Gerhard Bringmann

University of Wuerzburg, Würzburg, Bavaria, Germany

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Publications (671)1607.16 Total impact

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    ABSTRACT: Isoquinolines (IQs) are natural substances with an antibiotic potential we aim to optimize. Specifically, IQ-238 is a synthetic analog of the novel-type N,C-coupled naphthylisoquinoline (NIQ) alkaloid ancisheynine. Recently, we developed and tested other IQs such as IQ-143. By utilizing genome-wide gene expression data, metabolic network modelling and voronoi tessalation based data analysis–as well as cytotoxicity measurements, chemical properties calculations and principal component analysis of the NIQs–we show that IQ-238 has strong antibiotic potential for staphylococci and low cytotoxicity against murine or human cells. Compared to IQ-143, systemic effects are less pronounced. Most enzyme activity changes due to IQ-238 are located in the carbohydrate metabolism. Validation includes metabolite measurements on biological replicates. IQ-238 delineates key properties and a chemical space for a good therapeutic window. The combination of analysis methods allows suggestions for further lead development and yields an in-depth look at staphylococcal adaptation and network changes after antibiosis. Results are compared to eukaryotic host cells.
    International Journal of Medical Microbiology. 11/2014;
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    ABSTRACT: Potent compounds do not necessarily make the best drugs in the market. Consequently, with the aim to describe tools that may be fundamental for refining the screening of candidates for animal and preclinical studies and further development, molecules of different structural classes synthesized within the frame of a broad screening platform were evaluated for their trypanocidal activities, cytotoxicities against murine macrophages J774.1 and selectivity indices, as well as for their ligand efficiencies and structural chemical properties. To advance into their modes of action, we also describe the morphological and ultrastructural changes exerted by selected members of each compound class on the parasite Trypanosoma brucei. Our data suggest that the potential organelles targeted are either the flagellar pocket (compound 77, N-Arylpyridinium salt; 15, amino acid derivative with piperazine moieties), the endoplasmic reticulum membrane systems (37, bisquaternary bisnaphthalimide; 77, N-Arylpyridinium salt; 68, piperidine derivative), or mitochondria and kinetoplasts (88, N-Arylpyridinium salt; 68, piperidine derivative). Amino acid derivatives with fumaric acid and piperazine moieties (4, 15) weakly inhibiting cysteine proteases seem to preferentially target acidic compartments. Our results suggest that ligand efficiency indices may be helpful to learn about the relationship between potency and chemical characteristics of the compounds. Interestingly, the correlations found between the physico-chemical parameters of the selected compounds and those of commercial molecules that target specific organelles indicate that our rationale might be helpful to drive compound design toward high activities and acceptable pharmacokinetic properties for all compound families.
    Parasitology Research 11/2014; · 2.85 Impact Factor
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    ABSTRACT: The exciton chirality method (ECM) is commonly recognized as one of the best approaches to assign the absolute configuration of biaryls. This paper reports the first exception to this method for a simple biaryl system. ECD and VCD measurements in combination with DFT (B3LYP/6-311G*), TDDFT (CAM-B3LYP/6-311G*), and Coupled-Cluster (RI-SCS-CC2) calculations were used to determine the absolute configurations of axially chiral BODIPY DYEmers. The ECM fails to predict the sign of the intense CD couplet at 500 nm of the 1,1′-coupled dimer. The odd behavior was rationalized by considering the strong transition magnetic dipole associated with the 500 nm transition, which leads to an unexpected dominance of the μm coupling at the expense of the μμ one in these compounds. This is the first case in which a strong μm coupling hampers the use of the ECM, but this behavior should not be restricted to the BODIPY chromophore.
