ChemMedChem

Cover image for Vol. 8 Issue 3

March 2013

Volume 8, Issue 3

Pages 345–529

  1. Cover Pictures

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireviews
    7. Full Papers
    8. Book Reviews
    1. You have free access to this content
      Cover Picture: Efficient Stacking on Protein Amide Fragments (ChemMedChem 3/2013) (page 345)

      Michael Harder, Dr. Bernd Kuhn and Prof. Dr. François Diederich

      Version of Record online: 22 FEB 2013 | DOI: 10.1002/cmdc.201390005

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      The noncovalent interaction between medicinal chemistry-relevant heterocycles and protein amide groups was studied in detail in the Full Paper by Michael Harder, Bernd Kuhn, and Francois Diederich (p. 397 ff.). The front cover picture shows two examples of protein binding sites that expose backbone amides for ligand interaction: in the background, the extended beta sheet structure of an amyloid is shown, and in the top-right, the solvent-accessible surface of the active site of cathepsin L is displayed. The base of the S3 pocket, which is formed by a glycine-containing dipeptide fragment of the cathepsin L backbone, is highlighted. To optimally exploit the interaction with such motifs in ligand design, guidelines are devised based on extensive quantum chemical calculations on various arene/amide dimers. Both a correlation of the interaction strength with the magnitude of the fragment dipole moment and a significant energetic preference for an antiparallel alignment of the interacting dipole vectors could be demonstrated.

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      Inside Cover: Monitoring Binding of HIV-1 Capsid Assembly Inhibitors Using 19F Ligand-and 15N Protein-Based NMR and X-ray Crystallography: Early Hit Validation of a Benzodiazepine Series (ChemMedChem 3/2013) (page 346)

      Dr. Nathalie Goudreau, René Coulombe, Dr. Anne-Marie Faucher, Chantal Grand-Maître, Jean-Eric Lacoste, Dr. Christopher T. Lemke, Eric Malenfant, Yves Bousquet, Dr. Lee Fader, Dr. Bruno Simoneau, Jean-François Mercier, Steve Titolo and Dr. Stephen W. Mason

      Version of Record online: 22 FEB 2013 | DOI: 10.1002/cmdc.201390006

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      Mature HIV-1 capsid (CA) core is characterized by a fullerene cone-shaped structure made of hexamers and pentamers. Inhibition of its assembly is a novel mechanism through which to target HIV-1. The inside cover picture shows the characterization of potent CA assembly inhibitors (orange) as N-terminal domain (NTD) binders using 19F NMR and X-ray co-crystallography. For more details, see the Full Paper by Nathalie Goudreau, René Coulombe et al. on p. 405 ff.

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      Back Cover: Computational Studies Identifying Entry Inhibitor Scaffolds Targeting the Phe 43 Cavity of HIV-1 gp120 (ChemMedChem 3/2013) (page 532)

      Cristina Tintori, Manikandan Selvaraj, Dr. Roger Badia, Dr. Bonaventura Clotet, Dr. José A. Esté and Prof. Maurizio Botta

      Version of Record online: 22 FEB 2013 | DOI: 10.1002/cmdc.201390009

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      The back cover picture shows the process of discovering small-molecule inhibitors of the gp120–CD4 protein[BOND]protein interaction by means of pharmacophore modeling and structure-based drug design. The screening campaign identified novel scaffolds for development of anti-HIV-1 agents. For more details, see the Full Paper by Maurizio Botta et al. on p. 475 ff.

  2. Graphical Abstract

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

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

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireviews
    7. Full Papers
    8. Book Reviews
    1. Modern Subunit Vaccines: Development, Components, and Research Opportunities (pages 360–376)

      Dr. Peter Michael Moyle and Prof. Istvan Toth

      Version of Record online: 11 JAN 2013 | DOI: 10.1002/cmdc.201200487

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      The subunit approach: Despite their excellent track record, traditional vaccine approaches have failed for several high priority diseases. Subunit vaccines offer hope for new, safer, highly characterized vaccines. Herein we discuss key components for next-generation subunit vaccine development.

  5. Minireviews

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireviews
    7. Full Papers
    8. Book Reviews
    1. Polycyclic Peptide Therapeutics (pages 377–384)

      Dr. Vanessa Baeriswyl and Prof. Christian Heinis

      Version of Record online: 25 JAN 2013 | DOI: 10.1002/cmdc.201200513

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      Turning therapeutic circles: Several polycyclic peptides isolated from natural sources are established drugs. Using some of the most prominent examples, the attractive properties of the ring-shaped structures are discussed. In a second part, recently developed strategies that allow engineering of artificial polycyclic peptides to a broader range of targets are highlighted.

