@article{RiadZlotosHolzgrabe2015, author = {Riad, Noura M. and Zlotos, Darius P. and Holzgrabe, Ulrike}, title = {Crystal structure of 5,11-dihydropyrido[2,3-b][1,4]benzodiazepin-6-one.}, series = {Acta Crystallographica Section E Crystallographic Communications}, volume = {E71}, journal = {Acta Crystallographica Section E Crystallographic Communications}, doi = {10.1107/S2056989015006817}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149627}, pages = {o304-o305}, year = {2015}, abstract = {The title compound, C\(_{12}\)H\(_{9}\)N\(_{3}\)O, is an inter­mediate in the synthesis of the muscarinic M2 receptor antagonist AFDX-384. The seven-membered ring adopts a boat conformation and the dihedral angle between the planes of the aromatic rings is 41.51 (9)°. In the crystal, mol­ecules are linked into [001] chains of alternating inversion dimers formed by pairs of N-H・・・O hydrogen bonds and pairs of N-H・・・N hydrogen bonds. In both cases, R\(_{2}\)\(^{2}\)(8) loops are generated.}, language = {en} } @article{SchmidtSkafGavriletal.2017, author = {Schmidt, Marianne and Skaf, Josef and Gavril, Georgiana and Polednik, Christine and Roller, Jeanette and Kessler, Michael and Holzgrabe, Ulrike}, title = {The influence of Osmunda regalis root extract on head and neck cancer cell proliferation, invasion and gene expression}, series = {BMC Complementary and Alternative Medicine}, volume = {17}, journal = {BMC Complementary and Alternative Medicine}, number = {518}, doi = {10.1186/s12906-017-2009-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158704}, year = {2017}, abstract = {Background: According to only a handful of historical sources, Osmunda regalis, the royal fern, has been used already in the middle age as an anti-cancer remedy. To examine this ancient cancer cure, an ethanolic extract of the roots was prepared and analysed in vitro on its effectiveness against head and neck cancer cell lines. Methods: Proliferation inhibition was measured with the MTT assay. Invasion inhibition was tested in a spheroid-based 3-D migration assay on different extracellular matrix surfaces. Corresponding changes in gene expression were analysed by qRT-PCR array. Induction of apoptosis was measured by fluorescence activated cell sorting (FACS) with the Annexin V binding method. The plant extract was analysed by preliminary phytochemical tests, liquid chromatography/mass spectroscopy (LC-MS) and thin layer chromatography (TLC). Anti-angiogenetic activity was determined by the tube formation assay. Results: O. regalis extract revealed a growth inhibiting effect on the head and neck carcinoma cell lines HLaC78 and FaDu. The toxic effect seems to be partially modulated by p-glycoprotein, as the MDR-1 expressing HLaC79-Tax cells were less sensitive. O. regalis extract inhibited the invasion of cell lines on diverse extracellular matrix substrates significantly. Especially the dispersion of the highly motile cell line HlaC78 on laminin was almost completely abrogated. Motility inhibition on laminin was accompanied by differential gene regulation of a variety of genes involved in cell adhesion and metastasis. Furthermore, O. regalis extract triggered apoptosis in HNSCC cell lines and inhibited tube formation of endothelial cells. Preliminary phytochemical analysis proved the presence of tannins, glycosides, steroids and saponins. Liquid chromatography/mass spectroscopy (LC-MS) revealed a major peak of an unknown substance with a molecular mass of 864.15 Da, comprising about 50\% of the total extract. Thin layer chromatography identified ferulic acid to be present in the extract. Conclusion: The presented results justify the use of royal fern extracts as an anti-cancer remedy in history and imply a further analysis of ingredients.