Publications by authors named "Martin Zehl"

85 Publications

Endophytic sp. LN303 from Edelweiss Produces Emestrin and Two New 2-Hydroxy-4 Pyridone Alkaloids.

ACS Omega 2021 Jan 15;6(3):2184-2191. Epub 2021 Jan 15.

Department of Pharmacognosy, University of Vienna, 1090 Vienna, Austria.

In the search for new antibiotics, several fungal endophytes were isolated from the medicinal plant subsp. (Edelweiss). The extract from one of these fungi classified as sp. displayed broad-spectrum antibiotic activity against gram-negative bacteria and fungi. Further investigation into the composition of this extract using bioactivity-guided fractionation, HRMS, and nuclear magnetic resonance revealed two new 4-hydroxy-2-pyridone alkaloids (, ) and emestrin (), an epidithiodioxopiperazine not previously known to be produced by a member of Cordycipitaceae. Further testing of purified compounds and proved that they are devoid of antibiotic activity, and all the activities observed in the crude extract could be assigned to emestrin (), whose configuration was confirmed by crystallographic data. This study demonstrates, for the first time, that endophytic fungi from Edelweiss can produce new compounds, prompting further investigation into them for drug discovery.
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http://dx.doi.org/10.1021/acsomega.0c05472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841945PMC
January 2021

Class IV Lasso Peptides Synergistically Induce Proliferation of Cancer Cells and Sensitize Them to Doxorubicin.

iScience 2020 Dec 10;23(12):101785. Epub 2020 Nov 10.

Department of Pharmacognosy, University of Vienna, Vienna 1090, Austria.

Heterologous expression of a biosynthesis gene cluster from sp. resulted in the discovery of two unique class IV lasso peptides, felipeptins A1 and A2. A mixture of felipeptins stimulated proliferation of cancer cells, while having no such effect on the normal cells. Detailed investigation revealed, that pre-treatment of cancer cells with a mixture of felipeptins resulted in downregulation of the tumor suppressor Rb, making the cancer cells to proliferate faster. Pre-treatment with felipeptins made cancer cells considerably more sensitive to the anticancer agent doxorubicin and re-sensitized doxorubicin-resistant cells to this drug. Structural characterization and binding experiments showed an interaction between felipeptins resulting in complex formation, which explains their synergistic effect. This discovery may open an alternative avenue in cancer treatment, helping to eliminate quiescent cells that often lead to cancer relapse.
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http://dx.doi.org/10.1016/j.isci.2020.101785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689547PMC
December 2020

Chemoselective Homologation-Deoxygenation Strategy Enabling the Direct Conversion of Carbonyls into ()-Halomethyl-Alkanes.

Org Lett 2020 10 10;22(19):7629-7634. Epub 2020 Sep 10.

Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse, 14, 1090 Vienna, Austria.

The sequential installation of a carbenoid and a hydride into a carbonyl, furnishing halomethyl alkyl derivatives, is reported. Despite the employment of carbenoids as nucleophiles in reactions with carbon-centered electrophiles, sp-type alkyl halides remain elusive materials for selective one-carbon homologations. Our tactic levers on using carbonyls as starting materials and enables uniformly high yields and chemocontrol. The tactic is flexible and is not limited to carbenoids. Also, diverse carbanion-like species can act as nucleophiles, thus making it of general applicability.
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http://dx.doi.org/10.1021/acs.orglett.0c02831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011987PMC
October 2020

Viennamycins: Lipopeptides Produced by a sp.

J Nat Prod 2020 08 31;83(8):2381-2389. Epub 2020 Jul 31.

Department of Pharmacognosy, University of Vienna, 1090 Vienna, Austria.

Extracts from sp. S4.7 isolated from the rhizosphere of edelweiss, an alpine medicinal plant, exhibited activity against Gram-positive bacteria. LC-HRMS analyses of the extracts resulted in the detection of two unknown, structurally related lipopeptides that were assumed to be responsible for the antibiotic activity. LC-MS guided isolation and structure elucidation of viennamycins A and B ( and ) by HR-MS/MS, 1D and 2D NMR, and Marfey's analyses revealed them to be novel compounds, with viennamycin A containing cysteic acid, a unique feature for lipopeptides. Tests for antibacterial, antifungal, and cytotoxic activities of purified viennamycins, both with and without divalent cations, did not reveal any bioactivity, suggesting that their biological function, which could not be determined in the tests used, is atypical for lipopeptides. The genome of sp. S4.7 was sequenced and analyzed, revealing the viennamycin biosynthetic gene cluster. Detailed bioinformatics-based analysis of the viennamycin gene cluster allowed elucidation of the biosynthetic pathway for these lipopeptides.
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http://dx.doi.org/10.1021/acs.jnatprod.0c00152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460545PMC
August 2020

Isolation and Characterization of Acetylcholinesterase Inhibitors from Piper longum and Binding Mode Predictions.

Planta Med 2020 Oct 15;86(15):1118-1124. Epub 2020 Jul 15.

Department of Pharmacognosy, Faculty of Pharmacy, Tehran University of Medical Science, Tehran, Iran.

Restoration of cholinergic function is considered a rational approach to enhance cognitive performance. Acetylcholinesterase inhibitors are still the best therapeutic option for Alzheimer's disease. The fruits of have been used in traditional medicines for the treatment of memory loss. It was demonstrated that the dichloromethane extract of these fruits is able to inhibit acetylcholinesterase. Thus, the aim of this study was to identify the contained acetylcholinesterase inhibitors. The active zones were presented via TLC-bioautography, and five compounds were isolated in the process of a bioassay-guided phytochemical investigation. Their structures were characterized as piperine, methyl piperate, guineenisine, pipercide, and pellitorine using spectroscopy and spectrometry methods (UV, IR, MS, H-, and C-NMR). acetylcholinesterase inhibitory activities of the isolates and their IC values were determined via a colorimetric assay. Three of them exhibited enzyme inhibitory activities, with piperine being the most potent compound (IC of 0.3 mM). In order to investigate the binding mode of the tested compounds, docking studies were performed using the X-ray crystal structure of acetylcholinesterase from with the Protein Data Bank code 1EVE. The content of the active compounds in the extract was determined by a developed HPLC method. Piperine was present in the maximum quantity in the fruits (0.57%), whereas methyl piperate contained the minimum content (0.10%).
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http://dx.doi.org/10.1055/a-1199-7084DOI Listing
October 2020

In Vitro Digestion of Grape Seed Oil Inhibits Phospholipid-Regulating Effects of Oxidized Lipids.

