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Molecules, Volume 21, Issue 6 (June 2016) – 141 articles

Cover Story (view full-size image): Natural products have always been exploited to promote health and have served as a valuable source for the discovery of new drugs. Besides others, they provide great potential for the treatment or prevention of cardiovascular and metabolic disorders, which are global health problems with rising prevalence. Certain natural compounds, such as dietary constituents, are known to bring relevant health benefits. Moreover, many plants are used in traditional medicine, and for some natural products, efficacy and safety have already been proven by clinical trials. Furthermore, statins and biguanides are prominent representatives of natural products (or their derivatives) in the fight against metabolic disease. View the paper
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1507 KiB  
Article
Uprolides N, O and P from the Panamanian Octocoral Eunicea succinea
by Daniel Torres-Mendoza, Yisett González, José Félix Gómez-Reyes, Héctor M. Guzmán, José Luis López-Perez, William H. Gerwick, Patricia L. Fernandez and Marcelino Gutiérrez
Molecules 2016, 21(6), 819; https://doi.org/10.3390/molecules21060819 - 22 Jun 2016
Cited by 11 | Viewed by 5693
Abstract
Three new diterpenes, uprolide N (1), uprolide O (2), uprolide P (3) and a known one, dolabellane (4), were isolated from the CH2Cl2-MeOH extract of the gorgonian octocoral Eunicea succinea, [...] Read more.
Three new diterpenes, uprolide N (1), uprolide O (2), uprolide P (3) and a known one, dolabellane (4), were isolated from the CH2Cl2-MeOH extract of the gorgonian octocoral Eunicea succinea, collected from Bocas del Toro, on the Caribbean coast of Panama. Their structures were determined using spectroscopic analyses, including 1D and 2D NMR and high-resolution mass spectrometry (HRMS) together with molecular modeling studies. Compounds 13 displayed anti-inflammatory properties by inhibiting production of Tumor Necrosis Factor (TNF) and Interleukin (IL)-6 induced by lipopolysaccharide (LPS) in murine macrophages. Full article
(This article belongs to the Special Issue Diterpene and Its Significance in Natural Medicine)
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2067 KiB  
Article
Anti-Inflammatory Effects of Melandrii Herba Ethanol Extract via Inhibition of NF-κB and MAPK Signaling Pathways and Induction of HO-1 in RAW 264.7 Cells and Mouse Primary Macrophages
by Yun Hee Jeong, You-Chang Oh, Won-Kyung Cho, Bohyoung Lee and Jin Yeul Ma
Molecules 2016, 21(6), 818; https://doi.org/10.3390/molecules21060818 - 22 Jun 2016
Cited by 20 | Viewed by 7358
Abstract
Melandrii Herba (MH) is a traditional Asian medicinal herb used to treat breast cancer, anuria, and diseases of lactation. However, its biological properties and molecular mechanisms have not been fully elucidated. The purpose of this study was to investigate the anti-inflammatory activity and [...] Read more.
Melandrii Herba (MH) is a traditional Asian medicinal herb used to treat breast cancer, anuria, and diseases of lactation. However, its biological properties and molecular mechanisms have not been fully elucidated. The purpose of this study was to investigate the anti-inflammatory activity and underlying molecular mechanism of MH ethanol extract (MHE) on the lipopolysaccharide (LPS)-mediated inflammatory response in macrophages. MHE cytotoxicity was determined using a cell counting kit (CCK) assay. The effects of MHE on the production of NO, inflammatory cytokines, and related proteins and mRNAs were determined using the Griess test, ELISA, Western blotting, and real-time RT-PCR, respectively. In addition, intracellular signaling pathways, such as NF-κB, MAPK, and HO-1, were analyzed using Western blotting. Our results revealed that MHE treatment significantly inhibited the secretion of NO and inflammatory cytokines, including TNF-α, IL-6, and IL-1β in macrophages, at sub-cytotoxic concentrations. Furthermore, MHE treatment inhibited iNOS expression and induced HO-1 expression. Finally, the transcriptional activities of NF-κB and MAPK activation were significantly suppressed by MHE in LPS-stimulated macrophages. The results indicate that MHE exerts anti-inflammatory effects by suppressing inflammatory mediator production via NF-κB and MAPK signaling pathways inhibition and induction of HO-1 expression in macrophages. Therefore, our results suggest the potential value of MHE as an inflammatory therapeutic agent developed from a natural substance. Full article
(This article belongs to the Section Natural Products Chemistry)
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1663 KiB  
Article
Synthesis and Evaluation of 99mTc-Labeled Dimeric Folic Acid for FR-Targeting
by Zhide Guo, Mengna Gao, Manli Song, Changrong Shi, Pu Zhang, Duo Xu, Linyi You, Rongqiang Zhuang, Xinhui Su, Ting Liu, Jin Du and Xianzhong Zhang
Molecules 2016, 21(6), 817; https://doi.org/10.3390/molecules21060817 - 22 Jun 2016
Cited by 22 | Viewed by 6803
Abstract
The folate receptor (FR) is overexpressed in a wide variety of human tumors. In our study, the multimeric concept was used to synthesize a dimeric folate derivative via a click reaction. The novel folate derivative (HYNIC-D1-FA2) was radiolabeled with [...] Read more.
The folate receptor (FR) is overexpressed in a wide variety of human tumors. In our study, the multimeric concept was used to synthesize a dimeric folate derivative via a click reaction. The novel folate derivative (HYNIC-D1-FA2) was radiolabeled with 99mTc using tricine and trisodium triphenylphosphine-3,3′,3″-trisulfonate (TPPTS) as coligands (99mTc-HYNIC-D1-FA2) and its in vitro physicochemical properties, ex vivo biodistribution and in vivo micro-SPECT/CT imaging as a potential FR targeted agent were evaluated. It is a hydrophilic compound (log P = −2.52 ± 0.13) with high binding affinity (IC50 = 19.06 nM). Biodistribution in KB tumor-bearing mice showed that 99mTc-HYNIC-D1-FA2 had high uptake in FR overexpressed tumor and kidney at all time-points, and both of them could obviously be inhibited when blocking with free FA in the blocking studies. From the in vivo micro-SPECT/CT imaging results, good tumor uptake of 99mTc-HYNIC-D1-FA2 was observed in KB tumor-bearing mice and it could be blocked obviously. Based on the results, this new radiolabeled dimeric FA tracer might be a promising candidate for FR-targeting imaging with high affinity and selectivity. Full article
(This article belongs to the Special Issue Molecular Imaging Probes)
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2630 KiB  
Article
Ultrahigh Pressure Processing Produces Alterations in the Metabolite Profiles of Panax ginseng
by Mee Youn Lee, Digar Singh, Sung Han Kim, Sang Jun Lee and Choong Hwan Lee
Molecules 2016, 21(6), 816; https://doi.org/10.3390/molecules21060816 - 22 Jun 2016
Cited by 11 | Viewed by 5538
Abstract
Ultrahigh pressure (UHP) treatments are non-thermal processing methods that have customarily been employed to enhance the quality and productivity of plant consumables. We aimed to evaluate the effects of UHP treatments on ginseng samples (white ginseng: WG; UHP-treated WG: UWG; red ginseng: RG; [...] Read more.