    Angewandte Chemie International Edition 10/2014; · 11.34 Impact Factor
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    ABSTRACT: Die Exciton-Chiralitäts-Methode (ECM) ist bekannt als einer der besten Ansätze zur Bestimmung der Absolutkonfiguration von Biarylen. Hier wird die erste echte Ausnahme für ein einfaches Biarylsystem beschrieben. Durch eine Kombination von ECD- und VCD-Messungen mit DFT- (B3LYP/6-311G*), TDDFT- (CAM-B3LYP/6-311G*) und “Coupled-Cluster”-Rechnungen (RI-SCS-CC2) wurden die Absolutkonfigurationen von BODIPY-DYEmers mit Chiralitätsachse bestimmt. Für das 1,1′-verknüpfte Dimer sagt die ECM das falsche Vorzeichen für das CD-Couplet bei 500 nm voraus. Dieses ungewöhnliche Verhalten kann mit dem starken magnetischen Übergangsdipolmoment der Anregung bei 500 nm erklärt werden, das zu einer unerwarteten Dominanz der μm- gegenüber der μμ-Kopplung führt. Damit sind diese Dimere der erste Fall, in dem eine starke μm-Kopplung die Verwendung der ECM verhindert. Dieses Verhalten sollte nicht auf den BODIPY-Chromophor beschränkt sein.
    Angewandte Chemie 10/2014;
  • ChemInform 08/2014; 45(34).
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    ABSTRACT: β,β'-Bisporphyrins are intrinsically chiral porphyrin dimers with fascinating properties. The configurational stability at their axes can be directed by variation of the central metal atoms. Herein, we present a regioselective functionalization of the monomeric 2-amino-tetraphenyl-porphyrin as a versatile substrate for dimerization by oxidative coupling. By simple variation of the reaction conditions (solvent and oxidant), the oxidation selectively gave either the axially chiral C,C-coupled diaminobisporphyrin in high yields or, under Ullmann conditions, the twofold N,C-linked achiral dimer, also in good yields. A generalized mechanism for the coupling reaction is proposed based on DFT calculations. The axially chiral β,β'-coupled porphyrin dimers were isolated as racemic mixtures, but can be resolved by HPLC on a chiral phase. TDDFT and coupled-cluster calculations were used to explain the spectroscopic properties of the aminoporphyrins and their dimers and to elucidate the absolute configurations of the C,C-coupled bisporphyrins.
    Chemistry - A European Journal 02/2014; · 5.93 Impact Factor
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    ABSTRACT: Decandrinin (1), an unprecedented C9-spiro-fused 7,8-seco-ent-abietane, was obtained from the bark of an Indian mangrove, Ceriops decandra, collected in the estuary of Godavari, Andhra Pradesh. The constitution and the relative configuration of 1 were determined by HRMS (ESI) and extensive NMR investigations, and the absolute configuration by circular dichroism (CD) and optical-rotatory dispersion (ORD) spectroscopy in combination with quantum-chemical calculations. Decandrinin is the first 7,8-seco-ent-abietane.
    Beilstein Journal of Organic Chemistry 01/2014; 10:276-81. · 2.80 Impact Factor
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    ABSTRACT: Ancistrocladus (Ancistrocladaceae) is an Old World genus of woody lianas, occurring in tropical Africa and Southeast Asia. Its species produce a number of structurally unique naphthylisoquinoline alkaloids with promising activities against the pathogens of tropical infectious diseases and against HIV. Species identification for phytochemical and pharmacological research is difficult because diagnostic reproductive features are frequently not available. Using enrichment and subcloning, and a 454 shotgun sequencing technique with semi-automatized SSR motif screening, we have successfully developed a set of primers that amplify microsatellite loci across most Ancistrocladus species. The primers are designed to support species identification of indeterminate samples. Twelve markers from a total of 99 tested loci were identified as suitable for cross-species amplification. The markers produced distinct species clusters in a STRUCTURE analysis and a principal coordinate analysis (PCoA) based on a test sampling consisting of 21 samples from six different Ancistrocladus species. When applied to 74 samples of Ancistrocladus congolensis s.l., a complex of morphologically similar species from tropical Central Africa, these markers showed medium to high variability in ten populations. A STRUCTURE analysis of the A. congolensis s.l. samples revealed five distinct clusters, confirming three of the five taxonomically recognized units and also indicating the presence of a hitherto unrecognized species in the region. The taxonomic status of the recently described new species A. ileboensis is supported by our results. The novel microsatellite markers developed in this study enable rapid screening of samples and provide an efficient tool for species identification and detection of cryptic taxa.