Biomolecules 2020 05 2;10(5). Epub 2020 May 2.

Department of Physiological Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria.

The intake of dietary lipids is known to affect the composition of phospholipids in gastrointestinal cells, thereby influencing passive lipid absorption. However, dietary lipids rich in polyunsaturated fatty acids, such as vegetable oils, are prone to oxidation. Studies investigating the phospholipid-regulating effect of oxidized lipids are lacking. We aimed at identifying the effects of oxidized lipids from moderately (18.8 ± 0.39 meq O/kg oil) and highly (28.2 ± 0.39 meq O/kg oil) oxidized and in vitro digested cold-pressed grape seed oils on phospholipids in human gastric tumor cells (HGT-1). The oils were analyzed for their antioxidant constituents as well as their oxidized triacylglycerol profile by LC-MS/MS before and after a simulated digestion. The HGT-1 cells were treated with polar oil fractions containing epoxidized and hydroperoxidized triacylglycerols for up to six hours. Oxidized triacylglycerols from grape seed oil were shown to decrease during the in vitro digestion up to 40% in moderately and highly oxidized oil. The incubation of HGT-1 cells with oxidized lipids from non-digested oils induced the formation of cellular phospholipids consisting of unsaturated fatty acids, such as phosphocholines PC (18:1/22:6), PC (18:2/0:0), phosphoserine PS (42:8) and phosphoinositol PI (20:4/0:0), by about 40%-60%, whereas the incubation with the in vitro digested oils did not affect the phospholipid metabolism. Hence, the gastric conditions inhibited the phospholipid-regulating effect of oxidized triacylglycerols (oxTAGs), with potential implications in lipid absorption.
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http://dx.doi.org/10.3390/biom10050708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277833PMC
May 2020

spp. From the Marine Sponge : Analyses of Secondary Metabolite Biosynthesis Gene Clusters and Some of Their Products.

Front Microbiol 2020 18;11:437. Epub 2020 Mar 18.

Department of Pharmacognosy, University of Vienna, Vienna, Austria.

Actinomycete bacteria from marine environments represent a potential source for new antibiotics and anti-tumor drugs. Ten strains belonging to the genus isolated from the marine sponge collected at the bottom of the Trondheim fjord (Norway) were screened for antibiotic activity. Since only few isolates proved to be bioactive in the conditions tested, we decided to gain an insight into their biosynthetic potential using genome sequencing and analysis. Draft genomes were analyzed for the presence of secondary metabolite biosynthesis gene clusters (BGCs) using antiSMASH software. BGCs specifying both known and potentially novel secondary metabolites were identified, suggesting that these isolates might be sources for new bioactive compounds. The results of this analysis also implied horizontal transfer of several gene clusters between the studied isolates, which was especially evident for the lantibiotic- and thiopeptide-encoding BGCs. The latter implies the significance of particular secondary metabolites for the adaptation of to the spatially enclosed marine environments such as marine sponges. Two bioactive isolates, one showing activity against both yeast and , and one only against yeast were analyzed in details, leading to the identification of cycloheximide, linearmycins, and echinomycins that are presumably responsible for the observed bioactivities.
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http://dx.doi.org/10.3389/fmicb.2020.00437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093587PMC
March 2020

Structure-Activity Relationships of Novel Thiazole-Based Modafinil Analogues Acting at Monoamine Transporters.

J Med Chem 2020 01 30;63(1):391-417. Epub 2019 Dec 30.

Neuroscience Laboratory , Paracelsus Medical University , A-5020 Salzburg , Austria.

Atypical dopamine reuptake inhibitors, such as modafinil, are used for the treatment of sleeping disorders and investigated as potential therapeutics against cocaine addiction and for cognitive enhancement. Our continuous effort to find modafinil analogues with higher inhibitory activity on and selectivity toward the dopamine transporter (DAT) has previously led to the promising thiazole-containing derivatives CE-103, CE-111, CE-123, and CE-125. Here, we describe the synthesis and activity of a series of compounds based on these scaffolds, which resulted in several new selective DAT inhibitors and gave valuable insights into the structure-activity relationships. Introduction of the second chiral center and subsequent chiral separations provided all four stereoisomers, whereby the -configuration on both generally exerted the highest activity and selectivity on DAT. The representative compound of this series was further characterized by , , and studies that have demonstrated both safety and efficacy profile of this compound class.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01938DOI Listing
January 2020

Peptide-Targeted Polyplexes for Aerosol-Mediated Gene Delivery to CD49f-Overexpressing Tumor Lesions in Lung.

Mol Ther Nucleic Acids 2019 Dec 18;18:774-786. Epub 2019 Oct 18.

Laboratory of MacroMolecular Cancer Therapeutics (MMCT), Center of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria. Electronic address:

Peptide ligands can enhance delivery of nucleic acid-loaded nanoparticles to tumors by promoting their cell binding and internalization. Lung tumor lesions accessible from the alveolar side can be transfected, in principle, using gene vectors delivered as an aerosol. The cell surface marker CD49f (Integrin α6) is frequently upregulated in metastasizing, highly aggressive tumors. In this study, we utilize a CD49f binding peptide coupled to linear polyethylenimine (LPEI) promoting gene delivery into CD49f-overexpressing tumor cells in vitro and into lung lesions in vivo. We have synthesized a molecular conjugate based on LPEI covalently attached to the CD49f binding peptide CYESIKVAVS via a polyethylene glycol (PEG) spacer. Particles formed with plasmid DNA were small (<200 nm) and could be aerosolized without causing major aggregation or particle loss. In vitro, CD49f targeting significantly improved plasmid uptake and reporter gene expression on both human and murine tumor cell lines. For evaluation in vivo, localization and morphology of 4T1 murine triple-negative breast cancer tumor lesions in the lung of syngeneic BALB/c mice were identified by MRI. Polyplexes applied via intratracheal aerosolization were well tolerated and resulted in measurable transgene activity of the reporter gene firefly luciferase in tumor areas by bioluminescence imaging (BLI). Transfectability of tumors correlated with their accessibility for the aerosol. With CD49f-targeted polyplexes, luciferase activity was considerably increased and was restricted to the tumor area.
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http://dx.doi.org/10.1016/j.omtn.2019.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861568PMC
December 2019

Antiplasmodial activity of triterpenes isolated from the methanolic leaf extract of Combretum racemosum P. Beauv.

