Molecules, Volume 18, Issue 3 (March 2013) – 82 articles , Pages 2458-3640

Phytochemical investigation of the 80% ethanol extract of the bulbs of Lycoris radiata resulted in the isolation of five new Amaryllidaceae alkaloids: (+)-5,6-dehydrolycorine (1), (+)-3α,6β-diacetyl-bulbispermine (2), (+)-3α-hydroxy-6β-acetyl- bulbispermine (3), (+)-8,9-methylenedioxylhomolycorine-N-oxide (5), and 5,6-dihydro-5- methyl-2-hydroxyphenanthridine (7), together with two known compounds, (+)-3α-methoxy- 6β-acetylbulbispermine (4) and (+)-homolycorine- N-oxide (6). Structural elucidation of all the compounds were performed by spectral methods such as 1D and 2D (¹H-¹H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. Alkaloid 1 showed potent cytotoxicity against astrocytoma and glioma cell lines (CCF-STTG1, CHG-5, SHG-44, and U251), as well as HL-60, SMMC-7721, and W480 cell lines with IC₅₀ values of 9.4–11.6 μM. Additonally, compound 1 exhibited antimalarial activity with IC₅₀ values of 2.3 μM for D-6 strain and 1.9 μM for W-2 strain of Plasmodium falciparum. Full article

The aim of the present study was to optimize a chromatographic method for the analysis of atorvastatin (acid and lactone forms), ortho- and para-hydroxyatorvastatin by using an experimental design approach. Optimization experiments were conducted through a process of screening and optimization. The purpose of a screening design is to identify the factors that have significant effects on the selected chromatographic responses, and for this purpose a full 2³ factorial design was used. The location of the true optimum was established by applying Derringer’s desirability function, which provides simultaneously optimization of all seven responses. The ranges of the independent variables used for the optimization were content of acetonitrile in mobile phase (60–70%), temperature of column (30–40 °C) and flow rate (0.8–1.2 mL min⁻¹). The influences of these independent variables were evaluated for the output responses: retention time of first peak (p-hydroxyatorvastatin) and of last peak (atorvastatin, lactone form), symmetries of all four peaks and relative retention time of p-hydroxyatorvastatin. The primary goal of this investigation was establishing a new simple and sensitive method that could be used in analysis of biological samples. The method was validated and successfully applied for determination of atorvastatin (acid and lactone forms) and its metabolites in plasma. Full article

Pentaherb formula (PHF) has been proven to improve the quality of life of children with atopic dermatitis without side effects. The aim of this study was to elucidate the potential anti-inflammatory and anti-allergic activities of PHF, Moutan Cortex (Danpi/DP) and gallic acid (GA) using human basophils (KU812 cells), which are crucial effector cells in allergic inflammation. PHF, DP and GA could significantly suppress the expression of allergic inflammatory cytokine IL-33-upregulated intercellular adhesion molecule (ICAM)-1, and the release of chemokines CCL2, CCL5, CXCL8 and inflammatory cytokine IL-6 from KU812 cells (all p < 0.05). With the combined use of dexamethasone (0.01 μg/mL) and GA (10 μg/mL), the suppression of ICAM-1 expression and CCL5 and IL-6 release of IL-33-activated KU812 cells were significantly greater than the use of GA alone (all p < 0.05). The suppression of the IL-33-induced activation of intracellular signalling molecules p38 mitogen activated protein kinase, nuclear factor-kB and c-Jun amino-terminal kinase in GA-treated KU812 cells could be the underlying mechanism for the suppression on ICAM-1, chemokines and cytokines. The combined use of dexamethasone with the natural products PHF or DP or GA might therefore enhance the development of a novel therapeutic modality for allergic inflammatory diseases with high potency and fewer side effects. Full article

A number of novel benzimidazolium salts having aryl substituents such as N-phenyl, 4-chlorophenyl and various alkyl substituents were synthesized. Their microwave-assisted catalytic activities were evaluated in Heck-Mizoroki and Suzuki-Miyaura cross-coupling reactions using a catalytic system consisting of Pd(OAc)₂/K₂CO₃ in DMF/H₂O under mild reaction conditions with consistent high yields, except those of 2-bromopyridine. Full article

A series of substituted ethyl 1-[(tert-butoxycarbonyl)amino]-2-methyl-5- (1-methyl-1H-indol-3-yl)-4-[(1-methyl-1H-indol-3-yl)carbonyl]-1H-pyrrole-3-carboxylates were prepared in excellent yields (82-98%) by one-pot reactions between β-dicarbonyl compounds 12a–e and 1,2-diaza-1,3-diene (DD) 13. Derivatives 10a,c–e, deazaanalogues of the bis-indole alkaloid topsentin, screened by the National Cancer Institute (Bethesda, MD, USA) in the in vitro one dose primary anticancer assay against a panel of about 60 human tumor cell lines, showed no significant activity, with the exception of compound 9e, which showed moderate activity against the HOP-92 cell line of the non small cell lung cancer sub-panel and the SNB-75 cell line of the CNS sub-panel. Full article

This present work describes the application of liquid chromatograpy-solid phase extraction-nuclear magnetic resonance spectroscopy to analyse Alternaria alternata crude extracts. Altenusin (1), alternariol (2), 3'-hydroxyalternariol monomethyl ether (3), and alternariol monomethyl ether (4), were separated and identified. High-resolution mass spectrometry confirmed the proposed structures. The cytotoxic effects of these compounds towards plants were determined using soybean (Glycine max) cell cultures as a model. EC₅₀ values which range from 0.11 (±0.02) to 4.69 (±0.47) μM showed the high cytotoxicity of these compounds. Full article

Methyl antcinate A (MAA) is an ergostane-type triterpenoid extracted from the fruiting bodies of Antrodia camphorate that has been reported to be a cytotoxic agent towards some types of cancer cells, such as oral cancer and liver cancer. Cancer stem cells (CSCs) are a particular population within cancer cells which are responsible for tumor initiation, drug resistance and metastasis and targeting CSCs is an emerging area in cancer therapy. In this study, we examine the effect of MAA on cancer stem-like cells in the MCF7 human breast cancer cell line. Although MAA displayed very low cytotoxic effect towards MCF7 under normal culture conditions, it did show good inhibitory effects on the self-renewal capability which was examined by mammosphere culture including primary and secondary sphere. MAA also inhibited cell migration ability of MCF7 sphere cells. By western blot analysis, MAA was shown to suppress the expression of heat shock protein 27 and increase the expression of IkBα and p53. In conclusion, our data demonstrate that MAA has anti-CSC activity and is worthy of future development of potent anticancer agents. Full article

The need to explore new alternative therapeutic strategies and chemoprevention methods for hepatocellular carcinoma is growing significantly. Selenium is a trace element that plays a critical role in physiological processes, and is used in cancer chemoprevention. The aim of this work was to test in vitro the effect of sodium selenite on the human hepatoma cell lines, HepG2 and Huh7, to assess its effect on the expression of GPX1, SELK and SELENBP1 and also to evaluate its action on inflammation determinants such as cytokines. Our results show that: (i) the increase observed for the GPX1 and SELK expression is correlated with an increase in the sodium selenite concentration, also evidencing an inverse association between the levels of these two proteins and SELENBP1; (ii) the selenium concentrations evaluated in protein extracts increase in proportional way with the selenite concentrations used in the treatment, suggesting that other selenoproteins can also be modulated and should be evaluated in further studies, and (iii) some cytokines, VEGF and three pro-inflammatory cytokines, i.e., IL-6, IL-8, and IL-17, decreased with an increasing selenite concentration. Finally, interactomic studies show that GPX1 and SELK, and the four pro-inflammatory cytokines are functionally correlated evidencing a putative anti-inflammatory role for the selenite. Full article

A new hydroxychavicol dimer, 2-(g'-hydroxychavicol)-hydroxychavicol (1), was isolated from the roots of Piper betle Linn. along with five known compounds, hydroxychavicol (2), aristololactam A II (3), aristololactam B II (4), piperolactam A (5) and cepharadione A (6). The structures of these isolated compounds were elucidated by spectroscopic methods. Compounds 1 and 2 exhibited inhibitory effects on the generation of superoxide anion and the release of elastase by human neutrophils. Full article

N-acetylneuraminic acid (Neu5Ac) represents the most common terminal carbohydrate residue in many mammalian glycoconjugates and is directly involved in a number of different physiological as well as pathological cellular processes. Endogenous sialic acids derive from the biosynthetic precursor molecule N-acetyl-D-mannosamine (ManNAc). Interestingly, N-acyl-analogues of D-mannosamine (ManN) can also be incorporated and converted into corresponding artificial sialic acids by eukaryotic cells. Within this study, we optimized a protocol for the chemical synthesis of various peracetylated ManN derivatives resulting in yields of approximately 100%. Correct molecular structures of the obtained products ManNAc, N-propanoyl-ManN (ManNProp) and N-butyl-ManN (ManNBut) were verified by GC-, ESI-MS- and NMR-analyses. By applying these substances to human umbilical vein endothelial cells (HUVECs), we could show that each derivative was metabolized to the corresponding N-acylneuraminic acid variant and subsequently incorporated into nascent glycoproteins. To investigate whether natural and/or artificial sialic acid precursors are able to modulate the angiogenic capacity of HUVECs, a spheroid assay was performed. By this means, an increase in total capillary length has been observed when cells incorporated N-butylneuraminic acid (Neu5But) into their glycoconjugates. In contrast, the natural precursor ManNAc inhibited the growth of capillaries. Thus, sialic acid precursors may represent useful agents to modulate blood vessel formation. Full article