    Taxon 01/2014; 63(2). · 2.78 Impact Factor
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    ABSTRACT: Eight streptophenazines (A-H) have been identified so far as products of Streptomyces strain HB202, which was isolated from the sponge Halichondria panicea from the Baltic Sea. The variation of bioactivities based on small structural changes initiated further studies on new derivatives. Three new streptophenazines (I-K) were identified after fermentation in the present study. In addition, revised molecular structures of streptophenazines C, D, F and H are proposed. Streptophenazines G and K exhibited moderate antibacterial activity against the facultative pathogenic bacterium Staphylococcus epidermidis and against Bacillus subtilis. All tested compounds (streptophenazines G, I-K) also showed moderate activities against PDE 4B.
    Marine Drugs 01/2014; 12(4):1699-714. · 3.98 Impact Factor
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    ABSTRACT: From the endophytic fungus Pestalotiopsis sp. isolated from the leaves of the Chinese mangrove, Rhizophora mucronata, two novel hybrid sesquiterpene-cyclopaldic acid metabolites with an unusual carbon skeleton, named pestalotiopens A and B, were obtained, together with the already known phytotoxin altiloxin B. Pestalotiopen B even contains a third, triketide-derived module. The constitutions and the absolute configurations of the new metabolites and of altiloxin B were unambiguously determined by a combination of spectroscopic methods and quantum-chemical optical-rotatory dispersion (ORD) and circular dichroism (CD) calculations. A biosynthetic pathway to pestalotiopens A and B is proposed with altiloxin B as one of the suggested precursors. Pestalotiopen A shows moderate antimicrobial activity against Enterococcus faecalis.
    Chemistry - A European Journal 10/2013; · 5.93 Impact Factor
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    ABSTRACT: From the wild-type strain Steptomyces sp. AK 671, three nitrogen-containing octaketides were isolated, bhimamycins F, H and I, besides the known azaanthraquinone utahmycin A and polyketide shunt products SEK 4, SEK 4b, mutactin, dehydromutactin and EM18. The structures were characterized by MS and NMR experiments. The hitherto unknown absolute configuration of the two enantiomers of EM18 was determined by online-CD spectroscopy and quantum-chemical CD calculations. Bhimamycins H and I show weak antibacterial activities, whereas the enzyme phosphodiesterase 4 is strongly inhibited by bhimamycins H and I, which has never been reported for nitrogen-containing octaketides. In addition, bhimamycin H inhibits the enzyme glycogen synthase kinase-3β.The Journal of Antibiotics advance online publication, 18 September 2013; doi:10.1038/ja.2013.82.
    The Journal of Antibiotics 09/2013; · 2.19 Impact Factor
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    ABSTRACT: We present a new class of hybrid molecules consisting of the established antiplasmodial drugs primaquine and chloroquine. No drug is known to date that acts comparably against all stages of Plasmodium in its life cycle. Starting from available precursors, we designed and synthesized a new-generation compound consisting of both primaquine and chloroquine components, with the intent to produce agents that exhibit bioactivity against different stages of the parasite's life cycle. In vitro, the hybrid molecule 3 displays activity against both asexual and sexual P. falciparum blood stages as well as P. berghei sporozoites and liver stages. In vivo, the hybrid elicits activity against P. berghei liver and blood stages. Our results successfully validate the concept of utilizing one compound to combine different modes of action that attack different Plasmodium stages in the mammalian host. It is our hope that the novel design of such compounds will outwit the pathogen in the spread of drug resistance. Based on the optimized synthetic pathway, the compound is accessible in a smooth and versatile way and open for potential further molecular modification.
    International journal of medical microbiology: IJMM 08/2013; · 4.54 Impact Factor
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    ABSTRACT: Radical diversification: Through the discovery of diverse indolosesquiterpene dimers in a strain heterologously expressing the xiamycin biosynthesis genes, the analysis of mutants, and biotransformation studies, it has been inferred that a single flavoprotein mediates NC and NN aryl coupling reactions, as well as the formation of a cyclic ether (oxiamycin). Synthetic emulation of this unusual transformation provides evidence for a radical-based mechanism.