J Ethnopharmacol 2020 Jan 28;247:112203. Epub 2019 Aug 28.

Department of Pharmacognosy, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria. Electronic address:

Ethnopharmacological Relevance: Combretum racemosum showed activity in previous ethnopharmacological investigations of some Combretum species used in malaria treatment in parts of West Africa.

Aim Of The Study: This study aimed at confirming the antimalarial potential of this plant by an activity-guided isolation of its active principles.

Materials And Methods: A crude methanolic leaf extract of Combretum racemosum and fractions thereof obtained by partition with chloroform and n-butanol were investigated for antiplasmodial activity against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Repeated chromatographic separations were conducted on the chloroform fraction to isolate bioactive compounds for further tests on antiplasmodial activity. The characterization of the isolated substances was performed by applying NMR- and MS-techniques (ESI-MS, HR-ESIMS, 1D and 2D NMR).

Results: The chloroform fraction (D10: IC = 33.8 ± 1.5 μg/mL and W2: IC = 27.8 ± 2.9 μg/mL) exhibited better antiplasmodial activity than the n-butanol fraction (D10: IC = 78.1 ± 7.3 μg/mL and W2: IC = 78 ± 15 μg/mL) as well as the methanolic raw extract (D10: IC = 64.2 ± 2.7 μg/mL and W2: IC = 65.8 ± 14.9 μg/mL). Thus, the focus of the phytochemical investigation was laid on the chloroform fraction, which led to the identification of four ursane-type (19α-hydroxyasiatic acid (1), 6β,23-dihydroxytormentic acid (4), madecassic acid (8), nigaichigoside F1 (10)) and four oleanane-type (arjungenin (2), combregenin (5), terminolic acid (7), arjunglucoside I (11)) triterpenes, as well as abscisic acid (9). Compounds 1 and 2, 4 and 5, 7 and 8 as well as 10 and 11 were isolated as isomeric mixtures in fractions CR-A, CR-C, CR-E and CR-H, respectively. All isolated compounds and mixtures exhibited moderate to low activity, with madecassic acid being most active (D10: IC = 28 ± 12 μg/mL and W2: IC = 17.2 ± 4.3 μg/mL).

Conclusion: This paper reports for the first time antiplasmodial principles from C. racemosum and thereby gives reason to the traditional use of the plant.
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http://dx.doi.org/10.1016/j.jep.2019.112203DOI Listing
January 2020

Simultaneous Analysis of Epoxidized and Hydroperoxidized Triacylglycerols in Canola Oil and Margarine by LC-MS.

J Agric Food Chem 2019 Sep 28;67(36):10174-10184. Epub 2019 Aug 28.

The progress of lipid oxidation in foods is evaluated by measuring the peroxides and their scission products. However, hydrogen abstraction-independent pathways are not considered by commonly applied methods despite the known reactivity of epoxides toward biomolecules. Herein, a novel liquid chromatography tandem-mass spectrometry method was developed to detect hydroperoxidized and epoxidized triacylglycerols (TAGs) without derivatization or hydrolyzation of food samples. Epoxidized TAGs could be detected in refined canola oil at concentrations of 96.8 ± 2.08 μM, while only 5.77 ± 0.04 μM hydroperoxidized TAGs could be determined. In contrast to canola oil, margarine was more resistant to lipid oxidation since generation of epoxidized TAGs could only be marginally enhanced from 21.7 ± 0.48 to 28.8 ± 0.64 μM in margarine after treatment at 180 °C for 60 min, as also reflected by a peroxide value of 0.80 ± 0.00 mequiv O/kg, which remained unchanged. The new method allows the assessment of food safety by the simultaneous measurement of hydroperoxidized and epoxidized TAGs without hydrolysis and laborious sample preparation.
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http://dx.doi.org/10.1021/acs.jafc.9b03601DOI Listing
September 2019

The Novel Atypical Dopamine Uptake Inhibitor -CE-123 Partially Reverses the Effort-Related Effects of the Dopamine Depleting Agent Tetrabenazine and Increases Progressive Ratio Responding.

Front Pharmacol 2019 28;10:682. Epub 2019 Jun 28.

Department of Psychological Sciences, University of Connecticut, Storrs, CT, United States.

Animal studies of effort-based choice behavior are being used to model effort-related motivational dysfunctions in humans. With these procedures, animals are offered a choice between high-effort instrumental actions leading to highly valued reinforcers vs. low effort/low reward options. Several previous studies have shown that dopamine (DA) uptake inhibitors, including GBR12909, lisdexamfetamine, methylphenidate, and PRX-14040, can reverse the effort-related effects of the vesicular monoamine transport blocker tetrabenazine, which inhibits DA storage. Because many drugs that block DA transport act as major stimulants that also release DA, and produce a number of undesirable side effects, there is a need to develop and characterize novel atypical DA transport inhibitors. -CE-123 (--((benzhydrylsulfinyl) methyl)thiazole) is a recently developed analog of modafinil with the biochemical characteristics of an atypical DA transport blocker. The present paper describes the enantioselective synthesis and initial chemical characterization of -CE-123, as well as behavioral experiments involving effort-based choice and microdialysis studies of extracellular DA. Rats were assessed using the fixed ratio 5/chow feeding choice test. Tetrabenazine (1.0 mg/kg) shifted choice behavior, decreasing lever pressing and increasing chow intake. -CE-123 was coadministered at doses ranging from 6.0 to 24.0 mg/kg, and the highest dose partially but significantly reversed the effects of tetrabenazine, although this dose had no effect on fixed ratio responding when administered alone. Additional experiments showed that -CE-123 significantly increased lever pressing on a progressive ratio/chow feeding choice task and that the effective dose (24.0 mg/kg) increased extracellular DA in nucleus accumbens core. In summary, -CE-123 has the behavioral and neurochemical profile of a compound that can block DA transport, reverse the effort-related effects of tetrabenazine, and increase selection of high-effort progressive ratio responding. This suggests that -CE-123 or a similar compound could be useful as a treatment for effort-related motivational dysfunction in humans.
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http://dx.doi.org/10.3389/fphar.2019.00682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611521PMC
June 2019

N, N', N″-trisubstituted guanidines: Synthesis, characterization and evaluation of their leishmanicidal activity.