One novel triterpene cycloartane-type, named hirtinone (1), six protolimonoids – nilocitin (2), dihydronilocitin B (3), melianone epimers (4) and (5), piscidinol A (6) and melianone lactone (7), one tertranortriterpenoid, hirtin (8), and one sesquiterpene, spathulenol (9), were identified in the fruits of Trichilia hirta. The structures were established by 1D and 2D NMR (¹H and ¹³C-NMR, DEPTQ, ¹H-¹H-COSY, ¹H-¹H-NOESY, HSQC and HMBC), high resolution mass spectroscopy (HR-ESI-MS) and infrared (IR) spectral data. Full article

Three new triterpene glycosides, named ulososide F (1), urabosides A (2) and B (3), together with the previously reported ulososide A (4), were isolated from the Caribbean marine sponge Ectyoplasia ferox. Their structures were elucidated using extensive interpretation of 1D and 2D-NMR data, as well as HRESIMS. The aglycon of all compounds is a rare 30-norlonastane and the sugar residues were identified after acid hydrolysis and GC analyses. Cytotoxicities of the isolated compounds were evaluated against Jurkat and CHO cell lines by a MTT in vitro assay as well as a hemolysis assay. Unexpectedly, all these saponin derivatives showed very low activity in our bioassays. Full article

The direct nucleophilic addition of alkyl amines to the α(δ')-carbon atom of dimethyl (E)-hex-2-en-4-ynedioate to generate α,β-dehydroamino acid derivatives is reported. Herein, we have studied the reactivity of various primary and secondary alkyl amines in the α-selective nucleophilic conjugate addition to conjugated dimethyl (E)-hex-2-en-4-ynedioate. The reaction with primary alkyl amines gives only the (2E,4E)-stereoisomer, while that with secondary alkyl amines gives the (2E,4E) and (2Z,4E)-stereoisomers of dimethyl (2-alkylamino)-muconic ester. Full article

Alkaloids with allelopathic activity are not as well-known as other allelochemicals. Our study revealed that total alkaloids from seeds of the medicinal plant Peganum harmala L. possessed significant growth inhibitory effect on four treated plants, with dicot plants (lettuce and amaranth) being more sensitive than the tested monocot plants (wheat and ryegrass). Further investigation led to the isolation of harmaline and harmine as the main active ingredients in the total alkaloids of P. harmala seeds. Harmaline exerted potent inhibitory effects on seedling growth of treated plants, especially dicots, inhibiting root elongation of lettuce and amaranth by 31% and 47% at a very low concentration (5 µg/mL), whereas harmine exhibited much weaker non-selective inhibitory effect on the plants. Considering the high yield and poor utilization of P. harmala in China, we anticipate that this plant could be exploited as an alternative weed management tool in the future. Full article

The aim of this study was to determine volatile compounds in dry dog foods and their possible influence on sensory aromatic profile. Grain-free dry dog foods were compared to dry dog foods manufactured with grain, but also with different protein sources for their aromatic volatiles. Solid-phase microextraction/gas chromatography/mass spectrometry was used to determine the aromatic compounds present in the headspace of these samples. Partial Least Squares regression was performed to correlate the instrumental aromatic data with the descriptive aroma analysis data. A total of 54 aromatic compounds were tentatively identified in the dry dog food samples, with aldehydes and ketones being the most represented organic volatiles group. Grain-added products were on the average higher in total volatiles than grain-free products. Partial Least Squares regression analysis indicated possible connections with sensory aromatic profile and grain-added samples, such as rancid aroma and aldehydes, especially hexanal. The results of this study showed that dry dog foods are products with complex odor characteristics and that grain-free products are less aromatic. Full article

A series of 2-pyrazolines 5–9 have been synthesized from α,β-unsaturated ketones 2–4. New 2-pyrazoline derivatives 13–15 bearing benzenesulfonamide moieties were then synthesized by condensing the appropriate chalcones 2–4 with 4-hydrazinyl benzenesulfonamide hydrochloride. Ethyl [1,2,4] triazolo[3,4-c][1,2,4]triazino[5,6-b]-5H-indole-5-ethanoate (26) and 1-(5H-[1,2,4]triazino[5,6-b] indol-3-yl)-3-methyl-1H-pyrazol-5(4H)-one (32) were synthesized from 3-hydrazinyl-5H-[1,2,4]triazino[5,6-b]indole (24). On the other hand ethyl[1,2,4]triazolo[3,4-c][1,2,4]triazino[5,6-b]-5,10-dihydroquinoxaline- 5-ethanoate (27) and 1-(5,10-dihydro-[1,2,4]triazino[5,6-b]quinoxalin-3-yl)-3-methyl-1H-pyrazol-5(4H)-one (33) were synthesized from 3-hydrazinyl-5,10-dihydro-[1,2,4]triazino[5,6-b]quinoxaline (25) by reaction with diethyl malonate or ethyl acetoacetate, respectively. Condensation of 6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (1') with compound 24 or 25 afforded the corresponding Schiff's bases 36 and 37, respectively. Reaction of the Schiff's base 37 with benzoyl hydrazine or acetic anhydride afforded benzohydrazide derivative 39 and the cyclized compound 40, respectively. Furthermore, the pyrazole derivatives 42–44 were synthesized by cyclization of hydrazine derivative 25 with the prepared chalcones 2–4. All the newly synthesized compounds have been characterized on the basis of IR and ¹H-NMR spectral data as well as physical data. Antimicrobial activity against the organisms E. coli ATCC8739 and P. aeruginosa ATCC 9027 as examples of Gram-negative bacteria, S. aureus ATCC 6583P as an example of Gram-positive bacteria and C. albicans ATCC 2091 as an example of a yeast-like fungus have been studied using the Nutrient Agar (NA) and Sabouraud Dextrose Agar (SDA) diffusion methods. The best performance was found for the compounds 16, 17, 19 and 20. Full article

Several families of photosensitizers are currently being scrutinized for antimicrobial photodynamic therapy applications. Differences in physical and photochemical properties can lead to different localization patterns as well as differences in singlet oxygen production and decay when the photosensitizers are taken up by bacterial cells. We have examined the production and fate of singlet oxygen in Escherichia coli upon photosensitization with three structurally-different cationic photosensitizers, namely New Methylene Blue N (NMB), a member of the phenothiazine family, ACS268, a hydrophobic porphyrin with a single cationic alkyl chain, and zinc(II)-tetramethyltetrapyridinoporphyrazinium salt, a phthalocyanine-like photosensitizer with four positive charges on the macrocycle core. The kinetics of singlet oxygen production and decay indicate different localization for the three photosensitizers, whereby NMB appears to localize in an aqueous-like microenvironment, whereas ACS268 localizes in an oxygen-shielded site, highly reactive towards singlet oxygen. The tetracationic zinc(II) tetrapyridinoporphyrazine is extensively aggregated in the bacteria and fails to produce any detectable singlet oxygen. Full article

The present study investigates the anti-hyperlipidemic and antihyperglycemic effects and mechanism in high-fat (HF)-fed mice of cell suspension culture of Eriobotrya japonica (TA), which contains a great number of pentacyclic terpenoids. Firstly, C57BL/6J mice were randomly divided into two groups: the control (CON) group was fed with a low-fat diet (n = 9), whereas the experimental group was fed a 45% HF diet for 8 weeks. Afterwards, the CON group was treated with vehicle, whereas the HF group was subdivided into five groups and was orally given TA or rosiglitazone or not for 4 weeks. Blood and visceral adipose tissue, liver tissue and skeletal muscle were examined. Treatment with TA reduced body weight gain, weights of white adipose tissue (WAT) (including epididymal, perirenal, mesenteric WAT and visceral fat), and hepatic triacylglycerol content significantly without affecting food intake in diet-induced diabetic mice. TA effectively prevented HF diet-induced increases in the levels of blood glucose, insulin, leptin and HOMA-IR index (p < 0.001, p < 0.05, p < 0.05, p < 0.01, respectively) and attenuated insulin resistance. Treatment with TA, adipocytes in the visceral depots showed a reduction in size. TA effectively significantly increased the protein contents of phosphorylation of AMPK-α (Thr172) both in liver and adipose tissue. It is shown that TA exhibits hypolipidemic effect in HF-fed mice by decreasing gene expressions of fatty acid synthesis, including acyl-coenzyme A: diacylglycerol acyltransferase (DGAT) 2, which catalyzes the final step in the synthesis of triglycerides, and antidiabetic properties occurred as a result of decreased hepatic glucose production via phosphenolpyruvate carboxykinase (PEPCK) down- regulation, improved insulin sensitization and TA (at 1.0 g/kg dose) decreased expression of hepatic and adipose 11-β-hydroxysteroid dehydroxygenase (11β-HSD1) gene, which contributed in attenuating diabetic state. Futhermore, TA at doses of 0.5 and 1.0 g/kg had serum lipid-lowering action characterized by the inhibition of DGAT 1 expression. Thus, amelioration of diabetic and dyslipidemic state by TA in HF-fed mice occurred by regulation of PEPCK, DGAT2 and AMPK phosphorylation. Full article