    Angewandte Chemie International Edition 07/2013; · 11.34 Impact Factor
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    ABSTRACT: Three limonoids named thaixylomolins A-C (1-3), featuring two new motifs, were isolated from the seeds of a Thai mangrove, Xylocarpus moluccensis. The absolute configurations of these limonoids were determined by extensive NMR investigations, single-crystal X-ray diffraction analysis, and circular-dichroism spectroscopy in combination with quantum-chemical calculations. Thaixylomolin B exhibited inhibitory activity against nitric oxide production in lipopolysaccharide and IFN-γ-induced RAW264.7 murine macrophages with an IC50 value of 84.3 μM.
    Organic Letters 07/2013; · 6.14 Impact Factor
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    ABSTRACT: Isoplagiochin C 1 was prepared for the first time in enantiopure form from synthetic racemic material, using a novel stereochemical concept. This macrocyclic bisbibenzyl contains two biaryl axes. Of these, axis A is configurationally stable by its fixation within the macrocyclic framework, while axis B is stereochemically unstable. By diesterification of rac-1 with enantiopure (P)-1,1′-binaphthyl-2,2′-dicarboxylic acid, axis B is locked in its P-configuration, thus allowing the resolution and separate saponification of dilactones (PA,PB,P)-3 and (MA,PB,P)-3 to give the pure enantiomers of 1. This concept permits recycling of any undesired enantiomer of 1 by thermal equilibration of the respective diastereomer of 3.
    Tetrahedron Asymmetry 05/2013; 24(s 9–10):575–581. · 2.12 Impact Factor
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    ABSTRACT: Mbandakamines A (1) and B (2), isolated from the leaves of an as yet unidentified Congolese Ancistrocladus species, are the first dimeric naphthylisoquinoline alkaloids with an unsymmetrically coupled central biaryl axis. Their novel 6',1″-coupling type implies a hitherto unprecedented peri-peri coupling in one of the naphthalene parts, leading to the as yet highest steric hindrance at the central axis and a total of seven elements of chirality. Mbandakamine A exhibits good antimalarial activity.
    Organic Letters 05/2013; · 6.14 Impact Factor
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    ABSTRACT: Expanded porphyrins The synthesis of the long sought‐after pyrazole‐based expanded porphyrin and its homobimetallic nickel(II) and copper(II) complexes is described in the Full Paper by G. Bringmann, C. Brückner, F. Meyer et al. on page 5868 ff. Spectroscopic evidence, as well as structural parameters of this hexaphyrin analogue (named the Siamese‐twin porphyrin), proved it to be non‐aromatic, though each half of the molecule is fully conjugated. In the complexes, each metal ion is coordinated in a square‐planar fashion by a dianionic, porphyrin‐like {N4} binding pocket. The conformations of the diprotonated macrocycle and its metal complexes are all strongly twisted. The persistent helical twist permitted resolution of the enantiomeric helimers by HPLC on a chiral phase.
    Chemistry 05/2013; 19(19). · 5.83 Impact Factor
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    ABSTRACT: In most laboratories the screening for leishmanicidal compounds is carried out with Leishmania promastigotes or axenic amastigotes. However, the best approach to identify leishmanicidal compounds is the use of amastigotes residing in macrophages. Reporter gene-based assays are relatively new tools in the search for drugs against eucaryotic protozoa, permitting the development of faster, more automated assays. In this paper we report on the establishment of a rapid screening assay in 96-well format. A luciferase-transgenic (Luc-tg) L. major strain was generated and applied to infect bone marrow derived macrophages (BMDM). Amastigote infected BMDM were treated with different compound concentrations. Cells were lysed with a luciferin-containing buffer and the resulting luminescence was measured to determine the half-maximal inhibitory concentration (IC50 value). To validate this new amastigote screening assay, a library of a new class of quinolinium salts were synthesized and tested for leishmanicidal activity. Some of the quinolinium salts showed very promising activities, with IC50 values against intracellular amastigotes (IC50 < 1 μg/ml) and selectivity indices (SI > 20) that match the criteria of World Health Organization (WHO) for hits. Compound 21c (IC50 = 0.03 μg/ml; SI = 358) could become a new lead structure for the development of improved chemotherapeutical drugs against L. major. In summary we describe the establishment of a new 96-well format assay with Luc-transgenic L. major for the rapid screening of compounds for leishmanicidal activity against intracellular amastigotes and its application to the identification of a new class of quinolinium salts with most promising leishmanicidal activity.