    2. Carboxylic Acid (Bio)Isosteres in Drug Design (pages 385–395)

      Dr. Carlo Ballatore, Prof. Donna M. Huryn and Prof. Amos B. Smith III

      Version of Record online: 29 JAN 2013 | DOI: 10.1002/cmdc.201200585

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      A carboxylic switcheroo: Replacement of a carboxylic acid functional group in a drug or a drug candidate with an appropriate (bio)isostere can lead to derivatives with improved properties. As the outcome of any isosteric replacement cannot be readily predicted, the screening of a panel of isosteres is typically required. The availability of a relatively large set of potential carboxylic acid surrogates is thus critical to the success of the isosteric replacement strategy in drug design.

  6. Full Papers

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireviews
    7. Full Papers
    8. Book Reviews
    1. Efficient Stacking on Protein Amide Fragments (pages 397–404)

      Michael Harder, Dr. Bernd Kuhn and Prof. Dr. François Diederich

      Version of Record online: 25 JAN 2013 | DOI: 10.1002/cmdc.201200512

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      π-Stacking: Quantum chemical calculations and Protein Data Bank searches on N-methylacetamide/heteroarene stacking were performed, yielding new guidelines that will help future structure-based drug design. The stacking interaction depends on the relative orientation and the magnitude of the two dipole moments, as well as the π-electron density of the arene.

    2. Monitoring Binding of HIV-1 Capsid Assembly Inhibitors Using 19F Ligand-and 15N Protein-Based NMR and X-ray Crystallography: Early Hit Validation of a Benzodiazepine Series (pages 405–414)

      Dr. Nathalie Goudreau, René Coulombe, Dr. Anne-Marie Faucher, Chantal Grand-Maître, Jean-Eric Lacoste, Dr. Christopher T. Lemke, Eric Malenfant, Yves Bousquet, Dr. Lee Fader, Dr. Bruno Simoneau, Jean-François Mercier, Steve Titolo and Dr. Stephen W. Mason

      Version of Record online: 10 FEB 2013 | DOI: 10.1002/cmdc.201200580

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      CA all the way! Early hits from a series of benzodiazepine inhibitors of viral capsid protein (CA), a novel target against HIV, were characterized using NMR and X-ray co-crystallography. Ligand-based 19F NMR was used to confirm binding specificity and reversibility, and to identify the N-terminal domain (CANTD) as the molecular target. Protein-based NMR identified key residues involved in binding, while X-ray co-crystallography confirmed the binding site and mode. Conformationally restricted cyclic inhibitors further validated the possible binding modes.

    3. Synthesis and Biological Evaluation of Purine 2′-Fluoro-2′-deoxyriboside ProTides as Anti-influenza Virus Agents (pages 415–425)

      Dr. Silvia Meneghesso, Dr. Evelien Vanderlinden, Dr. Andrea Brancale, Prof. Jan Balzarini, Prof. Lieve Naesens and Prof. Christopher McGuigan

      Version of Record online: 5 FEB 2013 | DOI: 10.1002/cmdc.201200562

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      Tidal power: We report the synthesis and biological evaluation of several ProTides of 6-modified analogues of 2′-fluoro-2′-deoxyguanosine as anti-influenza agents. The superiority of the ProTides over the parent nucleosides was demonstrated in both influenza virus replication assays in MDCK cells and vRNP reconstitution assays in HEK-293T cells.

    4. Identification of a Small-Molecule Inhibitor of HIV-1 Assembly that Targets the Phosphatidylinositol (4,5)-bisphosphate Binding Site of the HIV-1 Matrix Protein (pages 426–432)

      Isaac Zentner, Luz-Jeannette Sierra, Ayesha K. Fraser, Lina Maciunas, Marie K. Mankowski, Dr. Andrei Vinnik, Dr. Peter Fedichev, Roger G. Ptak, Dr. Julio Martín-García and Dr. Simon Cocklin

      Version of Record online: 29 JAN 2013 | DOI: 10.1002/cmdc.201200577

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      PIP2-ing HIV-1 to the post! The discovery and characterization of a new small-molecule inhibitor (shown) of HIV-1 replication that targets the HIV-1 matrix (MA) protein is described. This novel agent exhibits a broad therapeutic spectrum, inhibiting all of the group M isolates tested, and functions via the novel mechanism of disrupting the critical phosphatidylinositol 4,5-bisphosphate (PI[4,5]P2)–MA interaction.