Fraxinellone, a well-known and significant naturally occurring compound isolated from Meliaceae and Rutaceae spp. has been widely used as a drug for the treatment of tumors. On the other hand, fraxinellone exhibited a variety of insecticidal activities including feeding-deterrent activity, inhibition of growth, and larvicidal activity. The present study focused on the antifeedant and larvicidal activities of fraxinellone against the larvae of Lepidoptera, including Mythimna separata, Agrotis ypsilon, Plutella xylostella, and one kind of sanitary pest, Culux pipiens pallens. Meanwhile, the ovicidal activities and the effects of fraxinellone on the larval development of M. separata were also observed. The LC₅₀ values of fraxinellone against 3rd instar larvae of M. separata, 2nd instar larvae of P. xylostella and 4th instar larvae of C. pipiens pallens were 15.95/6.43/3.60 × 10⁻² mg mL⁻¹, and its AFC₅₀ values against 5th instar larvae of M. separata, 2nd instar larvae of P. xylostella and 2nd instar larvae of A. ypsilon were 10.73/7.93/12.58 mg mL⁻¹, respectively. Compared with the control group, fraxinellone obviously inhibited the pupation rate and the growth of M. separata. Once M. separata was treated with fraxinellone at concentrations of 5.0, 10.0, and 20.0 mg mL⁻¹, respectively, the stages from the larvae to adulthood and the egg hatching duration were prolonged to 1/2/3, and 4/3/4 days, respectively. Additionally, fraxinellone strongly inhibited the development rate and the egg hatch proportion of M. separata. Full article

The new compound Z-4-2 was isolated from the fermentation broth of Streptomyces djakartensis NW35, together with the known compound N-acetyltryptamine (Z-9-2) by bioassay-guided fractionation. Its chemical structure was elucidated as (E)-2-methoxy-1,4 naphthoquinone-1-oxime (Z-4-2) mainly by NMR analyses and MS spectral data. Their antibacterial activities against bacteria were evaluated by the filter paper method. The results of indicated that these compounds possess significant antibacterial activities. Full article

The phytochemical study of Sida rhombifolia L. (Malvaceae) led to the isolation through chromatographic techniques of eleven secondary metabolites: sitosterol (1a) and stigmasterol (1b), sitosterol-3-O-b-D-glucopyranoside (2a) and stigmasterol-3-O-b-D-glucopyranoside (2b), phaeophytin A (3), 17³-ethoxypheophorbide A (4), 13²-hydroxy phaeophytin B (5), 17³-ethoxypheophorbide B (6), 5,7-dihydroxy-4'-methoxyflavone (7), cryptolepinone (8) and a salt of cryptolepine (9). Their structures were identified by ¹H- and ¹³C-NMR using one- and two-dimensional techniques. In addition, the vasorelaxant activity of cryptolepinone in rat mesenteric artery rings is reported herein for the first time. Full article

Racemic [(±)-4-isopropyl-1-methyl-7-oxa-cis-bicyclo[4.3.0]non-4-en-8-one] and optically active d,e-unsaturated lactones [(-)-(1R,6R)-4-isopropyl-1-methyl-7-oxabicyclo[4.3.0]non-4-en-8-one and (+)-(1S,6S)-4-isopropyl-1-methyl-7-oxabicyclo[4.3.0] non-4-en-8-one)] with the p-menthane system were obtained and their odoriferous properties were evaluated. Biotransformations of the racemic lactone with three fungal strains: Absidia cylindrospora AM336, Absidia glauca AM177 and Syncephalastrum racemosum AM105, were carried out. Microbial transformations afforded hydroxylactones with the hydroxy group in the allylic position. Full article

BINAP aminophosphines are prevalent N,P-bidentate, chiral ligands for asymmetric catalysis. While modification via the BINAP-nitrogen linkage is well explored and has provided a diverse body of derivatives, modification of the other substituents of the phosphorous center is another avenue in generating new congeners of this important class of chiral ligands. Herein reported are new BINAP aryl aminophosphines with electron rich or deficient substituents on the aryl rings. This scalable synthesis converted readily available starting material, (S)-BINOL, to a key intermediate (S)-NOBIN, from which the final chiral aminophosphines were prepared via a palladium-catalyzed, phosphonylation reaction. The aryl substituents are able to modify the electronic properties of the phosphorous center as indicated by the range of ³¹P-NMR shifts of these new ligands. A computational analysis was performed to linearly quantitate contributions to the ³¹P-NMR shifts from both resonance and field effects of the substituents. This correlation may be useful for designing and preparing other related aminophosphines with varying ligand properties. Full article

The present study investigates the chemical composition of the African plant Parkia biglobosa (Fabaceae) roots and barks by Liquid Chromatography - Electrospray Ionization and Direct Injection Tandem Mass Spectrometry analysis. Mass spectral data indicated that B-type oligomers are present, namely procyanidins and prodelphinidins, with their gallate and glucuronide derivatives, some of them in different isomeric forms. The analysis evidenced the presence of up to 40 proanthocyanidins, some of which are reported for the first time. In this study, the antiradical activity of extracts of roots and barks from Parkia biglobosa was evaluated using DPPH method and they showed satisfactory activities. Full article

Apocynin is the most employed inhibitor of NADPH oxidase (NOX), a multienzymatic complex capable of catalyzing the one-electron reduction of molecular oxygen to the superoxide anion. Despite controversies about its selectivity, apocynin has been used as one of the most promising drugs in experimental models of inflammatory and neurodegenerative diseases. Here, we aimed to study the chemical and biophysical properties of apocynin. The oxidation potential was determined by cyclic voltammetry (Epa = 0.76V), the hydrophobicity index was calculated (logP = 0.83) and the molar absorption coefficient was determined (e_275nm = 1.1 × 10⁴ M⁻¹ cm⁻¹). Apocynin was a weak free radical scavenger (as measured using the DPPH, peroxyl radical and nitric oxide assays) when compared to protocatechuic acid, used here as a reference antioxidant. On the other hand, apocynin was more effective than protocatechuic acid as scavenger of the non-radical species hypochlorous acid. Apocynin reacted promptly with the non-radical reactive species H₂O₂ only in the presence of peroxidase. This finding is relevant, since it represents a new pathway for depleting H₂O₂ in cellular experimental models, besides the direct inhibition of NADPH oxidase. This could be relevant for its application as an inhibitor of NOX4, since this isoform produces H₂O₂ and not superoxide anion. The binding parameters calculated by fluorescence quenching showed that apocynin binds to human serum albumin (HSA) with a binding affinity of 2.19 × 10⁴ M⁻¹. The association did not alter the secondary and tertiary structure of HSA, as verified by synchronous fluorescence and circular dichroism. The displacement of fluorescent probes suggested that apocynin binds to site I and site II of HSA. Considering the current biomedical applications of this phytochemical, the dissemination of these chemical and biophysical properties can be very helpful for scientists and physicians interested in the use of apocynin. Full article

Two new limonoids, toonins A (1) and B (2), and one new dihydrobenzofuran norlignan, toonin C (3), were isolated from the roots of Toona sinensis together with the ten known compounds 4-methoxy-6-(2′,4′-dihydroxy-6′-methylphenyl)-pyran-2-one (4), bourjotinolone A (5), proceranone (6), matairesinol (7), 4-hydroxy-3-methoxybenzene-ethanol (8), syringic acid (9), isoscopoletin (10), lyoniresinol (11), aloeemodin (12), and β-sitosterol (13). Their structures were elucidated on the basis of one- and two-dimensional spectroscopic analysis. Isolation of compounds 4, 6–13 from this plant is reported here for the first time. Full article

Several herbal beverages claim medicinal benefits due to their antioxidant properties. However, operational factors such as the extracted herbal component, preparation method or concentration levels, might influence their biological activity. To assess this effect, the antioxidant activity of beverages prepared with Camellia sinensis, Aspalathus linearis or Cochlospermum angolensis, used solely or mixed with different fruit, plant or algae extracts, was studied using different formulations (bags, leaves, roots, granulates, powders, liquids) and different preparation methods (infusion, solubilisation or promptly used). The DF₅₀ (dilution factor responsible for 50% of antioxidant activity) values were calculated to compare their antioxidant activity. A linear discriminant analysis was used to categorize the assayed samples according to their antioxidant activity and bioactive molecules profiles. The results indicated that antioxidant activity and antioxidant compounds are significantly affected by formulation and preparation method, but overall the labelled antioxidant benefits were validated. Green tea showed the highest activity, but with different behaviour within each used formulation. The high DF₅₀ values calculated for some products might be used to adjust the dietary dose or formulation, preventing also putative pro-oxidant effects. Hence, the obtained results might be useful to define the formulation of these highly consumed herbal beverages, enhancing their health effects. Full article

The manuscript describes the synthesis of 10-substituted dihydroartemisinin derivatives containing N-aryl phenylethenesulfonamide groups and their in vitro anti-tumor activities against the HT-29, MDA-MB-231, U87MG, H460, A549 and HL-60 cancer cell lines and the normal WI-38 cell line. Most tested compounds showed enhanced cytotoxic activities and good selectivity toward the MDA-MB-231, HT-29 and HL-60 cell lines, with IC₅₀ values in the single-digit μM range as compared with dihydroartemisinin (DHA), and all of them displayed less toxicity towards WI-38 cells. Among them, compounds 3c and 6c with trifluoromethoxy groups on the N-phenyl ring were found to be most active compounds against the six tested cancer cell lines. Full article

