ChemMedChem

Cover image for Vol. 4 Issue 2

February 13, 2009

Volume 4, Issue 2

Pages 133–295

  1. Cover Picture

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. Corrigendum
    6. News
    7. Review
    8. Concepts
    9. Communication
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. Cover Picture: Structure–Activity Relationship Analysis of the Peptide Deformylase Inhibitor 5-Bromo-1H-indole-3-acetohydroxamic Acid (ChemMedChem 2/2009) (page 133)

      Sylvain Petit, Yann Duroc, Valéry Larue, Carmela Giglione, Carole Léon, Coralie Soulama, Alexis Denis, Frédéric Dardel, Thierry Meinnel and Isabelle Artaud

      Article first published online: 5 FEB 2009 | DOI: 10.1002/cmdc.200990004

      Thumbnail image of graphical abstract

      The cover picture shows a “reverse” indole derivative in complex with Bacillus stearothermophilus peptide deformylase (PDF). This compound was selected from a structure–activity relationship study as a potent inhibitor of bacterial PDFs and shows antibacterial activity toward Bacillus subtilis as well as other pathogens such as Streptococcus pneumoniae and Staphylococcus aureus. For more details, see the Full Paper by I. Artaud et al. on p. 261 ff.

  2. Inside Cover

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. Corrigendum
    6. News
    7. Review
    8. Concepts
    9. Communication
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. Inside Cover: Tritium-Labeled N1-[3-(1H-imidazol-4-yl)propyl]-N2-propionylguanidine ([3H]UR-PI294), a High-Affinity Histamine H3 and H4 Receptor Radioligand / NG-Acylated Aminothiazolylpropylguanidines as Potent and Selective Histamine H2 Receptor Agonists (ChemMedChem 2/2009) (page 134)

      Patrick Igel, David Schnell, Günther Bernhardt, Roland Seifert, Armin Buschauer, Anja Kraus, Prasanta Ghorai, Tobias Birnkammer, Sigurd Elz and Stefan Dove

      Article first published online: 5 FEB 2009 | DOI: 10.1002/cmdc.200990005

      Thumbnail image of graphical abstract

      The inside cover picture shows the human histamine H2 receptor and the H2 and H3/H4 receptor-selective ligands identified. Bioisosteric replacement of the imidazole ring of the NG-acyl-imidazolylpropylguanidine with 2-aminothiazole yielded potent and selective H2 receptor agonists. In contrast, modification of the acyl group gave a high-affinity H3/H4-selective tritiated radioligand. For more details, see the Full Papers by A. Buschauer et al. on p. 225 ff and p. 232 ff.

  3. Graphical Abstract

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. Corrigendum
    6. News
    7. Review
    8. Concepts
    9. Communication
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. You have free access to this content
      Graphical Abstract: ChemMedChem 2/2009 (pages 135–141)

      Article first published online: 5 FEB 2009 | DOI: 10.1002/cmdc.200990006

  4. Corrigendum

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. Corrigendum
    6. News
    7. Review
    8. Concepts
    9. Communication
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. You have free access to this content
      Inhibition of hERG Channel Trafficking: An Under-Explored Mechanism for Drug-Induced QT Prolongation (page 141)

      Kap-Sun Yeung and Nicholas A. Meanwell

      Article first published online: 5 FEB 2009 | DOI: 10.1002/cmdc.200990007

      This article corrects:

      Inhibition of hERG Channel Trafficking: An Under-Explored Mechanism for Drug-Induced QT Prolongation

      Vol. 3, Issue 10, 1501–1502, Article first published online: 11 AUG 2008

  5. News

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. Corrigendum
    6. News
    7. Review
    8. Concepts
    9. Communication
    10. Full Papers
    11. Book Reviews
    12. Preview
  6. Review

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. Corrigendum
    6. News
    7. Review
    8. Concepts
    9. Communication
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. Peptides and Peptide Mimics as Modulators of Apoptotic Pathways (pages 146–160)

      Mar Orzáez, Anna Gortat, Laura Mondragón and Enrique Pérez-Payá

      Article first published online: 19 NOV 2008 | DOI: 10.1002/cmdc.200800246

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      Cells in the balance: Programmed cell death is an important and stringently controlled process. Aberrancies in its control mechanisms can lead to disease; overactive apoptosis can cause neurodegenerative disorders, whereas deficient apoptotic activity can lead to cancer. Therefore, controlling apoptotic pathways with peptides is showing increasing promise as a strategy in drug development.