}, language = {en} } @article{CecilRikanovicOhlsenetal.2011, author = {Cecil, Alexander and Rikanovic, Carina and Ohlsen, Knut and Liang, Chunguang and Bernhardt, Jorg and Oelschlaeger, Tobias A. and Gulder, Tanja and Bringmann, Gerd and Holzgrabe, Ulrike and Unger, Matthias and Dandekar, Thomas}, title = {Modeling antibiotic and cytotoxic effects of the dimeric isoquinoline IQ-143 on metabolism and its regulation in Staphylococcus aureus, Staphylococcus epidermidis and human cells}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68802}, year = {2011}, abstract = {Background: Xenobiotics represent an environmental stress and as such are a source for antibiotics, including the isoquinoline (IQ) compound IQ-143. Here, we demonstrate the utility of complementary analysis of both host and pathogen datasets in assessing bacterial adaptation to IQ-143, a synthetic analog of the novel type N,C-coupled naphthyl-isoquinoline alkaloid ancisheynine. Results: Metabolite measurements, gene expression data and functional assays were combined with metabolic modeling to assess the effects of IQ-143 on Staphylococcus aureus, Staphylococcus epidermidis and human cell lines, as a potential paradigm for novel antibiotics. Genome annotation and PCR validation identified novel enzymes in the primary metabolism of staphylococci. Gene expression response analysis and metabolic modeling demonstrated the adaptation of enzymes to IQ-143, including those not affected by significant gene expression changes. At lower concentrations, IQ-143 was bacteriostatic, and at higher concentrations bactericidal, while the analysis suggested that the mode of action was a direct interference in nucleotide and energy metabolism. Experiments in human cell lines supported the conclusions from pathway modeling and found that IQ-143 had low cytotoxicity. Conclusions: The data suggest that IQ-143 is a promising lead compound for antibiotic therapy against staphylococci. The combination of gene expression and metabolite analyses with in silico modeling of metabolite pathways allowed us to study metabolic adaptations in detail and can be used for the evaluation of metabolic effects of other xenobiotics.}, subject = {Staphylococcus aureus}, language = {en} } @article{MasicValenciaHernandezHazraetal.2015, author = {Masic, Anita and Valencia Hernandez, Ana Maria and Hazra, Sudipta and Glaser, Jan and Holzgrabe, Ulrike and Hazra, Banasri and Schurigt, Uta}, title = {Cinnamic Acid Bornyl Ester Derivatives from Valeriana wallichii Exhibit Antileishmanial In Vivo Activity in Leishmania major-Infected BALB/c Mice}, series = {PLoS One}, volume = {10}, journal = {PLoS One}, number = {11}, doi = {10.1371/journal.pone.0142386}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125354}, pages = {e0142386}, year = {2015}, abstract = {Human leishmaniasis covers a broad spectrum of clinical manifestations ranging from self-healing cutaneous leishmaniasis to severe and lethal visceral leishmaniasis caused among other species by Leishmania major or Leishmania donovani, respectively. Some drug candidates are in clinical trials to substitute current therapies, which are facing emerging drug-resistance accompanied with serious side effects. Here, two cinnamic acid bornyl ester derivatives (1 and 2) were assessed for their antileishmanial activity. Good selectivity and antileishmanial activity of bornyl 3-phenylpropanoate (2) in vitro prompted the antileishmanial assessment in vivo. For this purpose, BALB/c mice were infected with Leishmania major promastigotes and treated with three doses of 50 mg/kg/day of compound 2. The treatment prevented the characteristic swelling at the site of infection and correlated with reduced parasite burden. Transmitted light microscopy and transmission electron microscopy of Leishmania major promastigotes revealed that compounds 1 and 2 induce mitochondrial swelling. Subsequent studies on Leishmania major promastigotes showed the loss of mitochondrial transmembrane potential (ΔΨm) as a putative mode of action. As the cinnamic acid bornyl ester derivatives 1 and 2 had exhibited antileishmanial activity in vitro, and compound 2 in Leishmania major-infected BALB/c mice in vivo, they can be regarded as possible lead structures for the development of new antileishmanial therapeutic approaches.}, language = {en} } @article{GlaserSchurigtSuzukietal.2015, author = {Glaser, Jan and Schurigt, Uta and Suzuki, Brian M. and Caffrey, Connor R. and Holzgrabe, Ulrike}, title = {Anti-Schistosomal Activity of Cinnamic Acid Esters: Eugenyl}, series = {Molecules}, volume = {20}, journal = {Molecules}, doi = {10.3390/molecules200610873}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125712}, pages = {10873-10883}, year = {2015}, abstract = {Bornyl caffeate (1) was previously isolated by us from Valeriana (V.) wallichii rhizomes and identified as an anti-leishmanial substance. Here, we screened a small compound library of synthesized derivatives 1-30 for activity against schistosomula of Schistosoma (S.) mansoni. Compound 1 did not show any anti-schistosomal activity. However, strong phenotypic changes, including the formation of vacuoles, degeneration and death were observed after in vitro treatment with compounds 23 (thymyl cinnamate) and 27 (eugenyl cinnamate). Electron microscopy analysis of the induced vacuoles in the dying parasites suggests that 23 and 27 interfere with autophagy.