ChemMedChem

Cover image for Vol. 8 Issue 6

June 2013

Volume 8, Issue 6

Pages 865–1015

  1. Cover Pictures

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Minireview
    6. Communications
    7. Full Papers
    8. Book Reviews
    1. You have free access to this content
      Cover Picture: From a Multipotent Stilbene to Soluble Epoxide Hydrolase Inhibitors with Antiproliferative Properties (ChemMedChem 6/2013) (page 865)

      Estel.la Buscató, Dominik Büttner, Astrid Brüggerhoff, Franca-Maria Klingler, Julia Weber, Bastian Scholz, Dr. Aleksandra Živković, Prof. Dr. Rolf Marschalek, Prof. Dr. Holger Stark, Prof. Dr. Dieter Steinhilber, Prof. Dr. Helge B. Bode and Prof. Dr. Ewgenij Proschak

      Version of Record online: 24 MAY 2013 | DOI: 10.1002/cmdc.201390020

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      The front cover picture shows the structure of the multipotent bacterial isopropylstilbene identified as a novel soluble epoxide hydrolase (sEH) inhibitor with antiproliferative properties. This natural product served as a template for the design and synthesis of (E)-styryl-1H-benzo[d]imidazoles—easily accessible compounds with enhanced activity towards sEH. The modeled conformation of one of the designed compounds is shown in the foreground, and the background displays apoptotic cells after treatment with isopropylstilbene. For more details, see the Communication by Ewgenij Proschak et al. on p. 919 ff.

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      Inside Cover: Design, Synthesis, and Antibacterial Activity of Demethylvancomycin Analogues against Drug-Resistant Bacteria (ChemMedChem 6/2013) (page 866)

      Dr. Jun Chang, Si-Ji Zhang, Yong-Wei Jiang, Dr. Liang Xu, Dr. Jian-Ming Yu, Prof. Wen-Jiang Zhou and Prof. Dr. Xun Sun

      Version of Record online: 24 MAY 2013 | DOI: 10.1002/cmdc.201390021

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      The inside cover picture shows the proposed binding mode of a demethylvancomycin analogue (white) with the peptidoglycan of vancomycin-resistant Enterococcus faecalis (teal), in which the NH–π interaction is predicted to compensate for the diminished binding affinity caused by the breaking of a conserved NH ⋅ ⋅ ⋅ O hydrogen bond in drug-resistant bacteria. For more details, see the Full Paper by Wen-Jiang Zhou, Xun Sun et al. on p. 976 ff.

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      Back Cover: Structure–Activity Relationships of Quinoxaline-Based 5-HT3A and 5-HT3AB Receptor-Selective Ligands (ChemMedChem 6/2013) (page 1020)

      Dr. Andrew J. Thompson, Dr. Mark H. P. Verheij, Dr. Jacqueline E. van Muijlwijk-Koezen, Prof. Sarah C. R. Lummis, Prof. Rob Leurs and Dr. Iwan J. P. de Esch

      Version of Record online: 24 MAY 2013 | DOI: 10.1002/cmdc.201390024

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      The back cover picture shows the extracellular domains of two of the five subunits that make up a 5-HT3 receptor. Quinoxalines (general structure shown) bind with reasonable potency to this receptor, probably at the orthosteric binding site located between two adjacent subunits. Through modifications to the functional groups at the R1, R2 and R3 positions, the ability of these ligands to distinguish between homomeric 5-HT3AR and heteromeric 5-HT3AB receptors was probed. For more details, see the Full Paper by Sarah C. R. Lummis et al. on p. 946 ff.

  2. Graphical Abstract

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Minireview
    6. Communications
    7. Full Papers
    8. Book Reviews
    1. You have free access to this content
    2. You have free access to this content
  3. News

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Minireview
    6. Communications
    7. Full Papers
    8. Book Reviews
  4. Minireview

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Minireview
    6. Communications
    7. Full Papers
    8. Book Reviews
    1. Radiolabeled Heterobivalent Peptidic Ligands: an Approach with High Future Potential for in vivo Imaging and Therapy of Malignant Diseases (pages 883–890)

      Gabriel Fischer, Prof. Dr. Ralf Schirrmacher, Prof. Dr. Björn Wängler and Dr. Carmen Wängler

      Version of Record online: 5 APR 2013 | DOI: 10.1002/cmdc.201300081

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      Two-pronged synergism: We review the recently developed approach of using heterobivalent peptide ligands that interact concomitantly with different receptors on tumor cells. These ligands exhibit highly favorable tumor-targeting properties and pave the way for the development of drugs for specific, sensitive, and noninvasive tumor imaging and therapy.