    5. Novel Schiff-Base-Derived FabH Inhibitors with Dioxygenated Rings as Antibiotic Agents (pages 433–441)

      Dr. Yang Zhou, Dr. Qian-Ru Du, Dr. Jian Sun, Dr. Jing-Ran Li, Dr. Fei Fang, Dr. Dong-Dong Li, Dr. Yong Qian, Dr. Hai-Bin Gong, Prof. Jing Zhao and Prof. Hai-Liang Zhu

      Version of Record online: 7 FEB 2013 | DOI: 10.1002/cmdc.201200587

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      Fab(H)ulous! A series of Schiff base compounds were designed, synthesized and evaluated as potential inhibitors of β-ketoacyl-acyl carrier protein (ACP) synthase III (FabH). Among 21 compounds, compound 10 showed the most potent antibacterial activity (MIC=1.56–3.13 μg mL−1) and exhibited the most potent E. coli FabH inhibitory activity (IC50=1.6 μM). Docking simulation determined the probable binding conformation.

    6. Novel Type II Fatty Acid Biosynthesis (FAS II) Inhibitors as Multistage Antimalarial Agents (pages 442–461)

      Dr. Florian C. Schrader, Dr. Serghei Glinca, Dr. Julia M. Sattler, Dr. Hans-Martin Dahse, Gustavo A. Afanador, Prof. Dr. Sean T. Prigge, Prof. Dr. Michael Lanzer, Dr. Ann-Kristin Mueller, Prof. Dr. Gerhard Klebe and Prof. Dr. Martin Schlitzer

      Version of Record online: 22 JAN 2013 | DOI: 10.1002/cmdc.201200407

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      Through virtual screening and molecular modeling, two structurally novel inhibitors of type II fatty acid biosynthesis (FAS II) were identified that are effective against both pre-erythrocytic (liver stage) and blood-stage malaria parasites. These most promising derivatives were found to inhibit multiple stages of Plasmodium more potently than the gold standard primaquine.

    7. Design, Synthesis, in vitro MAO-B Inhibitory Evaluation, and Computational Studies of Some 6-Nitrobenzothiazole-Derived Semicarbazones (pages 462–474)

      Rati K. P. Tripathi, Omprakash Goshain and Senthil Raja Ayyannan

      Version of Record online: 16 JAN 2013 | DOI: 10.1002/cmdc.201200484

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      New binding site model: A series of 6-nitrobenzothiazole-deived semicarbazones were designed, synthesized, and evaluated in vitro as MAO-B inhibitors. Compound 28 (shown) emerged as the lead compound, with excellent MAO-B inhibitory profiles in both experimental (IC50: 0.004±0.001 μM) and computational (Ki: 1.08 μM) studies. A comprehensive three-site pharmacophore model is proposed which can be used for the design of newer MAO-B inhibitors.

    8. Computational Studies Identifying Entry Inhibitor Scaffolds Targeting the Phe 43 Cavity of HIV-1 gp120 (pages 475–483)

      Cristina Tintori, Manikandan Selvaraj, Dr. Roger Badia, Dr. Bonaventura Clotet, Dr. José A. Esté and Prof. Maurizio Botta

      Version of Record online: 12 FEB 2013 | DOI: 10.1002/cmdc.201200584

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      Antiviral identification: Using a virtual screening protocol, ∼250 000 commercially available compounds were theoretically evaluated for potential anti-HIV activity through disruption of the gp120–CD4 interface. Twenty hits were subsequently evaluated in vitro, identifying four novel chemical scaffolds with EC50 values ranging between 25–0.9 μM against wild-type (NL4-3) HIV-1-infected MT-4 cells. Phe 43 cavity of gp120 was confirmed as the target by a mutation experiment, being the Met 475 Ile mutant strain resistant to these agents.

    9. A Combination Strategy to Inhibit Pim-1: Synergism between Noncompetitive and ATP-Competitive Inhibitors (pages 484–496)

      Dr. Mattia Mori, Dr. Cristina Tintori, Dr. Robert Selwyne Arul Christopher, Dr. Marco Radi, Prof. Silvia Schenone, Dr. Francesca Musumeci, Dr. Chiara Brullo, Dr. Patrizia Sanità, Dr. Simona Delle Monache, Dr. Adriano Angelucci, Miroslava Kissova, Dr. Emmanuele Crespan, Dr. Giovanni Maga and Prof. Maurizio Botta

      Version of Record online: 22 FEB 2013 | DOI: 10.1002/cmdc.201200480

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      Synergism in inhibition: Through structure–activity relationship studies of known derivatives and a virtual screening campaign to identify novel compounds, ATP-competitive and noncompetitive Pim-1 inhibitors have been identified. These two classes of inhibitor exhibit a synergistic effect when tested in combination in enzymatic and cell-based assays. As such, these hits represent interesting leads for further development as anticancer agents.

