ChemMedChem

Cover image for Vol. 7 Issue 12

December 2012

Volume 7, Issue 12

Pages 2045–2242

  1. Cover Pictures

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Conference Report
    10. Book Review
    1. You have free access to this content
      Cover Picture: A DNA Methyltransferase Modulator Inspired by Peyssonenyne Natural Product Structures (ChemMedChem 12/2012) (page 2045)

      Dr. Patricia García-Domínguez, Mélanie Weiss, Ilaria Lepore, Prof. Dr. Rosana Álvarez, Prof. Dr. Lucia Altucci, Prof. Dr. Hinrich Gronemeyer and Prof. Dr. Ángel R. de Lera

      Article first published online: 26 NOV 2012 | DOI: 10.1002/cmdc.201290059

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      The front cover picture shows a knight that represents a derivative of the natural product peyssonenyne, a novel DNA methyl transferase (DNMT) epigenetic modulator, armed with a reactive diynone weapon. This chemical warrior was found to be toxic to normal human fibroblasts (BJ, left maze) and mouse embryo fibroblasts (MEF), but not to immortalized human fibroblasts (BJEL, right maze), a unique effect not observed with the classical DNMT inhibitor azacytidine. Based on this toxicity for normal cells, short-term or local application of this epigenetic modulator holds potential for therapy of diseases based on hyperproliferation of fibroblasts or other (pathological) scarring diseases. For more details, see the Full Paper by Lucia Altucci, Hinrich Gronemeyer, Ángel R. de Lera et al. on p. 2101 ff.. Illustration created by Alex Pelayo.

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      Inside Cover: Directed Modulation of Protein Kinase C Isozyme Selectivity with Bisubstrate-Based Inhibitors (ChemMedChem 12/2012) (page 2046)

      Loek T. M. van Wandelen, Dr. Jeroen van Ameijde, Ahmed S. A. Mady, Angelique E. M. Wammes, Alois Bode, Dr. Alex J. Poot, Dr. Rob Ruijtenbeek and Prof. Dr. Rob M. J. Liskamp

      Article first published online: 26 NOV 2012 | DOI: 10.1002/cmdc.201290060

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      The inside cover picture shows real-time peptide microarrays being used to discover selective peptides that are connected to a set of ATP analogues yielding bisubstrate-based inhibitors displaying tuneable selectivity amongst protein kinase C isozymes. For more details, see the Full Paper by Rob M. J. Liskamp et al. on p. 2113 ff.

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      Back Cover: Two-Photon Fluorescent Imaging of Myelination in the Spinal Cord (ChemMedChem 12/2012) (page 2248)

      Allison G. Condie, Prof. Stanton L. Gerson, Prof. Robert H. Miller and Prof. Yanming Wang

      Article first published online: 26 NOV 2012 | DOI: 10.1002/cmdc.201290063

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      The back cover picture shows 4-((E)-4-((E)-4-aminostyryl)-2,5-dimethoxystyryl)-N-methylaniline, a fluorescent imaging probe, termed CIC, that selectively binds to the myelin sheath that encases axons. In vivo imaging of the spinal cord in mouse models provides insight into multiple sclerosis and other demyelinating human diseases. For more details, see the Full Paper by Yanming Wang et al. on p. 2194 ff.

  2. Graphical Abstract

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Conference Report
    10. Book Review
    1. You have free access to this content
      Graphical Abstract: ChemMedChem 12/2012 (pages 2047–2054)

      Article first published online: 26 NOV 2012 | DOI: 10.1002/cmdc.201290061

  3. Corrigendum

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Conference Report
    10. Book Review
    1. You have free access to this content
      Corrigendum: Designing Multitarget Anti-inflammatory Agents: Chemical Modulation of the Lumiracoxib Structure toward Dual Thromboxane Antagonists–COX-2 Inhibitors (page 2054)

      Prof. Dr. Massimo Bertinaria, Dr. Mohammed Abrar Abdul Gaffar Shaikh, Dr. Carola Buccellati, Prof. Dr. Clara Cena, Dr. Barbara Rolando, Dr. Loretta Lazzarato, Prof. Roberta Fruttero, Prof. Alberto Gasco, Dr. Malvina Hoxha, Dr. Valérie Capra, Prof. Dr. Angelo Sala and Prof. Dr. G. Enrico Rovati

      Article first published online: 26 NOV 2012 | DOI: 10.1002/cmdc.201200509

  4. News

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Conference Report
    10. Book Review
  5. Minireview

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Conference Report
    10. Book Review
    1. Recent Advances in the Research of Heterocyclic Compounds as Antitubercular Agents (pages 2063–2075)

      Mi Yan and Prof. Shutao Ma

      Article first published online: 5 OCT 2012 | DOI: 10.1002/cmdc.201200339

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      Irresistible molecules: Tuberculosis remains a major global health problem, and so there is an urgent need to find novel antitubercular agents with enhanced activity and improved properties. This review highlights recent advances in the field of heterocyclic compounds as antitubercular agents, paying particular attention to their activity, mechanisms of action, toxicity, and structure–activity relationships.

