Recent Submissions

  • Tracheal brush cells release acetylcholine in response to bitter tastants for paracrine and autocrine signaling.

    Hollenhorst, Monika I; Jurastow, Innokentij; Nandigama, Rajender; Appenzeller, Silke; Li, Lei; Vogel, Jörg; Wiederhold, Stephanie; Althaus, Mike; Empting, Martin; Altmüller, Janine; et al. (Wiley, 2020-01-01)
    For protection from inhaled pathogens many strategies have evolved in the airways such as mucociliary clearance and cough. We have previously shown that protective respiratory reflexes to locally released bacterial bitter "taste" substances are most probably initiated by tracheal brush cells (BC). Our single-cell RNA-seq analysis of murine BC revealed high expression levels of cholinergic and bitter taste signaling transcripts (Tas2r108, Gnat3, Trpm5). We directly demonstrate the secretion of acetylcholine (ACh) from BC upon stimulation with the Tas2R agonist denatonium. Inhibition of the taste transduction cascade abolished the increase in [Ca2+]i in BC and subsequent ACh-release. ACh-release is regulated in an autocrine manner. While the muscarinic ACh-receptors M3R and M1R are activating, M2R is inhibitory. Paracrine effects of ACh released in response to denatonium included increased [Ca2+]i in ciliated cells. Stimulation by denatonium or with Pseudomonas quinolone signaling molecules led to an increase in mucociliary clearance in explanted tracheae that was Trpm5- and M3R-mediated. We show that ACh-release from BC via the bitter taste cascade leads to immediate paracrine protective responses that can be boosted in an autocrine manner. This mechanism represents the initial step for the activation of innate immune responses against pathogens in the airways.
  • Chemical synthesis of tripeptide thioesters for the biotechnological incorporation into the myxobacterial secondary metabolite argyrin via mutasynthesis.

    Siebert, David C B; Sommer, Roman; Pogorevc, Domen; Hoffmann, Michael; Wenzel, Silke C; Müller, Rolf; Titz, Alexander; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (Beilstein Institut, 2019-01-01)
    The argyrins are secondary metabolites from myxobacteria with antibiotic activity against Pseudomonas aeruginosa. Studying their structure-activity relationship is hampered by the complexity of the chemical total synthesis. Mutasynthesis is a promising approach where simpler and fully synthetic intermediates of the natural product's biosynthesis can be biotechnologically incorporated. Here, we report the synthesis of a series of tripeptide thioesters as mutasynthons containing the native sequence with a dehydroalanine (Dha) Michael acceptor attached to a sarcosine (Sar) and derivatives. Chemical synthesis of the native sequence ᴅ-Ala-Dha-Sar thioester required revision of the sequential peptide synthesis into a convergent strategy where the thioester with sarcosine was formed before coupling to the Dha-containing dipeptide.
  • From Wood to Tetrahydro-2-benzazepines in Three Waste-Free Steps: Modular Synthesis of Biologically Active Lignin-Derived Scaffolds.

    Elangovan, Saravanakumar; Afanasenko, Anastasiia; Haupenthal, Jörg; Sun, Zhuohua; Liu, Yongzhuang; Hirsch, Anna K H; Barta, Katalin; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (American Society for Chemistry, 2019-10-23)
    nherently complex, lignin-derived aromatic monomers comprising valuable structural moieties present in many pharmaceuticals would serve as ideal substrates for the construction of biologically active molecules. Here, we describe a strategy that incorporates all intrinsic functional groups present in platform chemicals obtained by lignin depolymerization into value-added amines, using sustainable catalytic methods and benign solvents. Our strikingly efficient protocol provides access to libraries of aminoalkyl-phenol derivatives and seven-membered N-heterocycles directly from wood in two, respectively three, waste-free steps. Several molecules in these libraries have shown promising antibacterial or anticancer activities, emphasizing the advantage of this modular synthetic strategy and the potential for drug discovery. The sustainable catalytic pathways presented here can lead to significant benefits for the pharmaceutical industry where reduction of hazardous waste is a prime concern, and the described strategies that lead to high-value products from non-edible biomass waste streams also markedly increase the economic feasibility of lignocellulosic biorefineries.
  • Spray-drying of inhalable, multifunctional formulations for the treatment of biofilms formed in cystic fibrosis.