  7. Concepts

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. Corrigendum
    6. News
    7. Review
    8. Concepts
    9. Communication
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. Toward Docking-Based Virtual Screening for Discovering Antitubulin Agents by Targeting Taxane and Colchicine Binding Sites (pages 161–163)

      Laurent Soulère

      Article first published online: 15 DEC 2008 | DOI: 10.1002/cmdc.200800319

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      Docking-based virtual screening: Flexible docking, scoring, and virtual screening of ligand databases are on the way to fulfilling the promise. Docking-based virtual screening that targets taxane and colchicine binding sites will certainly provide new antitubulin agents.

    2. Functional Proteomics on Zinc-Dependent Metalloproteinases using Inhibitor Probes (pages 164–170)

      Theo Klein, Paul P. Geurink, Hermen S. Overkleeft, Henk K. Kauffman and Rainer Bischoff

      Article first published online: 12 DEC 2008 | DOI: 10.1002/cmdc.200800284

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      Zinc-dependent metalloproteinases such as matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs) are potential therapeutic targets in many diseases. To better understand their complex role in health and disease, new methodology for activity determination is under development. This concept gives an overview of the available methods for activity-based proteomic research on these enzymes.

  8. Communication

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. Corrigendum
    6. News
    7. Review
    8. Concepts
    9. Communication
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. Nonglycosidic Agonists of Invariant NKT Cells for Use as Vaccine Adjuvants (pages 171–175)

      B. Gopal Reddy, Jonathan D. Silk, Mariolina Salio, Rengarajan Balamurugan, Dawn Shepherd, Gerd Ritter, Vincenzo Cerundolo and Richard R. Schmidt

      Article first published online: 21 JAN 2009 | DOI: 10.1002/cmdc.200800354

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      Based on the crystal structures of human α-GalCer–CD1d and iNKT–α-GalCer–CD1d complexes, nonglycosidic analogues of α-GalCer were synthesized. They activate iNKT cells resulting in dendritic cell maturation and the priming of antigen-specific T and B cells. Therefore, they are attractive adjuvants in vaccination strategies for cancer and infectious diseases.

  9. Full Papers

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. Corrigendum
    6. News
    7. Review
    8. Concepts
    9. Communication
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. Cytotoxic Rhodium(III) and Iridium(III) Polypyridyl Complexes: Structure–Activity Relationships, Antileukemic Activity, and Apoptosis Induction (pages 177–187)

      Mara Dobroschke, Yvonne Geldmacher, Ingo Ott, Melanie Harlos, Lisa Kater, Laura Wagner, Ronald Gust, William S. Sheldrick and Aram Prokop

      Article first published online: 19 DEC 2008 | DOI: 10.1002/cmdc.200800311

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      Whereas the cytostatic agentsmer-[RhX3(DMSO)(pp)] (X=Cl, Br; pp=phen, dpq) are considerably more potent than their facial isomers, this order is reversed for the analogous kinetically more inert IrIII polypyridyl complexes. The complexes induce specific apoptotic cell death in leukemia and lymphoma cells via the intrinsic mitochondrial pathway and cause negligible necrotic damage.

    2. Multi-Drug-Resistance-Reverting Agents: 2-Aryloxazole and 2-Arylthiazole Derivatives as Potent BCRP or MRP1 Inhibitors (pages 188–195)

      Nicola A. Colabufo, Francesco Berardi, Maria Grazia Perrone, Mariangela Cantore, Marialessandra Contino, Carmela Inglese, Mauro Niso and Roberto Perrone

      Article first published online: 12 JAN 2009 | DOI: 10.1002/cmdc.200800329

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      The 2-aryloxazole and 2-arylthiazole scaffolds were used for generating compounds that we characterized for their inhibitory activity toward ATP binding cassette transporters involved in multi-drug resistance, such as BCRP and MRP1, by using tumor cell lines overexpressing each transporter. These SAR studies are a significant step toward improving the inhibitory potency against P-glycoprotein, BCRP, and MRP1.

