Binary Mixtures and Acute Toxicity on Leaf-Cutting Ants
Molecules 2017, 22(4), 621; doi:10.3390/molecules22040621
Received: 6 March 2017 / Revised: 4 April 2017 / Accepted: 6 April 2017 / Published: 12 April 2017
PDF Full-text (1245 KB) | HTML Full-text | XML Full-text
Abstract
Leaf-cutting ants are pests of great economic importance due to the damage they cause to agricultural and forest crops. The use of organosynthetic insecticides is the main form of control of these insects. In order to develop safer technology, the objective of this
[...] Read more.
Leaf-cutting ants are pests of great economic importance due to the damage they cause to agricultural and forest crops. The use of organosynthetic insecticides is the main form of control of these insects. In order to develop safer technology, the objective of this work was to evaluate the formicidal activity of the essential oils of two Hyptis pectinata genotypes (chemotypes) and their major compounds on the leaf-cutting ants Acromyrmex balzani Emery and Atta sexdens rubropilosa Forel. Bioassays of exposure pathways (contact and fumigation) and binary mixtures of the major compounds were performed. The major compounds identified in the essential oils of H. pectinata were β-caryophyllene, caryophyllene oxide and calamusenone. The essential oils of H. pectinata were toxic to the ants in both exposure pathways. Essential oils were more toxic than their major compounds alone. The chemotype calamusenone was more toxic to A. balzani in both exposure pathways. A. sexdens rubropilosa was more susceptible to the essential oil of the chemotype β-caryophyllene in both exposure pathways. In general, the binary mixtures of the major compounds resulted in additive effect of toxicity. The essential oils of H. pectinata is a raw material of great potential for the development of new insecticides. Full article
(This article belongs to the collection Bioactive Compounds)
Figures

Figure 1

Open AccessArticle Optimized 4,5-Diarylimidazoles as Potent/Selective Inhibitors of Protein Kinase CK1δ and Their Structural Relation to p38α MAPK
Molecules 2017, 22(4), 522; doi:10.3390/molecules22040522
Received: 31 January 2017 / Revised: 17 March 2017 / Accepted: 20 March 2017 / Published: 24 March 2017
PDF Full-text (8128 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The involvement of protein kinase CK1δ in the pathogenesis of severe disorders such as Alzheimer’s disease, amyotrophic lateral sclerosis, familial advanced sleep phase syndrome, and cancer has dramatically increased interest in the development of effective small molecule inhibitors for both therapeutic application and
[...] Read more.
The involvement of protein kinase CK1δ in the pathogenesis of severe disorders such as Alzheimer’s disease, amyotrophic lateral sclerosis, familial advanced sleep phase syndrome, and cancer has dramatically increased interest in the development of effective small molecule inhibitors for both therapeutic application and basic research. Unfortunately, the design of CK1 isoform-specific compounds has proved to be highly complicated due to the existence of six evolutionarily conserved human CK1 members that possess similar, different, or even opposite physiological and pathophysiological implications. Consequently, only few potent and selective CK1δ inhibitors have been reported so far and structurally divergent approaches are urgently needed in order to establish SAR that might enable complete discrimination of CK1 isoforms and related p38α MAPK. In this study we report on design and characterization of optimized 4,5-diarylimidazoles as highly effective ATP-competitive inhibitors of CK1δ with compounds 11b (IC50 CK1δ = 4 nM, IC50 CK1ε = 25 nM), 12a (IC50 CK1δ = 19 nM, IC50 CK1ε = 227 nM), and 16b (IC50 CK1δ = 8 nM, IC50 CK1ε = 81 nM) being among the most potent CK1δ-targeting agents published to date. Inhibitor compound 11b, displaying potential as a pharmacological tool, has further been profiled over a panel of 321 protein kinases exhibiting high selectivity. Cellular efficacy has been evaluated in human pancreatic cancer cell lines Colo357 (EC50 = 3.5 µM) and Panc89 (EC50 = 1.5 µM). SAR is substantiated by X-ray crystallographic analysis of 16b in CK1δ and 11b in p38α. Full article
(This article belongs to the Special Issue Kinase Inhibitors)
Figures

Open AccessArticle Synthesis and Self-Assembly of Shape Amphiphiles Based on POSS-Dendron Conjugates
Molecules 2017, 22(4), 622; doi:10.3390/molecules22040622
Received: 16 February 2017 / Revised: 2 April 2017 / Accepted: 5 April 2017 / Published: 21 April 2017
PDF Full-text (3615 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Shape has been increasingly recognized as an important factor for self-assembly. In this paper, a series of shape amphiphiles have been built by linking polyhedral oligomeric silsesquioxane (POSS) and a dendron via linkers of different lengths. Three conjugates of octahedral silsesquioxanes (T8
[...] Read more.
Shape has been increasingly recognized as an important factor for self-assembly. In this paper, a series of shape amphiphiles have been built by linking polyhedral oligomeric silsesquioxane (POSS) and a dendron via linkers of different lengths. Three conjugates of octahedral silsesquioxanes (T8-POSS) and dendron are designed and synthesized and are referred to as isobutyl T8-POSS gallic acid derivatives (BPOSS-GAD-1, BPOSS-GAD-2, BPOSS-GAD-3). These samples have been fully characterized by 1H-NMR, 13C-NMR, Fourier transform infrared (FT-IR) spectroscopy and matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry to establish their chemical identity and purity. Driven by different interactions between POSS and dendron, ordered superstructure can be found upon self-assembly. The stabilities and structures of these samples are further studied by using differential scanning calorimetry (DSC), small-angle X-ray scattering (SAXS), wide-angle X-ray diffraction (WAXD), and molecular simulations. The results show that their melting points range from 74 °C to 143 °C and the molecular packing schemes in the assemblies can form lamellar structure of BPOSS-GAD-3 as determined by the different linkers. Full article
Figures

Open AccessArticle Bioavailable Citrus sinensis Extract: Polyphenolic Composition and Biological Activity
Molecules 2017, 22(4), 623; doi:10.3390/molecules22040623
Received: 7 March 2017 / Revised: 4 April 2017 / Accepted: 9 April 2017 / Published: 15 April 2017
PDF Full-text (3195 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Citrus plants contain large amounts of flavonoids with beneficial effects on human health. In the present study, the antioxidant and anti-inflammatory potential of bioavailable polyphenols from Citrus sinensis was evaluated in vitro and ex vivo, using the murine macrophages cell line J774A.1 and
[...] Read more.
Citrus plants contain large amounts of flavonoids with beneficial effects on human health. In the present study, the antioxidant and anti-inflammatory potential of bioavailable polyphenols from Citrus sinensis was evaluated in vitro and ex vivo, using the murine macrophages cell line J774A.1 and primary peritoneal macrophages. Following simulated gastro-intestinal digestion, the in vitro bioavailability of Citrus sinensis polyphenolic extract was assessed using the human cell line Caco-2 grown as monolayers on a transwell membrane. Data demonstrated a relative permeation of its compounds (8.3%). Thus, the antioxidant and anti-inflammatory effect of polyphenolic Citrus sinensis fraction (Cs) was compared to the bioavailable one (CsB). Results revealed that Citrus extract were able to reduce macrophages pro-inflammatory mediators, including nitric oxide, iNOS, COX-2 and different cytokines. Moreover, the effect of Citrus sinensis polyphenols was associated with antioxidant effects, such as a reduction of reactive oxygen species (ROS) and heme-oxygenase-1 (HO-1) increased expression. Our results provide evidence that the bioavailable polyphenolic constituents of the Citrus sinensis extract accumulate prevalently at intestinal level and could reach systemic circulation exerting their effect. The bioavailable fraction showed a higher anti-inflammatory and antioxidant potential compared to the initial extract, thus highlighting its potential nutraceutical value. Full article
(This article belongs to the Section Natural Products)
Figures

Open AccessArticle Protective Effect of Bicyclol on Anti-Tuberculosis Drug Induced Liver Injury in Rats
Molecules 2017, 22(4), 524; doi:10.3390/molecules22040524
Received: 9 January 2017 / Revised: 20 March 2017 / Accepted: 20 March 2017 / Published: 7 April 2017
PDF Full-text (2960 KB) | HTML Full-text | XML Full-text
Abstract
The present study was performed to investigate the effect of bicyclol, a synthetic anti-hepatitis drug with anti-oxidative and anti-inflammatory properties, on anti-tuberculosis (anti-TB) drug-induced liver injury and related mechanisms in rats. Bicyclol was given to rats by gavage 2 h before the oral
[...] Read more.
The present study was performed to investigate the effect of bicyclol, a synthetic anti-hepatitis drug with anti-oxidative and anti-inflammatory properties, on anti-tuberculosis (anti-TB) drug-induced liver injury and related mechanisms in rats. Bicyclol was given to rats by gavage 2 h before the oral administration of an anti-TB drug once a day for 30 days. Liver injury was evaluated by biochemical and histopathological examinations. Lipid peroxidation, mitochondrial function, and the activity of antioxidants were measured by spectrophotometric methods. Cytokines expression and CYP2E1 activity were determined by ELISA assay and liquid chromatography–tandem mass spectrometry (LC–MS/MS) analysis. The expressions of hepatic CYP2E1 and hepatocyte growth factor (HGF) were assessed by Western blotting. As a result, bicyclol significantly protected against anti-TB drug-induced liver injury by reducing the elevated serum aminotransferases levels and accumulation of hepatic lipids. Meanwhile, the histopathological changes were also attenuated in rats. The protective effect of bicyclol on anti-TB drug-induced hepatotoxicity was mainly due to its ability to attenuate oxidative stress, suppress the inflammatory cytokines and CYP2E1 expression, up-regulate the expression of HGF, and improve mitochondrial function. Furthermore, administration of bicyclol had no significant effect on the plasma pharmacokinetics of the anti-TB drug in rats. Full article
Figures

Open AccessArticle LC-ESI-MS/MS Identification of Biologically Active Phenolic Compounds in Mistletoe Berry Extracts from Different Host Trees
Molecules 2017, 22(4), 624; doi:10.3390/molecules22040624
Received: 22 March 2017 / Revised: 5 April 2017 / Accepted: 6 April 2017 / Published: 12 April 2017
PDF Full-text (1496 KB) | HTML Full-text | XML Full-text
Abstract
A new, rapid, sensitive and selective liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) method was developed to determine the content of flavonoid aglycones and phenolic acids in mistletoe berries (Viscum album L.) harvested from six different Polish host trees. Additionally, the total phenolic
[...] Read more.
A new, rapid, sensitive and selective liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) method was developed to determine the content of flavonoid aglycones and phenolic acids in mistletoe berries (Viscum album L.) harvested from six different Polish host trees. Additionally, the total phenolic content (TPC) and total flavonoid content (TFC) as well as an antioxidant and antiproliferative activity were evaluated for the first time. The plant material was selectively extracted using ultrasound assisted maceration with methanol/water (8:2) solution. The obtained TPC and TFC results varied from 7.146 to 9.345 mg GA g1 and from 1.888 to 2.888 mg Q g−1 of dry extracts, respectively. The LC-ESI-MS/MS analysis demonstrated the highest content of phenolic acids in mistletoe berries from Populus nigra ‘Italica’ L. and flavonoid aglycones in mistletoe berries from Tilia cordata Mill. (354.45 µg and 5.955 µg per g dry extract, respectively). The moderate antioxidant activity of investigated extracts was obtained. The studies revealed that the examined extracts decreased the proliferation of human colon adenocarcinoma cells line LS180 in a dose-dependent manner without cytotoxicity in the human colon epithelial cell line CCD 841 CoTr. Moreover, the obtained results suggest considerable impact of polyphenols on the anticancer activity of these extracts. Full article
(This article belongs to the collection Bioactive Compounds)
Figures

Figure 1a

Open AccessArticle The Effect and Mechanism of Transdermal Penetration Enhancement of Fu’s Cupping Therapy: New Physical Penetration Technology for Transdermal Administration with Traditional Chinese Medicine (TCM) Characteristics
Molecules 2017, 22(4), 525; doi:10.3390/molecules22040525
Received: 15 December 2016 / Revised: 9 March 2017 / Accepted: 22 March 2017 / Published: 27 March 2017
PDF Full-text (13027 KB) | HTML Full-text | XML Full-text
Abstract
Background: In this paper, a new type of physical penetration technology for transdermal administration with traditional Chinese medicine (TCM) characteristics is presented. Fu’s cupping therapy (FCT), was established and studied using in vitro and in vivo experiments and the penetration effect and mechanism
[...] Read more.
Background: In this paper, a new type of physical penetration technology for transdermal administration with traditional Chinese medicine (TCM) characteristics is presented. Fu’s cupping therapy (FCT), was established and studied using in vitro and in vivo experiments and the penetration effect and mechanism of FCT physical penetration technology was preliminarily discussed. Methods: With 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-ylacetic acid (indomethacin, IM) as a model drug, the establishment of high, medium, and low references was completed for the chemical permeation system via in vitro transdermal tests. Furthermore, using chemical penetration enhancers (CPEs) and iontophoresis as references, the percutaneous penetration effect of FCT for IM patches was evaluated using seven species of in vitro diffusion kinetics models and in vitro drug distribution; the IM quantitative analysis method in vivo was established using ultra-performance liquid chromatography-tandem mass spectrometry technology (UPLC-MS/MS), and pharmacokinetic parameters: area under the zero and first moment curves from 0 to last time t (AUC0–t, AUMC0–t), area under the zero and first moment curves from 0 to infinity (AUC0–∞, AUMC0–∞), maximum plasma concentration (Cmax) and mean residence time (MRT), were used as indicators to evaluate the percutaneous penetration effect of FCT in vivo. Additionally, we used the 3K factorial design to study the joint synergistic penetration effect on FCT and chemical penetration enhancers. Through scanning electron microscopy (SEM) and transmission electron microscope (TEM) imaging, micro- and ultrastructural changes on the surface of the stratum corneum (SC) were observed to explore the FCT penetration mechanism. Results: In vitro and in vivo skin permeation experiments revealed that both the total cumulative percutaneous amount and in vivo percutaneous absorption amount of IM using FCT were greater than the amount using CPEs and iontophoresis. Firstly, compared with the control group, the indomethacin skin percutaneous rate of the FCT low-intensity group (FCTL) was 35.52%, and the enhancement ratio (ER) at 9 h was 1.76X, roughly equivalent to the penetration enhancing effect of the CPEs and iontophoresis. Secondly, the indomethacin percutaneous ratio of the FCT middle-intensity group (FCTM) and FCT high-intensity group (FCTH) were 47.36% and 54.58%, respectively, while the ERs at 9 h were 3.58X and 8.39X, respectively. Thirdly, pharmacokinetic data showed that in vivo indomethacin percutaneous absorption of the FCT was much higher than that of the control, that of the FCTM was slightly higher than that of the CPE, and that of the FCTM group was significantly higher than all others. Meanwhile, variance analysis indicated that the combination of the FCT penetration enhancement method and the CPE method had beneficial effects in enhancing skin penetration: the significance level of the CPE method was 0.0004, which was lower than 0.001, meaning the difference was markedly significant; the significance level of the FCT was also below 0.0001 and its difference markedly significant. The significance level of factor interaction A × B was lower than 0.0001, indicating that the difference in synergism was markedly significant. Moreover, SEM and TEM images showed that the SC surfaces of Sprague-Dawley rats treated with FCT were damaged, and it was difficult to observe the complete surface structure, with SC pores growing larger and its special “brick structure” becoming looser. This indicated that the barrier function of the skin was broken, thus revealing a potentially major route of skin penetration. Conclusion: FCT, as a new form of transdermal penetration technology, has significant penetration effects with TCM characteristics and is of high clinical value. It is worth promoting its development. Full article
(This article belongs to the Special Issue Transdermal Delivery Systems: Current Landscape and Trends)
Figures