    Lababidi, Nashrawan; Ofosu Kissi, Eric; Elgaher, Walid A M; Sigal, Valentin; Haupenthal, Jörg; Schwarz, Bianca C; Hirsch, Anna K H; Rades, Thomas; Schneider, Marc; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Elsevier, 2019-11-28)
    Cystic fibrosis (CF) is a serious lung disease, commonly susceptible to Pseudomonas aeruginosa colonization. The dense mucus together with biofilm formation limit drug permeability and prevent the drug from reaching the site of action, causing treatment failure of the bacterial infection. Besides the use of antibiotics, the mucolytic agent N-acetylcysteine (NAC) is recommended to be co-administered in the treatment of CF. Although several formulations have been developed for inhalation therapy to improve the pulmonary condition in CF patients, there is still no comprehensive study on a combined multifunctional dry powder formulation of antibiotics with NAC. In this work, we developed an innovative multifunctional dry powder inhaler (DPI) formulation based on salt formation between NAC and antibiotics and characterized their solid state properties and physical stability. NAC could be spray dried together with three different antibiotics, azithromycin (Azi), tobramycin (Tobra) and ciprofloxacin (Cipro), without the use of organic solvents to form Azi/NAC, Tobra/NAC and Cipro/NAC DPI formulations. Solid-state characterization of these DPI formulations showed that they were amorphous after spray drying. Azi/NAC and Tobra/NAC form co-amorphous salt systems that were physically stable under storage at stress conditions. For particle characterization, the obtained mass median aerodynamic diameters were in a suitable range for inhalation (< 5.0μm). The multifunctional antibiotic/NAC formulations conserved or improved the antibiotic susceptibility and showed promising results regarding the inhibition of P. aeruginosa PA14 biofilm formation.
  • Surface state tunable energy and mass renormalization from homothetic quantum dot arrays.

    Piquero-Zulaica, Ignacio; Li, Jun; Abd El-Fattah, Zakaria M; Solianyk, Leonid; Gallardo, Iker; Monjas, Leticia; Hirsch, Anna K H; Arnau, Andres; Ortega, J Enrique; Stöhr, Meike; et al. (Royal Society of Chemistry, 2019-12-28)
    Quantum dot arrays in the form of molecular nanoporous networks are renowned for modifying the electronic surface properties through quantum confinement. Here we show that, compared to the pristine surface state, the band bottom of the confined states can exhibit downward shifts accompanied by a lowering of the effective masses simultaneous to the appearance of tiny gaps at the Brillouin zone boundaries. We observed these effects by angle resolved photoemission for two self-assembled homothetic (scalable) Co-coordinated metal-organic networks. Complementary scanning tunneling spectroscopy measurements confirmed these findings. Electron plane wave expansion simulations and density functional theory calculations provide insight into the nature of this phenomenon, which we assign to metal-organic overlayer-substrate interactions in the form of adatom-substrate hybridization. To date, the absence of the experimental band structure resulting from single metal adatom coordinated nanoporous networks has precluded the observation of the significant surface state renormalization reported here, which we infer to be general for low interacting and well-defined adatom arrays.
  • Flexible Fragment Growing Boosts Potency of Quorum Sensing Inhibitors against Pseudomonas aeruginosa Virulence.

    Zender, Michael; Witzgall, Florian; Kiefer, Alexander Felix; Kirsch, Benjamin; Maurer, Christine K; Kany, Andreas M; Xu, Ningna; Schmelz, Stefan; Börger, Carsten; Blankenfeldt, Wulf; et al. (Wiley-VCH, 2019-11-11)
    Hit-to-lead optimization is a critical phase in drug discovery. Herein, we report on the fragment-based discovery and optimization of 2-amino pyridine derivatives as a novel lead-like structure for the treatment of the dangerous opportunistic pathogen Pseudomonas aeruginosa . We pursue an innovative treatment strategy by interfering with the Pseudomonas Quinolone Signal (PQS) Quorum Sensing (QS) system leading to an abolishment of bacterial pathogenicity. Our compounds act on the PQS receptor (PqsR), a key transcription factor controlling the expression of various pathogenicity determinants. In this target-driven approach, we made use of biophysical screening via surface plasmon resonance (SPR) followed by isothermal titration calorimetry (ITC)-enabled enthalpic efficiency (EE) evaluation. Hit optimization then involved growth vector identification and exploitation. Astonishingly, the latter was successfully achieved by introducing flexible linkers rather than rigid motifs leading to a boost in activity on the target receptor and anti-virulence potency.
  • Hit evaluation of an α-helical peptide: Ala-scan, truncation and sidechain-to-sidechain macrocyclization of an RNA polymerase Inhibitor.