Computer simulations constitute the basis of the design and discovery of new drugs. This approach is not only significant with regards to finding new structures, but also for selecting the molecules with the highest probability of being useful in the diagnostic process and treatment of numerous diseases. In our work, we used computational software to analyze 32 new acetylcholinesterase (AChE) inhibitors and formulate ADMET predictions. To understand the influence of the structure of our derivatives on binding mode, we docked all structures to the active site of AChE and assigned some pharmacophoric features. Finally, we undertook a chemometric analysis of all the compounds on the basis of FT-IR, which gave us the possibility of performing a fast categorization of the analyzed compounds and design compounds with similar structures. Full article

A new sterol, (22R,23R,24R)-5α,8α-epidioxy-22,23-methylene-24-methyl-cholest-6,9(11)-dien-3β-ol (1), and two known sterols, (22R,23R,24R)-5α,8α-epidioxy-22,23-methylene-24-methylcholest-6-en-3β-ol (2) and 24-methylenecholestane-1α,3β,5α, 6β,11α-pentol (3), were isolated from the soft coral Sinularia gaweli. The structure of sterol 1 was established by spectroscopic methods and by comparison of the spectral data with those of known analogues. The cytotoxicity of sterols 1–3 towards various tumor cells is reported. Full article

Based on the hybrid pharmacophore design concept, a novel series of dual diaryl urea and N-acylhydrazone derivatives were synthesized and evaluated for their in vitro cytotoxicity by the standard MTT assay. The pharmacological results indicated that most compounds exhibited moderate to excellent activity. Moreover, compound 2g showed the most potent cytotoxicity against HL-60, A549 and MDA-MB-231 cell lines, with IC₅₀ values of 0.22, 0.34 and 0.41 μM, respectively, which was 3.8 to 22.5 times more active than the reference compounds sorafenib and PAC-1. The promising compound 2g thus emerges as a lead for further structural modifications. Full article

5-Episinuleptolide acetate (5EPA), a cytotoxic norcembranoidal diterpene recently identified from the Formosan soft coral Sinularia sp., exhibited potent activity against the K562, Molt 4 and HL 60 cancer cell lines. The antiproliferative assay, as well as the annexin V-FITC/propidium iodide (PI) apoptotic assay, indicated that the HL 60 cell line is the most sensitive one towards 5EPA. This diterpenoid led to caspases -3, -8, and -9 activation as well as PARP cleavage. It also induced ROS generation, calcium accumulation and disruption of mitochondrial membrane potential. Additionally, the expression levels of Hsp90 protein and several client proteins were downregulated in response to 5EPA treatment. These results suggest that 5EPA’s cytotoxic effect on HL 60 cells may be attributed to the inhibition of Hsp90 as well as the induction of mitochondrial stress which finally results in apoptotic cell death. Full article

A high performance liquid chromatography coupled with diode array and evaporative light scattering detection (HPLC-DAD-ELSD) method for simultaneous determination of eight major bioactive compounds including two flavonoids (rutin and eriodictyol-7-O-β-D-glucopyranoside), two isochlorogenic acids (isochlorogenic acid A and isochlorogenic acid C) and four triterpenoids (ilexhainanoside D, ilexsaponin A₁, ilexgenin A and ursolic acid) in Ilex hainanensis has been developed for the first time. The 283 nm wavelength was chosen for determination of two flavonoids and two isochlorogenic acids. ELSD was applied to determine four triterpenoids. The analysis was performed on an Agilent Zorbax SB-C₁₈ column (250 × 4.6 mm i.d., 5 µm) with gradient elution of 0.2% formic acid in water and acetonitrile. The method was validated for linearity, limit of detection, limit of quantification, precision, repeatability and accuracy. The proposed method has been successfully applied for simultaneous quantification of the analytes in four samples of Ilex hainanensis, which is helpful for quality control of this plant. Full article

Five new syringyl acylated flavonol glycosides, named leonurusoides A (1), B (2), C (3), D (4), and E (5), together with one known one 6 were obtained from the aerial parts of Leonurus japonicus. Their structures were elucidated by chemical and spectroscopic methods (UV, IR, HRESI-TOF-MS, 1D and 2D NMR). Compounds 1-6 showed triglyceride (TG) accumulation inhibitory effects in free fatty acid-induced HepG2 cells. Full article

The versatile oligosaccharide biopolymers, chitin and chitosan, are typically produced using enzymatic processes. However, these processes are usually costly because chitinases and chitosanases are available in limited quantities. Fortunately, a number of commercial enzymes can hydrolyze chitin and chitosan to produce long chain chitin or chitosan oligosaccharides. Here, a platform to screen for enzymes with chitinase and chitosanase activities using a single gel with glycol chitin or glycol chitosan as a substrate was applied. SDS-resistant chitinase and chitosanase activities were observed for pancreatin. Its chitotriosidase had an optimal hydrolysis pH of 4 in the substrate specificity assay. This activity was thermally unstable, but independent of 2-mercaptoethanol. This is the first time a chitotriosidase has been identified in the hog. This finding suggests that oligochitosaccharides can be mass-produced inexpensively using pancreatin. Full article

Fractionation of the chloroform extract of Wikstroemia coriacea led to the isolation of two new compounds, oleodaphnoic acid (1), a guaiane-type sesquiterpenoid, and coriaceol (2), an 1,5-diphenyl-1-pentanone analogue, together with nine known compounds. The structures of 1 and 2 were elucidated by extensive spectroscopic data analysis. The known compounds were oleodaphnal (3), indicanone (4), (5R,8R,8aR)-3,8-dimethyl-4,5,6,7,8,8a-hexahydro-5-(1-methylethenyl)-2(1H)-azulenone, (5), 1,5 diphenyl-1-pentanone (6), (+)-3-hydroxy-1,5-diphenyl-1-pentanone (7), umbelliferone (8), daphnoretin (9), β-sitostenone (10) and (−)-hinokinin (11). Full article

Polyphenols, antioxidant potential and color of three types of fortified Madeira wines were evaluated during the accelerated ageing, named as estufagem. The traditional estufagem process was set to 45 °C for 3 months. Overheating conditions, 1 month at 70 °C, were also examined. Total polyphenols (TP), total monomeric anthocyanins (TMA) and total flavonoids (TF) were assessed by spectrophotometric methods, while individual polyphenols and furans were simultaneously determined by HPLC-DAD. Antioxidant potential (AP) was estimated by ABTS, DPPH and FRAP assays, while color was evaluated by Glories and CIELab. Traditional estufagem decreased the TP and AP up to 20% and 26%, respectively, with final values similar to other wines. TMA of the Madeira wines from red grapes decreased during estufagem. Six hydroxybenzoic acids, three hydroxycinnamic acids, one stilbene, three flavonols and three flavan-3-ols were found in these wines. The prominent phenolics were hydroxycinnamates and hydroxybenzoates, even after estufagem. Most polyphenols decreased, with the exception of caffeic, ferulic, p-coumaric, gallic and syringic acids. Finally, both chromatic systems revealed that all wines tended to similar chromatic characteristics after estufagem. The study suggests that estufagem can be applied without high impact on polyphenols and antioxidant potential of these fortified wines. Full article

In an effort to find potent inhibitors of the protein kinases DYRK1A and CDK1/Cyclin B, a systematic in vitro evaluation of 2,500 plant extracts from New Caledonia and French Guyana was performed. Some extracts were found to strongly inhibit the activity of these kinases. Four aristolactams and one lignan were purified from the ethyl acetate extracts of Oxandra asbeckii and Goniothalamus dumontetii, and eleven aporphine alkaloids were isolated from the alkaloid extracts of Siparuna pachyantha, S. decipiens, S. guianensis and S. poeppigii. Among these compounds, velutinam, aristolactam AIIIA and medioresinol showed submicromolar IC₅₀ values on DYRK1A. Full article

The roles of cytochrome P450 monooxygenases (CYPs) from Streptomyces spp. which are called the “treasure islands” for natural products for medicine and antibiotics are not well understood. Substrate specificity studies on CYPs may give a solution for elucidation of their roles. Based on homology sequence information, the CYP105D7 of a soluble cytochrome P450 known as heme protein from Streptomyces avermitilis MA4680 was expressed using the T7 promoter of the bacterial expression vector pET24ma, over-expressed in Escherichia coli system and characterized. An engineered whole cell system for daidzein hydroxylation was constructed using an exogenous electron transport system from ferredoxin reductase (PdR) and ferredoxin (Pdx). Also, an in vitro reaction study showed the purified CYP105D7 enzyme, using NADH-dependent-reducing equivalents of a redox partner from Pseudomonas putida, hydroxylated daidzein at the 3' position of the B ring to produce 7,3,'4' trihydroxyisoflavone. The hydroxylated position was confirmed by GC-MS analysis. The turnover number of the enzyme was 0.69 μmol 7,3,'4'-trihydroxyisoflavone produced per μmol P450 per min. This enzyme CYP105D7 represents a novel type of 3'-hydroxylase for daidzein hydroxylation. A P450 inhibitor such as coumarin significantly (ca.98%) inhibited the daidzein hydroxylation activity. Full article