Eur J Med Chem 2019 Jun 21;171:116-128. Epub 2019 Mar 21.

Laboratório de Química Orgânica Fina, Departamento de Química e Biologia, Faculdade de Ciências e Tecnologia, Universidade Estadual Paulista - UNESP, Campus de Presidente Prudente, Rua Roberto Simonsen, 305, 19060-900, Presidente Prudente, SP, Brazil; Programa de Pós-Graduação em Ciência e Tecnologia de Materiais (POSMAT), Universidade Estadual Paulista - UNESP, São Paulo, Brazil. Electronic address:

Leishmaniasis is a group of diseases caused by protozoan parasites from the genus Leishmania. There are estimated 1.3 million new cases annually with a mortality of 20,000-30,000 per year, when patients are left untreated. Current chemotherapeutic drugs available present high toxicity and low efficacy, the latter mainly due to the emergence of drug-resistant parasites, which makes discovery of novel, safe, and efficacious antileishmanial drugs mandatory. The present work reports the synthesis, characterization by ESI-MS, H and C NMR, and FTIR techniques as well as in vitro and in vivo evaluation of leishmanicidal activity of guanidines derivatives presenting lower toxicity. Among ten investigated compounds, all being guanidines containing a benzoyl, a benzyl, and a substituted phenyl moiety, LQOF-G2 (IC 5.6 μM; SI = 131.8) and LQOF-G7 (IC 7.1 μM; SI = 87.1) were the most active against L. amazonensis intracellular amastigote, showing low cytotoxicity to the host cells according to their selectivity index. The most promising compound, LQOF-G2, was further evaluated in an in vivo model and was able to decrease 60% of the parasite load in foot lesions at a dose of 0.25 mg/kg/day. Moreover, this guanidine derivative demonstrated reduced hepatotoxicity compared to other leishmanicidal compounds and did not show nephrotoxicity, as determined by the analyses of biomarkers of hepatic damage and renal function, which make this compound a potential new hit for therapy against leishmaniasis.
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http://dx.doi.org/10.1016/j.ejmech.2019.03.032DOI Listing
June 2019

Secondary metabolites from lichen as potent inhibitors of advanced glycation end products and vasodilative agents.

Fitoterapia 2018 Nov 16;131:182-188. Epub 2018 Oct 16.

SONAS, EA921, Universtiy of Angers, SFR QUASAV, Faculty of Health Sciences, Department of Pharmacy, 16 Bd Daviers, 49045, Angers, France.

Secondary metabolites from lichens are known for exhibiting various biological effects such as anti-inflammatory, antioxidant and antibacterial activities. Despite this wide range of reported biological effects, their impact on the formation of advanced glycation end products (AGEs) remains vastly unexplored. The latter are known contributors to lifestyle and age-related diseases such as Alzheimer and Parkinson. Moreover, the development of atherosclerosis and arterial stiffness is causally linked to the formation of AGEs. With this in mind, the present work evaluated the inhibitory effects of secondary lichen metabolites on the formation of pentosidine-like AGEs' by using an in vitro, Maillard reaction based, fluorescence assay. Overall, thirty-seven natural and five synthetically modified compounds were tested, eighteen of which exhibiting IC values in the range of 0.05 to 0.70 mM. This corresponds to 2 to 32 fold of the inhibitory activity of aminoguanidine. Targeting one major inhibiting mechanism of AGEs formation, all compounds were additionally evaluated on their radical scavenging capacities in an DPPH assay. Furthermore, as both AGEs' formation and hypertension are major risk factors for atherosclerosis, compounds that were available in sufficient amounts were also tested for their vasodilative effects. Overall, and though some of the active compounds were previously reported cytotoxic, present results highlight the interesting potential of secondary lichen metabolites as anti-AGEs and vasodilative agents.
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http://dx.doi.org/10.1016/j.fitote.2018.10.015DOI Listing
November 2018

Evaluation of Apricot, Bilberry, and Elderberry Pomace Constituents and Their Potential To Enhance the Endothelial Nitric Oxide Synthase (eNOS) Activity.

ACS Omega 2018 Sep 5;3(9):10545-10553. Epub 2018 Sep 5.

Faculty of Life Sciences, Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.

Pomace, the press residue from different fruits accumulating as waste product in food industry, contains high amounts of secondary metabolites that could be utilized for health-related applications. This study aims at evaluating the potential of pomaces of apricot, bilberry, and elderberry to serve as a source for endothelial nitric oxide synthase (eNOS)-activating compounds. Five extracts obtained from the lyophilized pomace of apricot and elderberry with solvents of different polarity were found to enhance A23187-stimulated eNOS activity when tested at 50 μg/mL in an [C]-l-arginine to [C]-l-citrulline conversion assay in the human endothelium-derived cell line EA.hy926 ( < 0.05). The bioassay-guided fractionation of the extracts obtained with methanol/water (70:30) led to several active fractions from apricot pomace ( < 0.05) and elderberry pomace ( < 0.01). Liquid chromatography-mass spectrometry-based chemical analysis of the extracts and active fractions pointed mainly to triterpenoic acids as active compounds. One particular dihydroxytriterpenoic acid, characteristic for elderberry, was enriched as the main compound in the two most active fractions and might serve as a promising lead structure for further studies.
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http://dx.doi.org/10.1021/acsomega.8b00638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173479PMC
September 2018

Lanostane Triterpenes from Gloeophyllum odoratum and Their Anti-Influenza Effects.

Planta Med 2019 Feb 21;85(3):195-202. Epub 2018 Aug 21.

Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna, Austria.

In an screening for anti-influenza agents from European polypores, the fruit body extract of dose-dependently inhibited the cytopathic effect of the H3N2 influenza virus A/Hong Kong/68 (HK/68) in Madin Darby canine kidney cells with a 50% inhibitory concentration (IC) of 15 µg/mL, a noncytotoxic concentration. After a chromatographic work-up, eight lanostane triterpenes (1: -8: ) were isolated and their structures were elucidated based on high-resolution electrospray ionization mass spectrometry analyses, and one- and two-dimensional nuclear magnetic resonance experiments. Constituents 1: (gloeophyllin K) and 2: (gloeophyllin L) are reported here for the first time, and compounds 5: , 7: , and 8: have not been described for the investigated fungal material so far. The highest activity was determined for trametenolic acid B (3: ) against HK/68 and the 2009 pandemic H1N1 strain A/Jena/8178/09 with IC values of 14 and 11 µM, respectively. In a plaque reduction assay, this compound was able to bind to cell-free viruses and to neutralize their infectivity.
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http://dx.doi.org/10.1055/a-0690-9236DOI Listing
February 2019

Resveratrol Inhibits Key Steps of Steroid Metabolism in a Human Estrogen-Receptor Positive Breast Cancer Model: Impact on Cellular Proliferation.