    Kamal, Ahmed Ashraf Moustafa; Habib, Monica; Haupenthal, Joerg; Hartmann, Rolf Wolfgang; Empting, Martin; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (De Gruyter, 2019-02-25)
    RNA polymerase (RNAP) remains a relatively underexplored target with only rifampicin and fidaxomicin in clinical use. Hence, the concurrent rise in bacterial resistance rate urges the search for novel RNAP inhibitors with novel mode of action. In this work, we investigated the impact of several systematic modifications including sidechain-to-sidechain macrocylization in α-helical content and biological activity of a previously identified inhibitory sigma factor fragment. Ala-scan results, peptide truncation from both the N- and C- terminus, and modifications inspired by other RNAP inhibitors revealed novel structure activity relationships but did not yield a superior sequence. Additionally, four insertion points for non-natural amino acids bearing side chains required for macrocylization were explored. Linear precursors showed improved stabilization of α-helical content compared to the original sequence as demonstrated by CD spectroscopy. However, this increase in α-helicity did not translate into improved biological activity. Instead, complete abolishment of RNAP inhibitory activity occurred. We hypothesize three possible reasons for such discrepancy and offer basis for further optimization efforts for this peptidic RNAP inhibitor.
  • Proteomic and Membrane Lipid Correlates of Reduced Host Defense Peptide.

    Kohler, Christian; Proctor, Richard A; Bayer, Arnold S; Yeaman, Michael R; Lalk, Michael; Engelmann, Susanne; Mishra, Nagendra N; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (MPDI, 2019-09-28)
    We previously described a transposon mutant in Staphylococcus aureus strain SH1000 that exhibited reduced susceptibility to cationic thrombin-induced platelet microbicidal proteins (tPMPs). The transposon insertion site was mapped to the gene snoD, the staphylococcal nuo orthologue. Hence, further studies have been performed to understand how this mutation impacts susceptibility to tPMP, by comparing proteomics profiling and membrane lipid analyses of the parent vs. mutant strains. Surprisingly, the mutant showed differential regulation of only a single protein when cultivated aerobically (FadB), and only a small number of proteins under anaerobic growth conditions (AdhE, DapE, Ddh, Ald1, IlvA1, AgrA, Rot, SA2366, and SA2367). Corresponding to FadB impact on lipid remodeling, membrane fatty acid analyses showed that the snoD mutant contained more short chain anteiso-, but fewer short chain iso-branched chain fatty acids under both aerobic and anaerobic conditions vs. the parental strain. Based upon these proteomic and membrane compositional data, a hypothetical "network" model was developed to explain the impact of the snoD mutation upon tPMP susceptibility.
  • Anti-biofilm Agents against Pseudomonas aeruginosa: A Structure-Activity Relationship Study of C-Glycosidic LecB Inhibitors

    Sommer, Roman; Rox, Katharina; Wagner, Stefanie; Hauck, Dirk; Henrikus, Sarah S; Newsad, Shelby; Arnold, Tatjana; Ryckmans, Thomas; Brönstrup, Mark; Imberty, Anne; et al. (American Chemical Society, 2019-10-24)
    Biofilm formation is a key mechanism of antimicrobial resistance. We have recently reported two classes of orally bioavailable C-glycosidic inhibitors of the Pseudomonas aeruginosa lectin LecB with antibiofilm activity. They proved efficient in target binding, were metabolically stable, nontoxic, selective, and potent in inhibiting formation of bacterial biofilm. Here, we designed and synthesized six new carboxamides and 24 new sulfonamides for a detailed structure-activity relationship for two clinically representative LecB variants. Sulfonamides generally showed higher inhibition compared to carboxamides, which was rationalized based on crystal structure analyses. Substitutions at the thiophenesulfonamide increased binding through extensive contacts with a lipophilic protein patch. These metabolically stable compounds showed a further increase in potency toward the target and in biofilm inhibition assays. In general, we established the structure-activity relationship for these promising antibiofilm agents and showed that modification of the sulfonamide residue bears future optimization potential.
  • Virtual Screening Against Carbohydrate-Binding Proteins: Evaluation and Application to Bacterial Burkholderia ambifaria Lectin.