Three new acyclic monoterpenoids named (2E)-3,7-dimethylocta-2,6-dienoate-6-O-a-L-arabinopyranosyl-(1®6)-b-D-glucopyranoside (1), (3Z,6E)-3,7-dimethyl-3,6-octadiene-1,2,8-triol (2) and (6E)-7-methyl-3-methylene-6-octene-1,2,8-triol (3) were isolated from Acanthopanax sessiliflorus fruits, along with three known monoterpenoid compounds. The structures of the new compounds were determined by means of extensive spectroscopic analysis (1D, 2D NMR and HRESIMS) and chemical methods. Full article

A sensitive and accurate ultra-performance liquid chromatography coupled with triple quadrupole mass (UPLC-MS/MS) method was developed for the determination of quercetin-3-O-β-D-glucopyranoside-(4→1)-α-L-rhamnoside (QGR) in rat plasma using rutin as internal standard. Chromatographic separation was achieved on a Acquity BEH C₁₈ column (100 mm × 2.1 mm, 1.7 μm) with a gradient elution of acetonitrile and 0.10% formic acid (v/v) at a flow rate of 0.4 mL/min. QGR and rutin were detected using electrospray negative ionization mass spectrometry in the multiple reaction monitoring (MRM) mode. The method demonstrated good linearity and did not show any endogenous interference with the QGR and rutin peaks. This method was successfully applied to a pharmacokinetic study of QGR in rats after intravenous (20 mg/kg) and oral (40 mg/kg) administration, and the results showed that the compound was poorly absorbed, with an absolute bioavailability of approximately 3.41%. Full article

Oleanolic acid (OA) is a triterpenoid and a fantastic molecule with many beneficial effects. However, high-doses and long-term use can produce adverse effects. This study aimed to characterize the hepatotoxic potential of OA. Mice were given OA at doses of 100–3,000 µmol/kg (45–1,350 mg/kg), po for 10 days, and the hepatotoxicity was determined by serum biochemistry, histopathology, and toxicity-related gene expression via real-time RT-PCR. Animal body weight loss was evident at OA doses of 1,000 µmol/kg and above. Serum alanine aminotransferase activities were increased in a dose-dependent manner, indicative of hepatotoxicity. Serum total bilirubin concentrations were increased, indicative of cholestasis. OA administration produced dose-dependent pathological lesions to the liver, including inflammation, hepatocellular apoptosis, necrosis, and feathery degeneration indicative of cholestasis. These lesions were evident at OA doses of 500 µmol/kg and above. Real-time RT-PCR revealed that OA produced dose-dependent increases in acute phase proteins (MT-1, Ho-1, Nrf2 and Nqo1), decreases in bile acid synthesis genes (Cyp7a1 and Cyp8b1), and decreases in liver bile acid transporters (Ntcp, Bsep, Oatp1a1, Oatp1b2, and Ostβ). Thus, the clinical use of OA and OA-type triterpenoids should balance the beneficial effects and toxicity potentials. Full article

The essential oil of Pectis brevipedunculata (EOPB), a Brazilian ornamental aromatic grass, is characterized by its high content of citral (81.9%: neral 32.7% and geranial 49.2%), limonene (4.7%) and α-pinene (3.4%). Vasodilation induced by EOPB and isolated citral was investigated in pre-contracted vascular smooth muscle, using thoracic aorta from Wistar Kyoto (WKY) rats which was prepared for isometric tension recording. EOPB promoted intense relaxation of endothelium-intact and denuded aortic rings with the concentration to induce 50% of the maximal relaxation (IC₅₀) of 0.044% ± 0.006% and 0.093% ± 0.015% (p < 0.05), respectively. The IC₅₀ values for citral in endothelium-intact and denuded rings were 0.024% ± 0.004% and 0.021% ± 0.004%, respectively (p > 0.05). In endothelium-intact aorta, EOPB-induced vasorelaxation was significantly reduced by L-NAME, a nitric oxide synthase inhibitor. The vasodilator activity of citral was increased in the KCl-contracted aorta and citral attenuated the contracture elicited by Ca²⁺ in depolarized aorta. EOPB and citral elicited vasorelaxation on thoracic aorta by affecting the NO/cyclic GMP pathway and the calcium influx through voltage-dependent L-type Ca²⁺ channels, respectively. Full article

Agarwood is the fragrant resin-infused wood derived from the wounded trees of Aquilaria species. It is a valuable non-timber forest product used in fragrances and as medicine. Reforestation for Aquilaria trees in combination with artificial agarwood-inducing methods serves as a way to supply agarwood and conserve of wild Aquilaria stock. However, the existing agarwood-inducing methods produce poor-quality agarwood at low yield. Our study evaluated a novel technique for producing agarwood in cultivated Aquilaria trees, called the whole-tree agarwood-inducing technique (Agar-Wit). Ten different agarwood inducers were used for comparison of Agar-Wit with three existing agarwood-inducing methods. For Aquilaria trees treated with these ten inducers, agarwood formed and spread throughout the entire tree from the transfusion point in the trunk to the roots and branches of the whole tree. Agarwood yield per tree reached 2,444.83 to 5,860.74 g, which is 4 to 28 times higher than that by the existing agarwood-inducing methods. Furthermore, this agarwood derived from Agar-Wit induction was found to have a higher quality compared with the existing methods, and similar to that of wild agarwood. This indicates Agar-Wit may have commercial potential. Induction of cultivated agarwood using this method could satisfy the significant demand for agarwood, while conserving and protecting the remaining wild Aquilaria trees. Full article

A donor-acceptor (D-A) type indoline dye, D149, was used as an electron donor in solution-processed organic solar cells (OSCs). For bulk-heterojunction (BHJ) type OSCs with PC₇₀BM as electron acceptor, the power conversion efficiency (PCE) is sensitive to the amount of D149 in the D149/PC₇₀BM blend film. When the concentration of D149 in the blend film was as low as 5%, the highest PCE of up to 1.29%, together with a short-circuit current density (Jsc) of 4.58 mA·cm⁻², an open-circuit voltage (Voc) of 0.90 V and a fill factor (FF) of 0.31, was achieved. In order to improve the PCE of D149-based OSCs, a bilayer-heterojunction configuration with C₇₀ as electron acceptor has been employed. By optimizing the thickness of the D149 layer and varying the electron- and hole-transport layers, a highest PCE of up to 2.28% with a Jsc of 4.38 mA·cm⁻², a Voc of 0.77 V, and an FF of 0.62 was achieved under AM 1.5G solar illumination (100 mW·cm⁻²). Full article

This work concerns the production of fibrous composite materials based on biodegradable polymers such as alginate, dibutyryl chitin (DBC) and poly-ε-caprolactone (PCL). For the production of fibres from these polymers, various spinning methods were used in order to obtain composite materials of different composition and structure. In the case of alginate fibres containing the nanoadditive tricalcium phosphate (TCP), the traditional method of forming fibres wet from solution was used. However in the case of the other two polymers the electrospinning method was used. Two model systems were tested for biocompatibility. The physicochemical and basic biological tests carried out show that the submicron fibres produced using PCL and DBC have good biocompatibility. The proposed hybrid systems composed of micrometric fibres (zinc and calcium alginates containing TCP) and submicron fibres (DBC and PCL) meet the requirements of regenerative medicine. The biomimetic fibre system, the presence of TCP nanoadditive, and the use of polymers with different resorption times provide a framework with specific properties on which bone cells are able to settle and proliferate. Full article

In the work described here, two techniques for the recovery of anthocyanins from potato peel were studied and compared. One of the techniques employed was supercritical fluid extraction (SFE) with pure CO₂ or with CO₂ and ethanol as cosolvent and the other technique was pressurized liquid extraction (PLE), where the solvent used was ethanol in water acidified to pH 2.6. The effects of pressure and temperature were studied and the anthocyanin contents obtained were statistically analyzed. In SFE the use of low pressure (100 bar) and high temperature (65 °C) was desirable for the anthocyanin extraction. With PLE the anthocyanin contents are increased considerably, and the best yields were obtained at 100 bar and 80 °C. This result is in correspondence with antioxidant activity index values (1.66) obtained in a DPPH antioxidant activity assay. In the extracts obtained with PLE the phenolic compounds were also determined, but the main compounds presented in the extract are anthocyanins. Full article

Polymethylmethacrylate–graphene (PMMA/RGO) nanocomposites were prepared via in situ bulk polymerization using two different preparation techniques. In the first approach, a mixture of graphite oxide (GO) and methylmethacrylate monomers (MMA) were polymerized using a bulk polymerization method with a free radical initiator. After the addition of the reducing agent hydrazine hydrate (HH), the product was reduced via microwave irradiation (MWI) to obtain R-(GO-PMMA) composites. In the second approach, a mixture of graphite sheets (RGO) and MMA monomers were polymerized using a bulk polymerization method with a free radical initiator to obtain RGO-(PMMA) composites. The composites were characterized by FTIR, ¹H-NMR and Raman spectroscopy and XRD, SEM, TEM, TGA and DSC. The results indicate that the composite obtained using the first approach, which involved MWI, had a better morphology and dispersion with enhanced thermal stability compared with the composites prepared without MWI. Full article