    Antimicrobial Agents and Chemotherapy 04/2013; · 4.57 Impact Factor
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    ABSTRACT: The 3+3-type synthesis of a pyrazole-based expanded porphyrin 22 H4 , a hexaphyrin analogue named Siamese-twin porphyrin, and its homobimetallic diamagnetic nickel(II) and paramagnetic copper(II) complexes, 22 Ni2 and 22 Cu2 , are described. The structure of the macrocycle composed of four pyrroles and two pyrazoles all linked by single carbon atoms, can be interpreted as two conjoined porphyrin-like subunits, with the two opposing pyrazoles acting as the fusion points. Variable-temperature 1D and 2D NMR spectroscopic analyses suggested a conformationally flexible structure for 22 H4 . NMR and UV/Vis spectroscopic evidence as well as structural parameters proved the macrocycle to be non-aromatic, though each half of the molecule is fully conjugated. UV/Vis and NMR spectroscopic titrations of the free base macrocycle with acid showed it to be dibasic. In the complexes, each metal ion is coordinated in a square-planar fashion by a dianionic, porphyrin-like {N4 } binding pocket. The solid-state structures of the dication and both metal complexes were elucidated by single-crystal diffractometry. The conformations of the three structures are all similar to each other and strongly twisted, rendering the molecules chiral. The persistent helical twist in the protonated form of the free base and in both metal complexes permitted resolution of these enantiomeric helimers by HPLC on a chiral phase. The absolute stereostructures of 22 H6 (2+) , 22 Ni2 , and 22 Cu2 were assigned by a combination of experimental electronic circular dichroism (ECD) investigations and quantum-chemical ECD calculations. The synthesis of the first member of this long-sought class of expanded porphyrin-like macrocycles lays the foundation for the study of the interactions of the metal centers within their bimetallic complexes.
    Chemistry - A European Journal 04/2013; · 5.93 Impact Factor
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    ABSTRACT: This article outlines theory and practice of the comparison of calculated and experimental electronic circular dichroism (ECD) curves to determine the absolute configuration of chiral molecules. The focus is on the evaluation of excited-state calculations giving hints at the identification of the correct bandwidth and the application of the so-called "UV shift" as a correction factor. A similarity factor is introduced, which helps to quantify the degree of matching of curves. In addition, a few common errors are described that can be made during the measurements of ECD and UV spectra-and advice is given of how to avoid these mistakes. All equations mentioned in the article are implemented in our SpecDis software, which has been developed to rapidly compare calculated ECD and UV curves with experimental ones, and to produce graphics in publication quality. Chirality 25:243-249, 2013. © 2013 Wiley Periodicals, Inc.