Ultrahigh pressure (UHP) treatments are non-thermal processing methods that have customarily been employed to enhance the quality and productivity of plant consumables. We aimed to evaluate the effects of UHP treatments on ginseng samples (white ginseng: WG; UHP-treated WG: UWG; red ginseng: RG; UHP-treated RG: URG; ginseng berries: GB; and UHP-treated GB: UGB) using metabolite profiling based on ultrahigh performance liquid chromatography-linear trap quadrupole-ion trap-tandem mass spectrometry (UHPLC-LTQ-IT-MS/MS) and gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). Multivariate data analyses revealed a clear demarcation among the GB and UGB samples, and the phenotypic evaluations correlated the highest antioxidant activities and the total phenolic and flavonoid compositions with the UGB samples. Overall, eight amino acids, seven organic acids, seven sugars and sugar derivatives, two fatty acids, three notoginsenosides, three malonylginsenosides, and three ginsenosides, were identified as significantly discriminant metabolites between the GB and UGB samples, with relatively higher proportions in the latter. Ideally, these metabolites can be used as quality biomarkers for the assessment of ginseng products and our results indicate that UHP treatment likely led to an elevation in the proportions of total extractable metabolites in ginseng samples. Full article
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1284 KiB  
Article
Aza-Michael Mono-addition Using Acidic Alumina under Solventless Conditions
by Giovanna Bosica and Roderick Abdilla
Molecules 2016, 21(6), 815; https://doi.org/10.3390/molecules21060815 - 22 Jun 2016
Cited by 31 | Viewed by 9817
Abstract
Aza-Michael reactions between primary aliphatic and aromatic amines and various Michael acceptors have been performed under environmentally-friendly solventless conditions using acidic alumina as a heterogeneous catalyst to selectively obtain the corresponding mono-adducts in high yields. Ethyl acrylate was the main acceptor used, although [...] Read more.
Aza-Michael reactions between primary aliphatic and aromatic amines and various Michael acceptors have been performed under environmentally-friendly solventless conditions using acidic alumina as a heterogeneous catalyst to selectively obtain the corresponding mono-adducts in high yields. Ethyl acrylate was the main acceptor used, although others such as acrylonitrile, methyl acrylate and acrylamide were also utilized successfully. Bi-functional amines also gave the mono-adducts in good to excellent yields. Such compounds can serve as intermediates for the synthesis of anti-cancer and antibiotic drugs. Full article
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1210 KiB  
Article
Essential Oil Variation from Twenty Two Genotypes of Citrus in Brazil—Chemometric Approach and Repellency Against Diaphorina citri Kuwayama
by Moacir Dos Santos Andrade, Leandro Do Prado Ribeiro, Paulo Cesar Borgoni, Maria Fátima das Graças Fernandes da Silva, Moacir Rossi Forim, João Batista Fernandes, Paulo Cezar Vieira, José Djair Vendramin and Marcos Antônio Machado
Molecules 2016, 21(6), 814; https://doi.org/10.3390/molecules21060814 - 22 Jun 2016
Cited by 11 | Viewed by 7518
Abstract
The chemical composition of volatile oils from 22 genotypes of Citrus and related genera was poorly differentiated, but chemometric techniques have clarified the relationships between the 22 genotypes, and allowed us to understand their resistance to D. citri. The most convincing similarities [...] Read more.
The chemical composition of volatile oils from 22 genotypes of Citrus and related genera was poorly differentiated, but chemometric techniques have clarified the relationships between the 22 genotypes, and allowed us to understand their resistance to D. citri. The most convincing similarities include the synthesis of (Z)-β-ocimene and (E)-caryophyllene for all 11 genotypes of group A. Genotypes of group B are not uniformly characterized by essential oil compounds. When stimulated with odor sources of 22 genotypes in a Y-tube olfactometer D. citri preferentially entered the arm containing the volatile oils of Murraya paniculata, confirming orange jasmine as its best host. C. reticulata × C. sinensis was the least preferred genotype, and is characterized by the presence of phytol, (Z)-β-ocimene, and β-elemene, which were not found in the most preferred genotype. We speculate that these three compounds may act as a repellent, making these oils less attractive to D. citri. Full article
(This article belongs to the Collection Bioactive Compounds)
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8974 KiB  
Article
An Ingenol Derived from Euphorbia kansui Induces Hepatocyte Cytotoxicity by Triggering G0/G1 Cell Cycle Arrest and Regulating the Mitochondrial Apoptosis Pathway in Vitro
by Xiaojing Yan, Li Zhang, Yudan Cao, Weifeng Yao, Yuping Tang and Anwei Ding
Molecules 2016, 21(6), 813; https://doi.org/10.3390/molecules21060813 - 22 Jun 2016
Cited by 16 | Viewed by 7848
Abstract
Natural product lingenol, a purified diterpenoid compound derived from the root of Euphorbia kansui, exerts serious hepatotoxicity; however, the molecular mechanisms remain to be defined. In the present study, cell counting Kit-8 (CCK-8), inverted phase contrast microscope and flow cytometry were used [...] Read more.
Natural product lingenol, a purified diterpenoid compound derived from the root of Euphorbia kansui, exerts serious hepatotoxicity; however, the molecular mechanisms remain to be defined. In the present study, cell counting Kit-8 (CCK-8), inverted phase contrast microscope and flow cytometry were used to demonstrate that lingenol significantly inhibited L-O2 cells proliferation, and induced cell cycle arrest and apoptosis. Moreover, the results investigated that lingenol markedly disrupted mitochondrial functions by high content screening (HCS). In addition, the up-regulation of cytochrome c, AIF and Apaf-1 and activation of caspases were found in L-O2 cells detected by Western blotting and ELISA assay, which was required for lingenol activation of cytochrome c-mediated caspase cascades and AIF-mediated DNA damage. Mechanistic investigations revealed that lingenol significantly down-regulated the Bcl-2/Bax ratio and enhanced the reactive oxygen species (ROS) in L-O2 cells. These data collectively indicated that lingenol modulation of ROS and Bcl-2/Bax ratio led to cell cycle arrest and mitochondrial-mediated apoptosis in L-O2 cells in vitro. All of these results will be helpful to reveal the hepatotoxicity mechanism of Euphorbia kansui and to effectively guide safer and better clinical application of this herb. Full article
(This article belongs to the Special Issue Diterpene and Its Significance in Natural Medicine)
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1400 KiB  
Article
The Changes in Color, Soluble Sugars, Organic Acids, Anthocyanins and Aroma Components in “Starkrimson” during the Ripening Period in China
by Yulian Liu, Nianlai Chen, Zonghuan Ma, Fei Che, Juan Mao and Baihong Chen
Molecules 2016, 21(6), 812; https://doi.org/10.3390/molecules21060812 - 22 Jun 2016
Cited by 22 | Viewed by 5580
Abstract
“Starkrimson” is a traditional apple cultivar that was developed a long time ago and was widely cultivated in the arid region of the northern Wei River of China. However, little information regarding the quality characteristics of “Starkrimson” fruit has been reported in this [...] Read more.