Front Pharmacol 2018 10;9:742. Epub 2018 Jul 10.

Division of Clinical Pharmacy and Diagnostics, Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria.

The role of resveratrol (RES) in preventing breast cancer is controversial, as low concentrations may stimulate the proliferation of estrogen-receptor alpha positive (ERα+) breast cancer cells. As metabolism is the key factor in altering cellular estrogens, thereby influencing breast tumor growth, we investigated the effects of RES on the formation of estrogen metabolites, namely 4-androstene-3,17-dione (AD), dehydroepiandrosterone (DHEA), dehydroepiandrosterone-3--sulfate (DHEA-S), estrone (E1), estrone-3-sulfate (E1-S), 17β-estradiol (E2), 17β-estradiol-3--(β-D-glucuronide) (E2-G), 17β-estradiol-3--sulfate (E2-S), 16α-hydroxy-17β-estradiol (estriol, E3), and testosterone (T) in ERα- MDA-MB-231 and ERα+ MCF-7 cells. Incubation of both of the cell lines with the hormone precursors DHEA and E1 revealed that sulfation and glucuronidation were preferred metabolic pathways for DHEA, E1 and E2 in MCF-7 cells, compared with in MDA-MB-231 cells, as the V values were significantly higher (DHEA-S: 2873.0 ± 327.4 fmol/10 cells/h, E1-S: 30.4 ± 2.5 fmol/10 cells/h, E2-S: 24.7 ± 4.9 fmol/10 cells/h, E2-G: 7.29 ± 1.36 fmol/10 cells/h). RES therefore significantly inhibited DHEA-S, E1-S, E2-S and E2-G formation in MCF-7, but not in MDA-MB-231 cells (Ks: E2-S, 0.73 ± 0.07 μM < E1-S, 0.94 ± 0.03 μM < E2-G, 7.92 ± 0.24 μM < DHEA-S, 13.2 ± 0.2 μM). Suppression of these metabolites subsequently revealed twofold higher levels of active E2, concomitant with an almost twofold increase in MCF-7 cell proliferation, which was the most pronounced upon the addition of 5 μM RES. As the content of RES in food is relatively low, an increased risk of breast cancer progression in women is likely to only be observed following the continuous consumption of high-dose RES supplements. Further long-term human studies simultaneously monitoring free estrogens and their conjugates are therefore highly warranted to evaluate the efficacy and safety of RES supplementation, particularly in patients diagnosed with ERα+ breast cancer.
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http://dx.doi.org/10.3389/fphar.2018.00742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048268PMC
July 2018

spp. From Ethiopia Producing Antimicrobial Compounds: Characterization via Bioassays, Genome Analyses, and Mass Spectrometry.

Front Microbiol 2018 12;9:1270. Epub 2018 Jun 12.

Department of Pharmacognosy, University of Vienna, Vienna, Austria.

A total of 416 actinomycete cultures were isolated from various unique environments in Ethiopia and tested for bioactivity. Six isolates with pronounced antimicrobial activity were chosen for taxonomic identification and further investigation. Morphological and cultural properties of the isolates were found to be consistent with those of the genus , which was further confirmed by phylogenetic analysis based on 16S rRNA gene sequences. One of the isolates, designated sp. Go-475, which displayed potent activity against both pathogenic yeasts and Gram-positive bacteria, was chosen for further investigation. Metabolite profiles and bioactivity of Go-475 incubated on wheat bran-based solid and soya flour-based liquid media were compared using high-resolution LC-MS. This allowed identification of several known compounds, and suggested the ability of Go-475 to produce new secondary metabolites. Major anti-bacterial compounds were purified from liquid cultures of Go-475, and their structures elucidated by NMR and HRMS as 8-O-methyltetrangomycin and 8-O-methyltetrangulol. In addition, many potentially novel metabolites were detected, the majority of which were produced in solid media-based fermentation. The genome sequence of sp. Go-475 was obtained using a hybrid assembly approach of high quality Illumina short read and low quality Oxford Nanopore long read data. The complete linear chromosome of 8,570,609 bp, featuring a G+C content of 71.96%, contains 7,571 predicted coding sequences, 83 t(m)RNA genes, and six operons. Analysis of the genome for secondary metabolite biosynthesis gene clusters further confirmed potential of this isolate to synthesize chemically diverse natural products, and allowed to connect certain clusters with experimentally confirmed molecules.
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http://dx.doi.org/10.3389/fmicb.2018.01270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007079PMC
June 2018

Chemical Composition of and the Effects on Tumor Invasiveness .

Front Pharmacol 2018 3;9:304. Epub 2018 Apr 3.

Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna, Vienna, Austria.

A detannified methanolic extract of L. attenuated the formation of cancer cell-induced circular chemorepellent induced defects (CCIDs) in the lymph endothelial cell barrier, which resemble entry ports for the intravasating tumor into the vasculature as a prerequisite for lymph node metastasis. Therefore, the composition of this extract was studied in an activity-guided approach. Since no data on the secondary metabolites of this plant were available, first phytochemical data were collected in the course of the fractionation of the extract. The study resulted in the identification of 14 substances, among them very rare iridoids, such as scrovalentinoside or koelzioside, and several flavonoids (e.g., nepitrin and homoplantaginin). One of the latter group, 2″--acetyl-homoplantaginin, is a new natural compound. In the most active fraction, the flavonoid hispidulin was identified as major component and the assay of the pure compound confirmed a contribution of hispidulin to the CCID-inhibitory effects of . The activity of the two major iridoids in this assay was less compared to hispidulin.
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http://dx.doi.org/10.3389/fphar.2018.00304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891616PMC
April 2018

Anti-Influenza Triterpene Saponins from the Bark of Burkea africana.

J Nat Prod 2018 03 2;81(3):515-523. Epub 2018 Feb 2.