Figure 1

Open AccessArticle Expression of Adenosine A2B Receptor and Adenosine Deaminase in Rabbit Gastric Mucosa ECL Cells
Molecules 2017, 22(4), 625; doi:10.3390/molecules22040625
Received: 10 March 2017 / Revised: 10 April 2017 / Accepted: 11 April 2017 / Published: 12 April 2017
PDF Full-text (1259 KB) | HTML Full-text | XML Full-text
Abstract
Adenosine is readily available to the glandular epithelium of the stomach. Formed continuously in intracellular and extracellular locations, it is notably produced from ATP released in enteric cotransmission. Adenosine analogs modulate chloride secretion in gastric glands and activate acid secretion in isolated parietal
[...] Read more.
Adenosine is readily available to the glandular epithelium of the stomach. Formed continuously in intracellular and extracellular locations, it is notably produced from ATP released in enteric cotransmission. Adenosine analogs modulate chloride secretion in gastric glands and activate acid secretion in isolated parietal cells through A2B adenosine receptor (A2BR) binding. A functional link between surface A2BR and adenosine deaminase (ADA) was found in parietal cells, but whether this connection is a general feature of gastric mucosa cells is unknown. Here we examine whether A2BR is expressed at the membrane of histamine-producing enterochromaffin-like (ECL) cells, the major endocrine cell type in the oxyntic mucosa, and if so, whether it has a vicinity relationship with ADA. We used a highly homogeneous population of rabbit ECL cells (size 7.5–10 µm) after purification by elutriation centrifugation. The surface expression of A2BR and ADA proteins was assessed by flow cytometry and confocal microscopy. Our findings demonstrate that A2BR and ADA are partially coexpressed at the gastric ECL cell surface and that A2BR is functional, with regard to binding of adenosine analogs and adenylate cyclase activation. The physiological relevance of A2BR and ADA association in regulating histamine release is yet to be explained. Full article
(This article belongs to the Special Issue Adenosine Receptors)
Figures

Open AccessFeature PaperArticle Synthesis and Antitumor Activity of New Group 3 Metallocene Complexes
Molecules 2017, 22(4), 526; doi:10.3390/molecules22040526
Received: 25 February 2017 / Revised: 17 March 2017 / Accepted: 22 March 2017 / Published: 28 March 2017
PDF Full-text (590 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The quest for alternative drugs with respect to the well-known cis-platin and its derivatives, which are still used in more than 50% of the treatment regimens for patients suffering from cancer, is highly needed. In this context, organometallic compounds, which are defined
[...] Read more.
The quest for alternative drugs with respect to the well-known cis-platin and its derivatives, which are still used in more than 50% of the treatment regimens for patients suffering from cancer, is highly needed. In this context, organometallic compounds, which are defined as metal complexes containing at least one direct covalent metal-carbon bond, have recently been found to be promising anticancer drug candidates. A series of new metallocene complexes with scandium, yttrium, and neodymium have been prepared and characterized. Some of these compounds show a very interesting anti-proliferative activity in triple negative breast cancer cell line (MDA.MB231) and the non-hormone sensitive prostate cancer cell line (DU145). Moreover, the interaction of some of them with biological membranes, evaluated using liposomes as bio-membrane mimetic model systems, seems to be relevant. The biological activity of these compounds, particularly those based on yttrium, already effective at low concentrations on both cancer cell lines, should be taken into account with regard to new therapeutic approaches in anticancer therapy. Full article
(This article belongs to the Section Organometallic Chemistry)
Figures

Open AccessArticle One–Pot Phosphate-Mediated Synthesis of Novel 1,3,5-Trisubstituted Pyridinium Salts: A New Family of S. aureus Inhibitors
Molecules 2017, 22(4), 626; doi:10.3390/molecules22040626
Received: 17 March 2017 / Revised: 7 April 2017 / Accepted: 9 April 2017 / Published: 12 April 2017
PDF Full-text (3315 KB) | HTML Full-text | XML Full-text
Abstract
Polysubstituted pyridinium salts are valuable pharmacophores found in many biologically active molecules. Their synthesis typically involves the use of multistep procedures or harsh reaction conditions. Here, we report water-based phosphate mediated reaction conditions that promote the condensation of arylacetaldehydes with amines to give
[...] Read more.
Polysubstituted pyridinium salts are valuable pharmacophores found in many biologically active molecules. Their synthesis typically involves the use of multistep procedures or harsh reaction conditions. Here, we report water-based phosphate mediated reaction conditions that promote the condensation of arylacetaldehydes with amines to give 1,3,5-pyridinium salts. The reaction, carried out at pH 6, provides conditions suitable for the use of less stable aldehydes and amines in this Chichibabin pyridine condensation. The evaluation of selected 1,3,5-trisubstituted pyridinium salts highlighted that they can inhibit the growth of S. aureus in the low μg/mL range. The synthetic accessibility of these compounds and preliminary growth inhibition data may pave the way towards the discovery of new anti-bacterials based on the 1,3,5-trisubstituted pyridinium scaffold. Full article
(This article belongs to the Special Issue Women in Organic Chemistry)
Figures

Open AccessArticle The Structure–Antioxidant Activity Relationship of Ferulates
Molecules 2017, 22(4), 527; doi:10.3390/molecules22040527
Received: 22 December 2016 / Revised: 22 March 2017 / Accepted: 23 March 2017 / Published: 25 March 2017
Cited by 1 | PDF Full-text (1222 KB) | HTML Full-text | XML Full-text
Abstract
The antioxidant activity of ferulic acid (1), iso-ferulic acid (2), coniferyl aldehyde (3), methyl ferulate (4), and ethyl ferulate (5) were investigated using 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and ferric-reducing antioxidant power (FRAP) assays
[...] Read more.
The antioxidant activity of ferulic acid (1), iso-ferulic acid (2), coniferyl aldehyde (3), methyl ferulate (4), and ethyl ferulate (5) were investigated using 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and ferric-reducing antioxidant power (FRAP) assays and autoxidation of triacylglycerols of commercially available sunflower oil (TGSO). The compounds tested for ability to scavenge ABTS radical cations was in the order of ferulic acid > coniferyl aldehyde ≈ iso-ferulic acid > ethyl ferulate ≈ methyl ferulate. The results of the FRAP assay for ferulic acid, iso-ferulic acid, and coniferyl aldehyde were similar to and higher than those of methyl ferulate and ethyl ferulate. In the lipid system, iso-ferulic acid showed weak antioxidant activity. The other ferulates exhibited much stronger, yet similar, activities. Full article
(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products)
Figures

Figure 1

Open AccessArticle Pro-Angiogenic Effects of Low Dose Ethoxidine in a Murine Model of Ischemic Hindlimb: Correlation between Ethoxidine Levels and Increased Activation of the Nitric Oxide Pathway
Molecules 2017, 22(4), 627; doi:10.3390/molecules22040627
Received: 3 March 2017 / Revised: 3 April 2017 / Accepted: 6 April 2017 / Published: 12 April 2017
PDF Full-text (2479 KB) | HTML Full-text | XML Full-text
Abstract
Ethoxidine, a benzo[c]phenanthridine derivative, has been identified as a potent inhibitor of topoisomerase I in cancer cell lines. Our group has reported paradoxical properties of ethoxidine in cellular processes leading to angiogenesis on endothelial cells. Because low concentration ethoxidine is able to favor
[...] Read more.
Ethoxidine, a benzo[c]phenanthridine derivative, has been identified as a potent inhibitor of topoisomerase I in cancer cell lines. Our group has reported paradoxical properties of ethoxidine in cellular processes leading to angiogenesis on endothelial cells. Because low concentration ethoxidine is able to favor angiogenesis, the present study aimed to investigate the ability of 10−9 M ethoxidine to modulate neovascularization in a model of mouse hindlimb ischemia. After inducing unilateral hindlimb ischemia, mice were treated for 21 days with glucose 5% or with ethoxidine, to reach plasma concentrations equivalent to 10–9 M. Laser Doppler analysis showed that recovery of blood flow was 1.5 fold higher in ethoxidine-treated mice in comparison with control mice. Furthermore, CD31 staining and angiographic studies confirmed an increase of vascular density in ethoxidine-treated mice. This ethoxidine-induced recovery was associated with an increase of NO production through an enhancement of eNOS phosphorylation on its activator site in skeletal muscle from ischemic hindlimb. Moreover, real-time RT-PCR and western blots have highlighted that ethoxidine has pro-angiogenic properties by inducing a significant enhancement in vegf transcripts and VEGF expression, respectively. These findings suggest that ethoxidine could contribute to favor neovascularization after an ischemic injury by promoting the NO pathway and VEGF expression. Full article
Figures

Open AccessArticle Synthesis and Antiproliferative Activity of Novel All-Trans-Retinoic Acid-Podophyllotoxin Conjugate towards Human Gastric Cancer Cells
Molecules 2017, 22(4), 628; doi:10.3390/molecules22040628
Received: 22 February 2017 / Revised: 2 April 2017 / Accepted: 10 April 2017 / Published: 17 April 2017
PDF Full-text (6893 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
With the purpose of creating a multifunctional drug for gastric cancer treatment, a novel all-trans-retinoic acid (ATRA) conjugate with podophyllotoxin (PPT) was designed and synthesized, and its in vitro antiproliferative activity was evaluated against human gastric cancer cell
[...] Read more.
With the purpose of creating a multifunctional drug for gastric cancer treatment, a novel all-trans-retinoic acid (ATRA) conjugate with podophyllotoxin (PPT) was designed and synthesized, and its in vitro antiproliferative activity was evaluated against human gastric cancer cell lines using CCK-8 assay. The conjugate, P-A, exhibited significant anticancer activity against MKN-45 and BGC-823 cells with IC50 values of 0.419 ± 0.032 and 0.202 ± 0.055 μM, respectively. Moreover, P-A efficiently triggered cell cycle arrest and induced apoptosis in MKN-45 and BGC-823 cells due to modulation of cell cycle arrest- (CDK1, CDK2, CyclinA and CyclinB1) and apoptosis- (cleaved caspase-3, -8 and -9) related proteins, respectively. Further mechanism studies revealed that P-A could increase the expression levels of RARα and RARβ, and decrease the level of RARγ in MKN-45 and BGC-823 cells. Finally, P-A inhibited the ERK1/2 and AKT signaling in the above two cancer cell lines. More importantly, the underlying mechanisms of P-A were similar to those of precursor PPT but different with the other precursor ATRA. Together, the conjugate P-A was a promising candidate for the potential treatment of human gastric cancer. Full article
Figures

Figure 1

Open AccessArticle Subcritical Fluid Extraction of Chinese Quince Seed: Optimization and Product Characterization
Molecules 2017, 22(4), 528; doi:10.3390/molecules22040528
Received: 1 March 2017 / Revised: 15 March 2017 / Accepted: 22 March 2017 / Published: 25 March 2017
PDF Full-text (1191 KB) | HTML Full-text | XML Full-text
Abstract
Chinese quince seed (CQS) is an underutilized oil source and a potential source of unsaturated fatty acids and α-tocopherol-rich oil. Subcritical fluid (SCF) extraction is executed at lower pressures and temperatures than the pressures and temperatures used in supercritical fluid extraction. However, no
[...] Read more.
Chinese quince seed (CQS) is an underutilized oil source and a potential source of unsaturated fatty acids and α-tocopherol-rich oil. Subcritical fluid (SCF) extraction is executed at lower pressures and temperatures than the pressures and temperatures used in supercritical fluid extraction. However, no studies on the SCF extraction of CQS oil are reported. Therefore, the objective of this study was to evaluate the use of SCF for the extraction of CQS oil and to compare the use of SCF with the classical Soxhlet (CS) and supercritical CO2 (SC-CO2) extraction methods. Response surface methodology (RSM) was used to investigate the extraction conditions: temperature (45–65 °C), time (30–50 min), and solvent/solid ratio (5–15 mL/g). The optimization results showed that the highest yield (27.78%) was obtained at 56.18 °C, 40.20 min, and 12.57 mL/g. The oil extracted by SCF had a higher unsaturated fatty acid content (86.37%–86.75%), higher α-tocopherol content (576.0–847.6 mg/kg), lower acid value (3.97 mg/g), and lower peroxide value (0.02 meq O2/kg) than extractions using CS and SC-CO2 methods. The SCF-defatted meal of oilseed exhibited the highest nitrogen solubility index (49.64%) and protein dispersibility index (50.80%), demonstrating that SCF extraction was a promising and efficient technique as an alternative to CS and SC-CO2 methods, as very mild operating conditions and an eco-friendly solvent can be used in the process with maximum preservation of the quality of the meal. Full article
(This article belongs to the Special Issue Sub- and Supercritical Fluids and Green Chemistry)
Figures