  5. Communications

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Minireview
    6. Communications
    7. Full Papers
    8. Book Reviews
    1. Design, Synthesis and Biological Evaluation of Trimethine Cyanine Dyes as Fluorescent Probes for the Detection of Tau Fibrils in Alzheimer’s Disease Brain and Olfactory Epithelium (pages 891–897)

      Jiamin Gu, Upendra Rao Anumala, Dr. Roland Heyny-von Haußen, Jana Hölzer, Valérie Goetschy-Meyer, Dr. Gerhard Mall, Prof. Dr. Ingrid Hilger, Dr. Christian Czech and Prof. Dr. Boris Schmidt

      Version of Record online: 16 APR 2013 | DOI: 10.1002/cmdc.201300090

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      Shedding light on grey matter: Fluorescent trimethine cyanines were evaluated as imaging probes for neurofibrillary tangles in post-mortem brain sections of Alzheimer's disease patients. These probes bind to neurofibrillary tangles with high contrast and selectivity over amyloid β plaques.

    2. Discovery and Characterization of ACT-335827, an Orally Available, Brain Penetrant Orexin Receptor Type 1 Selective Antagonist (pages 898–903)

      Dr. Michel A. Steiner, Dr. John Gatfield, Dr. Catherine Brisbare-Roch, Dr. Hendrik Dietrich, Dr. Alexander Treiber, Dr. Francois Jenck and Dr. Christoph Boss

      Version of Record online: 15 APR 2013 | DOI: 10.1002/cmdc.201300003

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      Stress relief: Orexin neuropeptides regulate arousal and stress processing through orexin receptor type 1 (OXR-1) and 2 (OXR-2) signaling. A selective OXR-1 antagonist, represented by a phenylglycine-amide substituted tetrahydropapaverine derivative (ACT-335827), is described that is orally available, penetrates the brain, and decreases fear, compulsive behaviors and autonomic stress reactions in rats.

    3. A Facile Hydroxyindole Carboxylic Acid Based Focused Library Approach for Potent and Selective Inhibitors of Mycobacterium Protein Tyrosine Phosphatase B (pages 904–908)

      Dr. Li-Fan Zeng, Dr. Jie Xu, Dr. Yantao He, Dr. Rongjun He, Li Wu, Andrea M. Gunawan and Prof. Dr. Zhong-Yin Zhang

      Version of Record online: 8 APR 2013 | DOI: 10.1002/cmdc.201300115

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      Focused on Mtb: A facile hydroxyindole carboxylic acid based focused amide library was designed to target both the PTP active site and a unique nearby pocket for enhanced affinity and selectivity. HTS of the library led to the identification of a highly potent and selective inhibitor, 11 a, of mPTPB, an essential virulence factor for Mycobacterium tuberculosis. Compound 11 a shows high cellular activity and is capable of reversing the altered immune responses induced by mPTPB in macrophages.

    4. Selective Bisubstrate Inhibitors with Sub-nanomolar Affinity for Protein Kinase Pim-1 (pages 909–913)

      Dr. Ramesh Ekambaram, Dr. Erki Enkvist, Dr. Angela Vaasa, Dr. Marje Kasari, Gerda Raidaru, Prof. Stefan Knapp and Dr. Asko Uri

      Version of Record online: 24 APR 2013 | DOI: 10.1002/cmdc.201300042

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      Potent and selective: The unique nature of the ATP binding pocket structure of Pim family protein kinases (PKs) was used for the development of bisubstrate inhibitors and a fluorescent probe with sub-nanomolar affinity. Conjugates of arginine-rich peptides with two ATP mimetic scaffolds were synthesized and tested as inhibitors of Pim-1. Against a panel of 124 protein kinases, a novel ARC–PIM conjugate selectively inhibited PKs of the Pim family.