Cyclopentyl methyl ether (CPME) has been used in chemical synthesis as an alternative to hazardous solvents. According to some earlier investigation by others, CPME has low acute or subchronic toxicity with moderate irritation and negative mutagenicity and negative skin sensitization (Local Lymph Node Assay). Calculated Permitted Daily Exposure (PDE) value of CPME obtained by our 28-day oral toxicity test is 1.5 mg/day, and CPME is thus assumed to be a class 2 equivalent solvent in the ICH (International Conference on Harmonization) Harmonized Tripartite Guideline Q3C (R5). Wide synthetic utility and a detailed toxicity study suggest CPME as a green and sustainable solvent of choice for modern chemical transformations. Full article

Chemical investigation of Croton pullei (Euphorbiaceae) collected in the Brazilian Amazon region was revisited. The chemical composition of the essential oils of leaves and stems was analyzed by GC/MS. It was found that both the oils comprise mainly terpenes, among which linalool was the major one (24.90 and 39.72%, respectively). Phytochemical investigation of the stem methanol extract led to the isolation of a new natural product from the glutarimide alkaloid group named N-[2,6-dioxo-1-(2-phenylethyl)-3-piperidinyl]-acetamide, confirming that C. pullei is a rich source of this class of alkaloids. The hexane and methanol extracts of the stems of C. pullei showed moderate antibacterial and antifungal activity and the highest inhibition was observed when the methanol extract was tested against Staphylococcus aureus CCMB 262 and CCMB 263. Full article

Substituted 4-hydroxyquinolines were synthesized from anilines and diethyl 2-(ethoxymethylene)malonate by the Gould-Jacobs reaction via cyclization of the intermediate anilinomethylenemalonate followed by hydrolysis and decarboxylation. The 4-hydroxyquinolines reacted with phosphorous oxychloride to form 4-chloroquinolines, which reacted on heating with diethyl sodiomethylmalonate in DMF to yield moderate yields of substituted ethyl 2-(quinolin-4-yl)propanoates, many of which showed potent antimicrobial activity against Helicobacter pylori. Full article

Momordica foetida Schumach. et Thonn. (Cucurbitaceae) is a perennial climbing herb with tendrils, found in swampy areas in Central Uganda. Antidiabetic and antilipogenic activities were reported for some Momordica species, however the mechanism of action is still unknown. Oxidative stress may represent an important pathogenic mechanism in obesity-associated metabolic syndrome. The present study evaluated free radical scavenging capacity of different concentrations of aqueous, methanolic and dichloromethane leaf extracts of Momordica foetida Schumach. et Thonn. and the ability of these extracts to inhibit in vitro plasma lipid peroxidation; in addition, healthy human adipose mesenchymal stem cell cultures were used in order to test the hypothesis that these extracts may affect adipocyte differentiation. Results obtained in this study suggested that aqueous extract might be useful in preventing metabolic syndrome. Full article

Methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) is a synthetic derivative of oleanolic acid, a triterpene, with apoptosis-inducing activity in a wide range of cancer cells. Induction of apoptosis by CDDO-Me is associated with the generation of reactive oxygen species (ROS) and inhibition of telomerase activity. In the present study, we investigated the role of ROS in inhibition of telomerase by CDDO-me. Treatment of MiaPaCa-2 and Panc-1 pancreatic cancer cell lines with CDDO-Me induced the production of hydrogen peroxide and superoxide anions and inhibited the telomerase activity. Pretreatment of cells with N-acetylcycsteine, a general purpose antioxidant or overexpression of glutathione peroxidase (GPx) or superoxide dismutase-1 (SOD-1) blocked the telomerase inhibitory activity of CDDO-Me. Furthermore, blocking ROS generation also prevented the inhibition of hTERT gene expression, hTERT protein production and expression of a number of hTERT–regulatory proteins by CDDO-Me (e.g., c-Myc, Sp1, NF-κB and p-Akt). Data also showed that Akt plays an important role in the activation of telomerase activity. Together, these data suggest that inhibition of telomerase activity by CDDO-Me is mediated through a ROS-dependent mechanism; however, more work is needed to fully understand the role of ROS in down-regulation of hTERT gene and hTERT-regulatory proteins by CDDO-Me. Full article

A novel series of N-sulfonyl homoserine lactone derivatives 5a–l has been designed, synthesized and evaluated for quorum sensing inhibitory activities towards violacein production. Of the compounds synthesized, compound 5h was found to possess an excellent level of enantiopurity (99.2% e.e.). The results indicated that compounds bearing an ortho substituent on their phenyl ring exhibited excellent levels of inhibitory activity against violacein production. Compounds 5h and 5k in particular, with IC₅₀ values of 1.64 and 1.66 µM, respectively, were identified as promising lead compounds for further structural modification. Full article

By means of density functional theory, the adsorption properties of O₂ molecule on both isolated and N-graphene supported gold clusters have been studied. The N-graphene is modeled by a C₆₅NH₂₂ cluster of finite size. The results indicate that the catalytic activity and the O₂ adsorption energies of odd-numbered Au clusters are larger than those of adjacent even-numbered ones. The O₂ molecule is in favor of bonding to the bridge sites of odd-numbered Au clusters, whereas for odd-numbered ones, the end-on adsorption mode is favored. The perpendicular adsorption orientation on N-graphene is preferred than the parallel one for Au₂, Au₃ and Au₄ clusters, while for Au₅, Au₆ and Au₇, the parallel ones are favored. When O₂ is adsorbed on N-graphene supported Au clusters, the adsorption energies are largely increased compared with those on gas-phase ones. The increased adsorption energies would significantly facilitate the electron transfer from Au d-orbital to π* orbital of O₂, which would further weakening the O–O bond and therefore enhancing the catalytic activity. The carbon atoms on N-graphene could anchor the clusters, which could make them more difficult to structural distortion, therefore enhance their stability. Full article

Phenolic compounds were extracted from European and Japanese grapevine species (Vitis vinifera and V. coignetiae) seeds using 80% methanol or 80% acetone. The total content of phenolic compounds was determined utilizing Folin-Ciocalteu’s phenol reagent, while the content of tannins was assayed by the vanillin and BSA precipitation methods. Additionally, the DPPH free radical and ABTS cation radical scavenging activities and the reduction power of the extracts were measured. The HPLC method was applied to determine the phenolic compounds, such as phenolic acids and catechins. The seeds contained large amounts of tannins and gallic acid and observable quantities of catechins, p-coumaric, ferulic and caffeic acids. The dominant form of phenolic acids in the extracts was the ester-bound form. The content of total phenolics was higher in the European grape V. vinifera seeds, which also contained more tannins, catechins and phenolic acids, except for caffeic acid. Extracts from V. vinifera seeds showed better radical scavenger properties and stronger reducing power. The total contents of phenolic compounds and tannins in acetone extracts were higher than in methanolic extracts. Acetone extracts also exhibited stronger antiradical properties as well as stronger reducing power. Full article

We describe a new method of combinatorial screening in which building blocks, instead of being linked together chemically, are placed on the surface of nanoparticles. Two- or three-dimensional structures form on the surface of these particles through the close approach of different building blocks, with sufficient flexibility to be able to adapt and interact with putative binding sites in biological systems. The particles assemble without the need for formation of chemical bonds, so libraries comprised of many structures can be prepared rapidly, with large quantities of material available for testing. Screening methods can include solid and solution-phase binding assays, or tissue culture models, for example looking for structures which can change the behaviour of cells in a disease-modifying manner. Full article

Herein, we report the design, synthesis and trypanocidal activity of some novel trisubstituted imidazole derivatives. These heterocyclic derivatives were structurally planned by exploring the concept of molecular hybridisation between two arylhydrazones derived from megazol, which has potent trypanocidal activity. The trypanocidal activity of these triarylimidazole derivatives was evaluated against infective trypomastigote forms of T. cruzi and the derivative 2'-(4-bromophenyl)-1-methyl-5'-phenyl-1H,3'H-2,4'-biimidazol-3'-ol showed moderate biological activity (IC₅₀ = 23.9 µM) when compared to benznidazole, a standard trypanocidal drug. These compounds did not present cytotoxic effects at concentrations near the trypanocidal IC₅₀, being considered a good starting point for the development of new anti-Chagas drug candidates. Full article

A new pregnane steroid, 1, and three known analogues 2–4, have been isolated from a gorgonian Carijoa sp. collected from the South China Sea. The planar structure and relative configuration of 1 were elucidated from comprehensive spectroscopic data. Its absolute configuration was determined by application of the modified Mosher method. Compounds 1, 3 and 4 exhibited cytotoxicity against the human hepatoma cell line Bel-7402, with IC₅₀ values of 9.33, 11.02 and 18.68 µM, respectively. Additionally, compound 1 exhibited promising antibacterial activity against Pseudomona puido, with a MIC value of 31 nM, which is approximately 5-fold more potent than ciprofloxacin (MIC = 156 nM). Full article