    Dingjan, Tamir; Gillon, Émilie; Imberty, Anne; Pérez, Serge; Titz, Alexander; Ramsland, Paul A; Yuriev, Elizabeth; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (American Chemical Society, 2018-09-24)
    Bacterial adhesion to human epithelia via lectins constitutes a therapeutic opportunity to prevent infection. Specifically, BambL (the lectin from Burkholderia ambifaria) is implicated in cystic fibrosis, where lectin-mediated bacterial adhesion to fucosylated lung epithelia is suspected to play an important role. We employed structure-based virtual screening to identify inhibitors of BambL-saccharide interaction with potential therapeutic value. To enable such discovery, a virtual screening protocol was iteratively developed via 194 retrospective screening protocols against 4 bacterial lectins (BambL, BC2L-A, FimH, and LecA) with known ligands. Specific attention was given to the rigorous evaluation of retrospective screening, including calculation of analytical errors for enrichment metrics. The developed virtual screening workflow used crystallographic constraints, pharmacophore filters, and a final manual selection step. The protocol was applied to BambL, predicting 15 active compounds from virtual libraries of approximately 7 million compounds. Experimental validation using fluorescence polarization confirmed micromolar inhibitory activity for two compounds, which were further characterized by isothermal titration calorimetry and surface plasmon resonance. Subsequent testing against LecB from Pseudomonas aeruginosa demonstrated binding specificity of one of the hit compounds. This report demonstrates the utility of virtual screening protocols, integrating ligand-based pharmacophore filtering and structure-based constraints, in the search for bacterial lectin inhibitors.
  • Lectin antagonists in infection, immunity, and inflammation.

    Meiers, Joscha; Siebs, Eike; Zahorska, Eva; Titz, Alexander; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Elsevier, 2019-08-27)
    Lectins are proteins found in all domains of life with a plethora of biological functions, especially in the infection process, immune response, and inflammation. Targeting these carbohydrate-binding proteins is challenged by the fact that usually low affinity interactions between lectin and glycoconjugate are observed. Nature often circumvents this process through multivalent display of ligand and lectin. Consequently, the vast majority of synthetic antagonists are multivalently displayed native carbohydrates. At the cost of disadvantageous pharmacokinetic properties and possibly a reduced selectivity for the target lectin, the molecules usually possess very high affinities to the respective lectin through ligand epitope avidity. Recent developments include the advent of glycomimetic or allosteric small molecule inhibitors for this important protein class and their use in chemical biology and drug research. This evolution has culminated in the transition of the small molecule GMI-1070 into clinical phase III. In this opinion article, an overview of the most important developments of lectin antagonists in the last two decades with a focus on the last five years is given
  • Inverting Small Molecule-Protein Recognition by the Fluorine Gauche Effect: Selectivity Regulated by Multiple H→F Bioisosterism.

    Bentler, Patrick; Bergander, Klaus; Daniliuc, Constantin G; Mück-Lichtenfeld, Christian; Jumde, Ravindra P; Hirsch, Anna K H; Gilmour, Ryan; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany (Wiley-VCH, 2019-08-05)
    Fluorinated motifs have a venerable history in drug discovery, but as C(sp3 )-F-rich 3D scaffolds appear with increasing frequency, the effect of multiple bioisosteric changes on molecular recognition requires elucidation. Herein we demonstrate that installation of a 1,3,5-stereotriad, in the substrate for a commonly used lipase from Pseudomonas fluorescens does not inhibit recognition, but inverts stereoselectivity. This provides facile access to optically active, stereochemically well-defined organofluorine compounds (up to 98 % ee). Whilst orthogonal recognition is observed with fluorine, the trend does not hold for the corresponding chlorinated substrates or mixed halogens. This phenomenon can be placed on a structural basis by considering the stereoelectronic gauche effect inherent to F-C-C-X systems (σ→σ*). Docking reveals that this change in selectivity (H versus F) with a common lipase results from inversion in the orientation of the bound substrate being processed as a consequence of conformation. This contrasts with the stereochemical interpretation of the biogenetic isoprene rule, whereby product divergence from a common starting material is also a consequence of conformation, albeit enforced by two discrete enzymes.
  • Rational Adaptation of L3MBTL1 Inhibitors to Create Small-Molecule Cbx7 Antagonists.