    Chirality 04/2013; 25(4):243-9. · 1.72 Impact Factor

Publication Stats

4k Citations
1,607.16 Total Impact Points

Institutions

  • 1989–2014
    • University of Wuerzburg
      • • Institute of Organic Chemistry
      • • Institute of Pharmacy and Food Chemistry
      • • Julius-von-Sachs-Institut of Biosciences
      Würzburg, Bavaria, Germany
  • 2013
    • Helmholtz Centre for Ocean Research Kiel
      Kiel, Schleswig-Holstein, Germany
    • Jinan University (Guangzhou, China)
      Shengcheng, Guangdong, China
    • Universität Heidelberg
      • Department of Infectious Diseases, Virology
      Heidelburg, Baden-Württemberg, Germany
  • 2003–2013
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
  • 2012
    • University of Yaoundé II
      Jaúnde, Centre Region, Cameroon
    • Chinese Academy of Sciences
      Peping, Beijing, China
  • 2007–2012
    • Central Drug Research Institute
      • Medicinal and Process Chemistry Division (CDRI)
      Lucknow, Uttar Pradesh, India
    • Central University of Venezuela
      Caracas, Distrito Federal, Venezuela
  • 2011
    • University of Bayreuth
      Bayreuth, Bavaria, Germany
    • National Institutes of Health
      • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
      Bethesda, MD, United States
    • University of Connecticut
      • Department of Chemistry
      Storrs, CT, United States
    • University of Lucknow
      • Department of Chemistry
      Lucknow, Uttar Pradesh, India
    • Ocean University of China
      • Department of Pharmacology, Marine Drug and Food Institute
      Tsingtao, Shandong Sheng, China
  • 2008–2011
    • Northeast Institute of Geography and Agroecology
      • • Institute of Microbiology
      • • Institute of Oceanology
      Beijing, Beijing Shi, China
  • 2010
    • ETH Zurich
      • Laboratory of Organic Chemistry
      Zürich, Zurich, Switzerland
    • Leidos Biomedical Research
      Maryland, United States
    • Christian-Albrechts-Universität zu Kiel
      • Otto Diels Department of Organic Chemistry
      Kiel, Schleswig-Holstein, Germany
  • 1995–2010
    • Provinciaal Instituut voor Hygiëne, Antwerpen
      Antwerpen, Flanders, Belgium
    • University of Veterinary Medicine in Vienna
      Wien, Vienna, Austria
    • Max Planck Institute for Experimental Medicine
      Göttingen, Lower Saxony, Germany
    • Philipps-Universität Marburg
      • Institute for Physiological Chemistry
      Marburg an der Lahn, Hesse, Germany
    • Chestnut Hill College
      Boston, Massachusetts, United States
  • 1994–2010
    • Max Planck Institute for Solid State Research
      Stuttgart, Baden-Württemberg, Germany
    • Universitätsklinikum Erlangen
      Erlangen, Bavaria, Germany
  • 2006–2007
    • Friedrich-Schiller-University Jena
      • Institut für Physikalische Chemie
      Jena, Thuringia, Germany
    • Technische Universität Kaiserslautern
      • Fachbereich für Chemie
      Kaiserslautern, Rhineland-Palatinate, Germany
  • 2005
    • Ludwig-Maximilians-University of Munich
      München, Bavaria, Germany
  • 2004
    • Johannes Gutenberg-Universität Mainz
      • Institut für Physiologische Chemie
      Mainz, Rhineland-Palatinate, Germany
  • 2001–2004
    • Heinrich-Heine-Universität Düsseldorf
      • Institut für Pharmazeutische Biologie und Biotechnologie
      Düsseldorf, North Rhine-Westphalia, Germany
    • Vrije Universiteit Brussel
      Bruxelles, Brussels Capital Region, Belgium
  • 2002
    • Universität zu Lübeck
      Lübeck Hansestadt, Schleswig-Holstein, Germany
    • University of Botswana
      • Department of Chemistry
      Gaborone, South East District, Botswana
  • 2000
    • University of Peradeniya
      • Department of Chemistry
      Kandy, Central Province, Sri Lanka
  • 1999
    • Swiss Tropical and Public Health Institute
      Bâle, Basel-City, Switzerland
    • University of KwaZulu-Natal
      Port Natal, KwaZulu-Natal, South Africa
  • 1994–1998
    • National Cancer Institute (USA)
      • • Division of Cancer Treatment and Diagnosis
      • • Developmental Therapeutics Program
      Bethesda, MD, United States
  • 1997
    • Universität Paderborn
      • Department of Chemistry
      Paderborn, North Rhine-Westphalia, Germany
  • 1985–1986
    • University of Münster
      • Institute of Organic Chemistry
      Muenster, North Rhine-Westphalia, Germany