The aim of the study was to investigate the ameliorative effects and the mechanism of action of L-2-oxothiazolidine-4-carboxylate (OTC) on acetaminophen (APAP)-induced hepatotoxicity in mice. Mice were randomly divided into six groups: normal control group, APAP only treated group, APAP + 25 mg/kg OTC, APAP + 50 mg/kg OTC, APAP + 100 mg/kg OTC, and APAP + 100 mg/kg N-acetylcysteine (NAC) as a reference control group. OTC treatment significantly reduced serum alanine aminotransferase and aspartate aminotransferase levels in a dose dependent manner. OTC treatment was markedly increased glutathione (GSH) production and glutathione peroxidase (GSH-px) activity in a dose dependent manner. The contents of malondialdehyde and 4-hydroxynonenal in liver tissues were significantly decreased by administration of OTC and the inhibitory effect of OTC was similar to that of NAC. Moreover, OTC treatment on APAP-induced hepatotoxicity significantly reduced the formation of nitrotyrosin and terminal deoxynucleotidyl transferase dUTP nick end labeling positive areas of liver tissues in a dose dependent manner. Furthermore, the activity of caspase-3 in liver tissues was reduced by administration of OTC in a dose dependent manner. The ameliorative effects of OTC on APAP-induced liver damage in mice was similar to that of NAC. These results suggest that OTC has ameliorative effects on APAP-induced hepatotoxicity in mice through anti-oxidative stress and anti-apoptotic processes. Full article

Twenty-five polysubstituted phthalazinone derivatives were synthesized and tested for their antifungal activity against a panel of pathogenic and clinically important yeasts and filamentous fungi. Among them, the compound 4-(4-chlorobenzyl)-2-methylphthalazin-1(2H)-one (5) exhibited a remarkable antifungal activity against standardised strains of dermatophytes and Cryptococcus neoformans, as well as against some clinical isolates. A physicochemical study performed on compound 5 revealed its conformational and electronic characteristics, providing us with useful data for the future design of novel related antifungal analogues. Full article

Terminalia chebula, native to Southeast Asia, is a popular medicinal plant in Ayurveda. It has been previously reported to have strong antioxidant and anti-inflammatory efficacy. In this study, we aimed to investigate if fruit extract from T. chebula might protect neuronal cells against ischemia and related diseases by reduction of oxidative damage and inflammation in rat pheochromocytoma cells (PC12) using in vitro oxygen-glucose deprivation followed by reoxygenation (OGD-R) ischemia and hydrogen peroxide (H₂O₂) induced cell death. Cell survival was evaluated by a 2-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Free radical scavenging, lipid peroxidation and nitric oxide inhibition were measured by diphenyl-1-picrylhydrazyl (DPPH), thiobarbituric acid (TBA) and Griess reagent, respectively. We found that T. chebula extract: (1) increases the survival of cells subjected to OGD-R by 68%, and H₂O₂ by 91.4%; (2) scavenges the DPPH free radical by 96% and decreases malondialdehyde (MDA) levels from 237.0 ± 15.2% to 93.7 ± 2.2%; (3) reduces NO production and death rate of microglia cells stimulated by lipopolysaccharide (LPS). These results suggest that T. chebula extract has the potential as a natural herbal medicine, to protect the cells from ischemic damage and the possible mechanism might be the inhibition of oxidative and inflammatory processes. Full article

Bastadins-6, -9 and -16 isolated from the marine sponge Ianthella basta displayed in vitro cytostatic and/or cytotoxic effects in six human and mouse cancer cell lines. The in vitro growth inhibitory effects of these bastadins were similar in cancer cell lines sensitive to pro-apoptotic stimuli versus cancer cell lines displaying various levels of resistance to pro-apoptotic stimuli. While about ten times less toxic than the natural cyclic bastadins, the synthetically derived 5,5'-dibromohemibastadin-1 (DBHB) displayed not only in vitro growth inhibitory activity in cancer cells but also anti-angiogenic properties. At a concentration of one tenth of its in vitro growth inhibitory concentration, DBHB displayed actual antimigratory effects in mouse B16F10 melanoma cells without any sign of cytotoxicity and/or growth inhibition. The serum concentration used in the cell culture media markedly influenced the DBHB-induced antimigratory effects in the B16F10 melanoma cell population. We are currently developing a specific inhalation formulation for DBHB enabling this compound to avoid plasmatic albumin binding through its direct delivery to the lungs to combat primary as well as secondary (metastases) tumors. Full article

A series of novel thiourea and urea derivatives containing 1,2,4-triazole moieties were synthesized and evaluated for their antifungal and larvicidal activity. Triazole derivatives 3a–e and 4a–e were synthesized by reacting thiocarbohydrazide with thiourea and urea compounds 1a–e and 2a–e, respectively, in a 130–140 °C oil bath. The proposed structures of all the synthesized compounds were confirmed using elemental analysis, UV, IR, ¹H-NMR and mass spectroscopy. All compounds were evaluated for antifungal activity against plant pathogens, larvicidal and biting deterrent activity against the mosquito Aedes aegypti L. and in vitro cytotoxicity and anti-inflammatory activity against some human cell lines. Phomopis species were the most sensitive fungi to these compounds. Compounds 1b, 1c, 3a and 4e demonstrated selectively good activity against Phomopis obscurans and only 1b and 4e showed a similar level of activity against P. viticola. Compound 3d, with a LD₅₀ value of 67.9 ppm, followed by 1c (LD₅₀ = 118.8 ppm) and 3e (LD₅₀ = 165.6 ppm), showed the highest toxicity against Aedes aegypti larvae. Four of these compounds showed biting deterrent activity greater than solvent control, with the highest activity being seen for 1c, with a proportion not biting (PNB) value of 0.75, followed by 1e, 2b and 1a. No cytotoxicity was observed against the tested human cancer cell lines. No anti-inflammatory activity was observed against NF-kB dependent transcription induced by phorbol myristate acetate (PMA) in human chondrosarcoma cells. Full article

Three series of 3-(2-aminoheterocycle)-4-benzyloxyphenylbenzamide derivatives, 2-aminooxazoles, 2-aminothiazoles, and 2-amino-6H-1,3,4-thiadizines were designed, synthesized and evaluated as β-secretase (BACE-1) inhibitors. Preliminary structure-activity relationships revealed that the existence of a 2-amino-6H-1,3,4-thiadizine moiety and α-naphthyl group were favorable for BACE-1 inhibition. Among the synthesized compounds, 5e exhibited the most potent BACE-1 inhibitory activity, with an IC₅₀ value of 9.9 μΜ and it exhibited high brain uptake potential in Madin-Darby anine kidney cell lines (MDCK) and a Madin-Darby canine kidney-multidrug resistance 1 (MDCK-MDR1) model. Full article

A series of novel N-(3-substituted aryl/alkyl-4-oxo-1,3-thiazolidin-2-ylidene)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamides 2a–e were synthesized by the addition of ethyl a-bromoacetate and anhydrous sodium acetate in dry ethanol to N-(substituted aryl/alkylcarbamothioyl)-4-[5-(4-methylphenyl)-3-(trifluoro-methyl)-1H-pyrazol-1-yl]benzene sulfonamides 1a–e, which were synthesized by the reaction of alkyl/aryl isothiocyanates with celecoxib. The structures of the isolated products were determined by spectral methods and their anti-inflammatory, analgesic, antioxidant, anticancer and anti-HCV NS5B RNA-dependent RNA polymerase (RdRp) activities evaluated. The compounds were also tested for gastric toxicity and selected compound 1a was screened for its anticancer activity against 60 human tumor cell lines. These investigations revealed that compound 1a exhibited anti-inflammatory and analgesic activities and further did not cause tissue damage in liver, kidney, colon and brain compared to untreated controls or celecoxib. Compounds 1c and 1d displayed modest inhibition of HCV NS5B RdRp activity. In conclusion, N-(ethylcarbamothioyl)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (1a) may have the potential to be developed into a therapeutic agent. Full article

In order to develop potential glucosamine-6-phosphate synthase inhibitors and anti-fungal agents, twenty five oleanolic acid oxime esters were synthesized in an efficient way. The structures of the new compounds were confirmed by MS, HRMS, ¹H-NMR and ¹³C-NMR. Preliminary studies based on means of the Elson-Morgan method indicated that many compounds exhibited some inhibitory activity of glucosamine-6-phosphate synthase (GlmS), and the original fungicidal activities results showed that some of the compounds exhibited good fungicidal activities towards Sclerotinia sclerotiorum (Lib.) de Bary, Rhizoctonia solani Kuhn and Botrytis cinerea Pers at the concentration of 50 µg/mL. These compounds would thus merit further study and development as antifungal agents. Full article

A series of novel N-phenylbenzamide derivatives were synthesized and their anti-EV 71 activities were assayed in vitro. Among the compounds tested, 3-amino-N-(4-bromophenyl)-4-methoxybenzamide (1e) was active against the EV 71 strains tested at low micromolar concentrations, with IC₅₀ values ranging from 5.7 ± 0.8–12 ± 1.2 μM, and its cytotoxicity to Vero cells (TC₅₀ = 620 ± 0.0 μM) was far lower than that of pirodavir (TC₅₀ = 31 ± 2.2 μM). Based on these results, compound 1e is a promising lead compound for the development of anti-EV 71 drugs. Full article