    Simhadri, Chakravarthi; Daze, Kevin D; Douglas, Sarah F; Milosevich, Natalia; Monjas, Leticia; Dev, Amarjot; Brown, Tyler M; Hirsch, Anna K H; Wulff, Jeremy E; Hof, Fraser; et al. (Wiley, 2019-08-06)
    Chromobox homolog 7 (Cbx7) is an epigenetic modulator that is an important driver of multiple cancers. It is a methyl reader protein that operates by recognizing and binding to methylated lysine residues on specific partners. Herein we report our efforts to create low-molecular-weight inhibitors of Cbx7 by making rational structural adaptations to inhibitors of a different methyl reader protein, L3MBTL1, inhibitors that had previously been reported to be inactive against Cbx7. We evaluated each new inhibitor for Cbx7 inhibition by fluorescence polarization assay, and also confirmed the binding of selected inhibitors to Cbx7 by saturation-transfer difference NMR spectroscopy. This work identified multiple small-molecule inhibitors with modest (IC50 : 257-500 μm) potency.
  • Absorption of Anthocyanin Rutinosides after Consumption of a Blackcurrant ( Ribes nigrum L.) Extract.

    Röhrig, Teresa; Kirsch, Verena; Schipp, Dorothea; Galan, Jens; Richling, Elke; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (American Chemical Society, 2019-06-19)
    The dominant anthocyanins in blackcurrant are delphinidin-3-O-rutinoside and cyanidin-3-O-rutinoside. Data on their absorption and distribution in the human body are limited. Therefore, we performed a human pilot study on five healthy male volunteers consuming a blackcurrant (Ribes nigrum L.) extract. The rutinosides and their degradation products gallic acid and protocatechuic acid were determined in plasma and urine. The rutinosides’ concentrations peaked in both plasma and urine samples within 2 h of extract ingestion. The recoveries of delphinidin-3-O-rutinoside and cyanidin-3-O-rutinoside from urine samples were 0.040 ± 0.011% and 0.048 ± 0.016%, respectively, over a 48 h period. Protocatechuic acid concentration increased significantly after ingestion of the blackcurrant extract. Our results show that after ingestion of a blackcurrant extract containing delphinidin-3-O-rutinoside and cyanidin-3-O-rutinoside, significant quantities of biologically active compounds circulated in the plasma and were excreted via urine. Furthermore, these results contribute to the understanding of anthocyanin metabolism in humans.
  • Induction of rare conformation of oligosaccharide by binding to calcium-dependent bacterial lectin: X-ray crystallography and modelling study.

    Lepsik, Martin; Sommer, Roman; Kuhaudomlarp, Sakonwan; Lelimousin, Mickaël; Paci, Emanuele; Varrot, Annabelle; Titz, Alexander; Imberty, Anne; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Elsevier, 2019-09-01)
    Pathogenic micro-organisms utilize protein receptors (lectins) in adhesion to host tissues, a process that in some cases relies on the interaction between lectins and human glycoconjugates. Oligosaccharide epitopes are recognized through their three-dimensional structure and their flexibility is a key issue in specificity. In this paper, we analysed by X-ray crystallography the structures of the LecB lectin from two strains of Pseudomonas aeruginosa in complex with Lewis x oligosaccharide present on cell surfaces of human tissues. An unusual conformation of the glycan was observed in all binding sites with a non-canonical syn orientation of the N-acetyl group of N-acetyl-glucosamine. A PDB-wide search revealed that such an orientation occurs only in 4% of protein/carbohydrate complexes. Theoretical chemistry calculations showed that the observed conformation is unstable in solution but stabilised by the lectin. A reliable description of LecB/Lewis x complex by force field-based methods had proven especially challenging due to the special feature of the binding site, two closely apposed Ca2+ ions which induce strong charge delocalisation. By comparing various force-field parametrisations, we propose a general strategy which will be useful in near future for designing carbohydrate-based ligands (glycodrugs) against other calcium-dependent protein receptors.
  • Fragment-Based Discovery of a Qualified Hit Targeting the Latency-Associated Nuclear Antigen of the Oncogenic Kaposi's Sarcoma-Associated Herpesvirus/Human Herpesvirus 8.