    3. (2,2-Diphenyl-[1,3]oxathiolan-5-ylmethyl)-(3-phenyl-propyl)-amine: a Potent and Selective 5-HT1A Receptor Agonist (pages 196–203)

      Silvia Franchini, Annalisa Tait, Adolfo Prandi, Claudia Sorbi, Rossella Gallesi, Michela Buccioni, Gabriella Marucci, Carla De Stefani, Antonio Cilia and Livio Brasili

      Article first published online: 19 DEC 2008 | DOI: 10.1002/cmdc.200800276

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      A selective 5-HT1Areceptor agonist: A new series of ligands acting at 5-HT1A serotonin receptor were identified. Among them (2,2-diphenyl-[1,3]oxathiolan-5-yl-methyl)-(3-phenyl-propyl)amine (shown) possesses outstanding activity (pKi=8.72, pD2=7.67, Emax=85) and selectivity (5-HT1A1D>150), and represents a new 5-HT1A agonist chemotype.

    4. Development and Validation of a Pharmacophore-Based QSAR Model for the Prediction of CNS Activity (pages 204–209)

      Rafael Gozalbes, Frédérique Barbosa, Eric Nicolaï, Dragos Horvath and Nicolas Froloff

      Article first published online: 18 DEC 2008 | DOI: 10.1002/cmdc.200800282

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      A QSAR model for the prediction of CNS activity was developed and validated based on data from an in-house database of “drug-like” compounds. The model has demonstrated its applicability for novel chemical structures and its usefulness for the design of CNS-focused compound libraries.

    5. Similarity-Based Virtual Screening with a Bayesian Inference Network (pages 210–218)

      Ammar Abdo and Naomie Salim

      Article first published online: 12 DEC 2008 | DOI: 10.1002/cmdc.200800290

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      An inference network model for molecular similarity searching: The similarity search problem is modeled using inference or evidential reasoning under uncertainty. The inference network model treats similarity searching as an evidential reasoning process in which multiple sources of evidence about compounds and reference structures are combined to estimate resemblance probabilities.

    6. Structural Modifications of DAPY Analogues with Potent Anti-HIV-1 Activity (pages 219–224)

      Xiao-Qing Feng, Yong-Hong Liang, Zhao-Sen Zeng, Fen-Er Chen, Jan Balzarini, Christophe Pannecouque and Erik De Clercq

      Article first published online: 17 DEC 2008 | DOI: 10.1002/cmdc.200800334

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      A novel series of diarylpyrimidine analogues (DAPYs) featuring a naphthyl moiety at the C4 position were designed, with all compounds exhibiting strong activity against wild-type HIV-1.

    7. Tritium-Labeled N1-[3-(1H-imidazol-4-yl)propyl]-N2-propionylguanidine ([3H]UR-PI294), a High-Affinity Histamine H3 and H4 Receptor Radioligand (pages 225–231)

      Patrick Igel, David Schnell, Günther Bernhardt, Roland Seifert and Armin Buschauer

      Article first published online: 19 DEC 2008 | DOI: 10.1002/cmdc.200800349

      Thumbnail image of graphical abstract

      Histamine mediates its various functions through four histamine receptor subtypes. The H3 subtype is mainly found in the central nervous system, where it modulates the release of histamine and other neurotransmitters, whereas the H4 subtype plays a crucial role in inflammatory and immunological processes. Herein, the synthesis and characterization of a conveniently accessible tritiated radioligand is reported that proved to be a versatile pharmacological probe.

    8. NG-Acylated Aminothiazolylpropylguanidines as Potent and Selective Histamine H2 Receptor Agonists (pages 232–240)

      Anja Kraus, Prasanta Ghorai, Tobias Birnkammer, David Schnell, Sigurd Elz, Roland Seifert, Stefan Dove, Günther Bernhardt and Armin Buschauer

      Article first published online: 15 DEC 2008 | DOI: 10.1002/cmdc.200800296

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      Bioisosteric replacement of the guanidino group in arpromidine-like histamine H2 receptor (H2R) agonists by an acylguanidine moiety is useful for obtaining potent H2R agonists with improved oral bioavailability and blood–brain barrier penetration. We show that bioisosteric replacement of the imidazole ring in NG-acylated imidazolylpropylguanidines by a 2-aminothiazol-5-yl group resulted in potent H2R agonists with much greater selectivity for the human H2R over H3 and H4 receptors.