    5. Potent Inhibitors of Phosphatidylinositol 3 (PI3) Kinase that have Antiproliferative Activity Only When Delivered as Prodrug Forms (pages 914–918)

      Nathan J. O'Brien, Syazwani Amran, Jelena Medan, Ben Cleary, Dr. Leslie W. Deady, Dr. Ian G. Jennings, Dr. Philip E. Thompson and Dr. Belinda M. Abbott

      Version of Record online: 8 APR 2013 | DOI: 10.1002/cmdc.201200583

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      Prodrugs for PI3K: A series of substituted analogues of the phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002 were prepared and found to potently inhibit the isolated enzyme but not MCF7 cell proliferation. Two tetrazolyl-substituted analogues were further derivatized as prodrugs resulting in restoration of cell-based activity. These data provide a conceptual model for development of tumor-targeting prodrug forms of cell-impermeable PI3K inhibitors.

    6. From a Multipotent Stilbene to Soluble Epoxide Hydrolase Inhibitors with Antiproliferative Properties (pages 919–923)

      Estel.la Buscató, Dominik Büttner, Astrid Brüggerhoff, Franca-Maria Klingler, Julia Weber, Bastian Scholz, Dr. Aleksandra Živković, Prof. Dr. Rolf Marschalek, Prof. Dr. Holger Stark, Prof. Dr. Dieter Steinhilber, Prof. Dr. Helge B. Bode and Prof. Dr. Ewgenij Proschak

      Version of Record online: 17 APR 2013 | DOI: 10.1002/cmdc.201300057

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      Inspired by nature: Natural product isopropylstilbene was identified as an inhibitor of soluble epoxide hydrolase exhibiting antiproliferative properties. Following the natural product inspired design approach, a library of (E)-styryl-1H-benzo[d]imidazoles was synthesized and evaluated with recombinant enzyme and on several cancer cell lines.

    7. Rhenium Complexes with Visible-Light-Induced Anticancer Activity (pages 924–927)

      Anja Kastl, Sandra Dieckmann, Kathrin Wähler, Timo Völker, Lena Kastl, Anna Lena Merkel, Dr. Adina Vultur, Dr. Batool Shannan, Dr. Klaus Harms, Prof. Dr. Matthias Ocker, Prof. Dr. Wolfgang J. Parak, Dr. Meenhard Herlyn and Prof. Dr. Eric Meggers

      Version of Record online: 8 APR 2013 | DOI: 10.1002/cmdc.201300060

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      Shedding light on the matter: Rhenium(I) indolato complexes with highly potent visible-light-triggered antiproliferative activity (complex 1: EC50 light=0.1 μM vs EC50 dark=100 μM) in 2D- and 3D-organized cancer cells are reported and can be traced back to an efficient generation of singlet oxygen, causing rapid morphological changes and an induction of apoptosis.

    8. Synthesis, Antitumor Evaluation and Docking Study of Novel 4-Anilinoquinazoline Derivatives as Potential Epidermal Growth Factor Receptor (EGFR) Inhibitors (pages 928–933)

      Dr. Guo-Wu Rao, Geng-Jie Xu, Dr. Jian Wang, Dr. Xu-Liang Jiang and Dr. Hai-Bo Li

      Version of Record online: 2 MAY 2013 | DOI: 10.1002/cmdc.201300120

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      Strike a pose! A series of 4-anilinoquinazolines were designed, synthesized and evaluated in vitro against lung and breast cancer cell lines. Several compounds were found to be endowed with cytotoxicity in the low micromolar range. Molecular docking suggests that these compounds bind to EGFR in a similar manner to known EGFR inhibitors.