    Kirsch, Philine; Jakob, Valentin; Oberhausen, Kevin; Stein, Saskia C; Cucarro, Ivano; Schulz, Thomas F; Empting, Martin; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (American Chemical Society, 2019-04-25)
    The latency-associated nuclear antigen (LANA) is required for latent replication and persistence of Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8. It acts via replicating and tethering the virus episome to the host chromatin and exerts other functions. We conceived a new approach for the discovery of antiviral drugs to inhibit the interaction between LANA and the viral genome. We applied a biophysical screening cascade and identified the first LANA binders from small, structurally diverse compound libraries. Starting from a fragment-sized scaffold, we generated optimized hits via fragment growing using a dedicated fluorescence-polarization-based assay as the structure-activity-relationship driver. We improved compound potency to the double-digit micromolar range. Importantly, we qualified the resulting hit through orthogonal methods employing EMSA, STD-NMR, and MST methodologies. This optimized hit provides an ideal starting point for subsequent hit-to-lead campaigns providing evident target-binding, suitable ligand efficiencies, and favorable physicochemical properties.
  • Protein-Templated Dynamic Combinatorial Chemistry: Brief Overview and Experimental Protocol

    Hartman, Alwin M.; Gierse, Robin M.; Hirsch, Anna K. H.; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Wiley, 2019-05-03)
    Dynamic combinatorial chemistry (DCC) is a powerful tool to identify bioactive compounds. This efficient technique allows the target to select its own binders and circumvents the need for synthesis and biochemical evaluation of all individual derivatives. An ever‐increasing number of publications report the use of DCC on biologically relevant target proteins. This minireview complements previous reviews by focusing on the experimental protocol and giving detailed examples of essential steps and factors that need to be considered, such as protein stability, buffer composition and cosolvents.
  • Replacement of an Indole Scaffold Targeting Human 15-Lipoxygenase-1 Using Combinatorial Chemistry.

    Prismawan, Deka; van der Vlag, Ramon; Guo, Hao; Dekker, Frank J; Hirsch, Anna K H; HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany. (Wiley-Blackwell, 2019-05-01)
    Human 15-lipoxygenase-1 (15-LOX-1) belongs to the class of lipoxygenases, which catalyze oxygenation of polyunsaturated fatty acids, such as arachidonic and linoleic acid. Recent studies have shown that 15-LOX-1 plays an important role in physiological processes linked to several diseases such as airway inflammation disease, coronary artery disease, and several types of cancer such as rectal, colon, breast and prostate cancer. In this study, we aimed to extend the structural diversity of 15-LOX-1 inhibitors, starting from the recently identified indolyl core. In order to find new scaffolds, we employed a combinatorial approach using various aromatic aldehydes and an aliphatic hydrazide tail. This scaffold-hopping study resulted in the identification of the 3-pyridylring as a suitable replacement of the indolyl core with an inhibitory activity in the micromolar range (IC50=16±6 μm) and a rapid and efficient structure-activity relationship investigation.
  • Low-Dimensional Metal-Organic Coordination Structures on Graphene.

    Li, Jun; Solianyk, Leonid; Schmidt, Nico; Baker, Brian; Gottardi, Stefano; Moreno Lopez, Juan Carlos; Enache, Mihaela; Monjas, Leticia; van der Vlag, Ramon; Havenith, Remco W A; et al. (American Society of Chemistry, 2019-05-23)
    We report the formation of one- and two-dimensional metal-organic coordination structures from para-hexaphenyl-dicarbonitrile (NC-Ph6-CN) molecules and Cu atoms on graphene epitaxially grown on Ir(111). By varying the stoichiometry between the NC-Ph6-CN molecules and Cu atoms, the dimensionality of the metal-organic coordination structures could be tuned: for a 3:2 ratio, a two-dimensional hexagonal porous network based on threefold Cu coordination was observed, while for a 1:1 ratio, one-dimensional chains based on twofold Cu coordination were formed. The formation of metal-ligand bonds was supported by imaging the Cu atoms within the metal-organic coordination structures with scanning tunneling microscopy. Scanning tunneling spectroscopy measurements demonstrated that the electronic properties of NC-Ph6-CN molecules and Cu atoms were different between the two-dimensional porous network and one-dimensional molecular chains.
  • Comparing the Self-Assembly of Sexiphenyl-Dicarbonitrile on Graphite and Graphene on Cu(111).

    Schmidt, Nico; Li, Jun; Gottardi, Stefano; Moreno-Lopez, Juan Carlos; Enache, Mihaela; Monjas, Leticia; van der Vlag, Ramon; Havenith, Remco W A; Hirsch, Anna K H; Stöhr, Meike; et al. (Wiley-Blackwell, 2019-04-01)
    A comparative study on the self-assembly of sexiphenyl-dicarbonitrile on highly oriented pyrolytic graphite and single-layer graphene on Cu(111) is presented. Despite an overall low molecule-substrate interaction, the close-packed structures exhibit a peculiar shift repeating every four to five molecules. This shift has hitherto not been reported for similar systems and is hence a unique feature induced by the graphitic substrates.

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