“Starkrimson” is a traditional apple cultivar that was developed a long time ago and was widely cultivated in the arid region of the northern Wei River of China. However, little information regarding the quality characteristics of “Starkrimson” fruit has been reported in this area. To elucidate these characteristics, the color, soluble sugars, organic acids, anthocyanins and aroma components were measured during the ripening period through the use of high performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS). The results indicated that the changes in anthocyanin contents took place later than the changes in the Commission International Eclairage (CIE) parameters. Meanwhile, cyanidin 3-galactoside (cy3-gal), fructose, sucrose, glucose and malic acid were the primary organic compounds, and 1-butanol-2-methyl-acetate, 2-hexenal and 1-hexanol were the most abundant aroma components in the skin. Furthermore, rapidly changing soluble sugars and organic acid synchronization took place in the early ripening period, while rapidly changing aroma components occurred later, on the basis of fresh weight. This result suggested that the production of aroma components might be a useful index of apple maturity. Full article
(This article belongs to the Special Issue Structure-Activity Relationship of Natural Products)
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4164 KiB  
Article
Syk and IRAK1 Contribute to Immunopharmacological Activities of Anthraquinone-2-carboxlic Acid
by Jae Gwang Park, Young-Jin Son, Mi-Yeon Kim and Jae Youl Cho
Molecules 2016, 21(6), 809; https://doi.org/10.3390/molecules21060809 - 22 Jun 2016
Cited by 12 | Viewed by 5487
Abstract
Anthraquinone-2-carboxlic acid (9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid, AQCA) was identified as one of the major anthraquinones in Brazilian taheebo. Since there was no report explaining its immunopharmacological actions, in this study, we aimed to investigate the molecular mechanism of AQCA-mediated anti-inflammatory activity using reporter gene assays, [...] Read more.
Anthraquinone-2-carboxlic acid (9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid, AQCA) was identified as one of the major anthraquinones in Brazilian taheebo. Since there was no report explaining its immunopharmacological actions, in this study, we aimed to investigate the molecular mechanism of AQCA-mediated anti-inflammatory activity using reporter gene assays, kinase assays, immunoblot analyses, and overexpression strategies with lipopolysaccharide (LPS)-treated macrophages. AQCA was found to suppress the release of nitric oxide (NO) and prostaglandin (PG) E2 from LPS-treated peritoneal macrophages without displaying any toxic side effects. Molecular analysis revealed that AQCA was able to inhibit the activation of the nuclear factor (NF)-κB and activator protein (AP)-1 pathways by direct suppression of upstream signaling enzymes including interleukin-1 receptor-associated kinase 1 (IRAK1) and spleen tyrosine kinase (Syk). Therefore, our data strongly suggest that AQCA-mediated suppression of inflammatory responses could be managed by a direct interference of signaling cascades including IRAK and Syk, linked to the activation of NF-κB and AP-1. Full article
(This article belongs to the Section Molecular Diversity)
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5550 KiB  
Article
Novel 5-Substituted 2-(Aylmethylthio)-4-chloro-N-(5-aryl-1,2,4-triazin-3-yl)benzenesulfonamides: Synthesis, Molecular Structure, Anticancer Activity, Apoptosis-Inducing Activity and Metabolic Stability
by Beata Żołnowska, Jarosław Sławiński, Aneta Pogorzelska, Krzysztof Szafrański, Anna Kawiak, Grzegorz Stasiłojć, Mariusz Belka, Szymon Ulenberg, Tomasz Bączek and Jarosław Chojnacki
Molecules 2016, 21(6), 808; https://doi.org/10.3390/molecules21060808 - 22 Jun 2016
Cited by 16 | Viewed by 6988
Abstract
A series of novel 5-substituted 2-(arylmethylthio)-4-chloro-N-(5-aryl-1,2,4-triazin-3-yl) benzenesulfonamide derivatives 2760 have been synthesized by the reaction of aminoguanidines with an appropriate phenylglyoxal hydrate in glacial acetic acid. A majority of the compounds showed cytotoxic activity toward the human cancer cell [...] Read more.
A series of novel 5-substituted 2-(arylmethylthio)-4-chloro-N-(5-aryl-1,2,4-triazin-3-yl) benzenesulfonamide derivatives 2760 have been synthesized by the reaction of aminoguanidines with an appropriate phenylglyoxal hydrate in glacial acetic acid. A majority of the compounds showed cytotoxic activity toward the human cancer cell lines HCT-116, HeLa and MCF-7, with IC50 values below 100 μM. It was found that for the analogues 3638 the naphthyl moiety contributed significantly to the anticancer activity. Cytometric analysis of translocation of phosphatidylserine as well as mitochondrial membrane potential and cell cycle revealed that the most active compounds 37 (HCT-116 and HeLa) and 46 (MCF-7) inhibited the proliferation of cells by increasing the number of apoptotic cells. Apoptotic-like, dose dependent changes in morphology of cell lines were also noticed after treatment with 37 and 46. Moreover, triazines 37 and 46 induced caspase activity in the HCT-116, HeLa and MCF-7 cell lines. Selected compounds were tested for metabolic stability in the presence of pooled human liver microsomes and NADPH, both R2 and Ar = 4-CF3-C6H4 moiety in 2-(R2-methylthio)-N-(5-aryl-1,2,4-triazin-3-yl)benzenesulfonamides simultaneously increased metabolic stability. The results pointed to 37 as a hit compound with a good cytotoxicity against HCT-116 (IC50 = 36 μM), HeLa (IC50 = 34 μM) cell lines, apoptosis-inducing activity and moderate metabolic stability. Full article
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1020 KiB  
Review
Natural Products to Counteract the Epidemic of Cardiovascular and Metabolic Disorders
by Birgit Waltenberger, Andrei Mocan, Karel Šmejkal, Elke H. Heiss and Atanas G. Atanasov
Molecules 2016, 21(6), 807; https://doi.org/10.3390/molecules21060807 - 22 Jun 2016
Cited by 131 | Viewed by 20781
Abstract
Natural products have always been exploited to promote health and served as a valuable source for the discovery of new drugs. In this review, the great potential of natural compounds and medicinal plants for the treatment or prevention of cardiovascular and metabolic disorders, [...] Read more.