    10. Optimization of Marine Triterpene Sipholenols as Inhibitors of Breast Cancer Migration and Invasion (pages 497–510)

      Ahmed I. Foudah, Dr. Sandeep Jain, Belnaser A. Busnena and Dr. Khalid A. El Sayed

      Version of Record online: 12 FEB 2013 | DOI: 10.1002/cmdc.201200516

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      Sipholenol A, a sipholane triterpene from Callyspongia siphonella, and its analogues are shown to have antimigratory activity in metastatic human breast cancer cells, while exhibiting no cytotoxicity towards normal epithelial cells. Evaluation of 19,20-anhydrosipholenol A 4β-benzoate ester against 451 human protein kinases identified protein tyrosine kinase 6 as a potential target. Sipholane triterpenoids represent novel antimigratory marine natural products with potential for development against metastatic malignancies.

    11. Structure–Activity Relationships of Glucosamine-Derived Glycerolipids: the Role of the Anomeric Linkage, the Cationic Charge and the Glycero Moiety on the Antitumor Activity (pages 511–520)

      Dr. Yaozu Xu, Makanjuola Ogunsina, Dr. Pranati Samadder, Prof. Gilbert Arthur and Prof. Frank Schweizer

      Version of Record online: 15 JAN 2013 | DOI: 10.1002/cmdc.201200489

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      GAELs under the microscope: A systematic structure–activity study of the effects of the anomeric linkage, the cationic charge and the glycero moiety on the antitumor activity of 1-O-hexadecyl-2-O-methyl-3-O-(2′-amino-2′-deoxy-β-D-glucopyranosyl)-sn-glycerol and its analogues revealed that the O-glycosidic linkage and the amino group are both critical to potency. The mechanism of action of this class of compounds was confirmed to be apoptosis-independent.

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      A “Clickable” MTX Reagent as a Practical Tool for Profiling Small-Molecule–Intracellular Target Interactions via MASPIT (pages 521–526)

      Dr. Martijn D. P. Risseeuw, Dries J. H. De Clercq, Dr. Sam Lievens, Dr. Ulrik Hillaert, Dr. Davy Sinnaeve, Freya Van den Broeck, Prof. Dr. José C. Martins, Prof. Dr. Jan Tavernier and Prof. Dr. Serge Van Calenbergh

      Version of Record online: 22 JAN 2013 | DOI: 10.1002/cmdc.201200493

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      The future of fusion: A versatile MTX reagent allowed rapid γ-selective conjugation to yield fusion compounds appropriate for MASPIT, a three-hybrid system enabling the identification of mammalian cytosolic proteins that interact with small molecules of interest. Examination of MTX fusion compounds of three structurally diverse molecules in MASPIT demonstrates the versatility of this approach to uncover new intracellular targets.

  7. Book Reviews

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireviews
    7. Full Papers
    8. Book Reviews
    1. Applications of Transition Metal Catalysis in Drug Discovery and Development. Edited by Matthew L. Crawley and Barry M. Trost (pages 527–528)

      Dr. Vittorio Farina

      Version of Record online: 6 DEC 2012 | DOI: 10.1002/cmdc.201200537

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      Wiley, Hoboken 2012. 376 pp., hardcover, €80.40.—ISBN 978-0-470-63132-4

    2. Anti-Inflammatory Drug Discovery. Edited by Jeremy I. Levin and Stefan Laufer (pages 528–529)

      Prof. Stefan Jaroch

      Version of Record online: 28 DEC 2012 | DOI: 10.1002/cmdc.201200569

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      RSC Publishing, Cambridge 2012. 432 pp., hardcover, £159.99.—ISBN 978-1-84973-534-6

    3. Targets and Emerging Therapies for Schizophrenia. Edited by Jeffrey S. Albert and Michael W. Wood (page 529)

      Prof. Simon Ward

      Version of Record online: 16 JAN 2013 | DOI: 10.1002/cmdc.201200589

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      Wiley, Hoboken 2012. 494 pp., hardcover, $175.00.—ISBN 978-0-470-32282-6

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