Department of Pharmacognosy, Faculty of Life Sciences , University of Vienna , Althanstraße 14 , 1090 Vienna , Austria.

In an in vitro cytopathic effect inhibition assay with the H3N2 influenza virus A/Hong Kong/68 (HK/68), the bark extract of Burkea africana was found to be a promising antiviral lead with an IC value of 5.5 μg/mL without noteworthy cytotoxicity in Madin Darby canine kidney cells. After several chromatographic steps, triterpene saponins of the lupane and oleanane types were identified as the bioactive principles. In total, eight new triterpene saponins (1-8) with four so far undescribed aglycone structures were isolated and characterized via HRESIMS, GC-MS, and 1D and 2D NMR spectroscopy. Their anti-influenza virus activity on HK/68 and the 2009 pandemic H1N1 strain A/Jena/8178/09 revealed the most potent effects by compounds 7 and 8, with IC values between 0.05 and 0.27 μM. This is the first time triterpene saponins have been reported as constituents of the investigated plant material.
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http://dx.doi.org/10.1021/acs.jnatprod.7b00774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869419PMC
March 2018

Heterocyclic Analogues of Modafinil as Novel, Atypical Dopamine Transporter Inhibitors.

J Med Chem 2017 11 9;60(22):9330-9348. Epub 2017 Nov 9.

Neuroscience Laboratory, Paracelsus Medical University , 5020 Salzburg, Austria.

Modafinil is a wake promoting compound with high potential for cognitive enhancement. It is targeting the dopamine transporter (DAT) with moderate selectivity, thereby leading to reuptake inhibition and increased dopamine levels in the synaptic cleft. A series of modafinil analogues have been reported so far, but more target-specific analogues remain to be discovered. It was the aim of this study to synthesize and characterize such analogues and, indeed, a series of compounds were showing higher activities on the DAT and a higher selectivity toward DAT versus serotonin and norepinephrine transporters than modafinil. This was achieved by substituting the amide moiety by five- and six-membered aromatic heterocycles. In vitro studies indicated binding to the cocaine pocket on DAT, although molecular dynamics revealed binding different from that of cocaine. Moreover, no release of dopamine was observed, ruling out amphetamine-like effects. The absence of neurotoxicity of a representative analogue may encourage further preclinical studies of the above-mentioned compounds.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01313DOI Listing
November 2017

The Impacts of Genistein and Daidzein on Estrogen Conjugations in Human Breast Cancer Cells: A Targeted Metabolomics Approach.

Front Pharmacol 2017 5;8:699. Epub 2017 Oct 5.

Division of Clinical Pharmacy and Diagnostics, Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria.

The beneficial effect of dietary soy food intake, especially for women diagnosed with breast cancer, is controversial, as data has shown that the soy isoflavones genistein and daidzein may even stimulate the proliferation of estrogen-receptor alpha positive (ERα+) breast cancer cells at low concentrations. As genistein and daidzein are known to inhibit key enzymes in the steroid metabolism pathway, and thus may influence levels of active estrogens, we investigated the impacts of genistein and daidzein on the formation of estrogen metabolites, namely 17β-estradiol (E2), 17β-estradiol-3-(β-D-glucuronide) (E2-G), 17β-estradiol-3-sulfate (E2-S) and estrone-3-sulfate (E1-S) in estrogen-dependent ERα+ MCF-7 cells. We found that both isoflavones were potent inhibitors of E1 and E2 sulfation (85-95% inhibition at 10 μM), but impeded E2 glucuronidation to a lesser extent (55-60% inhibition at 10 μM). The stronger inhibition of E1 and E2 sulfation compared with E2 glucuronidation was more evident for genistein, as indicated by significantly lower inhibition constants for genistein [Ks: E2-S (0.32 μM) < E1-S (0.76 μM) < E2-G (6.01 μM)] when compared with those for daidzein [Ks: E2-S (0.48 μM) < E1-S (1.64 μM) < E2-G (7.31 μM)]. Concomitant with the suppression of E1 and E2 conjugation, we observed a minor but statistically significant increase in E2 concentration of approximately 20%. As the content of genistein and daidzein in soy food is relatively low, an increased risk of breast cancer development and progression in women may only be observed following consumption of high-dose isoflavone supplements. Further long-term human studies monitoring free estrogens and their conjugates are therefore highly warranted to evaluate the potential side effects of high-dose genistein and daidzein, especially in patients diagnosed with ERα+ breast cancer.
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http://dx.doi.org/10.3389/fphar.2017.00699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5633874PMC
October 2017

Allspice and Clove As Source of Triterpene Acids Activating the G Protein-Coupled Bile Acid Receptor TGR5.

Front Pharmacol 2017 17;8:468. Epub 2017 Jul 17.

Department of Pharmacognosy, Faculty of Life Sciences, University of ViennaVienna, Austria.

Worldwide, metabolic diseases such as obesity and type 2 diabetes have reached epidemic proportions. A major regulator of metabolic processes that gained interest in recent years is the bile acid receptor TGR5 (Takeda G protein-coupled receptor 5). This G protein-coupled membrane receptor can be found predominantly in the intestine, where it is mainly responsible for the secretion of the incretins glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). The aim of this study was (i) to identify plant extracts with TGR5-activating potential, (ii) to narrow down their activity to the responsible constituents, and (iii) to assess whether the intestinal microbiota produces transformed metabolites with a different activity profile. Chenodeoxycholic acid (CDCA) served as positive control for both, the applied cell-based luciferase reporter gene assay for TGR5 activity and the biotransformation assay using mouse fecal slurry. The suitability of the workflow was demonstrated by the biotransformation of CDCA to lithocholic acid resulting in a distinct increase in TGR5 activity. Based on a traditional Tibetan formula, 19 plant extracts were selected and investigated for TGR5 activation. Extracts from the commonly used spices (SaroE, clove), (PdioE, allspice), and (KgalE, aromatic ginger) significantly increased TGR5 activity. After biotransformation, only KgalE showed significant differences in its metabolite profile, which, however, did not alter its TGR5 activity compared to non-transformed KgalE. UHPLC-HRMS (high-resolution mass spectrometry) analysis revealed triterpene acids (TTAs) as the main constituents of the extracts SaroE and PdioE. Identification and quantification of TTAs in these two extracts as well as comparison of their TGR5 activity with reconstituted TTA mixtures allowed the attribution of the TGR5 activity to TTAs. ECs were determined for the main TTAs, i.e., oleanolic acid (2.2 ± 1.6 μM), ursolic acid (1.1 ± 0.2 μM), as well as for the hitherto unknown TGR5 activators corosolic acid (0.5 ± 1.0 μM) and maslinic acid (3.7 ± 0.7 μM). In conclusion, extracts of clove, allspice, and aromatic ginger activate TGR5, which might play a pivotal role in their therapeutic use for the treatment of metabolic diseases. Moreover, the TGR5 activation of SaroE and PdioE could be pinpointed solely to TTAs.
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http://dx.doi.org/10.3389/fphar.2017.00468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511840PMC
July 2017

Acetylated Furostene Glycosides from Solanum gilo Fruits.