  6. Full Papers

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Minireview
    6. Communications
    7. Full Papers
    8. Book Reviews
    1. An Efficient Bioorthogonal Strategy Using CuAAC Click Chemistry for Radiofluorinations of SNEW Peptides and the Role of Copper Depletion (pages 935–945)

      Marc Pretze, Manuela Kuchar, Dr. Ralf Bergmann, Prof. Dr. Jörg Steinbach, Prof. Dr. Jens Pietzsch and Dr. Constantin Mamat

      Version of Record online: 4 APR 2013 | DOI: 10.1002/cmdc.201300053

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      Introduction and removal: Fluorine-18-labeled radiotracers based on SNEW peptides with high affinity for the EphB2 receptor were developed through a bioorthogonal CuAAC approach. The copper species must be removed to circumvent loss in biological activity. Radiopharmacological characterizations of a selected 18F-labeled peptide were initially carried out in vitro and then in vivo using Wistar rats.

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      Structure–Activity Relationships of Quinoxaline-Based 5-HT3A and 5-HT3AB Receptor-Selective Ligands (pages 946–955)

      Dr. Andrew J. Thompson, Dr. Mark H. P. Verheij, Dr. Jacqueline E. van Muijlwijk-Koezen, Prof. Sarah C. R. Lummis, Prof. Rob Leurs and Dr. Iwan J. P. de Esch

      Version of Record online: 2 MAY 2013 | DOI: 10.1002/cmdc.201300032

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      One atom makes the difference: By using a fragment screen as an efficient route to design novel ligands, we identified quinoxalines as high-affinity binders to 5-HT3 receptors. New synthesis routes allowed the development a series of compounds able to distinguish 5-HT3A receptors from 5-HT3AB receptors, revealing that a single atom is sufficient to change the selectivity profile of a compound.

    3. MAO Inhibitory Activity of 2-Arylbenzofurans versus 3-Arylcoumarins: Synthesis, in vitro Study, and Docking Calculations (pages 956–966)

      Dr. Giulio Ferino, Prof. Enzo Cadoni, Dr. Maria João Matos, Dr. Elias Quezada, Prof. Eugenio Uriarte, Prof. Lourdes Santana, Dr. Santiago Vilar, Dr. Nicholas P. Tatonetti, Matilde Yáñez, Dolores Viña, Dr. Carmen Picciau, Dr. Silvia Serra and Prof. Giovanna Delogu

      Version of Record online: 15 APR 2013 | DOI: 10.1002/cmdc.201300048

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      A tale of two scaffolds: Herein we describe the synthesis, in vitro inhibition of MAO-A and MAO-B, reversibility studies, and docking calculations for two groups of 2-arylbenzofurans and 3-arylcoumarins. A comparative study of both scaffolds was performed.

    4. Optimization of Triazine Nitriles as Rhodesain Inhibitors: Structure–Activity Relationships, Bioisosteric Imidazopyridine Nitriles, and X-ray Crystal Structure Analysis with Human Cathepsin L (pages 967–975)

      Dr. Veronika Ehmke, Edwin Winkler, Dr. David W. Banner, Dr. Wolfgang Haap, Dr.  W. Bernd Schweizer, Dr. Matthias Rottmann, Dr. Marcel Kaiser, Céline Freymond, Prof. Dr. Tanja Schirmeister and Prof. Dr. François Diederich

      Version of Record online: 9 MAY 2013 | DOI: 10.1002/cmdc.201300112

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      Out of the HAT: SAR studies on rhodesain inhibitors deciphered the binding preferences, giving Ki values in the single-digit nanomolar range. A bioisosteric imidazopyridine scaffold led to lower electrophilicity of the nitrile headgroup, resulting in reduced off-target effects. X-ray crystal structures of hCatL in complex with a triazine nitrile inhibitor and in the apo form shed light on the binding mode and hydration state of the active site.

    5. Design, Synthesis, and Antibacterial Activity of Demethylvancomycin Analogues against Drug-Resistant Bacteria (pages 976–984)

      Dr. Jun Chang, Si-Ji Zhang, Yong-Wei Jiang, Dr. Liang Xu, Dr. Jian-Ming Yu, Prof. Wen-Jiang Zhou and Prof. Dr. Xun Sun

      Version of Record online: 10 APR 2013 | DOI: 10.1002/cmdc.201300011

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      The best of five: N-Substituted demethylvancomycin derivatives were rationally designed and synthesized by using a structure-based approach. One of the compounds was found to exhibit more potent antibacterial activity against drug-resistant bacteria than vancomycin or demethylvancomycin, suggesting its promise as an antibacterial drug candidate.