Open AccessArticle Metronomic Cordycepin Therapy Prolongs Survival of Oral Cancer-Bearing Mice and Inhibits Epithelial-Mesenchymal Transition
Molecules 2017, 22(4), 629; doi:10.3390/molecules22040629
Received: 14 February 2017 / Revised: 6 April 2017 / Accepted: 10 April 2017 / Published: 13 April 2017
PDF Full-text (3486 KB) | HTML Full-text | XML Full-text
Abstract
Cordycepin (3′-deoxyadenosine) is a natural compound abundantly found in Cordyceps sinesis in natural and fermented sources. In this study, we examined the effects of cordycepin in a human oral squamous cell carcinoma (OSCC) xenograft model. Cordycepin was administered in a regular, low-dose and
[...] Read more.
Cordycepin (3′-deoxyadenosine) is a natural compound abundantly found in Cordyceps sinesis in natural and fermented sources. In this study, we examined the effects of cordycepin in a human oral squamous cell carcinoma (OSCC) xenograft model. Cordycepin was administered in a regular, low-dose and prolonged schedule metronomic therapy. Two doses of cordycepin (25 mg/kg, 50 mg/kg) were administrated five days a week for eight consecutive weeks. The tumor volumes were reduced and survival time was significantly prolonged from 30.3 ± 0.9 days (control group) to 56 days (50 mg/kg group, the day of tumor-bearing mice were sacrificed for welfare consideration). The weights of mice did not change and liver, renal, and hematologic functions were not compromised. Cordycepin inhibited the OSCC cell viability in vitro (IC50 122.4–125.2 μM). Furthermore, morphological characteristics of apoptosis, increased caspase-3 activity and G2/M cell cycle arrest were observed. In wound healing assay, cordycepin restrained the OSCC cell migration. Cordycepin upregulated E-cadherin and downregulated N-cadherin protein expression, implying inhibition of epithelial-mesenchymal transition (EMT). The immunohistochemical staining of xenograft tumor with E-cadherin and vimentin validated in vitro results. In conclusion, metronomic cordycepin therapy showed effective tumor control, prolonged survival and low toxicities. Cytotoxicity against cancer cells with apoptotic features and EMT inhibition were observed. Full article
Figures

Figure 1

Open AccessArticle New Acorane-Type Sesquiterpene from Acorus calamus L.
Molecules 2017, 22(4), 529; doi:10.3390/molecules22040529
Received: 5 March 2017 / Revised: 21 March 2017 / Accepted: 22 March 2017 / Published: 26 March 2017
PDF Full-text (2404 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
A new sesquiterpene, named neo-acorane A (1), and two known ones, acoric acid (2) and calamusin D (3), were isolated from a 95% ethanol extract of the rhizome parts of Acorus calamus L. Their structures were elucidated
[...] Read more.
A new sesquiterpene, named neo-acorane A (1), and two known ones, acoric acid (2) and calamusin D (3), were isolated from a 95% ethanol extract of the rhizome parts of Acorus calamus L. Their structures were elucidated by spectroscopic methods, and the absolute configurations were determined by single-crystal X-ray diffraction analysis. Compounds 1 and 2 are nonisoprenoid sesquiterpenoids, likely biosynthesized from an acorane-type sesquiterpene by oxidative fission of the six- or five-membered ring. Moreover, compounds 1 (10 μM), 2 (5 μM and 10 μM) and 3 (10 μM) showed cell proliferation activity on the SK-N-BE (2) cell line. Full article
(This article belongs to the Section Natural Products)
Figures

Figure 1

Open AccessArticle Hydrogen Sulphide Production in Healthy and Ulcerated Gastric Mucosa of Rats
Molecules 2017, 22(4), 530; doi:10.3390/molecules22040530
Received: 27 January 2017 / Revised: 13 March 2017 / Accepted: 22 March 2017 / Published: 27 March 2017
PDF Full-text (2190 KB) | HTML Full-text | XML Full-text
Abstract
Hydrogen sulphide (H2S) is produced endogenously via two enzymes dependent on pyridoxal phosphate (PLP): cystathionine beta-synthase (CBS, EC 4.2.1.22), cystathionase γ-liase (CTH, EC 4.4.1.1), and a third, 3-mercaptopyruvate sulfurtransferase (MPST, EC 2.8.1.2). H2S strengthens the defence mechanisms of the
[...] Read more.
Hydrogen sulphide (H2S) is produced endogenously via two enzymes dependent on pyridoxal phosphate (PLP): cystathionine beta-synthase (CBS, EC 4.2.1.22), cystathionase γ-liase (CTH, EC 4.4.1.1), and a third, 3-mercaptopyruvate sulfurtransferase (MPST, EC 2.8.1.2). H2S strengthens the defence mechanisms of the gastric mucosal barrier, and plays an important role in gastroprotection, including the increased resistance to damage caused by various irritants and non-steroidal anti-inflammatory drugs. The study was conducted to determine the role of H2S in ulcerated gastric mucosa of rats caused by immobilization in cold water (WRS). The activity and expression of γ-cystathionase, cystathionine β-synthase, 3-mercaptopyruvate sulfurtransferase, and rhodanese was compared with healthy mucosa, together with H2S generation, and cysteine, glutathione, and cystathionine levels. The results showed that the defence mechanism against stress is associated with stimulation of the production of H2S in the tissue and confirmed the observed advantageous effect of H2S on healing of gastric ulcers. In case of animals pretreated with exogenous sources of H2S and NaHS, and some changes observed in the ulcerated gastric mucosa tend to return to values found in the healthy tissue, a finding that is in accordance with the previously determined gastroprotective properties of H2S. The results presented in this paper point to the possible role of rhodanese in H2S production in the gastric mucosa of rats, together with the earlier mentioned three enzymes, which are all active in this tissue. Full article
(This article belongs to the Special Issue Sulfur Atom: Element for Adaptation to an Oxidative Environment 2016)
Figures

Figure 1

Open AccessArticle N-(2,2-Dimethyl-1-(quinolin-2-yl)propylidene) arylaminonickel Complexes and Their Ethylene Oligomerization
Molecules 2017, 22(4), 630; doi:10.3390/molecules22040630
Received: 30 March 2017 / Revised: 10 April 2017 / Accepted: 11 April 2017 / Published: 13 April 2017
PDF Full-text (574 KB) | HTML Full-text | XML Full-text
Abstract
A series of N-(2,2-dimethyl-1-(quinolin-2-yl)propylidene) arylamines was sophisticatedly synthesized and reacted with nickel(II) bromine for the formation of the corresponding nickel complexes. All the organic compounds were characterized by IR, NMR spectra and elemental analysis, while all the nickel complexes were characterized by
[...] Read more.
A series of N-(2,2-dimethyl-1-(quinolin-2-yl)propylidene) arylamines was sophisticatedly synthesized and reacted with nickel(II) bromine for the formation of the corresponding nickel complexes. All the organic compounds were characterized by IR, NMR spectra and elemental analysis, while all the nickel complexes were characterized by IR spectra and elemental analysis. On activation with ethylaluminium sesquichloride (EASC) and modified methylaluminoxane (MMAO), all nickel precatalysts exhibited good activities toward ethylene oligomerization, indicating the positive efficiency of gem-dimethyl substitutents; in which major hexenes were obtained with MMAO. The catalytic parameters were verified, and the steric and electronic influences of substituents with ligands were observed, with a slight change of activities under different ethylene pressures. Full article
(This article belongs to the Special Issue Organometallic Catalysis for Olefin Polymerization/Oligomerization)
Figures

Open AccessArticle Loss of the Phenolic Hydroxyl Group and Aromaticity from the Side Chain of Anti-Proliferative 10-Methyl-aplog-1, a Simplified Analog of Aplysiatoxin, Enhances Its Tumor-Promoting and Proinflammatory Activities
Molecules 2017, 22(4), 631; doi:10.3390/molecules22040631
Received: 13 March 2017 / Revised: 5 April 2017 / Accepted: 11 April 2017 / Published: 13 April 2017
PDF Full-text (2562 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Aplysiatoxin (ATX) is a protein kinase C (PKC) activator with potent tumor-promoting activity. In contrast, 10-methyl-aplog-1 (1), a simplified analog of ATX, was anti-proliferative towards several cancer cell lines without significant tumor-promoting and proinflammatory activities. To determine the effects of the
[...] Read more.
Aplysiatoxin (ATX) is a protein kinase C (PKC) activator with potent tumor-promoting activity. In contrast, 10-methyl-aplog-1 (1), a simplified analog of ATX, was anti-proliferative towards several cancer cell lines without significant tumor-promoting and proinflammatory activities. To determine the effects of the phenolic group on the biological activities of 1, we synthesized new derivatives (2, 3) that lack the phenolic hydroxyl group and/or the aromatic ring. Compound 2, like 1, showed potent anti-proliferative activity against several cancer cell lines, but little with respect to tumor-promoting and proinflammatory activities. In contrast, 3 exhibited weaker growth inhibitory activity, and promoted inflammation and tumorigenesis. The binding affinity of 3 for PKCδ, which is involved in growth inhibition and apoptosis, was several times lower than those of 1 and 2, possibly due to the absence of the hydrogen bond and CH/π interaction between its side chain and either Met-239 or Pro-241 in the PKCδ-C1B domain. These results suggest that both the aromatic ring and phenolic hydroxyl group can suppress the proinflammatory and tumor-promoting activities of 1 and, therefore, at least the aromatic ring in the side chain of 1 is indispensable for developing anti-cancer leads with potent anti-proliferative activity and limited side effects. In accordance with the binding affinity, the concentration of 3 necessary to induce PKCδ-GFP translocation to the plasma membrane and perinuclear regions in HEK293 cells was higher than that of 1 and 2. However, the translocation profiles for PKCδ-GFP due to induction by 13 were similar. Full article
(This article belongs to the Special Issue Cutting-Edge Organic Chemistry in Japan)
Figures

Open AccessArticle Choerosponins A and B, Two New Cytotoxic Bridged-Ring Ketones and the Determination of Their Absolute Configurations
Molecules 2017, 22(4), 531; doi:10.3390/molecules22040531
Received: 2 March 2017 / Revised: 21 March 2017 / Accepted: 23 March 2017 / Published: 27 March 2017
PDF Full-text (979 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Bioactivity-directed fractionation of antitumor compounds from the stem barks of Choerospondias axillaries (Roxb.) Burtt et Hill (Anacardiaceae) afforded two new cytotoxic bridged-ring ketones, choerosponins A (1) and B (2), and their structures were elucidated by spectroscopic methods; their stereochemistry
[...] Read more.
Bioactivity-directed fractionation of antitumor compounds from the stem barks of Choerospondias axillaries (Roxb.) Burtt et Hill (Anacardiaceae) afforded two new cytotoxic bridged-ring ketones, choerosponins A (1) and B (2), and their structures were elucidated by spectroscopic methods; their stereochemistry was determined by NOE difference experiments, CD spectra and the modified Mosher’s method. Compound 1 has a rare dioxatricyclo skeleton. Flow cytometry and SRB methods were employed to evaluate the antitumor activity of the two compounds against tsFT210, HCT-15, HeLa, A2780 and MCF-7 cell lines, and both of them showed strong cytotoxicity. MTT and paper disc methods were also used to evaluate their anti-hypoxia and antibacterial activities, and both of them showed no apparent activities. Full article
Figures

Figure 1

Open AccessArticle A Network-Based Pharmacology Study of the Herb-Induced Liver Injury Potential of Traditional Hepatoprotective Chinese Herbal Medicines
Molecules 2017, 22(4), 632; doi:10.3390/molecules22040632
Received: 2 March 2017 / Revised: 6 April 2017 / Accepted: 12 April 2017 / Published: 14 April 2017
PDF Full-text (1636 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Herbal medicines are widely used for treating liver diseases and generally regarded as safe due to their extensive use in Traditional Chinese Medicine practice for thousands of years. However, in recent years, there have been increased concerns regarding the long-term risk of Herb-Induced
[...] Read more.
Herbal medicines are widely used for treating liver diseases and generally regarded as safe due to their extensive use in Traditional Chinese Medicine practice for thousands of years. However, in recent years, there have been increased concerns regarding the long-term risk of Herb-Induced Liver Injury (HILI) in patients with liver dysfunction. Herein, two representative Chinese herbal medicines: one—Xiao-Chai-Hu-Tang (XCHT)—a composite formula, and the other—Radix Polygoni Multiflori (Heshouwu)—a single herb, were analyzed by network pharmacology study. Based on the network pharmacology framework, we exploited the potential HILI effects of XCHT and Heshouwu by predicting the molecular mechanisms of HILI and identified the potential hepatotoxic ingredients in XCHT and Heshouwu. According to our network results, kaempferol and thymol in XCHT and rhein in Heshouwu exhibit the largest number of liver injury target connections, whereby CASP3, PPARG and MCL1 may be potential liver injury targets for these herbal medicines. This network pharmacology assay might serve as a useful tool to explore the underlying molecular mechanism of HILI. Based on the theoretical predictions, further experimental verification should be performed to validate the accuracy of the predicted interactions between herbal ingredients and protein targets in the future. Full article
Figures