Natural products have always been exploited to promote health and served as a valuable source for the discovery of new drugs. In this review, the great potential of natural compounds and medicinal plants for the treatment or prevention of cardiovascular and metabolic disorders, global health problems with rising prevalence, is addressed. Special emphasis is laid on natural products for which efficacy and safety have already been proven and which are in clinical trials, as well as on plants used in traditional medicine. Potential benefits from certain dietary habits and dietary constituents, as well as common molecular targets of natural products, are also briefly discussed. A glimpse at the history of statins and biguanides, two prominent representatives of natural products (or their derivatives) in the fight against metabolic disease, is also included. The present review aims to serve as an “opening” of this special issue of Molecules, presenting key historical developments, recent advances, and future perspectives outlining the potential of natural products for prevention or therapy of cardiovascular and metabolic disease. Full article
(This article belongs to the Special Issue Effects of Natural Products in the Context of Cardiometabolic Disease)
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9927 KiB  
Review
Exploiting the Biosynthetic Potential of Type III Polyketide Synthases
by Yan Ping Lim, Maybelle K. Go and Wen Shan Yew
Molecules 2016, 21(6), 806; https://doi.org/10.3390/molecules21060806 - 22 Jun 2016
Cited by 53 | Viewed by 16045
Abstract
Polyketides are structurally and functionally diverse secondary metabolites that are biosynthesized by polyketide synthases (PKSs) using acyl-CoA precursors. Recent studies in the engineering and structural characterization of PKSs have facilitated the use of target enzymes as biocatalysts to produce novel functionally optimized polyketides. [...] Read more.
Polyketides are structurally and functionally diverse secondary metabolites that are biosynthesized by polyketide synthases (PKSs) using acyl-CoA precursors. Recent studies in the engineering and structural characterization of PKSs have facilitated the use of target enzymes as biocatalysts to produce novel functionally optimized polyketides. These compounds may serve as potential drug leads. This review summarizes the insights gained from research on type III PKSs, from the discovery of chalcone synthase in plants to novel PKSs in bacteria and fungi. To date, at least 15 families of type III PKSs have been characterized, highlighting the utility of PKSs in the development of natural product libraries for therapeutic development. Full article
(This article belongs to the Special Issue Polyketides)
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4150 KiB  
Article
Synthesis of Chiral, Enantiopure Allylic Amines by the Julia Olefination of α-Amino Esters
by Fabio Benedetti, Federico Berti, Lidia Fanfoni, Michele Garbo, Giorgia Regini and Fulvia Felluga
Molecules 2016, 21(6), 805; https://doi.org/10.3390/molecules21060805 - 21 Jun 2016
Cited by 3 | Viewed by 6472
Abstract
The four-step conversion of a series of N-Boc-protected l-amino acid methyl esters into enantiopure N-Boc allylamines by a modified Julia olefination is described. Key steps include the reaction of a lithiated phenylalkylsulfone with amino esters, giving chiral β-ketosulfones, and the [...] Read more.
The four-step conversion of a series of N-Boc-protected l-amino acid methyl esters into enantiopure N-Boc allylamines by a modified Julia olefination is described. Key steps include the reaction of a lithiated phenylalkylsulfone with amino esters, giving chiral β-ketosulfones, and the reductive elimination of related α-acetoxysulfones. The overall transformation takes place under mild conditions, with good yields, and without loss of stereochemical integrity, being in this respect superior to the conventional Julia reaction of α-amino aldehydes. Full article
(This article belongs to the Special Issue Synthesis of Bioactive Compounds from the Chiral Pool)
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622 KiB  
Article
Flavonoid Glycosides and Their Derivatives from the Herbs of Scorzonera austriaca Wild
by Yang Xie, Qiu-Shi Guo and Guang-Shu Wang
Molecules 2016, 21(6), 803; https://doi.org/10.3390/molecules21060803 - 21 Jun 2016
Cited by 12 | Viewed by 4717
Abstract
Five flavonoid glycosides and two derivatives were isolated from the herbs of Scorzonera austriaca Wild by silica gel column chromatography and preparative HPLC. Their structures were identified, using chemical and spectroscopic methods, as 5,7,4′-trihydroxyflavone 6-C-(2''-O-β-d-glucopyranosyl β-d [...] Read more.
Five flavonoid glycosides and two derivatives were isolated from the herbs of Scorzonera austriaca Wild by silica gel column chromatography and preparative HPLC. Their structures were identified, using chemical and spectroscopic methods, as 5,7,4′-trihydroxyflavone 6-C-(2''-O-β-d-glucopyranosyl β-d-glucopyranoside) (1), 5,7,3′,4′-tetrahydroxyflavone 6-C-(2''-O-β-d-glucopyranosyl β-d-glucopyranoside) (2), quercetin 3-O-rutinoside (3), 5,7,4′-trihydroxyflavone 6-C-β-d-glucopyranoside (4), 3′-methoxy-5,7,4′-trihydroxyflavone 6-C-β-d-glucopyranoside (5), 5,7,4′-trihydroxyflavone 8-C-(6''-O-trans-caffeoyl β-d-glucopyranoside) (6), and 5,7,3′,4′-tetrahydroxyflavone 8-C-(6''-O-trans-caffeoyl β-d-glucopyranoside) (7). Compounds 6 and 7 are new flavonoid glycoside derivatives, and compounds 15 were isolated from the herbs of Scorzonera austriaca for the first time. Compounds 6 and 7 were also assayed for their hepatoprotective activities with rat hepatocytes in vitro. Full article
(This article belongs to the Section Natural Products Chemistry)
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2686 KiB  
Article
Synthesis and Characterization of a Novel Borazine-Type UV Photo-Induced Polymerization of Ceramic Precursors
by Dan Wei, Lixin Chen, Tingting Xu, Weiqi He and Yi Wang
Molecules 2016, 21(6), 801; https://doi.org/10.3390/molecules21060801 - 21 Jun 2016
Cited by 8 | Viewed by 5347
Abstract
A preceramic polymer of B,B′,B′′-(dimethyl)ethyl-acrylate-silyloxyethyl-borazine was synthesized by three steps from a molecular single-source precursor and characterized by Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectrometry. Six-member borazine rings and acrylate groups were effectively introduced into the preceramic polymer to activate [...] Read more.
A preceramic polymer of B,B′,B′′-(dimethyl)ethyl-acrylate-silyloxyethyl-borazine was synthesized by three steps from a molecular single-source precursor and characterized by Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectrometry. Six-member borazine rings and acrylate groups were effectively introduced into the preceramic polymer to activate UV photo-induced polymerization. Photo-Differential Scanning Calorimetry (Photo-DSC) and real-time FTIR techniques were adapted to investigate the photo-polymerization process. The results revealed that the borazine derivative exhibited dramatic activity by UV polymerization, the double-bond conversion of which reached a maximum in 40 s. Furthermore, the properties of the pyrogenetic products were studied by scanning electron microscopy (SEM) and X-ray diffraction (XRD), which proved the ceramic annealed at 1100 °C retained the amorphous phase. Full article
(This article belongs to the Section Molecular Diversity)
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1575 KiB  
Article
Capsaicin Synthesis Requires in Situ Phenylalanine and Valine Formation in in Vitro Maintained Placentas from Capsicum chinense
by Fray M. Baas-Espinola, Lizbeth A. Castro-Concha, Felipe A. Vázquez-Flota and María L. Miranda-Ham
Molecules 2016, 21(6), 799; https://doi.org/10.3390/molecules21060799 - 21 Jun 2016
Cited by 13 | Viewed by 8507
Abstract
Capsaicinoids (CAP) are nitrogenous metabolites formed from valine (Val) and phenylalanine (Phe) in the placentas of hot Capsicum genotypes. Placentas of Habanero peppers can incorporate inorganic nitrogen into amino acids and have the ability to secure the availability of the required amino acids [...] Read more.