    6. Synthesis and Anti-herpetic Activity of Phosphoramidate ProTides (pages 985–993)

      Munmun Maiti, Leentje Persoons, Prof. Graciela Andrei, Prof. Robert Snoeck, Prof. Jan Balzarini and Prof. Piet Herdewijn

      Version of Record online: 18 APR 2013 | DOI: 10.1002/cmdc.201300035

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      Key to membrane permeability: The introduction of the pivaloyloxymethyl (POM) moiety as a carboxyl protecting group has shown promise in the design of antiviral phosphoramidate prodrugs for the intracellular delivery of nucleoside monophosphates. Antiviral data also support the substitution of a primary amine with a secondary amine in the intracellular delivery of ProTide analogues.

    7. Synthesis and in vitro Evaluation of West Nile Virus Protease Inhibitors Based on the 2-{6-[2-(5-Phenyl-4H-{1,2,4]triazol-3-ylsulfanyl)acetylamino]benzothiazol-2-ylsulfanyl}acetamide Scaffold (pages 994–1001)

      Sanjay Samanta, Ting Liang Lim and Prof. Yulin Lam

      Version of Record online: 25 APR 2013 | DOI: 10.1002/cmdc.201300114

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      Damming the West Nile: An in vitro assay for West Nile virus (WNV) NS2B-NS3 protease resulted in the discovery of 2-{6-[2-(5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)acetylamino]benzothiazol-2-ylsulfanyl}acetamides as a new class of inhibitors against this enzyme. Optimization of the lead compound led to an uncompetitive WNV NS2B-NS3 inhibitor with an IC50 value of 3.4±0.2 μM.

    8. Synthesis and Evaluation of Water-Soluble Prodrugs of Ursodeoxycholic Acid (UDCA), an Anti-apoptotic Bile Acid (pages 1002–1011)

      Dr. Peter I. Dosa, Dr. Tim Ward, Dr. Rui E. Castro, Prof. Dr. Cecília M. P. Rodrigues and Prof. Dr. Clifford J. Steer

      Version of Record online: 2 MAY 2013 | DOI: 10.1002/cmdc.201300059

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      Quick release: A series of water-soluble prodrugs of the anti-apoptotic bile acid UDCA were prepared, including a novel phosphoryloxymethyl carboxylate (POMC) prodrug. The POMC prodrug was bioactivated to UDCA by alkaline phosphatase more rapidly than a prodrug with a phosphate directly linked to an alcohol. Both of these prodrugs showed significant in vitro anti-apoptotic activity.

  7. Book Reviews

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    2. Cover Pictures
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    4. News
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    6. Communications
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    8. Book Reviews
    1. Bioisosteres in Medicinal Chemistry. Edited by Nathan Brown (page 1012)

      Prof. Lennart Bunch

      Version of Record online: 28 MAR 2013 | DOI: 10.1002/cmdc.201300117

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      Wiley-VCH, Weinheim 2012. XVIII+237 pp., hardcover, €119.—ISBN 978-3-527-33015-7

    2. Innovations in Biomolecular Modeling and Simulations. Edited by Tamar Schlick (pages 1012–1014)

      Prof. Modesto Orozco

      Version of Record online: 9 APR 2013 | DOI: 10.1002/cmdc.201300052

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      RSC, Cambridge 2012. Two volumes, 734 pp., hardcover, £259.99.—ISBN 978-1-84973-410-3 (complete set)

    3. Cancer Epigenetics: Biomolecular Therapeutics for Human Cancer. Edited by Antonio Giordano and Marcella Macaluso (pages 1014–1015)

      Prof. Julian Blagg

      Version of Record online: 22 APR 2013 | DOI: 10.1002/cmdc.201300152

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      Wiley–Blackwell, Hoboken 2011. 436 pp., hardcover, $149.95.—ISBN 978-0-471-71096-7

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