Figure 1

Open AccessArticle Constituents of the Roots of Dichapetalum pallidum and Their Anti-Proliferative Activity
Molecules 2017, 22(4), 532; doi:10.3390/molecules22040532
Received: 27 February 2017 / Revised: 22 March 2017 / Accepted: 23 March 2017 / Published: 27 March 2017
PDF Full-text (1776 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
As part of our search for bioactive compounds from the Dichapetalaceae, repeated chromatographic purification of the roots of a hitherto unexamined species, Dichapetalum pallidum, led to the isolation of the newly occurring 7-hydroxydichapetalin P (1) and the known dichapetalins A
[...] Read more.
As part of our search for bioactive compounds from the Dichapetalaceae, repeated chromatographic purification of the roots of a hitherto unexamined species, Dichapetalum pallidum, led to the isolation of the newly occurring 7-hydroxydichapetalin P (1) and the known dichapetalins A (2) and X (3). Also isolated were the known compounds friedelin-2,3-lactone (4), friedelan-3-one (6), friedelan-3β-ol (7) and pomolic (8), as well as the dipeptide aurantiamide acetate (5). The compounds were characterized by direct interpretation of their IR, 1D NMR and 2D NMR spectral data and by comparison of their physico-chemical data, including their chromatographic profiles, with the literature and authentic samples in our compound library for the genus Dichapetalum. The compounds were assayed for their anti-proliferative activities against the human T-lymphocytic leukemia (Jurkat), acute promyelocytic leukemia (HL-60) and T-lymphoblast-like leukemia (CEM) cell lines. Overall, dichapetalin X showed the strongest (3.14 μM) and broadest cytotoxic activities against all the leukemic cell lines tested, exhibiting even stronger activities than the standard compound, curcumin. Full article
(This article belongs to the Special Issue Natural Product: A Continuing Source of Novel Drug Leads)
Figures

Figure 1

Open AccessArticle Artesunate Enhances the Cytotoxicity of 5-Aminolevulinic Acid-Based Sonodynamic Therapy against Mouse Mammary Tumor Cells In Vitro
Molecules 2017, 22(4), 533; doi:10.3390/molecules22040533
Received: 3 February 2017 / Revised: 18 March 2017 / Accepted: 25 March 2017 / Published: 27 March 2017
PDF Full-text (2896 KB) | HTML Full-text | XML Full-text
Abstract
Sonodynamic therapy (SDT) kills tumor cells through the synergistic effects of ultrasound (US) and a sonosensitizer agent. 5-Aminolevulinic acid (5-ALA) has been used as a sonodynamic sensitizer for cancer treatment. However, studies have shown that 5-ALA-based SDT has limited efficacy against malignant tumors.
[...] Read more.
Sonodynamic therapy (SDT) kills tumor cells through the synergistic effects of ultrasound (US) and a sonosensitizer agent. 5-Aminolevulinic acid (5-ALA) has been used as a sonodynamic sensitizer for cancer treatment. However, studies have shown that 5-ALA-based SDT has limited efficacy against malignant tumors. In this study, we examined whether artesunate (ART) could enhance the cytotoxicity of 5-ALA-based SDT against mouse mammary tumor (EMT-6) cells in vitro. In the ART, ART + US, ART + 5-ALA, and ART + 5-ALA + US groups, the cell survival rate correlated with ART concentration, and decreased with increasing concentrations of ART. Morphologically, many apoptotic and necrotic cells were observed in the ART + 5-ALA + US group. The percentage of reactive oxygen species-positive cells in the ART + 5-ALA + US group was also significantly higher than that in the 5-ALA group (p = 0.0228), and the cell death induced by ART + 5-ALA + US could be inhibited by the antioxidant N-acetylcysteine. These results show that ART offers great potential in enhancing the efficacy of 5-ALA-based SDT for the treatment of cancer. However, these results are only based on in vitro studies, and further in vivo studies are required. Full article
(This article belongs to the Special Issue Artemisinin: Against Malaria, Cancer and Viruses)
Figures

Figure 1

Open AccessArticle Synthesis of Curcuminoids and Evaluation of Their Cytotoxic and Antioxidant Properties
Molecules 2017, 22(4), 633; doi:10.3390/molecules22040633
Received: 23 February 2017 / Revised: 4 April 2017 / Accepted: 11 April 2017 / Published: 14 April 2017
PDF Full-text (651 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Curcumin (1) and ten derivatives (211) were synthesized and evaluated as cytotoxic and antioxidant agents. The results of primary screening by Sulforhodamine B assay against five human cancer cell lines (U-251 MG, glioblastoma; PC-3, human prostatic; HCT-15,
[...] Read more.
Curcumin (1) and ten derivatives (211) were synthesized and evaluated as cytotoxic and antioxidant agents. The results of primary screening by Sulforhodamine B assay against five human cancer cell lines (U-251 MG, glioblastoma; PC-3, human prostatic; HCT-15, human colorectal; K562, human chronic myelogenous leukemia; and SKLU-1, non-small cell lung cancer) allowed us to calculate the half maximal inhibitory concentration (IC50) values for the more active compounds against HCT-15 and K562 cell lines. Compounds 2 and 10 were the most active against both cell lines and were more active than curcumin itself. Thiobarbituric acid reactive substances (TBARS) assay showed that 7 has potent activity; even stronger than curcumin, α-tocopherol, and quercetin. Full article
Figures

Open AccessArticle Synthesis and Spectral Properties of meso-Arylbacteriochlorins, Including Insights into Essential Motifs of their Hydrodipyrrin Precursors
Molecules 2017, 22(4), 634; doi:10.3390/molecules22040634
Received: 13 March 2017 / Revised: 8 April 2017 / Accepted: 11 April 2017 / Published: 14 April 2017
PDF Full-text (4276 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Synthetic bacteriochlorins—analogues of bacteriochlorophylls, Nature’s near-infrared absorbers—are attractive for diverse photochemical studies. meso-Arylbacteriochlorins have been prepared by the self-condensation of a dihydrodipyrrin–carbinol or dihydrodipyrrin–acetal following an Eastern-Western (E-W) or Northern-Southern (N-S) joining process. The bacteriochlorins bear a gem-dimethyl group in each pyrroline
[...] Read more.
Synthetic bacteriochlorins—analogues of bacteriochlorophylls, Nature’s near-infrared absorbers—are attractive for diverse photochemical studies. meso-Arylbacteriochlorins have been prepared by the self-condensation of a dihydrodipyrrin–carbinol or dihydrodipyrrin–acetal following an Eastern-Western (E-W) or Northern-Southern (N-S) joining process. The bacteriochlorins bear a gem-dimethyl group in each pyrroline ring to ensure stability toward oxidation. The two routes differ in the location of the gem-dimethyl group at the respective 3- or 2-position in the dihydrodipyrrin, and the method of synthesis of the dihydrodipyrrin. Treatment of a known 3,3-dimethyldihydrodipyrrin-1-carboxaldehyde with an aryl Grignard reagent afforded the dihydrodipyrrin-1-(aryl)carbinol, and upon subsequent acetylation, the corresponding dihydrodipyrrin-1-methyl acetate (dihydrodipyrrin–acetate). Self-condensation of the dihydrodipyrrin–acetate gave a meso-diarylbacteriochlorin (E-W route). A 2,2-dimethyl-5-aryldihydrodipyrrin-1-(aryl)carbinol underwent self-condensation to give a trans-A2B2-type meso-tetraarylbacteriochlorin (N-S route). In each case, the aromatization process entails a 2e/2H+ (aerobic) dehydrogenative oxidation following the dihydrodipyrrin self-condensation. Comparison of a tetrahydrodipyrrin–acetal (0%) versus a dihydrodipyrrin–acetal (41%) in bacteriochlorin formation and results with various 1-substituted dihydrodipyrrins revealed the importance of resonance stabilization of the reactive hydrodipyrrin intermediate. Altogether 10 new dihydrodipyrrins and five new bacteriochlorins have been prepared. The bacteriochlorins exhibit characteristic bacteriochlorophyll-like absorption spectra, including a Qy band in the region 726–743 nm. Full article
Figures

Open AccessArticle Novel Sulfamethoxazole Ureas and Oxalamide as Potential Antimycobacterial Agents
Molecules 2017, 22(4), 535; doi:10.3390/molecules22040535
Received: 2 March 2017 / Revised: 23 March 2017 / Accepted: 24 March 2017 / Published: 28 March 2017
PDF Full-text (1484 KB) | HTML Full-text | XML Full-text
Abstract
Infections caused by Mycobacterium tuberculosis (Mtb.) and nontuberculous mycobacteria (NTM) are considered to be a global health problem; current therapeutic options are limited. Sulfonamides have exhibited a wide range of biological activities including those against mycobacteria. Based on the activity of
[...] Read more.
Infections caused by Mycobacterium tuberculosis (Mtb.) and nontuberculous mycobacteria (NTM) are considered to be a global health problem; current therapeutic options are limited. Sulfonamides have exhibited a wide range of biological activities including those against mycobacteria. Based on the activity of 4-(3-heptylureido)-N-(5-methylisoxazol-3-yl)benzenesulfonamide against NTM, we designed a series of homologous sulfamethoxazole-based n-alkyl ureas (C1–C12), as well as several related ureas and an oxalamide. Fifteen ureas and one oxalamide were synthesized by five synthetic procedures and characterized. They were screened for their activity against Mtb. and three NTM strains (M. avium, M. kansasii). All of them share antimycobacterial properties with minimum inhibitory concentration (MIC) values starting from 2 µM. The highest activity showed 4,4′-[carbonylbis(azanediyl)]bis[N-(5-methylisoxazol-3-yl)benzenesulfonamide] with MIC of 2–62.5 µM (i.e., 1.07–33.28 µg/mL). Among n-alkyl ureas, methyl group is optimal for the inhibition of both Mtb. and NTM. Generally, longer alkyls led to increased MIC values, heptyl being an exception for NTM. Some of the novel derivatives are superior to parent sulfamethoxazole. Several urea and oxalamide derivatives are promising antimycobacterial agents with low micromolar MIC values. Full article
(This article belongs to the Special Issue Sulfonamides)
Figures

Scheme 1

Open AccessArticle Stability of Bioactive Compounds in Broccoli as Affected by Cutting Styles and Storage Time
Molecules 2017, 22(4), 636; doi:10.3390/molecules22040636
Received: 1 March 2017 / Revised: 10 April 2017 / Accepted: 11 April 2017 / Published: 15 April 2017
PDF Full-text (1463 KB) | HTML Full-text | XML Full-text
Abstract
Broccoli contains bioactive molecules and thus its consumption is related with the prevention of chronic and degenerative diseases. The application of wounding stress to horticultural crops is a common practice, since it is the basis for the fresh-cut produce industry. In this study,
[...] Read more.
Broccoli contains bioactive molecules and thus its consumption is related with the prevention of chronic and degenerative diseases. The application of wounding stress to horticultural crops is a common practice, since it is the basis for the fresh-cut produce industry. In this study, the effect of four different cutting styles (CSs) (florets (CS1), florets cut into two even pieces (CS2), florets cut into four even pieces (CS3), and florets processed into chops (CS4)) and storage time (0 and 24 h at 20 °C) on the content of bioactive compounds in broccoli was evaluated. Immediately after cutting, 5-O-caffeoylquinic acid and caffeic acid content increased by 122.4% and 41.6% in CS4 and CS2, respectively. Likewise, after storage, 3-O-caffeoylquinic acid and 5-O-caffeoylquinic acid increased by 46.7% and 98.2%, respectively in CS1. Glucoerucin and gluconasturtiin content decreased by 62% and 50%, respectively in CS3; whereas after storage most glucosinolates increased in CS1. Total isothiocyanates, increased by 133% immediately in CS4, and after storage CS1 showed 65% higher levels of sulforaphane. Total ascorbic acid increased 35% after cutting in CS2, and remained stable after storage. Results presented herein would allow broccoli producers to select proper cutting styles that preserve or increase the content of bioactive molecules. Full article
(This article belongs to the Special Issue Recent Advances in Plant Phenolics)
Figures

Figure 1

Open AccessArticle 3,4-Dihydroxybenzalactone Suppresses Human Non-Small Cell Lung Carcinoma Cells Metastasis via Suppression of Epithelial to Mesenchymal Transition, ROS-Mediated PI3K/AKT/MAPK/MMP and NFκB Signaling Pathways
Molecules 2017, 22(4), 537; doi:10.3390/molecules22040537
Received: 9 February 2017 / Revised: 17 March 2017 / Accepted: 20 March 2017 / Published: 28 March 2017
PDF Full-text (15410 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
3,4-Dihydroxybenzalactone (DBL) was isolated from Phellinus linteus (PL), which is a folk medicine possessing various physiological effects. In this study, we used highly metastatic A549 cells to investigate efficacy of DBL inhibition of cancer metastasis and possible mechanisms. The results revealed DBL inhibited
[...] Read more.
3,4-Dihydroxybenzalactone (DBL) was isolated from Phellinus linteus (PL), which is a folk medicine possessing various physiological effects. In this study, we used highly metastatic A549 cells to investigate efficacy of DBL inhibition of cancer metastasis and possible mechanisms. The results revealed DBL inhibited migratory and invasive abilities of cancer cells at noncytotoxic concentrations. We found DBL suppressed enzymatic activities, protein expression, and RNA levels of matrix metalloproteinase (MMP)-2 and MMP-9. Western blot results showed DBL decreased phosphoinositide 3-kinase (PI3K)/AKT, phosphorylation status of mitogen-activated protein kinases (MAPKs), and focal adhesion kinase (FAK)/paxillin, which correlated with cell migratory ability. DBL also affected epithelial to mesenchymal transition (EMT)-related biomarkers. In addition, DBL enhanced cytoprotective effects through elevated antioxidant enzymes including heme oxygenase 1 (HO-1), catalase, glutathione peroxidase (GPx), and superoxide dismutase (SOD). Moreover, DBL influenced the nuclear translocation of nuclear factor κB (NFκB), nuclear factor erythroid 2-related factor 2 (Nrf2), Snail, and Slug in A549 cells. Taken together, these results suggested that treatment with DBL may act as a potential candidate to inhibit lung cancer metastasis by inhibiting MMP-2 and -9 via affecting PI3K/AKT, MAPKs, FAK/paxillin, EMT/Snail and Slug, Nrf2/antioxidant enzymes, and NFκB signaling pathways. Full article
(This article belongs to the collection Bioactive Compounds)
Figures