Capsaicinoids (CAP) are nitrogenous metabolites formed from valine (Val) and phenylalanine (Phe) in the placentas of hot Capsicum genotypes. Placentas of Habanero peppers can incorporate inorganic nitrogen into amino acids and have the ability to secure the availability of the required amino acids for CAP biosynthesis. In order to determine the participation of the placental tissue as a supplier of these amino acids, the effects of blocking the synthesis of Val and Phe by using specific enzyme inhibitors were analyzed. Isolated placentas maintained in vitro were used to rule out external sources′ participation. Blocking Phe synthesis, through the inhibition of arogenate dehydratase, significantly decreased CAP accumulation suggesting that at least part of Phe required in this process has to be produced in situ. Chlorsulfuron inhibition of acetolactate synthase, involved in Val synthesis, decreased not only Val accumulation but also that of CAP, pointing out that the requirement for this amino acid can also be fulfilled by this tissue. The presented data demonstrates that CAP accumulation in in vitro maintained placentas can be accomplished through the in situ availability of Val and Phe and suggests that the synthesis of the fatty acid chain moiety may be a limiting factor in the biosynthesis of these alkaloids. Full article
(This article belongs to the Special Issue Capsaicin)
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648 KiB  
Article
Synthesis and Anticancer Activities of Novel Guanylhydrazone and Aminoguanidine Tetrahydropyran Derivatives
by Fábio Pedrosa Lins Silva, Bruna Braga Dantas, Gláucia Veríssimo Faheina Martins, Demétrius Antônio Machado De Araújo and Mário Luiz Araújo de Almeida Vasconcellos
Molecules 2016, 21(6), 671; https://doi.org/10.3390/molecules21060671 - 21 Jun 2016
Cited by 12 | Viewed by 5315
Abstract
In this paper we present the convenient syntheses of six new guanylhydrazone and aminoguanidine tetrahydropyran derivatives 27. The guanylhydrazone 2, 3 and 4 were prepared in 100% yield, starting from corresponding aromatic ketones 8ac and aminoguanidine hydrochloride [...] Read more.
In this paper we present the convenient syntheses of six new guanylhydrazone and aminoguanidine tetrahydropyran derivatives 27. The guanylhydrazone 2, 3 and 4 were prepared in 100% yield, starting from corresponding aromatic ketones 8ac and aminoguanidine hydrochloride accessed by microwave irradiation. The aminoguanidine 5, 6 and 7 were prepared by reduction of guanylhydrazone 24 with sodium cyanoborohydride (94% yield of 5, and 100% yield of 6 and 7). The aromatic ketones 8ac were prepared from the Barbier reaction followed by the Prins cyclization reaction (two steps, 63%–65% and 95%–98%). Cytotoxicity studies have demonstrated the effects of compounds 27 in various cancer and normal cell lines. That way, we showed that these compounds decreased cell viabilities in a micromolar range, and from all the compounds tested we can state that, at least, compound 3 can be considered a promising molecule for target-directed drug design. Full article
(This article belongs to the Section Bioorganic Chemistry)
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Article
Antileishmanial Activity and Structure-Activity Relationship of Triazolic Compounds Derived from the Neolignans Grandisin, Veraguensin, and Machilin G
by Eduarda C. Costa, Tatiana B. Cassamale, Diego B. Carvalho, Lauriane S. S. Bosquiroli, Mariáh Ojeda, Thalita V. Ximenes, Maria F. C. Matos, Mônica C. T. Kadri, Adriano C. M. Baroni and Carla C. P. Arruda
Molecules 2016, 21(6), 802; https://doi.org/10.3390/molecules21060802 - 20 Jun 2016
Cited by 31 | Viewed by 6403
Abstract
Sixteen 1,4-diaryl-1,2,3-triazole compounds 419 derived from the tetrahydrofuran neolignans veraguensin 1, grandisin 2, and machilin G 3 were tested against Leishmania (Leishmania) amazonensis intracellular amastigotes. Triazole compounds 419 were synthetized via Click Chemistry strategy by [...] Read more.
Sixteen 1,4-diaryl-1,2,3-triazole compounds 419 derived from the tetrahydrofuran neolignans veraguensin 1, grandisin 2, and machilin G 3 were tested against Leishmania (Leishmania) amazonensis intracellular amastigotes. Triazole compounds 419 were synthetized via Click Chemistry strategy by 1,3-dipolar cycloaddition between terminal acetylenes and aryl azides containing methoxy and methylenedioxy groups as substituents. Our results suggest that most derivatives were active against intracellular amastigotes, with IC50 values ranging from 4.4 to 32.7 µM. The index of molecular hydrophobicity (ClogP) ranged from 2.8 to 3.4, reflecting a lipophilicity/hydrosolubility rate suitable for transport across membranes, which may have resulted in the potent antileishmanial activity observed. Regarding structure-activity relationship (SAR), compounds 14 and 19, containing a trimethoxy group, were the most active (IC50 values of 5.6 and 4.4 µM, respectively), with low cytotoxicity on mammalian cells (SI = 14.1 and 10.6). These compounds induced nitric oxide production by the host macrophage cells, which could be suggested as the mechanism involved in the intracellular killing of parasites. These results would be useful for the planning of new derivatives with higher antileishmanial activities. Full article
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Article
Antioxidative, Antibacterial, and Food Functional Properties of the Half-Fin Anchovy Hydrolysates-Glucose Conjugates Formed via Maillard Reaction
by Ru Song, Peiyu Yang, Rongbian Wei and Guanqiang Ruan
Molecules 2016, 21(6), 795; https://doi.org/10.3390/molecules21060795 - 20 Jun 2016
Cited by 27 | Viewed by 6692
Abstract
The antioxidative, antibacterial, and food functional properties of the half-fin anchovy hydrolysates (HAHp)-glucose conjugates formed by Maillard reaction (MR) were investigated, respectively. Results of sugar and amino acid contents loss rates, browning index, and molecular weight distribution indicated that the initial pH of [...] Read more.