}, language = {en} } @article{GlaserSchultheisMolletal.2015, author = {Glaser, Jan and Schultheis, Martina and Moll, Heidrun and Hazra, Banasri and Holzgrabe, Ulrike}, title = {Antileishmanial and Cytotoxic Compounds from Valeriana wallichii and Identification of a Novel Nepetolactone Derivative}, series = {Molecules}, volume = {20}, journal = {Molecules}, number = {4}, doi = {10.3390/molecules20045740}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125320}, pages = {5740-5753}, year = {2015}, abstract = {The chloroform extract of Valeriana wallichii (V. wallichii) rhizomes was investigated to elucidate the structures responsible for reported antileishmanial activity. Besides bornyl caffeate (1, already been reported by us previously), bioassay-guided fractionation resulted in two additional cinnamic acid derivatives 2-3 with moderate leishmanicidal activity. The structure of a novel nepetolactone derivative 4 having a cinnamic acid moiety was elucidated by means of spectral analysis. To the best of our knowledge villoside aglycone (5) was isolated from this plant for the first time. The bioassay-guided fractionation yielded two new (compounds 6-7) and two known valtrates (compounds 8-9) with leishmanicidal potential against Leishmania major (L. major) promastigotes. In addition, β-bisabolol (10), α-kessyl alcohol (11), valeranone (12), bornyl isovalerate (13) and linarin-2-O-methylbutyrate (14) were identified. This is the first report on the isolation of 4'-demethylpodophyllotoxin (15), podophyllotoxin (16) and pinoresinol (17) in V. wallichii. In total thirteen known and four new compounds were identified from the extract and their cytotoxic and antileishmanial properties were evaluated.}, language = {en} } @article{MontoyaPelaezSierraAlzateetal.2013, author = {Montoya Pel{\´a}ez, Guillermo L. and Sierra, Jelver A. and Alzate, Fernando and Holzgrabe, Ulrike and Ramirez-Pineda, Jos{\´e} R.}, title = {Pentacyclic triterpenes from Cecropia telenitida with immunomodulatory activity on dendritic cells}, series = {Revista Brasileira de Farmacognosia - Brazilian Journal of Pharmacognosy}, volume = {23}, journal = {Revista Brasileira de Farmacognosia - Brazilian Journal of Pharmacognosy}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131851}, pages = {754-761}, year = {2013}, abstract = {Pentacyclic triterpenes are a large family of plant metabolites that exhibit a wide array of biological activities. The genus Cecropia, which encompasses many plant species, has been used as traditional medicine for the treatment of inflammatory diseases and is known to produce many active pentacyclic triterpenes. In this study we investigated the chemical composition of a pentacyclic triterpene fraction from the roots of Cecropia telenitida Cuatrec., Urticaceae. A novel compound, which we termed yarumic acid, and four known molecules (serjanic acid, spergulagenic acid A, 20-hydroxy-ursolic acid and goreishic acid I) were isolated and characterised. In a dendritic cell (DC)-based assay, we demonstrated that non-toxic doses of these pentacyclic triterpenes inhibited the secretion of at least one of the proinflammatory cytokines tested (IL-1 beta, IL-12p40, IL-12p70, TNF-alpha). Spergulagenic acid A also inhibited nitric oxide production in lipopolysaccharide-stimulated dendritic cell. Serjanic acid and spergulagenic acid A, which were the most potent abundant compounds in the pentacyclic triterpene fraction, showed the most activity in the dendritic cell-based assay. These results show that all pentacyclic triterpenes might contribute to the anti-inflammatory activities of C. telenitida. Moreover, yarumic acid as well as the four known pentacyclic triterpenes, can be exploited as potential immunomodulatory/anti-inflammatory agents.