Figure 1

Open AccessCommunication Discovery of an Octahedral Silicon Complex as a Potent Antifungal Agent
Molecules 2017, 22(4), 637; doi:10.3390/molecules22040637
Received: 11 February 2017 / Revised: 5 April 2017 / Accepted: 12 April 2017 / Published: 15 April 2017
PDF Full-text (2498 KB) | HTML Full-text | XML Full-text
Abstract
Octahedral transition metal complexes have been shown to have tremendous applications in chemical biology and medicinal chemistry. Meanwhile, structural transition metals can be replaced by inert octahedral silicon in a proof-of-principle study. We here introduce the first example of octahedral silicon complexes, which
[...] Read more.
Octahedral transition metal complexes have been shown to have tremendous applications in chemical biology and medicinal chemistry. Meanwhile, structural transition metals can be replaced by inert octahedral silicon in a proof-of-principle study. We here introduce the first example of octahedral silicon complexes, which can very well serve as an efficient antimicrobial agent. The typical silicon arenediolate complex 1 {[(phen)2Si(OO)](PF6)2, with phen = 1,10-phenanthroline, OO = 9,10-phenanthrenediolate} exhibited significant inhibition towards the growth of Cryptococcus neoformans with MIC and MFC values of 4.5 and 11.3 μM, respectively. Moreover, it was fungicidal against both proliferative and quiescent Cryptococcus cells. This work may set the stage for the development of novel antifungal drugs based upon hexacoodinate silicon scaffolds. Full article
(This article belongs to the Special Issue Advances in Silicon Chemistry)
Figures

Open AccessArticle Determination of Vancomycin in Human Serum by Cyclodextrin-Micellar Electrokinetic Capillary Chromatography (CD-MEKC) and Application for PDAP Patients
Molecules 2017, 22(4), 538; doi:10.3390/molecules22040538
Received: 21 February 2017 / Revised: 18 March 2017 / Accepted: 22 March 2017 / Published: 28 March 2017
PDF Full-text (873 KB) | HTML Full-text | XML Full-text
Abstract
A simple and sensitive cyclodextrin-micellar electrokinetic capillary chromatography (CD-MEKC) method with UV detection was developed and validated for the determination of vancomycin (VCM) in serum. The separation was achieved in 14 min at 25 °C with a fused-silica capillary column of 40.2 cm
[...] Read more.
A simple and sensitive cyclodextrin-micellar electrokinetic capillary chromatography (CD-MEKC) method with UV detection was developed and validated for the determination of vancomycin (VCM) in serum. The separation was achieved in 14 min at 25 °C with a fused-silica capillary column of 40.2 cm × 75 μm i.d. (effective length 30.2 cm) and a run buffer containing 25 mM borate buffer with 50 mM sodium dodecylsulfonate (SDS) (pH 9.5) and 2% sulfobutyl-β-cyclodextrin (sulfobutyl-β-CD). Under optimal conditions for biological samples, good separations with high efficiency and short analysis time were achieved. Several parameters affecting the drug separation from biological matrices were studied, including buffer types, concentrations, and pHs. The methods were validated over the range of 0.9998–99.98 µg/mL. Calibration curves of VCM also showed good linearity (r2 > 0.999). Intra- and interday precisions (relative standard deviation, RSD) were less than 5.80% and 7.38%, and lower limit of quantification (LLOQ) were lower than 1.0 μg/mL. The mean recoveries ranged between 84.03% and 91.69%. The method was successfully applied for monitoring VCM concentrations in serum of patients with peritoneal dialysis-associated peritonitis (PDAP). The assay should be applicable to pharmacokinetic studies and routine therapeutic drug monitoring of this drug in serum. Full article
Figures

Figure 1

Open AccessArticle Optimization of Ultrasound-Assisted Extraction of Antioxidants from the Mung Bean Coat
Molecules 2017, 22(4), 638; doi:10.3390/molecules22040638
Received: 13 March 2017 / Revised: 9 April 2017 / Accepted: 12 April 2017 / Published: 15 April 2017
PDF Full-text (1064 KB) | HTML Full-text | XML Full-text
Abstract
Mung bean (Vigna radiata) sprout is commonly consumed as a vegetable, while the coat of the germinated mung bean is a waste. In this paper, an ultrasound-assisted extraction method has been developed to extract natural antioxidants from the seed coat of
[...] Read more.
Mung bean (Vigna radiata) sprout is commonly consumed as a vegetable, while the coat of the germinated mung bean is a waste. In this paper, an ultrasound-assisted extraction method has been developed to extract natural antioxidants from the seed coat of mung bean. Several experimental parameters—which included ethanol concentration, solvent/material ratio, ultrasound extraction time, temperature, and power—were studied in single-factor experiments. The interaction of three key experimental parameters (ethanol concentration, solvent/material ratio, and ultrasonic extraction time) was further investigated by response surface method. Besides, traditional extracting methods, including maceration and Soxhlet extraction methods, were also carried out for comparison. The results suggested that the best extracting condition was 37.6% (v/v) of ethanol concentration, 35.1:1 mL/g of solvent/material ratio and ultrasonic extraction of 46.1 min at 70 °C under 500 W ultrasonic irradiation. The antioxidant capacity (178.28 ± 7.39 µmol Trolox/g DW) was much stronger than those obtained by the maceration extraction process (158.66 ± 4.73 µmol Trolox/g DW) and the Soxhlet extraction process (138.42 ± 3.63 µmol Trolox/g DW). In addition, several antioxidant components in the extract were identified and quantified. This study is helpful for value-added utilization of the waste from germinated mung bean. Full article
Figures

Figure 1

Open AccessArticle Assessment of the Anti-Hyperglycaemic, Anti-Inflammatory and Antioxidant Activities of the Methanol Extract of Moringa Oleifera in Diabetes-Induced Nephrotoxic Male Wistar Rats
Molecules 2017, 22(4), 439; doi:10.3390/molecules22040439
Received: 18 November 2016 / Revised: 18 February 2017 / Accepted: 7 March 2017 / Published: 23 March 2017
Cited by 1 | PDF Full-text (1240 KB) | HTML Full-text | XML Full-text
Abstract
Diabetes mellitus is an endocrine disease of multiple aetiologies in insulin secretion. A deficiency in insulin results in hyperglycemia with metabolic disturbances of biomolecules. Moringa oleifera (MO) is endemic in the tropics with a variety of ethnomedicinal importance. The leaf of this plant
[...] Read more.
Diabetes mellitus is an endocrine disease of multiple aetiologies in insulin secretion. A deficiency in insulin results in hyperglycemia with metabolic disturbances of biomolecules. Moringa oleifera (MO) is endemic in the tropics with a variety of ethnomedicinal importance. The leaf of this plant has been reported to possess antioxidant and medicinal properties that may be helpful in the treatment and management of diabetes and its associated complications. Diabetes was induced intraperitoneally in rats by a single dose of streptozotocin (55 mg/kg) and treated with methanolic extract of Moringa oleifera (250 mg/kg b.wt) for six weeks. Forty-eight (48) adult male Wistar strain rats were randomly divided into four groups: normal control (NC), Moringa oleifera treated control rats (NC + MO), diabetic rats (DM) and Moringa oleifera treated diabetic rats (DM + MO). Estimation of antioxidant capacity, total polyphenols, flavonoids and flavonols content of Moringa oleifera extract was performed and serum biochemical markers were evaluated. Antioxidants such as catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD) activities, glutathione (GSH) and inflammatory biomarkers were determined in the kidney. Results showed high antioxidant capacities of MO extract and improved serum biochemical markers, whilst lipid peroxidation (MDA) levels were reduced in non-diabetic and diabetic rats after MO treatment when compared to normal control. Subsequent administration of MO led to an increased concentration of serum albumin, globulin and total protein with a decrease in the level of MDA, and improvements in CAT, SOD, GSH, GPx, (tumour necrosis factor-alpha)TNF-α and (interleukin-6)IL-6. MO contains potent phytochemical constituents that offer protective action against diabetic-induced renal damage, reactive oxygen species (ROS) and inflammation and could therefore play a role in reducing diabetic complications, particularly in developing countries such as in Africa where the majority cannot afford orthodox medicine. Full article
(This article belongs to the Special Issue Polyphenols and Cardiovascular Disease)
Figures

Open AccessArticle Evaluation of Polyphenolic Content, Antioxidant and Diuretic Activities of Six Fumaria Species
Molecules 2017, 22(4), 639; doi:10.3390/molecules22040639
Received: 20 February 2017 / Revised: 7 April 2017 / Accepted: 8 April 2017 / Published: 15 April 2017
PDF Full-text (1646 KB) | HTML Full-text | XML Full-text
Abstract
Romanian traditional medicine describes the use of aerial parts of Fumaria species to treat hepatobiliary diseases as well as diuretic agents. The present study aims to investigate the chemical composition, antioxidant properties, and diuretic effects of several Fumaria species. LC/MS analysis revealed that
[...] Read more.
Romanian traditional medicine describes the use of aerial parts of Fumaria species to treat hepatobiliary diseases as well as diuretic agents. The present study aims to investigate the chemical composition, antioxidant properties, and diuretic effects of several Fumaria species. LC/MS analysis revealed that Fumaria species contain phenolic acids and high amounts of flavonoids with rutin and isoquercitrin as main compounds. Concerning antioxidant capacity, the most significant results were obtained for F. capreolata and F. vailantii. Both species showed a good correlation between the antioxidant capacity and a high amount of flavonoids. Furthermore, the extracts of F. officinalis and F. schleicheri produced a strong increase in urinary volumetric excretion of saline-loaded rats, 24 h after the oral administration of a single dose of 250 mg/kg bw. Moreover, both extracts of F. officinalis and F. schleicheri increased the urinary excretion of Na+ and K+. Results from the present study offer a new perspective concerning the chemical composition and bioactivities of traditionally used fumitory species. Full article
(This article belongs to the Section Natural Products)
Figures

Figure 1

Open AccessArticle Bioactive Constituents Obtained from the Seeds of Lepidium apetalum Willd
Molecules 2017, 22(4), 540; doi:10.3390/molecules22040540
Received: 25 January 2017 / Revised: 24 March 2017 / Accepted: 25 March 2017 / Published: 28 March 2017
PDF Full-text (1295 KB) | HTML Full-text | XML Full-text
Abstract
Three new compounds, apetalumosides C1 (1), D (2), and 1-thio--d-glucopyranosyl(1→1)-1-thio-α-d-glucopyranoside (3), together with twenty-two known ones (4–25) were obtained from the seeds of Lepidium apetalum Willd. Among the known isolates, 58, 10
[...] Read more.
Three new compounds, apetalumosides C1 (1), D (2), and 1-thio--d-glucopyranosyl(1→1)-1-thio-α-d-glucopyranoside (3), together with twenty-two known ones (4–25) were obtained from the seeds of Lepidium apetalum Willd. Among the known isolates, 58, 1013, 1620, and 25 were obtained from the genus for the first time; 4, 14, 15, and 2124 were isolated from the species for the first time. Meanwhile, the NMR data of 16 was first reported here. Their structures were determined by means of chemical and spectroscopic methods. On the other hand, their inhibitory effects on sodium oleate-induced triglyceride (TG) overloading in HepG2 cells were evaluated. As a result, two new compounds (1 and 2), together with known isolates 7–11, 13, 14, 16–18, 20, 21, and 25 possessed significant inhibitory effects in the cells. Full article
(This article belongs to the Section Natural Products)
Figures

Figure 1

Open AccessArticle Expeditious Synthesis of Dianionic-Headed 4-Sulfoalkanoic Acid Surfactants
Molecules 2017, 22(4), 640; doi:10.3390/molecules22040640
Received: 22 March 2017 / Revised: 11 April 2017 / Accepted: 12 April 2017 / Published: 16 April 2017
PDF Full-text (1955 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
4-Sulfoalkanoic acids are a class of important dianionic-headed surfactants. Various 4-sulfoalkanoic acids with straight C8, C10, C12, C14, C16, and C18 chains were synthesized expeditiously through the radical addition of methyl 2-((ethoxycarbonothioyl)thio)acetate to linear terminal olefins and subsequent oxidation with peroxyformic acid. This
[...] Read more.
4-Sulfoalkanoic acids are a class of important dianionic-headed surfactants. Various 4-sulfoalkanoic acids with straight C8, C10, C12, C14, C16, and C18 chains were synthesized expeditiously through the radical addition of methyl 2-((ethoxycarbonothioyl)thio)acetate to linear terminal olefins and subsequent oxidation with peroxyformic acid. This is a useful and convenient strategy for the synthesis of dianionic-headed surfactants with a carboxylic acid and sulfonic acid functionalities in the head group region. Full article
(This article belongs to the Section Organic Synthesis)
Figures

Open AccessArticle Thiazine-2-thiones as Masked 1-Azadienes in Cascade Dimerization Reactions)
Molecules 2017, 22(4), 541; doi:10.3390/molecules22040541
Received: 28 February 2017 / Revised: 24 March 2017 / Accepted: 26 March 2017 / Published: 28 March 2017
PDF Full-text (2812 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
We report the unexpected formation of a 1-azadiene dimer from 4,6-diphenyl-3,6-dihydro-2H-1,3-thiazine-2-thiones under prolonged microwave irradiation. In this manner, thiazine-2-thiones act as “masked” 1-azadiene equivalents, which makes them useful synthetic tools to access complex heterocyclic frameworks. We compare this dimerization with earlier
[...] Read more.
We report the unexpected formation of a 1-azadiene dimer from 4,6-diphenyl-3,6-dihydro-2H-1,3-thiazine-2-thiones under prolonged microwave irradiation. In this manner, thiazine-2-thiones act as “masked” 1-azadiene equivalents, which makes them useful synthetic tools to access complex heterocyclic frameworks. We compare this dimerization with earlier approaches and elaborate on the observed diastereoselectivity. Full article
(This article belongs to the Special Issue MCRs and Related One-Pot Organic Synthesis)
Figures