The antioxidative, antibacterial, and food functional properties of the half-fin anchovy hydrolysates (HAHp)-glucose conjugates formed by Maillard reaction (MR) were investigated, respectively. Results of sugar and amino acid contents loss rates, browning index, and molecular weight distribution indicated that the initial pH of HAHp played an important role in the process of MR between HAHp and glucose. HAHp-glucose Maillard reaction products (HAHp-G MRPs) demonstrated enhanced antioxidative activities of reducing power and scavenging DPPH radicals compared to control groups. HAHp-G MRPs produced from the condition of pH 9.6 displayed the strongest reducing power. The excellent scavenging activity on DPPH radicals was found for HAHp(5.6)-G MRPs which was produced at pH 5.6. Additionally, HAHp(5.6)-G MRPs showed variable antibacterial activities against Escherichia coli, Pseudomonas fluorescens, Proteus vulgaris, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis, Bacillus megaterium, and Sarcina lutea, with the MIC values ranging from 8.3 to 16.7 μg/mL. Result of scanning electron microscopy (SEM) on E. coli suggested that HAHp(5.6)-G MRPs exhibited antibacterial activity by destroying the cell integrity through membrane permeabilization. Moreover, HAHp(5.6)-G MRPs had excellent foaming ability and stability at alkaline conditions of pH 8.0, and showed emulsion properties at acidic pH 4.0. These results suggested that specific HAHp-G MRPs should be promising functional ingredients used in foods. Full article
(This article belongs to the Collection Bioactive Compounds)
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Article
Discovery of Novel Allopurinol Derivatives with Anticancer Activity and Attenuated Xanthine Oxidase Inhibition
by Yong Li, Ting-Ting Cao, Shanchun Guo, Qiu Zhong, Cai-Hu Li, Ying Li, Lin Dong, Shilong Zheng, Guangdi Wang and Shu-Fan Yin
Molecules 2016, 21(6), 771; https://doi.org/10.3390/molecules21060771 - 20 Jun 2016
Cited by 13 | Viewed by 7420
Abstract
A series of pyrazolo[3,4-d]pyrimidine derivatives related to allopurinol has been synthesized and evaluated for its cytotoxicity against a panel of three cancer cell lines as well as its xanthine oxidase (XOD) inhibitory activities. Among them, compound 4 showed potent cytotoxicity with IC50 [...] Read more.
A series of pyrazolo[3,4-d]pyrimidine derivatives related to allopurinol has been synthesized and evaluated for its cytotoxicity against a panel of three cancer cell lines as well as its xanthine oxidase (XOD) inhibitory activities. Among them, compound 4 showed potent cytotoxicity with IC50 values of 25.5 and 35.2 μM against human hepatoma carcinoma cell lines, BEL-7402 and SMMC-7221, respectively. The anticancer activity of 4 was comparable to that of Tanespimycin (17-N-allylamino-17-demethoxy geldanamycin, 17-AAG) that inhibited the growth of BEL-7402 and SMMC-7221 cells at IC50 values of 12.4 and 9.85 μM, respectively. However, unlike allopurinol, which is also a strong inhibitor of XOD, compound 4 is a much weaker XOD inhibitor, suggesting that the anticancer activities of the allopurinol derivatives may not be associated with XOD inhibition. Moreover, the cytotoxicity of 4 toward normal cells is significantly lower than that of 17-AAG, making 4 a promising lead compound for further optimization of structure-activity relationships that may lead to anticancer agents of clinical utility. Full article
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Article
In Vitro Assessment of CYP-Mediated Drug Interactions for Kinsenoside, an Antihyperlipidemic Candidate
by Shaheed Ur Rehman, Min Sun Choi, In Sook Kim, Zengwei Luo, Yongbo Xue, Guangming Yao, Yonghui Zhang and Hye Hyun Yoo
Molecules 2016, 21(6), 800; https://doi.org/10.3390/molecules21060800 - 18 Jun 2016
Cited by 4 | Viewed by 5836
Abstract
Kinsenoside, the herb-derived medicine isolated from the plant Anoect chilus, has diverse pharmacological actions, and it is considered to be a promising antihyperlipidemic drug candidate. This study evaluates the effects of kinsenoside on CYP enzyme-mediated drug metabolism in order to predict the [...] Read more.
Kinsenoside, the herb-derived medicine isolated from the plant Anoect chilus, has diverse pharmacological actions, and it is considered to be a promising antihyperlipidemic drug candidate. This study evaluates the effects of kinsenoside on CYP enzyme-mediated drug metabolism in order to predict the potential for kinsenoside-drug interactions. Kinsenoside was tested at different concentrations of 0.1, 0.3, 1, 3, 10, 30, and 100 µM in human liver microsomes. The c Cktail probe assay based on liquid chromatography-tandem mass spectrometry was conducted to measure the CYP inhibitory effect of kinsenoside. Subsequently, the metabolism profiles of amlodipine and lovastatin in human liver microsomes were analyzed following co-incubation with kinsenoside. The concentration levels of the parent drug and the major metabolites were compared with the kinsenoside-cotreated samples. The effect of kinsenoside was negligible on the enzyme activity of all the CYP isozymes tested even though CYP2A6 was slightly inhibited at higher concentrations. The drug-drug interaction assay also showed that the concomitant use of kinsenoside has a non-significant effect on the concentration of lovastatin or amlodipine, and their major metabolites. So, it was concluded that there is almost no risk of drug interaction between kinsenoside and CYP drug substrates via CYP inhibition. Full article
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Article
The Deformation of Polydimethylsiloxane (PDMS) Microfluidic Channels Filled with Embedded Circular Obstacles under Certain Circumstances
by Changhyun Roh, Jaewoong Lee and Chankyu Kang
Molecules 2016, 21(6), 798; https://doi.org/10.3390/molecules21060798 - 18 Jun 2016
Cited by 14 | Viewed by 7255
Abstract
Experimental investigations were conducted to determine the influence of polydimethylsiloxane (PDMS) microfluidic channels containing aligned circular obstacles (with diameters of 172 µm and 132 µm) on the flow velocity and pressure drop under steady-state flow conditions. A significant PDMS bulging was observed when [...] Read more.
Experimental investigations were conducted to determine the influence of polydimethylsiloxane (PDMS) microfluidic channels containing aligned circular obstacles (with diameters of 172 µm and 132 µm) on the flow velocity and pressure drop under steady-state flow conditions. A significant PDMS bulging was observed when the fluid flow initially contacted the obstacles, but this phenomenon decreased in the 1 mm length of the microfluidic channels when the flow reached a steady-state. This implies that a microfluidic device operating with steady-state flows does not provide fully reliable information, even though less PDMS bulging is observed compared to quasi steady-state flow. Numerical analysis of PDMS bulging using ANSYS Workbench showed a relatively good agreement with the measured data. To verify the influence of PDMS bulging on the pressure drop and flow velocity, theoretical analyses were performed and the results were compared with the experimental results. The measured flow velocity and pressure drop data relatively matched well with the classical prediction under certain circumstances. However, discrepancies were generated and became worse as the microfluidic devices were operated under the following conditions: (1) restricted geometry of the microfluidic channels (i.e., shallow channel height, large diameter of obstacles and a short microchannel length); (2) operation in quasi-steady state flow; (3) increasing flow rates; and (4) decreasing amount of curing agent in the PDMS mixture. Therefore, in order to obtain reliable data a microfluidic device must be operated under appropriate conditions. Full article
(This article belongs to the Special Issue Micro/Nano Fluidics and Bio-MEMS)
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Review
Capsaicin, Nociception and Pain
by Bárbara Frias and Adalberto Merighi
Molecules 2016, 21(6), 797; https://doi.org/10.3390/molecules21060797 - 18 Jun 2016
Cited by 136 | Viewed by 24255
Abstract
Capsaicin, the pungent ingredient of the hot chili pepper, is known to act on the transient receptor potential cation channel vanilloid subfamily member 1 (TRPV1). TRPV1 is involved in somatic and visceral peripheral inflammation, in the modulation of nociceptive inputs to spinal cord [...] Read more.