Grewia asiatica L., is a species native to south Asia from Pakistan, east to Cambodia, cultivated primarily for its edible fruit and well-reputed for its diverse medicinal uses. Fruits are a rich source of nutrients such as proteins, amino acids, vitamins, and minerals and contain various bioactive compounds, like anthocyanins, tannins, phenolics and flavonoids. Different parts of this plant possess different pharmacological properties. Leaves have antimicrobial, anticancer, antiplatelet and antiemetic activities; fruit possess anticancer, antioxidant, radioprotective and antihyperglycemic properties; while stem bark possesses analgesic and anti-inflammatory activities. This review focuses on the botanical description, phytochemistry, nutritional studies and pharmacological properties of this plant. Full article

Photocycloaddition, along with subsequent transformation of the photocycloadducts, provides expeditious ways to construct various structures. The photo-induced reactions of α-diketones have been reported to proceed via different reaction pathways with the involvement of one or two of the carbonyl groups. Photoinduced reactions of cyclic α-diketones including N-acetylisatin, phenanthrenequinone and isoquinolinetrione with different C=C containing compounds could take place via [2 + 2], [4 + 2] or [4 + 4] photocycloaddition pathways. We have investigated the photoreactions of these cyclic α-diketones with different types of alkenes and alkynes, with a focus on the unusual cascade reactions initiated by the photocycloaddition reactions of these cyclic α-diketones and the applications of these photocycloaddition reactions along with the transformation of the photocycloadducts. In this paper, we discuss the diverse photo-cycloaddition pathways found in the photocycloaddition of o-diones leading to various photocycloadducts and the potential applications of these reactions via further transformation reactions of the adducts. Full article

Myoglobin, a simple oxygen binding protein, was reconstituted with various types of synthetic hemes to manipulate the heme-globin interactions. From the paramagnetic NMR analysis, small heme was found to rotate rapidly about the iron-histidine bond upon. This is a novel and typical example for the fluctuation of protein. The dynamic NMR analysis indicated that the 360° rotational rate of a small heme was 1,400 s⁻¹ at room temperature. The X-ray analyses revealed that the tertiary structure of globin containing the smallest heme was closely similar to that of native protein despite extensive destruction of the specific heme-globin interactions. The functional analyses of O₂ binding showed that the loose heme-globin contacts do not significantly affect the oxygen binding. On the other hand, the rearrangement of tetrapyrrole array and the non-planar deformation in porphyrin ring significantly affect the functional properties of myoglobin. These results, taken together, indicate that the essential factors to regulate the myoglobin function are hidden under the molecular shape of prosthetic group rather than in the nonbonded heme-globin contacts. Full article

The Click-to-Chelate approach is a highly efficient strategy for the radiolabeling of molecules of medicinal interest with technetium and rhenium-tricarbonyl cores. Reaction of azide-functionalized molecules with alkyne prochelators by the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC; click reaction) enables the simultaneous synthesis and conjugation of tridentate chelating systems for the stable complexation of the radiometals. In many cases, the functionalization of (bio)molecules with the ligand system and radiolabeling can be achieved by convenient one-pot procedures. Since its first report in 2006, Click-to-Chelate has been applied to the development of numerous novel radiotracers with promising potential for translation into the clinic. This review summarizes the use of the Click-to-Chelate approach in radiopharmaceutical sciences and provides a perspective for future applications. Full article

Selenium (Se34 79) is a metalloid which is close to sulfur (S) in terms of properties. The Se concentration in soil varies with type, texture and organic matter content of the soil and with rainfall. Its assimilation by plants is influenced by the physico-chemical properties of the soil (redox status, pH and microbial activity). The presence of Se in the atmosphere is linked to natural and anthropogenic activities. Selenoproteins, in which selenium is present as selenocysteine, present an important role in many body functions, such as antioxidant defense and the formation of thyroid hormones. Some selenoprotein metabolites play a role in cancer prevention. In the immune system, selenium stimulates antibody formation and activity of helper T cells, cytotoxic T cells and Natural Killer (NK) cells. The mechanisms of intestinal absorption of selenium differ depending on the chemical form of the element. Selenium is mainly absorbed in the duodenum and caecum by active transport through a sodium pump. The recommended daily intake of selenium varies from 60 μg/day for women, to 70 μg/day for men. In growing ruminants the requirements are estimated at 100 μg/kg dry matter and 200 μg/Kg for pregnant or lactating females. A deficiency can cause reproductive disorders in humans and animals. Full article

Humans can detect and discriminate a vast number of odours. The number perceived as distinguishable is estimated to be more than ten thousand. Humans are capable of distinguishing even slight alterations in the structure of an odorous molecule. A pair of enantiomers of an odorant, which possess the same molecular structures except for the chiral position, can trigger profoundly different odour perceptions. How precisely can humans and their olfactory system detect and discriminate such a great variety of odours and such subtle differences in the molecular structures? In a series of studies, we have attempted to examine the relationship between mood change, odour and its physiological effects, by focusing on the possible verbal and non-verbal changes in humans induced by smelling the fragrances of essential oils as well as linalool and its enantiometric isomers. In this article, we provide an overview of our recent verbal and non-verbal studies. We then discuss how our findings may contribute to the assessment of psychophysiological responses of essential oils as well as how our research can contribute to the study of human chemoreception science, by shedding light on the sophistication of the olfactory system in its ability to detect and discriminate odors. Full article

Single-chain polymeric nanoparticles are artificial folded soft nano-objects of ultra-small size which have recently gained prominence in nanoscience and nanotechnology due to their exceptional and sometimes unique properties. This review focuses on the current state of the investigations of click chemistry techniques for highly-efficient single-chain nanoparticle construction. Additionally, recent progress achieved for the use of well-defined single-chain nanoparticles in some promising fields, such as nanomedicine and catalysis, is highlighted. Full article

Solanum nudum Dunal steroids have been reported as being antimalarial compounds; however, their concentration in plants is low, meaning that the species could be threatened by over-harvesting for this purpose. Swern oxidation was used for hemisynthesis of diosgenone (one of the most active steroidal sapogenin diosgenin compounds). Eighteen structural analogues were prepared; three of them were found to be more active than diosgenone (IC₅₀ 27.9 μM vs. 10.1 μM, 2.9 μM and 11.3 μM). The presence of a 4-en-3-one grouping in the A-ring of the compounds seems to be indispensable for antiplasmodial activity; progesterone (having the same functional group in the steroid A-ring) has also displayed antiplasmodial activity. Quantitative correlations between molecular structure and bioactivity were thus explored in diosgenone and several derivatives using well-established 3D-QSAR techniques. The models showed that combining electrostatic (70%) and steric (30%) fields can explain most variance regarding compound activity. Malarial parasitemia in mice became reduced by oral administration of two diosgenone derivatives. Full article

Despite the advances in molecular biology and biochemistry, the prognosis of patients suffering from tumor diseases remains poor. The limited therapeutic success can be explained by the insufficient performance of the common chemotherapeutic drugs that lack the ability to specifically target tumor tissues. Recently peptide radiopharmaceuticals have been developed that enable the concurrent imaging and therapy of tumors expressing a specific target. Here, with a special emphasis on the synthesis of the building blocks required for the complexation of metallic radioisotopes, the requirements to the design and synthesis of radiolabeled peptides for clinical applications are described. Full article

In this review, we discuss emerging technologies for drug discovery, which yields novel molecular scaffolds based on natural product-inspired non-traditional peptides expressed using the translation machinery. Unlike natural products, these technologies allow for constructing mRNA-encoding libraries of macrocyclic peptides containing non-canonical sidechains and N-methyl-modified backbones. The complexity of sequence space in such libraries reaches as high as a trillion (>10¹²), affording initial hits of high affinity ligands against protein targets. Although this article comprehensively covers several related technologies, we discuss in greater detail the technical development and advantages of the Random non-standard Peptide Integration Discovery (RaPID) system, including the recent identification of inhibitors against various therapeutic targets. Full article

I read with interest the article by Lee et al. entitled “Inhibitory Effect and Mechanism of Antiproliferation of Isoatriplicolide Tiglate (PCAC) from Paulownia Coreana” [1]. This article is quite interesting and the authors should be complimented for the significant amount of work they have done. The purpose of this letter is to call attention to the need for some clarification on the name of the plant described in this article. Lee et al. state: “Paulownia coreana has traditionally been used as the medicine and health food in the treatment of cancer and infectious diseases.” and elsewhere: “In fact, many cancer research studies have been conducted using traditional medicinal plants such as P. coreana.” [1]. Full article

In a Comment recently published in Molecules [1], Prof. C. Wiart took issue with our identification of the plant species used in our work as Paulownia coreana. Although this name was assigned by H. Uyeki in 1925 [2], appears as such in handbooks of Korean flora [3], and examples of its use can be found in the recent literature [4–9], after reviewing the arguments and references presented in [1], we now recognize that this is no longer considered an accepted species name, and therefore we wish to revise our assignment to Pauwlonia tormentosa (Thunb.) Steud. We thank Prof. Wiart for bringing this fact to our attention and apologize to the readership of Molecules for any confusion caused by our previous classification of the species. [...] Full article

An article by Sasidharan et al. recently published in the journal Molecules [1] claimed to show the hepatoprotective effects of lantadene A against acetaminophen-induced liver damage in mice. While reading this paper, I came across certain points that need to be clarified and taken up in the interest of science and other scientists working in this area. Full article