Figure 1

Open AccessArticle Establishing Reliable Cu-64 Production Process: From Target Plating to Molecular Specific Tumor Micro-PET Imaging
Molecules 2017, 22(4), 641; doi:10.3390/molecules22040641
Received: 21 February 2017 / Revised: 4 April 2017 / Accepted: 11 April 2017 / Published: 17 April 2017
PDF Full-text (6177 KB) | HTML Full-text | XML Full-text
Abstract
Copper-64 is a useful radioisotope for positron emission tomography (PET). Due to the wide range of applications, the demand of 64Cu with low metallic impurities is increasing. Here we report a simple method for the efficient production of high specific activity 64
[...] Read more.
Copper-64 is a useful radioisotope for positron emission tomography (PET). Due to the wide range of applications, the demand of 64Cu with low metallic impurities is increasing. Here we report a simple method for the efficient production of high specific activity 64Cu using a cyclotron for biomedical application. We designed new equipment based on the plating of enriched 64Ni as the target, and used automated ion exchange chromatography to purify copper-64 efficiently after irradiation and dissolution of the target in good radiochemical and chemical yield and purity. The 64Cu radionuclide produced using 99.32% enriched 64Ni with a density of 61.4 ± 5.0 mg/cm2, reaching a total radioactivity greater than 200 mCi, with specific activity up to 5.6 GBq/μmoL. It was further incorporated into modified monoclonal antibody DOTA-rituximab to synthesize 64Cu-DOTA-rituximab, which was used successfully for micro-PET imaging. Full article
Figures

Figure 1

Open AccessArticle Anti-Proliferative Effect of Triterpenoidal Glycosides from the Roots of Anemone vitifolia through a Pro-Apoptotic Way
Molecules 2017, 22(4), 642; doi:10.3390/molecules22040642
Received: 10 March 2017 / Revised: 12 April 2017 / Accepted: 13 April 2017 / Published: 17 April 2017
PDF Full-text (2128 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
A cytotoxicity-guided phytochemical investigation of Anemone vitifolia roots led to the isolation of six oleanane saponins (16), which were reported from the species for the first time. Their structures were determined by comparing its MS and NMR data with
[...] Read more.
A cytotoxicity-guided phytochemical investigation of Anemone vitifolia roots led to the isolation of six oleanane saponins (16), which were reported from the species for the first time. Their structures were determined by comparing its MS and NMR data with those in literature. Compounds 14 showed significant inhibitory effects on the proliferation of hepatocellular carcinoma HepG2 cells with IC50 values ranging from 2.0 to 8.5 μM, compared to positive control methotrexate with IC50 value of 15.8 μM. Flow cytometry analysis revealed that compounds 14 exerted anti-proliferative effects through a pro-apoptotic way of hepatocellular carcinoma cells. Full article
Figures

Figure 1

Open AccessArticle Bisarylureas Based on 1H-Pyrazolo[3,4-d]pyrimidine Scaffold as Novel Pan-RAF Inhibitors with Potent Anti-Proliferative Activities: Structure-Based Design, Synthesis, Biological Evaluation and Molecular Modelling Studies
Molecules 2017, 22(4), 542; doi:10.3390/molecules22040542
Received: 22 February 2017 / Revised: 24 March 2017 / Accepted: 24 March 2017 / Published: 29 March 2017
PDF Full-text (3355 KB) | HTML Full-text | XML Full-text
Abstract
RAF (Ras activating factor) kinases are important and attractive targets for cancer therapy. With the aim of discovering RAF inhibitors that bind to DFG-out inactive conformation created by the movement of Asp-Phe-Gly (DFG), we conducted structure-based drug design using the X-ray cocrystal structures
[...] Read more.
RAF (Ras activating factor) kinases are important and attractive targets for cancer therapy. With the aim of discovering RAF inhibitors that bind to DFG-out inactive conformation created by the movement of Asp-Phe-Gly (DFG), we conducted structure-based drug design using the X-ray cocrystal structures of BRAF (v-raf murine sarcoma viral oncogene homolog B1), starting from bisarylurea derivative based on 1H-pyrazolo[3,4-d]pyrimidine scaffold 1a. Most of the synthesized compounds showed good to excellent inhibitory activities against BRAFV600E kinase, possessed moderate to potent anti-proliferative activities against four tumor cell lines (A375, HT-29, PC-3 and A549) and good selectivity towards cancer cells rather normal cells (Madin-Darby canine kidney, MDCK). The most promising compound, 1v, exhibited potent inhibitory activity against not only BRAFV600E (half maximal inhibitory concentration, IC50 = 23.6 nM) but also wild-type BRAF (IC50 = 51.5 nM) and C-RAF (IC50 = 8.5 nM), and effective cellular anti-proliferative activities against A375, HT-29, PC-3 and A549 cell lines as well as a very good selectivity profile. Moreover, compound 1v mainly arrested the A375 cell line in the G0/G1 stage, and showed significant suppression of MEK (mitogen-activated protein kinase kinase) phosphorylation in A375 and HT-29 cell lines. Taken together, the optimal compound 1v showed excellent in vitro potency as a pan-RAF inhibitor. In addition, the promise of compound 1v was further confirmed by molecular dynamics simulation and binding free energy calculations. Full article
(This article belongs to the Section Medicinal Chemistry)
Figures

Figure 1

Open AccessArticle Attenuation of Bleomycin-Induced Pulmonary Fibrosis in Rats with S-Allyl Cysteine
Molecules 2017, 22(4), 543; doi:10.3390/molecules22040543
Received: 14 February 2017 / Revised: 20 March 2017 / Accepted: 24 March 2017 / Published: 29 March 2017
PDF Full-text (2861 KB) | HTML Full-text | XML Full-text
Abstract
Pulmonary fibrosis is a complex disease with high mortality and morbidity. As there are currently no effective treatments, development of new strategies is essential for improving therapeutic outcomes. S-allyl cysteine (SAC) is a constituent of aged garlic extract that has demonstrated efficacy
[...] Read more.
Pulmonary fibrosis is a complex disease with high mortality and morbidity. As there are currently no effective treatments, development of new strategies is essential for improving therapeutic outcomes. S-allyl cysteine (SAC) is a constituent of aged garlic extract that has demonstrated efficacy as an antioxidant and anti-inflammatory agent. The current study examines the effects of SAC on pulmonary fibrosis induced by a single intratracheal instillation of bleomycin (2.5 mg/kg). SAC was administered to rats as 0.15% SAC-containing diet from seven days prior to instillation up until the conclusion of the experiment (14 days post-instillation). SAC significantly reduced collagen mRNA expression and protein deposition (33.3 ± 2.7 μg/mg and 28.2 ± 2.1 μg/mg tissue in vehicle- and SAC-treated rats, respectively), and decreased fibrotic area, as assessed histologically. In the rats’ lungs, SAC also attenuated the increased expression of transforming growth factor-β1 (TGF-β1), a central regulator of myofibroblast recruitment, activation, and differentiation. While bleomycin instillation increased the number of myofibroblasts within the lung mesenchymal area, this change was significantly reduced by SAC treatment. SAC may exert efficacy as an anti-fibrotic by attenuating myofibroblast differentiation through TGF-β1-mediated fibroproliferative processes. Thus, our results indicate SAC may be useful for the prevention or treatment of pulmonary fibrosis. Full article
(This article belongs to the Special Issue The Chemistry of Alliums)
Figures

Figure 1

Open AccessCommunication An Expedient Total Synthesis of Triciribine
Molecules 2017, 22(4), 643; doi:10.3390/molecules22040643
Received: 6 March 2017 / Revised: 11 April 2017 / Accepted: 11 April 2017 / Published: 17 April 2017
PDF Full-text (1257 KB) | HTML Full-text | XML Full-text
Abstract
In the present paper, we report an expedient total synthesis of triciribine, a tricyclic 7-deazapurine nucleoside and protein kinase B (AKT ) inhibitor, in 35% overall yield. Our synthesis route features a highly regioselective substitution of 1-N-Boc-2-methylhydrazine and a trifluoroacetic acid
[...] Read more.
In the present paper, we report an expedient total synthesis of triciribine, a tricyclic 7-deazapurine nucleoside and protein kinase B (AKT ) inhibitor, in 35% overall yield. Our synthesis route features a highly regioselective substitution of 1-N-Boc-2-methylhydrazine and a trifluoroacetic acid catalyzed one-pot transformation which combined the deprotection of the tert-butylcarbonyl (Boc) group and ring closure reaction together to give a tricyclic nucleobase motif. Full article
(This article belongs to the Section Organic Synthesis)
Figures

Open AccessArticle Systematic Understanding of the Mechanism of Salvianolic Acid A via Computational Target Fishing
Molecules 2017, 22(4), 644; doi:10.3390/molecules22040644
Received: 6 March 2017 / Revised: 8 April 2017 / Accepted: 12 April 2017 / Published: 17 April 2017
PDF Full-text (1859 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Salvianolic acid A (SAA) is one of the most abundant water-soluble and potent anti-oxidative compounds isolated from Danshen, a traditional Chinese medicine. A systematic overview of its mechanism of action is yet to be performed. In the present study, the druggability of SAA
[...] Read more.
Salvianolic acid A (SAA) is one of the most abundant water-soluble and potent anti-oxidative compounds isolated from Danshen, a traditional Chinese medicine. A systematic overview of its mechanism of action is yet to be performed. In the present study, the druggability of SAA was measured using the TCMSP server, and potential targets of SAA were identified by PharmMapper and DRAR-CPI. Intersecting targets were then assessed by GeneMANIA and GO pathway analysis, and drug-target-pathway networks were constructed to give a visual view. The results showed that SAA has good druggability, and 13 putative protein targets were identified. Network analysis showed that these targets were associated with cancer, metabolism and other physiological processes. In summary, SAA is predicted to target multiple proteins and pathways to form a network that exerts systematic pharmacological effects. Full article
Figures

Figure 1

Open AccessArticle A Specific Peptide with Calcium-Binding Capacity from Defatted Schizochytrium sp. Protein Hydrolysates and the Molecular Properties
Molecules 2017, 22(4), 544; doi:10.3390/molecules22040544
Received: 15 February 2017 / Revised: 19 March 2017 / Accepted: 23 March 2017 / Published: 29 March 2017
PDF Full-text (2011 KB) | HTML Full-text | XML Full-text
Abstract
Marine microorganisms have been proposed as a new kind of protein source. Efforts are needed in order to transform the protein-rich biological wastes left after lipid extraction into value-added bio-products. Thus, the utilization of protein recovered from defatted Schizochytrium sp. by-products presents an
[...] Read more.
Marine microorganisms have been proposed as a new kind of protein source. Efforts are needed in order to transform the protein-rich biological wastes left after lipid extraction into value-added bio-products. Thus, the utilization of protein recovered from defatted Schizochytrium sp. by-products presents an opportunity. A specific peptide Tyr-Leu (YL) with calcium-binding capacity was purified from defatted Schizochytrium sp. protein hydrolysates through gel filtration chromatography and RP-HPLC. The calcium-binding activity of YL reached 126.34 ± 3.40 μg/mg. The calcium-binding mechanism was investigated through ultraviolet, fluorescence and infrared spectroscopy. The results showed that calcium ions could form dative bonds with carboxyl oxygen atoms and amino nitrogen atoms as well as the nitrogen and oxygen atoms of amide bonds. YL-Ca exhibited excellent thermal stability and solubility, which was beneficial for its absorption and transport in the basic intestinal tract of the human body. Moreover, the cellular uptake of calcium in Caco-2 cells showed that YL-Ca could enhance calcium uptake efficiency and protect calcium ions against precipitation caused by dietary inhibitors such as tannic acid, oxalate, phytate and metal ions. The findings indicate that the by-product of Schizochytrium sp. is a promising source for making peptide-calcium bio-products as algae-based functional supplements for human beings. Full article
Figures

Figure 1

Open AccessArticle Rapid Determination of 30 Polyphenols in Tongmai Formula, a Combination of Puerariae Lobatae Radix, Salviae Miltiorrhizae Radix et Rhizoma, and Chuanxiong Rhizoma, via Liquid Chromatography-Tandem Mass Spectrometry
Molecules 2017, 22(4), 545; doi:10.3390/molecules22040545
Received: 20 February 2017 / Revised: 19 March 2017 / Accepted: 27 March 2017 / Published: 29 March 2017
PDF Full-text (526 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Tongmai formula (TMF) is a herbal preparation composed of three traditional Chinese medicinal materials: Puerariae Lobatae Radix (Gegen), Salviae Miltiorrhizae Radix et Rhizoma (Danshen) and Chuanxiong Rhizoma (Chuanxiong). It has been used to treat cardiovascular diseases for decades. To develop a reliable and
[...] Read more.
Tongmai formula (TMF) is a herbal preparation composed of three traditional Chinese medicinal materials: Puerariae Lobatae Radix (Gegen), Salviae Miltiorrhizae Radix et Rhizoma (Danshen) and Chuanxiong Rhizoma (Chuanxiong). It has been used to treat cardiovascular diseases for decades. To develop a reliable and convenient analytical method for a comprehensive determination of polyphenols in TMF and the ascertainment of their chemical correlations with its herbal components, a method combining high-performance liquid chromatography with electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) was developed and validated for rapid determination of 30 polyphenols in TMF and its three herbal components. The chromatographic separation was carried out on a Chromolith Fastgradient RP-18 endcapped 50-2 column using an optimized gradient elution. Statistical analysis of obtained data demonstrated that the method had a desirable linearity, precision, and accuracy, as well as excellent sensitivity. The obtained results indicated that, among the 30 polyphenols in TMF, 22 originated from Gegen, 6 originated from Danshen, and 2 originated from Chuanxiong. The major polyphenols in TMF have been identified as puerarin, mirificin, salvianolic acid B, salvianic acid A, 3’-hydroxypuerarin, 3’-methoxypuerarin, and salvianolic acid A, with a combined contribution of 19.2% of the preparation. The development and validation of this method will greatly facilitate future pharmacological studies of TMF and its herbal components, as well as polyphenols in cardiovascular therapies. Full article
(This article belongs to the collection Bioactive Compounds)
Figures