Capsaicin, the pungent ingredient of the hot chili pepper, is known to act on the transient receptor potential cation channel vanilloid subfamily member 1 (TRPV1). TRPV1 is involved in somatic and visceral peripheral inflammation, in the modulation of nociceptive inputs to spinal cord and brain stem centers, as well as the integration of diverse painful stimuli. In this review, we first describe the chemical and pharmacological properties of capsaicin and its derivatives in relation to their analgesic properties. We then consider the biochemical and functional characteristics of TRPV1, focusing on its distribution and biological effects within the somatosensory and viscerosensory nociceptive systems. Finally, we discuss the use of capsaicin as an agonist of TRPV1 to model acute inflammation in slices and other ex vivo preparations. Full article
(This article belongs to the Special Issue Capsaicin)
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Article
Construction of an Immobilized Thermophilic Esterase on Epoxy Support for Poly(ε-caprolactone) Synthesis
by Hui Ren, Zhen Xing, Jiebing Yang, Wei Jiang, Gang Zhang, Jun Tang and Quanshun Li
Molecules 2016, 21(6), 796; https://doi.org/10.3390/molecules21060796 - 18 Jun 2016
Cited by 11 | Viewed by 5616
Abstract
Developing an efficient immobilized enzyme is of great significance for improving the operational stability of enzymes in poly(ε-caprolactone) synthesis. In this paper, a thermophilic esterase AFEST from the archaeon Archaeoglobus fulgidus was successfully immobilized on the epoxy support Sepabeads EC-EP via covalent attachment, [...] Read more.
Developing an efficient immobilized enzyme is of great significance for improving the operational stability of enzymes in poly(ε-caprolactone) synthesis. In this paper, a thermophilic esterase AFEST from the archaeon Archaeoglobus fulgidus was successfully immobilized on the epoxy support Sepabeads EC-EP via covalent attachment, and the immobilized enzyme was then employed as a biocatalyst for poly(ε-caprolactone) synthesis. The enzyme loading and recovered activity of immobilized enzyme was measured to be 72 mg/g and 10.4 U/mg using p-nitrophenyl caprylate as the substrate at 80 °C, respectively. Through the optimization of reaction conditions (enzyme concentration, temperature, reaction time and medium), poly(ε-caprolactone) was obtained with 100% monomer conversion and low number-average molecular weight (Mn < 1300 g/mol). Further, the immobilized enzyme exhibited excellent reusability, with monomer conversion values exceeding 75% during 15 batch reactions. Finally, poly(ε-caprolactone) was enzymatically synthesized with an isolated yield of 75% and Mn value of 3005 g/mol in a gram-scale reaction. Full article
(This article belongs to the Special Issue Enzyme Immobilization 2016)
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Article
Synthesis of Bioactive 2-(Arylamino)thiazolo[5,4-f]-quinazolin-9-ones via the Hügershoff Reaction or Cu- Catalyzed Intramolecular C-S Bond Formation
by Damien Hédou, Carole Dubouilh-Benard, Nadège Loaëc, Laurent Meijer, Corinne Fruit and Thierry Besson
Molecules 2016, 21(6), 794; https://doi.org/10.3390/molecules21060794 - 18 Jun 2016
Cited by 9 | Viewed by 6759
Abstract
A library of thirty eight novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives (series 8, 10, 14 and 17) was prepared via the Hügershoff reaction and a Cu catalyzed intramolecular C-S bond formation, helped by microwave-assisted technology when required. The efficient [...] Read more.
A library of thirty eight novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives (series 8, 10, 14 and 17) was prepared via the Hügershoff reaction and a Cu catalyzed intramolecular C-S bond formation, helped by microwave-assisted technology when required. The efficient multistep synthesis of the key 6-amino-3-cyclopropylquinazolin-4(3H)-one (3) has been reinvestigated and performed on a multigram scale from the starting 5-nitroanthranilic acid. The inhibitory potency of the final products was evaluated against five kinases involved in Alzheimer’s disease and showed that some molecules of the 17 series described in this paper are particularly promising for the development of novel multi-target inhibitors of kinases. Full article
(This article belongs to the Collection Heterocyclic Compounds)
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Article
Anti-Inflammatory Effects of Agrimoniin-Enriched Fractions of Potentilla erecta
by Julia Hoffmann, Federica Casetti, Ute Bullerkotte, Birgit Haarhaus, Jan Vagedes, Christoph M. Schempp and Ute Wölfle
Molecules 2016, 21(6), 792; https://doi.org/10.3390/molecules21060792 - 18 Jun 2016
Cited by 29 | Viewed by 7624
Abstract
Potentilla erecta (PE) is a small herbaceous plant with four yellow petals belonging to the Rosaceae family. The rhizome of PE has traditionally been used as an antidiarrheal, hemostatic and antihemorrhoidal remedy. PE contains up to 20% tannins and 5% ellagitannins, mainly agrimoniin. [...] Read more.
Potentilla erecta (PE) is a small herbaceous plant with four yellow petals belonging to the Rosaceae family. The rhizome of PE has traditionally been used as an antidiarrheal, hemostatic and antihemorrhoidal remedy. PE contains up to 20% tannins and 5% ellagitannins, mainly agrimoniin. Agrimoniin is a hydrolyzable tannin that is a potent radical scavenger. In this study we tested the anti-inflammatory effect of four PE fractions with increasing amounts of agrimoniin obtained by Sephadex column separation. First, we analyzed in HaCaT keratinocytes the expression of cyclooxygenase-2 (COX-2) induced by ultraviolet-B (UVB) irradiation. As COX-2 catalyzes the metabolism of arachidonic acid to prostanoids such as PGE2, we also measured the PGE2 concentration in cell culture supernatants. PE inhibited UVB-induced COX-2 expression in HaCaT cells and dose-dependently reduced PGE2. The PE fraction with the highest agrimoniin amount (PE4) was the most effective in this experiment, whereas fraction PE1 containing mainly sugars had no effect. PE4 also dose dependently inhibited the phosphorylation of the epidermal growth factor receptor (EGFR) which plays a crucial role in UVB-mediated COX-2 upregulation. A placebo-controlled UV-erythema study with increasing concentrations of PE4 demonstrated a dose dependent inhibition of UVB-induced inflammation in vivo. Similarly, PE4 significantly reduced UVB-induced PGE2 production in suction blister fluid in vivo. In summary, PE fractions with a high agrimoniin content display anti-inflammatory effects in vitro and in vivo in models of UVB-induced inflammation. Full article
(This article belongs to the Special Issue Natural Products and Inflammation)
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Article
Cytotoxic and Pro-Apoptotic Effects of Cassane Diterpenoids from the Seeds of Caesalpinia sappan in Cancer Cells
by Han Bao, Le-Le Zhang, Qian-Yu Liu, Lu Feng, Yang Ye, Jin-Jian Lu and Li-Gen Lin
Molecules 2016, 21(6), 791; https://doi.org/10.3390/molecules21060791 - 18 Jun 2016
Cited by 29 | Viewed by 6489
Abstract
The chemical study on the seeds of Caesalpinia sappan led to the isolation of five new cassane diterpenoids, phanginins R‒T (13) and caesalsappanins M and N (4 and 5), together with seven known compounds 612 [...] Read more.