    9. Triclosan Derivatives: Towards Potent Inhibitors of Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis (pages 241–248)

      Joel S. Freundlich, Feng Wang, Catherine Vilchèze, Gulcin Gulten, Robert Langley, Guy A. Schiehser, David P. Jacobus, William R. Jacobs Jr. and James C. Sacchettini

      Article first published online: 7 JAN 2009 | DOI: 10.1002/cmdc.200800261

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      Overcoming resistance: Isoniazid (INH) is a frontline antitubercular drug that inhibits the enoyl acyl carrier protein reductase InhA. Novel inhibitors of InhA that are not cross-resistant to INH represent a significant goal in antitubercular chemotherapy. The design, synthesis, and biological activity of a series of triclosan-based inhibitors is reported, including their promising efficacy against INH-resistant strains of M. tuberculosis.

    10. Synthesis of Bicyclic N-Arylmethyl-Substituted Iminoribitol Derivatives as Selective Nucleoside Hydrolase Inhibitors (pages 249–260)

      Maya Berg, Gunther Bal, Annelies Goeminne, Pieter Van der Veken, Wim Versées, Jan Steyaert, Achiel Haemers and Koen Augustyns

      Article first published online: 29 DEC 2008 | DOI: 10.1002/cmdc.200800231

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      A series of bicyclicN-arylmethyl-substituted iminoribitols were synthesised and evaluated in vitro against T. vivax nucleoside hydrolase. The importance of the N–Asp40 interaction was confirmed and depends on an optimal pKa value, which can be influenced by substituents. The compounds were active inhibitors of nucleoside hydrolase (IAG-NH) and are inactive against human purine nucleoside phosphorylase.

    11. Structure–Activity Relationship Analysis of the Peptide Deformylase Inhibitor 5-Bromo-1H-indole-3-acetohydroxamic Acid (pages 261–275)

      Sylvain Petit, Yann Duroc, Valéry Larue, Carmela Giglione, Carole Léon, Coralie Soulama, Alexis Denis, Frédéric Dardel, Thierry Meinnel and Isabelle Artaud

      Article first published online: 3 DEC 2008 | DOI: 10.1002/cmdc.200800251

      Thumbnail image of graphical abstract

      SAR by NMR: A series of indole compounds derived from 5-bromo-1H-indole-3-acetohydroxamic acid were synthesized. Their inhibitory activities were evaluated against purified peptide deformylases (PDFs), and their antibacterial activities against B. subtilis, E. coli (wild type and tolC), and a variety of pathogens were also determined. The potency of the best inhibitors was related to the NMR footprints of the respective acids with 15N-labeled E. coli Ni-PDF.

    12. In vitro and in vivo Staining Characteristics of Small, Fluorescent, Aβ42-Binding D-Enantiomeric Peptides in Transgenic AD Mouse Models (pages 276–282)

      Thomas van Groen, Inga Kadish, Katja Wiesehan, Susanne A. Funke and Dieter Willbold

      Article first published online: 15 DEC 2008 | DOI: 10.1002/cmdc.200800289

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      Plaque visualisation: We identified three different D-enantiomeric peptides that bind to Alzheimer's amyloid β (Aβ1-42). As there is currently no definitive pre-mortem diagnosis for Alzheimer's disease, we investigated the peptides' suitability as molecular probes for in vivo imaging in transgenic mouse models.

    13. Pyridylalanine-Containing Hydroxamic Acids as Selective HDAC6 Inhibitors (pages 283–290)

      Stefan Schäfer, Laura Saunders, Sonja Schlimme, Vassil Valkov, Julia M. Wagner, Felix Kratz, Wolfgang Sippl, Eric Verdin and Manfred Jung

      Article first published online: 17 DEC 2008 | DOI: 10.1002/cmdc.200800196

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      Pyridylalanine inhibitors of histone deacetylase (HDAC) have been synthesized that show selectivity for the isoform HDAC6 over HDAC1 in vitro. This selectivity was also identified in cancer cells by analyzing tubulin versus histone acetylation. The compounds show decreased intrinsic cytotoxicity relative to pan-HDAC inhibitors, but show antiproliferative synergy with the proteasome inhibitor bortezomib.

  10. Book Reviews

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. Corrigendum
    6. News
    7. Review
    8. Concepts
    9. Communication
    10. Full Papers
    11. Book Reviews
    12. Preview
  11. Preview

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. Corrigendum
    6. News
    7. Review
    8. Concepts
    9. Communication
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. You have free access to this content
      Preview: ChemMedChem 3/2009 (page 295)

      Article first published online: 5 FEB 2009 | DOI: 10.1002/cmdc.200990009

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