Figure 1

Open AccessArticle Molecular Hybridization-Guided One-Pot Multicomponent Synthesis of Turmerone Motif-Fused 3,3′-Pyrrolidinyl-dispirooxindoles via a 1,3-Dipolar Cycloaddition Reaction
Molecules 2017, 22(4), 645; doi:10.3390/molecules22040645
Received: 23 March 2017 / Revised: 11 April 2017 / Accepted: 13 April 2017 / Published: 17 April 2017
PDF Full-text (9131 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Described herein is the development of a facile and efficient methodology for the synthesis of novel turmerone motif-fused 3,3′-pyrrolidinyl-dispirooxindoles 3–5 via a multicomponent 1,3-dipolar cycloaddition of dienones 2 with azomethine ylides (thermally generated in situfrom isatins and proline or thioproline or sarcosine). Products
[...] Read more.
Described herein is the development of a facile and efficient methodology for the synthesis of novel turmerone motif-fused 3,3′-pyrrolidinyl-dispirooxindoles 3–5 via a multicomponent 1,3-dipolar cycloaddition of dienones 2 with azomethine ylides (thermally generated in situfrom isatins and proline or thioproline or sarcosine). Products bearing four or three consecutive stereocenters consist of two oxindole moieties and a pyrrolidinyl core, including vicinal spiroquaternary stereocenters fused in one ring structure were smoothly obtained in high yields (up to 93% yield) with good diastereoselectivity (up to >20:1). Another valuable application of this method was for the design of new hybrid architectures for biological screening through the adequate fusion of these sub-units of turmerone and 3,3′-pyrrolidinyl-dispirooxindole, generating drug-like molecules. Full article
(This article belongs to the collection Heterocyclic Compounds)
Figures

Open AccessArticle Metajapogenins A–C, Pregnane Steroids from Shells of Metaplexis japonica
Molecules 2017, 22(4), 646; doi:10.3390/molecules22040646
Received: 16 March 2017 / Revised: 13 April 2017 / Accepted: 15 April 2017 / Published: 17 April 2017
PDF Full-text (1220 KB) | HTML Full-text | XML Full-text
Abstract
Phytochemical investigation of the shells of Metaplexis japonica (Thunb.) Makino, belonging to the family of Apocynaceae, afforded three new pregnane steroids, metajapogenins A–C, along with three known compounds. The structures of the new compounds were elucidated as 12β,14β,17β-trihydroxypregna-3,5-dien-7,20-dione, 12β,14β,17β,20β-tetrahydroxypregna-3,5-dien-7-one; 3β,12β,14β,17β-tetrahydroxypregn-5-ene-7,20-dione on the basis
[...] Read more.
Phytochemical investigation of the shells of Metaplexis japonica (Thunb.) Makino, belonging to the family of Apocynaceae, afforded three new pregnane steroids, metajapogenins A–C, along with three known compounds. The structures of the new compounds were elucidated as 12β,14β,17β-trihydroxypregna-3,5-dien-7,20-dione, 12β,14β,17β,20β-tetrahydroxypregna-3,5-dien-7-one; 3β,12β,14β,17β-tetrahydroxypregn-5-ene-7,20-dione on the basis of extensive spectroscopic evidence derived from 1D; 2D-NMR experiments and mass spectrometry. The known compounds included pergularin; 12-O-acetylpergularin; and pergularin-3-O-β-d-oleandropyranose; which were identified for the first time in the shells of M. japonica. Full article
(This article belongs to the Section Natural Products)
Figures

Figure 1

Open AccessArticle Volatiles Emitted at Different Flowering Stages of Jasminum sambac and Expression of Genes Related to α-Farnesene Biosynthesis
Molecules 2017, 22(4), 546; doi:10.3390/molecules22040546
Received: 3 February 2017 / Revised: 22 March 2017 / Accepted: 27 March 2017 / Published: 29 March 2017
PDF Full-text (4487 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Fresh jasmine flowers have been used to make jasmine teas in China, but there has been no complete information about volatile organic compound emissions in relation to flower developmental stages and no science-based knowledge about which floral stage should be used for the
[...] Read more.
Fresh jasmine flowers have been used to make jasmine teas in China, but there has been no complete information about volatile organic compound emissions in relation to flower developmental stages and no science-based knowledge about which floral stage should be used for the infusion. This study monitored volatile organic compounds emitted from living flowers of Jasminum sambac (L.) Ait. ‘Bifoliatum’ at five developmental stages and also from excised flowers. Among the compounds identified, α-farnesene, linalool, and benzyl acetate were most abundant. Since α-farnesene is synthesized through the Mevalonate pathway, four genes encoding 3-hydroxy-3-methylglutaryl coenzyme A synthase, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), farnesyl pyrophosphate synthase, and terpene synthase were isolated. Their expression patterns in living flowers at the five stages and in excised flowers coincided with the emission patterns of α-farnesene. Application of lovastatin, a HMGR inhibitor, significantly reduced the expression of the genes and greatly decreased the emission of α-farnesene. The sweet scent was diminished from lovastatin-treated flowers as well. These results indicate that α-farnesene is an important compound emitted from jasmine flowers, and its emission patterns suggest that flowers at the opening stage or flower buds 8 h after excision should be used for the infusion of tea leaves. Full article
(This article belongs to the Section Natural Products)
Figures

Figure 1

Open AccessArticle Chemical Constituents of Supercritical Extracts from Alpinia officinarum and the Feeding Deterrent Activity against Tribolium castaneum
Molecules 2017, 22(4), 647; doi:10.3390/molecules22040647
Received: 15 March 2017 / Revised: 14 April 2017 / Accepted: 15 April 2017 / Published: 18 April 2017
PDF Full-text (556 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Alpinia officinarum has been confirmed to possess bioactivities against some pests. In this work, a sample was obtained from A. officinarum rhizomes by supercritical fluid CO2 extraction (SFE). According to GC-MS analysis, the main chemical components for SFE-sample included benzylacetone (26.77%), 1,7-diphenyl-5-hydroxy-3-heptanone
[...] Read more.
Alpinia officinarum has been confirmed to possess bioactivities against some pests. In this work, a sample was obtained from A. officinarum rhizomes by supercritical fluid CO2 extraction (SFE). According to GC-MS analysis, the main chemical components for SFE-sample included benzylacetone (26.77%), 1,7-diphenyl-5-hydroxy-3-heptanone (17.78%), guaiacylacetone (10.03%) and benzenepropanal (7.42%). The essential oil of A. officinarum rhizomes (LD50 = 20.71 μg/adult) exhibited more contact toxicity than SFE extract (LD50 = 82.72 μg/adult) against Tribolium castaneum. From SFE extracts, one new compound, 1-phenyl-4-(16,17-dimethyl-9,13-octadiene)-5-isopentenyl-7-(4”-methoxyl-3”-hydroxyl-phenyl)-3-heptanone (3), together with five known compounds identified as 5-hydroxy-1,7-diphenyl-3-heptanone (1), 1,7-diphenyl-4-hepten-3-one (2), galangin (4), galangin-3-methyl ether (5) and pinocembrin (6), were isolated and their feeding deterrent activities against T. castaneum adults were assessed. It was found that compounds 16 had feeding deterrent activities against T. castaneum with feeding deterrent indices of 18.21%, 18.94%, 19.79%, 26.99%, 20.34%, and 35.81%, respectively, at the concentration of 1500 ppm. Hence, the essential oil and SFE extracts/compounds of A. officinarum rhizomes represent promising alternatives in the control of T. castaneum adults. Full article
Figures

Figure 1

Open AccessArticle Metal-Free α-C(sp3)–H Functionalized Oxidative Cyclization of Tertiary N,N-Diaryl Amino Alcohols: Theoretical Approach for Mechanistic Pathway
Molecules 2017, 22(4), 547; doi:10.3390/molecules22040547
Received: 21 February 2017 / Revised: 18 March 2017 / Accepted: 24 March 2017 / Published: 29 March 2017
PDF Full-text (1883 KB) | HTML Full-text | XML Full-text
Abstract
The mechanistic pathway of TEMPO/I2-mediated oxidative cyclization of N,N-diaryl amino alcohols 1 was investigated. Based on direct empirical experiments, three key intermediates (aminium radical cation 3, α-aminoalkyl radical 4, and iminium 5), four types of reactive species
[...] Read more.
The mechanistic pathway of TEMPO/I2-mediated oxidative cyclization of N,N-diaryl amino alcohols 1 was investigated. Based on direct empirical experiments, three key intermediates (aminium radical cation 3, α-aminoalkyl radical 4, and iminium 5), four types of reactive species (radical TEMPO, cationic TEMPO, TEMPO-I, and iodo radical), and three types of pathways ((1) SET/PCET mechanism; (2) HAT/1,6-H transfer mechanism; (3) ionic mechanism) were assumed. Under the assumption, nine free energy diagrams were acquired through density functional theory calculations. From the comparison of solution-phase free energy, some possible mechanisms were excluded, and then the chosen plausible mechanisms were concretized using the more stable intermediate 7. Full article
(This article belongs to the Special Issue Reactions of Hydrocarbons and other C‒H Compounds)
Figures

Figure 1

Open AccessArticle Growth Inhibition of Sulfate-Reducing Bacteria in Produced Water from the Petroleum Industry Using Essential Oils
Molecules 2017, 22(4), 648; doi:10.3390/molecules22040648
Received: 8 March 2017 / Revised: 13 April 2017 / Accepted: 15 April 2017 / Published: 19 April 2017
PDF Full-text (423 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Strategies for the control of sulfate-reducing bacteria (SRB) in the oil industry involve the use of high concentrations of biocides, but these may induce bacterial resistance and/or be harmful to public health and the environment. Essential oils (EO) produced by plants inhibit the
[...] Read more.
Strategies for the control of sulfate-reducing bacteria (SRB) in the oil industry involve the use of high concentrations of biocides, but these may induce bacterial resistance and/or be harmful to public health and the environment. Essential oils (EO) produced by plants inhibit the growth of different microorganisms and are a possible alternative for controlling SRB. We aimed to characterize the bacterial community of produced water obtained from a Brazilian petroleum facility using molecular methods, as well as to evaluate the antimicrobial activity of EO from different plants and their major components against Desulfovibrio alaskensis NCIMB 13491 and against SRB growth directly in the produced water. Denaturing gradient gel electrophoresis revealed the presence of the genera Pelobacter and Marinobacterium, Geotoga petraea, and the SRB Desulfoplanes formicivorans in our produced water samples. Sequencing of dsrA insert-containing clones confirmed the presence of sequences related to D. formicivorans. EO obtained from Citrus aurantifolia, Lippia alba LA44 and Cymbopogon citratus, as well as citral, linalool, eugenol and geraniol, greatly inhibited (minimum inhibitory concentration (MIC) = 78 µg/mL) the growth of D. alaskensis in a liquid medium. The same MIC was obtained directly in the produced water with EO from L. alba LA44 (containing 82% citral) and with pure citral. These findings may help to control detrimental bacteria in the oil industry. Full article
(This article belongs to the Special Issue Essential Oils: Chemistry and Bioactivity)
Figures

Open AccessArticle Black Tea High-Molecular-Weight Polyphenol-Rich Fraction Promotes Hypertrophy during Functional Overload in Mice
Molecules 2017, 22(4), 548; doi:10.3390/molecules22040548
Received: 16 February 2017 / Revised: 22 March 2017 / Accepted: 27 March 2017 / Published: 29 March 2017
PDF Full-text (2244 KB) | HTML Full-text | XML Full-text
Abstract
Mitochondria activation factor (MAF) is a high-molecular-weight polyphenol extracted from black tea that stimulates training-induced 5′ adenosine monophosphate-activated protein kinase (AMPK) activation and improves endurance capacity. Originally, MAF was purified from black tea using butanol and acetone, making it unsuitable for food preparation.
[...] Read more.
Mitochondria activation factor (MAF) is a high-molecular-weight polyphenol extracted from black tea that stimulates training-induced 5′ adenosine monophosphate-activated protein kinase (AMPK) activation and improves endurance capacity. Originally, MAF was purified from black tea using butanol and acetone, making it unsuitable for food preparation. Hence, we extracted a MAF-rich sample “E80” from black tea, using ethanol and water only. Here, we examined the effects of E80 on resistance training. Eight-week old C57BL/6 mice were fed with a normal diet or a diet containing 0.5% E80 for 4, 7 and 14 days under conditions of functional overload. It was found that E80 administration promoted overload-induced hypertrophy and induced phosphorylation of the Akt/mammalian target of rapamycin (mTOR) pathway proteins, such as Akt, P70 ribosomal protein S6 kinase (p70S6K), and S6 in the plantaris muscle. Therefore, functional overload and E80 administration accelerated mTOR signaling and increased protein synthesis in the muscle, thereby inducing hypertrophy. Full article
(This article belongs to the Special Issue Polyphenols and Antioxidants–The Chemistry of Tea)
Figures

Figure 1

Open AccessArticle Inhibitory Effect of Triterpenoids from Panax ginseng on Coagulation Factor X
Molecules 2017, 22(4), 649; doi:10.3390/molecules22040649
Received: 23 February 2017 / Revised: 9 April 2017 / Accepted: 11 April 2017 / Published: 24 April 2017
PDF Full-text (6326 KB) | HTML Full-text | XML Full-text
Abstract
Enzymes involved in the coagulation process have received great attention as potential targets for the development of oral anti-coagulants. Among these enzymes, coagulation factor Xa (FXa) has remained the center of attention in the last decade. In this study, 16 ginsenosides and two
[...] Read more.
Enzymes involved in the coagulation process have received great attention as potential targets for the development of oral anti-coagulants. Among these enzymes, coagulation factor Xa (FXa) has remained the center of attention in the last decade. In this study, 16 ginsenosides and two sapogenins were isolated, identified and quantified. To determine the inhibitory potential on FXa, the chromogenic substrates method was used. The assay suggested that compounds 5, 13 and 18 were mainly responsible for the anti-coagulant effect. Furthermore, these three compounds also possessed high thrombin selectivity in the thrombin inhibition assay. Furthermore, Glide XP from Schrödinger was employed for molecular docking to clarify the interaction between the bioactive compounds and FXa. Therefore, the chemical and biological results indicate that compounds 5 (ginsenoside Rg2), 13 (ginsenoside Rg3) and 18 (protopanaxtriol, PPT) are potential natural inhibitors against FXa. Full article
(This article belongs to the Special Issue Current Trends in Ginseng Research)
Figures