}, language = {en} } @article{HartungSeufertBergesetal.2012, author = {Hartung, Andreas and Seufert, Florian and Berges, Carsten and Gessner, Viktoria H. and Holzgrabe, Ulrike}, title = {One-Pot Ugi/Aza-Michael Synthesis of Highly Substituted 2,5-Diketopiperazines with Anti-Proliferative Properties}, series = {Molecules}, volume = {17}, journal = {Molecules}, number = {12}, doi = {10.3390/molecules171214685}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130423}, pages = {14685-14699}, year = {2012}, abstract = {The well-known Ugi reaction of aldehydes with amines, carboxylic acids and isocyanides leads to the formation of acyclic alpha-acylaminocarboxamides. Replacement of the carboxylic acid derivatives with beta-acyl substituted acrylic acids gives access to highly substituted 2,5-diketopiperazines in one single reaction-step without additives or complex reaction procedures. The obtained diketopiperazines show anti-proliferative effects on activated T cells and represent therefore potential candidates for targeting unwanted T cell-mediated immune responses.}, language = {en} } @article{GlaserSchultheisHazraetal.2014, author = {Glaser, Jan and Schultheis, Martina and Hazra, Sudipta and Hazra, Banazri and Moll, Heidrun and Schurigt, Uta and Holzgrabe, Ulrike}, title = {Antileishmanial Lead Structures from Nature: Analysis of Structure-Activity Relationships of a Compound Library Derived from Caffeic Acid Bornyl Ester}, doi = {10.3390/molecules19021394}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112835}, year = {2014}, abstract = {Bioassay-guided fractionation of a chloroform extract of Valeriana wallichii (V. wallichii) rhizomes lead to the isolation and identification of caffeic acid bornyl ester (1) as the active component against Leishmania major (L. major) promastigotes (IC50 = 48.8 µM). To investigate the structure-activity relationship (SAR), a library of compounds based on 1 was synthesized and tested in vitro against L. major and L. donovani promastigotes, and L. major amastigotes. Cytotoxicity was determined using a murine J774.1 cell line and bone marrow derived macrophages (BMDM). Some compounds showed antileishmanial activity in the concentration range of pentamidine and miltefosine which are the standard drugs in use. In the L. major amastigote assay compounds 15, 19 and 20 showed good activity with relatively low cytotoxicity against BMDM, resulting in acceptable selectivity indices. Molecules with adjacent phenolic hydroxyl groups exhibited elevated cytotoxicity against murine cell lines J774.1 and BMDM. The Michael system seems not to be essential for antileishmanial activity. Based on the results compound 27 can be regarded as new lead structure for further structure optimization}, language = {en} } @article{GuentzelSchillingHanioetal.2020, author = {G{\"u}ntzel, Paul and Schilling, Klaus and Hanio, Simon and Schlauersbach, Jonas and Schollmayer, Curd and Meinel, Lorenz and Holzgrabe, Ulrike}, title = {Bioinspired Ion Pairs Transforming Papaverine into a Protic Ionic Liquid and Salts}, series = {ACS Omega}, volume = {5}, journal = {ACS Omega}, number = {30}, doi = {10.1021/acsomega.0c02630}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230265}, pages = {19202-19209}, year = {2020}, abstract = {Microbial, mammalian, and plant cells produce and contain secondary metabolites, which typically are soluble in water to prevent cell damage by crystallization. The formation of ion pairs, for example, with carboxylic acids or mineral acids, is a natural blueprint to maintain basic metabolites in solution. Here, we aim at showing whether the mostly large carboxylates form soluble protic ionic liquids (PILs) with the basic natural product papaverine resulting in enhanced aqueous solubility. The obtained PILs were characterized by H-1-N-15 HMBC nuclear magnetic resonance (NMR) and in the solid state using X-ray powder diffraction, differential scanning calorimetry, and dissolution measurements. Furthermore, their supramolecular pattern in aqueous solution was studied by means of potentiometric and photometrical solubility, NMR aggregation assay, dynamic light scattering, zeta potential, and viscosity measurements. Thereby, we identified the naturally occurring carboxylic acids, citric acid, malic acid, and tartaric acid, as being appropriate counterions for papaverine and which will facilitate the formation of PILs with their beneficial characteristics, like the improved dissolution rate and enhanced apparent solubility.}, language = {en} }