The chemical study on the seeds of Caesalpinia sappan led to the isolation of five new cassane diterpenoids, phanginins R‒T (13) and caesalsappanins M and N (4 and 5), together with seven known compounds 612. Their structures were elucidated on the basis of NMR and HRESIMS analyses. The absolute configurations of compounds 1 and 4 were determined by the corresponding CD spectra. All the isolated compounds were tested for their cytotoxicity against ovarian cancer A2780 and HEY, gastric cancer AGS, and non-small cell lung cancer A549 cells. Compound 1 displayed significant toxicity against the four cell lines with the IC50 values of 9.9 ± 1.6 µM, 12.2 ± 6.5 µM, 5.3 ± 1.9 µM, and 12.3 ± 3.1 µM, respectively. Compound 1 induced G1 phase cell cycle arrest in A2780 cells. Furthermore, compound 1 dose-dependently induced A2780 cells apoptosis as evidenced by Hoechst 33342 staining, Annexin V positive cells, the up-regulated cleaved-PARP and the enhanced Bax/Bcl-2 ratio. What’s more, compound 1 also promoted the expression of the tumor suppressor p53 protein. These findings indicate that cassane diterpenoids might have potential as anti-cancer agents, and further in vivo animal studies and structural modification investigation are needed. Full article
(This article belongs to the Section Natural Products Chemistry)
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Article
Aldol Reactions of Axially Chiral 5-Methyl-2-(o-aryl)imino-3-(o-aryl)-thiazolidine-4-ones
by Sule Erol Gunal and Ilknur Dogan
Molecules 2016, 21(6), 788; https://doi.org/10.3390/molecules21060788 - 18 Jun 2016
Cited by 1 | Viewed by 4994
Abstract
Axially chiral 5-methyl-2-(o-aryl)imino-3-(o-aryl)-thiazolidine-4-ones have been subjected to aldol reactions with benzaldehyde to produce secondary carbinols which have been found to be separable by HPLC on a chiral stationary phase. Based on the reaction done on a single enantiomer resolved [...] Read more.
Axially chiral 5-methyl-2-(o-aryl)imino-3-(o-aryl)-thiazolidine-4-ones have been subjected to aldol reactions with benzaldehyde to produce secondary carbinols which have been found to be separable by HPLC on a chiral stationary phase. Based on the reaction done on a single enantiomer resolved via a chromatographic separation from a racemic mixture of 5-methyl-2-(α-naphthyl)imino-3-(α-naphthyl)-thiazolidine-4-one by HPLC on a chiral stationary phase, the aldol reaction was shown to proceed via an enolate intermediate. The axially chiral enolate of the thiazolidine-4-one was found to shield one face of the heterocyclic ring rendering face selectivity with respect to the enolate. The selectivities observed at C-5 of the ring varied from none to 11.5:1 depending on the size of the ortho substituent. Although the aldol reaction proceeded with a lack of face selectivity with respect to benzaldehyde, recrystallization returned highly diastereomerically enriched products. Full article
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Article
The Fungicidal Activity of Thymol against Fusarium graminearum via Inducing Lipid Peroxidation and Disrupting Ergosterol Biosynthesis
by Tao Gao, Hao Zhou, Wei Zhou, Liangbin Hu, Jian Chen and Zhiqi Shi
Molecules 2016, 21(6), 770; https://doi.org/10.3390/molecules21060770 - 18 Jun 2016
Cited by 123 | Viewed by 8119
Abstract
Thymol is a natural plant-derived compound that has been widely used in pharmaceutical and food preservation applications. However, the antifungal mechanism for thymol against phytopathogens remains unclear. In this study, we identified the antifungal action of thymol against Fusarium graminearum, an economically [...] Read more.
Thymol is a natural plant-derived compound that has been widely used in pharmaceutical and food preservation applications. However, the antifungal mechanism for thymol against phytopathogens remains unclear. In this study, we identified the antifungal action of thymol against Fusarium graminearum, an economically important phytopathogen showing severe resistance to traditional chemical fungicides. The sensitivity of thymol on different F. graminearum isolates was screened. The hyphal growth, as well as conidial production and germination, were quantified under thymol treatment. Histochemical, microscopic, and biochemical approaches were applied to investigate thymol-induced cell membrane damage. The average EC50 value of thymol for 59 F. graminearum isolates was 26.3 μg·mL−1. Thymol strongly inhibited conidial production and hyphal growth. Thymol-induced cell membrane damage was indicated by propidium iodide (PI) staining, morphological observation, relative conductivity, and glycerol measurement. Thymol induced a significant increase in malondialdehyde (MDA) concentration and a remarkable decrease in ergosterol content. Taken together, thymol showed potential antifungal activity against F. graminearum due to the cell membrane damage originating from lipid peroxidation and the disturbance of ergosterol biosynthesis. These results not only shed new light on the antifungal mechanism of thymol, but also imply a promising alternative for the control of Fusarium head blight (FHB) disease caused by F. graminearum. Full article
(This article belongs to the Section Natural Products Chemistry)
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Review
Emerging Roles of Toxin-Antitoxin Modules in Bacterial Pathogenesis
by Barbara Kędzierska and Finbarr Hayes
Molecules 2016, 21(6), 790; https://doi.org/10.3390/molecules21060790 - 17 Jun 2016
Cited by 95 | Viewed by 9983
Abstract
Toxin-antitoxin (TA) cassettes are encoded widely by bacteria. The modules typically comprise a protein toxin and protein or RNA antitoxin that sequesters the toxin factor. Toxin activation in response to environmental cues or other stresses promotes a dampening of metabolism, most notably protein [...] Read more.
Toxin-antitoxin (TA) cassettes are encoded widely by bacteria. The modules typically comprise a protein toxin and protein or RNA antitoxin that sequesters the toxin factor. Toxin activation in response to environmental cues or other stresses promotes a dampening of metabolism, most notably protein translation, which permits survival until conditions improve. Emerging evidence also implicates TAs in bacterial pathogenicity. Bacterial persistence involves entry into a transient semi-dormant state in which cells survive unfavorable conditions including killing by antibiotics, which is a significant clinical problem. TA complexes play a fundamental role in inducing persistence by downregulating cellular metabolism. Bacterial biofilms are important in numerous chronic inflammatory and infectious diseases and cause serious therapeutic problems due to their multidrug tolerance and resistance to host immune system actions. Multiple TAs influence biofilm formation through a network of interactions with other factors that mediate biofilm production and maintenance. Moreover, in view of their emerging contributions to bacterial virulence, TAs are potential targets for novel prophylactic and therapeutic approaches that are required urgently in an era of expanding antibiotic resistance. This review summarizes the emerging evidence that implicates TAs in the virulence profiles of a diverse range of key bacterial pathogens that trigger serious human disease. Full article
(This article belongs to the Special Issue Natural Toxins)
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