Figure 1

Open AccessArticle The ‘Molecule of the Month’ Website—An Extraordinary Chemistry Educational Resource Online for over 20 Years
Molecules 2017, 22(4), 549; doi:10.3390/molecules22040549
Received: 21 February 2017 / Revised: 27 March 2017 / Accepted: 27 March 2017 / Published: 29 March 2017
PDF Full-text (5608 KB) | HTML Full-text | XML Full-text
Abstract
The Molecule of the Month website (http://www.chm.bris.ac.uk/motm/motm.htm) is an educational resource that is celebrating its 20th anniversary. Here we reflect on its pioneering role in promoting new technology for visualizing and presenting chemical information on the web, as well as its achievements, as
[...] Read more.
The Molecule of the Month website (http://www.chm.bris.ac.uk/motm/motm.htm) is an educational resource that is celebrating its 20th anniversary. Here we reflect on its pioneering role in promoting new technology for visualizing and presenting chemical information on the web, as well as its achievements, as a free educational resource, both as a teaching aid and as a multi-user, multi-author learning platform. We discuss the legal aspects of such sites, as well as issues around how to make the content permanent. Finally, we look forward to how such sites may evolve in the future. Full article
(This article belongs to the Section Molecular Diversity)
Figures

Open AccessArticle Synthesis, Characterization, Antimicrobial and Antiproliferative Activity Evaluation of Cu(II), Co(II), Zn(II), Ni(II) and Pt(II) Complexes with Isoniazid-Derived Compound
Molecules 2017, 22(4), 650; doi:10.3390/molecules22040650
Received: 26 March 2017 / Revised: 11 April 2017 / Accepted: 14 April 2017 / Published: 19 April 2017
PDF Full-text (1342 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Hydrazone complexes of Cu(II), Co(II), Zn(II), Ni(II) and Pt(II) with N-isonicotinoyl-N′-(3-metoxy-2 hydroxybenzaldehyde)-hydrazone (HL) were synthesized and characterized by different physico-chemical techniques including elemental and thermal analysis, magnetic susceptibility measurements, molar electric conductivity, as well as IR (infrared), 1
[...] Read more.
Hydrazone complexes of Cu(II), Co(II), Zn(II), Ni(II) and Pt(II) with N-isonicotinoyl-N′-(3-metoxy-2 hydroxybenzaldehyde)-hydrazone (HL) were synthesized and characterized by different physico-chemical techniques including elemental and thermal analysis, magnetic susceptibility measurements, molar electric conductivity, as well as IR (infrared), 1H-NMR and 13C-NMR (hydrogen and carbon nuclear magnetic resonance, UV-Vis (ultraviolet-visible), FAB (fast atom bombardment), EPR (electron paramagnetic resonance), and mass spectroscopies. The crystal structure of ligand was determined by single crystal X-ray diffraction studies. Spectral data showed that hydrazone behaves as an ONO tridentate ligand through the azomethine nitrogen, phenolate and keto oxygen atoms. For the copper(II) complexes, metal–ligand bonding parameters were evaluated from the EPR spectra. These parameters indicate the presence of in-plane π bonding. In addition, the f values of complexes 14 indicate small distortion from planarity. The effect of these complexes on proliferation of human breast cancer (MCF-7 and SKBR-3), human melanoma (A375), lung adenocarcinoma cells (NCI-H1573) and their antibacterial activity against Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and Candida albicans strains were studied and compared with those of free ligand. The ligand and complexes 13 showed significant antimicrobial activity against the Gram-positive bacteria Staphylococcus aureus and Candida albicans in comparison to the control drugs. The complexes 24 could be potential antitumor agents, leading to a significant improvement of the cytotoxic activity when compared with HL. Full article
(This article belongs to the Special Issue Metal Based Drugs: Opportunities and Challenges)
Figures

Open AccessArticle Assessment of Lipophilicity Indices Derived from Retention Behavior of Antioxidant Compounds in RP-HPLC
Molecules 2017, 22(4), 550; doi:10.3390/molecules22040550
Received: 27 February 2017 / Revised: 26 March 2017 / Accepted: 27 March 2017 / Published: 29 March 2017
PDF Full-text (1244 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Reverse phase high pressure liquid chromatography was employed in order to evaluate the lipophilicity of antioxidant compounds from different classes, such as phenolic acids, flavanones, flavanols, flavones, anthocyanins, stilbenes, xantonoids, and proanthocyanidins. The retention time of each compound was measured using five different
[...] Read more.
Reverse phase high pressure liquid chromatography was employed in order to evaluate the lipophilicity of antioxidant compounds from different classes, such as phenolic acids, flavanones, flavanols, flavones, anthocyanins, stilbenes, xantonoids, and proanthocyanidins. The retention time of each compound was measured using five different HPLC columns: RP18 (LiChroCART, Purosphere RP-18e), C8 (Zorbax, Eclipse XDBC8), C16-Amide (Discovery RP-Amide C16), CN100 (Saulentechnik, Lichrosphere), and pentafluorophenyl (Phenomenex, Kinetex PFP), and the mobile phase consisted of methanol and water (0.1% formic acid) in different proportions. The measurements were conducted at two different column temperatures, room temperature (22 °C) and, in order to mimic the environment from the human body, 37 °C. Furthermore, principal component analysis (PCA) was used to obtain new lipophilicity indices and holistic lipophilicity charts. Additionally, highly representative depictions of the chromatographic behavior of the investigated compounds and stationary phases at different temperatures were obtained using two new chemometric approaches, namely two-way joining cluster analysis and sum of ranking differences. Full article
(This article belongs to the collection Bioactive Compounds)
Figures

Open AccessArticle Antifungal and Anti-Biofilm Activities of Acetone Lichen Extracts against Candida albicans
Molecules 2017, 22(4), 651; doi:10.3390/molecules22040651
Received: 20 February 2017 / Revised: 6 April 2017 / Accepted: 14 April 2017 / Published: 19 April 2017
PDF Full-text (251 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Candida albicans is a commensal coloniser of the human gastrointestinal tract and an opportunistic pathogen, especially thanks to its capacity to form biofilms. This lifestyle is frequently involved in infections and increases the yeast resistance to antimicrobials and immune defenses. In this context,
[...] Read more.
Candida albicans is a commensal coloniser of the human gastrointestinal tract and an opportunistic pathogen, especially thanks to its capacity to form biofilms. This lifestyle is frequently involved in infections and increases the yeast resistance to antimicrobials and immune defenses. In this context, 38 lichen acetone extracts have been prepared and evaluated for their activity against C. albicans planktonic and sessile cells. Minimum inhibitory concentrations of extracts (MICs) were determined using the broth microdilution method. Anti-biofilm activity was evaluated using tetrazolium salt (XTT) assay as the ability to inhibit the maturation phase (anti-maturation) or to eradicate a preformed 24 h old biofilm (anti-biofilm). While none of the extracts were active against planktonic cells, biofilm maturation was limited by 11 of the tested extracts. Seven extracts displayed both anti-maturation and anti-biofilm activities (half maximal inhibitory concentrations IC50_mat and IC50_biof ≤ 100 µg/mL); Evernia prunastri and Ramalina fastigiata were the most promising lichens (IC50_mat < 4 µg/mL and IC50_biof < 10 µg/mL). Chemical profiles of the active extracts performed by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) have been analyzed. Depsides, which were present in large amounts in the most active extracts, could be involved in anti-biofilm activities. This work confirmed that lichens represent a reservoir of compounds with anti-biofilm potential. Full article
(This article belongs to the Special Issue Lichens: Chemistry, Ecological and Biological Activities)
Open AccessArticle Physicochemical Properties of Jatropha Oil-Based Polyol Produced by a Two Steps Method
Molecules 2017, 22(4), 551; doi:10.3390/molecules22040551
Received: 10 February 2017 / Revised: 15 March 2017 / Accepted: 25 March 2017 / Published: 29 March 2017
PDF Full-text (4703 KB) | HTML Full-text | XML Full-text
Abstract
A low cost, abundant, and renewable vegetable oil source has been gaining increasing attention due to its potential to be chemically modified to polyol and thence to become an alternative replacement for the petroleum-based polyol in polyurethane production. In this study, jatropha oil-based
[...] Read more.
A low cost, abundant, and renewable vegetable oil source has been gaining increasing attention due to its potential to be chemically modified to polyol and thence to become an alternative replacement for the petroleum-based polyol in polyurethane production. In this study, jatropha oil-based polyol (JOL) was synthesised from non-edible jatropha oil by a two steps process, namely epoxidation and oxirane ring opening. In the first step, the effect of the reaction temperature, the molar ratio of the oil double bond to formic acid, and the reaction time on the oxirane oxygen content (OOC) of the epoxidised jatropha oil (EJO) were investigated. It was found that 4.3% OOC could be achieved with a molar ratio of 1:0.6, a reaction temperature of 60 °C, and 4 h of reaction. Consequently, a series of polyols with hydroxyl numbers in the range of 138–217 mgKOH/g were produced by oxirane ring opening of EJOs, and the physicochemical and rheological properties were studied. Both the EJOs and the JOLs are liquid and have a number average molecular weight (Mn) in the range of 834 to 1457 g/mol and 1349 to 2129 g/mol, respectively. The JOLs exhibited Newtonian behaviour, with a low viscosity of 430–970 mPas. Finally, the JOL with a hydroxyl number of 161 mgKOH/g was further used to synthesise aqueous polyurethane dispersion, and the urethane formation was successfully monitored by Fourier Transform Infrared (FTIR). Full article
Figures

Open AccessArticle Modification of Natural Eudesmane Scaffolds via Mizoroki-Heck Reactions
Molecules 2017, 22(4), 652; doi:10.3390/molecules22040652
Received: 3 March 2017 / Revised: 4 April 2017 / Accepted: 5 April 2017 / Published: 20 April 2017
PDF Full-text (4022 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The Mizoroki-Heck reaction was applied to substrates derived from isocostic and ilicic acids, important sesquiterpene components of Dittrichia viscosa L. Greuter that were extracted directly from plant material collected in Morocco. After optimization of the metallo-catalysis conditions, various aryl-groups were successfully introduced on
[...] Read more.
The Mizoroki-Heck reaction was applied to substrates derived from isocostic and ilicic acids, important sesquiterpene components of Dittrichia viscosa L. Greuter that were extracted directly from plant material collected in Morocco. After optimization of the metallo-catalysis conditions, various aryl-groups were successfully introduced on the exocyclic double bond with an exclusive E-configuration and without racemization. Full article
(This article belongs to the collection Bioactive Compounds)
Figures

Figure 1

Open AccessArticle Gamma-Aminobutyric Acid Increases the Production of Short-Chain Fatty Acids and Decreases pH Values in Mouse Colon
Molecules 2017, 22(4), 653; doi:10.3390/molecules22040653
Received: 10 March 2017 / Revised: 12 April 2017 / Accepted: 14 April 2017 / Published: 20 April 2017
PDF Full-text (8629 KB) | HTML Full-text | XML Full-text
Abstract
Gamma-Aminobutyric acid (GABA) could regulate physiological functions in the gastrointestinal tract. The present study aimed to investigate the effect of GABA on colon health in mice. The female Kunming mice were given GABA at doses of 5, 10, 20 and 40 mg/kg/d for
[...] Read more.
Gamma-Aminobutyric acid (GABA) could regulate physiological functions in the gastrointestinal tract. The present study aimed to investigate the effect of GABA on colon health in mice. The female Kunming mice were given GABA at doses of 5, 10, 20 and 40 mg/kg/d for 14 days. Afterwards, the short-chain fatty acids (SCFAs) concentrations, pH values, colon index, colon length and weight of colonic and cecal contents were determined to evaluate the effects of GABA on colon health. The results showed that intake of GABA could increase the concentrations of acetate, propionate, butyrate and total SCFAs in colonic and cecal contents, as well as the weight of colonic and cecal contents. The colon index and length of the 40 mg/kg/d GABA-treated group were significantly higher than those of the control group (p < 0.05). In addition, decrease of pH values in colonic and cecal contents was also observed. These results suggest that GABA may improve colon health. Full article
(This article belongs to the Section Medicinal Chemistry)
Figures

Open AccessArticle Absorption, Metabolic Stability, and Pharmacokinetics of Ginger Phytochemicals
Molecules 2017, 22(4), 553; doi:10.3390/molecules22040553
Received: 17 December 2016 / Revised: 27 February 2017 / Accepted: 1 March 2017 / Published: 30 March 2017
PDF Full-text (1091 KB) | HTML Full-text | XML Full-text
Abstract
We have previously demonstrated promising anticancer efficacy of orally-fed whole ginger extract (GE) in preclinical prostate models emphasizing the importance of preservation of the natural “milieu”. Essentially, GE primarily includes active ginger phenolics viz., 6-gingerol (6G), 8-gingerol (8G), 10-gingerol (10G), and 6-shogaol (6S).
[...] Read more.
We have previously demonstrated promising anticancer efficacy of orally-fed whole ginger extract (GE) in preclinical prostate models emphasizing the importance of preservation of the natural “milieu”. Essentially, GE primarily includes active ginger phenolics viz., 6-gingerol (6G), 8-gingerol (8G), 10-gingerol (10G), and 6-shogaol (6S). However, the druglikeness properties of active GE phenolics like solubility, stability, and metabolic characteristics are poorly understood. Herein, we determined the physicochemical and biochemical properties of GE phenolics by conducting in vitro assays and mouse pharmacokinetic studies with and without co-administration of ketoconazole (KTZ). GE phenolics showed low to moderate solubility in various pH buffers but were stable in simulated gastric and intestinal fluids, indicating their suitability for oral administration. All GE phenolics were metabolically unstable and showed high intrinsic clearance in mouse, rat, dog, and human liver microsomes. Upon oral administration of 250 mg/kg GE, sub-therapeutic concentrations of GE phenolics were observed. Treatment of plasma samples with β-glucuronidase (βgd) increased the exposure of all GE phenolics by 10 to 700-fold. Co-administration of KTZ with GE increased the exposure of free GE phenolics by 3 to 60-fold. Interestingly, when the same samples were treated with βgd, the exposure of GE phenolics increased by 11 to 60-fold, suggesting inhibition of phase I metabolism by KTZ but little effect on glucuronide conjugation. Correlating the in vitro and in vivo results, it is reasonable to conclude that phase II metabolism seems to be the predominant clearance pathway for GE phenolics. We present evidence that the first-pass metabolism, particularly glucuronide conjugation of GE phenolics, underlies low systemic exposure. Full article
(This article belongs to the Special Issue Cancer Chemoprevention)
Figures

Figure 1a