Planta Med 2017 Oct 18;83(14-15):1227-1232. Epub 2017 Jul 18.

Department of Pharmacognosy, University of Vienna, Vienna, Austria.

In continuation of our work on a traditional mixture of spices called "Nkui", used in Cameroon for its influence on women's reproductive health, we investigated the chemical composition of , one component of "Nkui". A methanolic extract was studied in detail. After dereplication of several known compounds, two furo-5-stene-derived saponin glycosides with acetylated sugar moieties were isolated. By extensive 1- and 2D NMR experiments and HR-MS and GC-MS methods, the structures were elucidated as 26-[(3‴,4‴,6‴-tri-O-acetyl)--D-glucopyranosyloxy]-22-hydroxyfurost-5-en-3-yl-O--L-rhamnopyranosyl-(1″→2')--D-glucopyranoside () and 26-[(3‴,4‴,6‴-tri-O-acetyl)--D-glucopyranosyloxy]-22-hydroxyfurost-5-en-3-yl-[O--L-rhamnopyranosyl-(1''''→4')-O--L-rhamnopyranosyl-(1″→2')]--D-glucopyranoside (), both new natural compounds.
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http://dx.doi.org/10.1055/s-0043-116491DOI Listing
October 2017

Isolation of eudesmanes from Pluchea odorata and evaluation of their effects on cancer cell growth and tumor invasiveness in vitro.

Phytochemistry 2017 Sep 26;141:37-47. Epub 2017 May 26.

Department of Pharmacognosy, University of Vienna, Althanstraße 14, 1090 Vienna, Austria. Electronic address:

The traditionally used Central American medicinal plant Pluchea odorata, known as an anti-inflammatory and cancer cell growth-inhibiting remedy, was subjected to bioassay-guided isolation. Structure elucidation by 1D- and 2D-NMR and MS techniques supported by ECD and UV spectroscopic data revealed seven structurally previously undescribed and eight known eudesmane-type sesquiterpenes. Furthermore, one previously undescribed and one known phytol-like alcohol were identified. All compounds were tested for their cytotoxicity in cancer cells and for their anti-invasive effects. Among the eudesmanes, 3α-(2',3'-epoxy-2'-methylbutyryloxy)-4α-hydroxy-11-hydroperoxy-eudesm-6-en-8-one exhibited the most potent cytotoxic activity with an IC value of 8.8 μM (after 48 h). Also in an in vitro model measuring the tumor-triggered breaching of the adjacent lymph endothelial cell barrier (3S*,4R*,5S*,10S*,2'R*,3'R*)-3-(2',3'-epoxy-2'-methylbutyryloxy)-4,7-dihydroxy-eudesm-11-en-8-one (IC = 47 μM) and (3S*,4R*,5R*,10S*,2'R*,3'R*)-3-(2',3'-epoxy-2'-methylbutyryloxy)-4-acetyloxy-6-methoxy-11-hydroxy-eudesm-6-en-8-one (IC = 73 μM) showed inhibitory activities. Furthermore, preliminary structure-activity relationships (SARs) of the eudesmanes were developed.
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http://dx.doi.org/10.1016/j.phytochem.2017.05.009DOI Listing
September 2017

Metabolism of Curcumin in Human Breast Cancer Cells: Impact of Sulfation on Cytotoxicity.

Planta Med 2017 Aug 7;83(12-13):1028-1034. Epub 2017 Apr 7.

Department of Pharmaceutical Chemistry, Division of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria.

Curcumin is a natural polyphenol with promising anticancer properties that undergoes pronounced metabolism in humans. In order to determine whether metabolism of curcumin also occurs in tumor cells and whether biotransformation has any impact on cytotoxicity, metabolism experiments were conducted with hormone-dependent ZR-75-1 and hormone-independent MDA-MB-231 human breast cancer cells. By using HPLC-ESI-Qq-TOF-MS, it was possible to identify one main metabolite, namely curcumin sulfate, in both cell lines. Its concentration in the cytoplasm and culture medium was 1.6- to 1.7-fold higher in ZR-75-1 cells than in MDA-MB-231 cells, concomitant with a 2-fold higher IC value in the ZR-75-1 cell line (14 µM compared to 7.3 µM). The net result of sulfation seems to lower the intracellular concentration of curcumin, thereby decreasing its growth inhibitory activity. Interestingly, for the first time, we also found the formation of a curcumin dimer in the cytoplasm but not in the cellular medium of both cell lines. Compared to curcumin sulfate, however, its maximal intracellular concentrations were up to 4-fold lower, indicating only a minor contribution to the overall curcumin clearance. In conclusion, our data elucidated the metabolism of curcumin in breast cancer cells, which must be considered in humans following oral uptake of dietary curcumin as a chemopreventive agent.
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http://dx.doi.org/10.1055/s-0043-107885DOI Listing
August 2017

Simultaneous quantification of estrogens, their precursors and conjugated metabolites in human breast cancer cells by LC-HRMS without derivatization.

J Pharm Biomed Anal 2017 May 22;138:344-350. Epub 2017 Feb 22.

Department of Pharmaceutical Chemistry, Division of Clinical Pharmacy and Diagnostics, University of Vienna, 1090 Vienna, Austria. Electronic address:

Liquid chromatography-mass spectrometry (LC-MS) is the state of the art technique for quantification of steroid hormones. Currently used methods are typically limited by the need of pre-column derivatization to increase ionization efficiency; however, this causes hydrolysis of conjugated metabolites. Our newly established LC-HRMS method is able to simultaneously quantify conjugated and unconjugated steroids without prior derivatization using deuterated internal standards and solid-phase extraction. This assay was validated according to ICH Q2(R1) guidelines for the analysis of the 10 main steroids of the estrogenic pathway, namely 4-androstene-3,17-dione, dehydroepiandrosterone (DHEA), DHEA-3-sulfate, estrone, 17β-estradiol, estriol (16α-OH-17β-estradiol), estrone-3-sulfate, 17β-estradiol-3-(β-d-glucuronide), 17β-estradiol-3-sulfate and testosterone. Assay performance characteristics were excellent with results for accuracy (98.8-101.2%), precision (mean: 2.05%, all ≤2.80%), stability over five freeze-thaw-cycles (95.7-100.4%) and SPE accuracy (96.9-102.0%), as well as suitable lower and upper limits of quantification for cell culture experiments (LLOQ 0.005-2ng/ml, ULOQ 3-2000ng/ml). Furthermore, we demonstrated the functionality of our method for the monitoring of steroid levels in the human breast cancer cell line MCF-7. This sensitive assay allows for the first time detailed investigations on estrogen metabolomics in breast cancer cells and may also apply to other estrogen-dependent tumor entities.
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http://dx.doi.org/10.1016/j.jpba.2017.02.033DOI Listing
May 2017

HPTLC Bioautography Guided Isolation of α-Glucosidase Inhibiting Compounds from Justicia secunda Vahl (Acanthaceae).

Phytochem Anal 2017 Mar 2;28(2):87-92. Epub 2016 Dec 2.

Department of Pharmacognosy, University of Vienna, Althanstraße 14, A-1090, Vienna, Austria.

Introduction: α-Glucosidase inhibitors form an essential basis for the development of novel drugs in diabetes type 2 treatment. Searching for α-glucosidase inhibitors in plants, TLC bioautographic assays have been established and improved within the last years. In traditional medicine, extracts from the leaves of Justicia secunda Vahl are used to treat diabetes mellitus symptoms.

Objective: To screen for α-glucosidase inhibitors in J. secunda via HPTLC bioautography. Methodology - Extracts from the leaves of J. secunda and fractions thereof were evaluated in terms of their α-glucosidase inhibiting potential by subjecting them to HPTLC bioautography. The aqueous (AQ) fraction deriving from the methanol extract was further fractionated via column chromatography on polystyrene Diaion® HP-20. Two AQ subfractions revealed active compounds, which were isolated via preparative HPTLC and semipreparative HPLC. Their identification and structure elucidation was achieved employing HPLC-ESI-MS , HRESI-MS, and NMR analyses.

Results: α-Glucosidase inhibitors were visualised as white zones on violet background on the TLC plate. The crude water extract, the methanol extract, and the methanol extract derived AQ fraction showed α-glucosidase inhibiting effects. In the latter, two diastereomeric mixtures responsible for the α-glucosidase inhibition were enriched. They were identified as the novel 2-caffeoyloxy-4-hydroxy-glutaric acid and the diastereomers secundarellone B and C.

Conclusion: The current study presents the α-glucosidase inhibiting potential of J. secunda supporting its traditional medicinal use in diabetes mellitus treatment. HPTLC bioautography screening for α-glucosidase inhibitors provides a simple and effective method for the investigation of complex samples, such as plant extracts. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/pca.2651DOI Listing
March 2017

Selective anticancer activity of the novel thiobenzanilide 63T against human lung adenocarcinoma cells.

Toxicol In Vitro 2016 Dec 19;37:148-161. Epub 2016 Sep 19.

Department of Medicinal Chemistry, University of Vienna, Vienna, Austria.

Previously, it has been reported that molecules built on the benzanilide and thiobenzanilide scaffold are the promising groups of compounds with several biological activities including antifungal, antimycotic, antibacterial, spasmolytic, and anticancer ones. In this study the mechanism of action of one selected thiobenzanilide derivative N,N'-(1,2-phenylene)bis3,4,5-trifluorobenzothioamide (63T) with strongest cytotoxic activity has been investigated for the first time in human lung adenocarcinoma (A549) and normal lung derived fibroblast (CCD39Lu) in a cell culture model. The results demonstrated, that 63T can be considered a selective anticancer compound. Based on these results, several experiments including the analysis of cellular morphology, cell phase distribution, cytoplasmic histone-associated DNA fragmentation, apoptosis, necrosis, and autophagy detection were performed to understand better the mechanism underlying the anticancer activity. The data showed that 63T is a small molecule compound, which selectively induces cancer cell death in a caspase independent pathway; moreover, the autophagic dose-dependent processes may be involved in the mechanism of cell death.
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http://dx.doi.org/10.1016/j.tiv.2016.09.017DOI Listing
December 2016

A novel heterocyclic compound targeting the dopamine transporter improves performance in the radial arm maze and modulates dopamine receptors D1-D3.

Behav Brain Res 2016 10 8;312:127-37. Epub 2016 Jun 8.

Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria. Electronic address:

A series of compounds targeting the dopamine transporter (DAT) haS been shown to improve memory performance most probably by re-uptake inhibition. Although specific DAT inhibitors are available, there is limited information about specificity, mechanism and in particular the effect on dopamine receptors. It was therefore the aim of the study to test the DAT inhibitor 4-(diphenyl-methanesulfinylmethyl)-2-methyl-thiazole (code: CE-111), synthetized in our laboratory for the specificity to target DAT, for the effects upon spatial memory and for induced dopamine receptor modulation. Re-uptake inhibition was tested for DAT (IC50=3.2μM), serotonin transporter, SERT (IC50=272291μM) and noradrenaline transporter, NET (IC50=174μM). Spatial memory was studied in the radial arm maze (RAM) in male Sprague-Dawley rats that were intraperitoneally injected with CE-111 (1 or 10mg/kg body weight). Performance in the RAM was improved using 1 and 10mg/kg body weight of CE-111. Training and treatment effects on presynaptic, postsynaptic and extrasynaptic D1 and D2- receptors and dopamine receptor containing complexes as well as on activated DAT were observed. CE-111 was crossing the blood-brain barrier comparable to modafinil and was identified as effective to improve memory performance in the RAM. Dopamine re-uptake inhibition along with modulations in dopamine receptors are proposed as potential underlying mechanisms.
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http://dx.doi.org/10.1016/j.bbr.2016.06.011DOI Listing
October 2016