  6. Communications

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Conference Report
    10. Book Review
    1. Discovery of Depsides and Depsidones from Lichen as Potent Inhibitors of Microsomal Prostaglandin E2 Synthase-1 Using Pharmacophore Models (pages 2077–2081)

      Julia Bauer, Dr. Birgit Waltenberger, Stefan M. Noha, Dr. Daniela Schuster, Prof. Dr. Judith M. Rollinger, Prof. Dr. Joel Boustie, Dr. Marylene Chollet, Prof. Dr. Hermann Stuppner and Prof. Dr. Oliver Werz

      Article first published online: 25 OCT 2012 | DOI: 10.1002/cmdc.201200345

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      Nature in silico: Virtual screening using validated pharmacophore models identified lichen depsides and depsidones as potential inhibitors of mPGES-1, an emerging target for NSAIDs. Evaluation of the virtual hits in a cell-free assay revealed physodic acid and perlatolic acid as potent inhibitors of mPGES-1 (IC50 = 0.4 and 0.43 μM, respectively), indicating that these natural products have potential as novel anti-inflammatory agents.

    2. Kinetic Template-Guided Tethering of Fragments (pages 2082–2086)

      Rebecca H. Nonoo, Prof. Alan Armstrong and Dr. David J. Mann

      Article first published online: 2 OCT 2012 | DOI: 10.1002/cmdc.201200404

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      Birds of a tether: A tethering strategy for the site-directed discovery of low-molecular-weight fragments that bind weakly to defined protein surfaces is described. A solvent-exposed protein thiol captures acrylamide-modified fragments in a conjugate addition reaction that requires a template to produce a measureable quantity of protein–fragment adduct, which can be rapidly identified by mass spectrometry.

    3. Lead Optimization of Thiazolo[5,4-c]piperidines: 3-Cyclobutoxy Linker as a Key Spacer for H3R Inverse Agonists (pages 2087–2092)

      Dr. Laurent Provins, Dr. Frédéric Denonne, Dr. Sylvain Célanire, Dr. Bernard Christophe, Sabine Defays, Christel Delaunoy, Dr. Marie-Laure Delporte, Thierry Demaude, Véronique Durieu, Dr. Michel Gillard, Delphine Hubert, Dr. Yves Lamberty, Dr. Geneviève Lorent, Dr. Anne Valade, Alain Vanbellinghen and Nathalie Van houtvin

      Article first published online: 5 OCT 2012 | DOI: 10.1002/cmdc.201200406

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      The simpler, the better: H3 histamine receptor (H3R) are of interest as therapeutic targets in cognitive and somnolence disorders. Here, lead optimization of H3R inverse agonists bearing a thiazolo[5,4-c]piperidine group gave rise to a clinical candidate with a much simpler unprecedented benzamide scaffold, displaying decreased hERG activity while maintaining high brain receptor occupancies.

  7. Full Papers

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Conference Report
    10. Book Review
    1. Structural Exploration of (3S,6S)-6-Benzhydryl-N-benzyltetrahydro-2H-pyran-3-amine Analogues: Identification of Potent Triple Monoamine Reuptake Inhibitors as Potential Antidepressants (pages 2093–2100)

      Dr. Soumava Santra, Dr. Sanjib Gogoi, Dr. Bhaskar Gopishetty, Tamara Antonio, Dr. Juan Zhen, Prof. Dr. Maarten E. A. Reith and Prof. Dr. Aloke K. Dutta

      Article first published online: 11 OCT 2012 | DOI: 10.1002/cmdc.201200352

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      Three in one! Asymmetric pyran-based compounds (2 g, 23 d, 31 a) show triple uptake inhibitor-like profiles. Compound 2 g exhibits a balanced potency at all three neurotransmitter reuptake transporters DAT, SERT, and NET. Compound 23 d shows the highest potency at SERT, whereas 31 a has the highest potency at NET. From in vivo forced swim tests with rats, 2 g effected a significant decrease in immobility relative to vehicle, indicating potential antidepressant properties.

    2. A DNA Methyltransferase Modulator Inspired by Peyssonenyne Natural Product Structures (pages 2101–2112)

      Dr. Patricia García-Domínguez, Mélanie Weiss, Ilaria Lepore, Prof. Dr. Rosana Álvarez, Prof. Dr. Lucia Altucci, Prof. Dr. Hinrich Gronemeyer and Prof. Dr. Ángel R. de Lera

      Article first published online: 9 OCT 2012 | DOI: 10.1002/cmdc.201200366

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      Everything in moderation: We characterized a new epigenetic modulator that incorporates the putative reactive functional group of the natural product peyssonenyne. This compound displays a profile of DNMT1 inhibition and DNMT3A activation. It is toxic to normal human fibroblasts (BJ) and mouse embryo fibroblasts (MEF), but not to immortalized human fibroblasts (BJEL), a unique effect not observed with the classical DNMT inhibitor azacytidine.

    3. Directed Modulation of Protein Kinase C Isozyme Selectivity with Bisubstrate-Based Inhibitors (pages 2113–2121)

      Loek T. M. van Wandelen, Dr. Jeroen van Ameijde, Ahmed S. A. Mady, Angelique E. M. Wammes, Alois Bode, Dr. Alex J. Poot, Dr. Rob Ruijtenbeek and Prof. Dr. Rob M. J. Liskamp

      Article first published online: 8 NOV 2012 | DOI: 10.1002/cmdc.201200349

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      More than the sum of its parts: A modular approach to tuning the selectivity of bisubstrate-based inhibitors towards highly homologous protein kinase C isozymes is explored. By systematically varying the ATP-competitive and pseudosubstrate peptide components, selectivity could be effectively modulated.

    4. Synthesis and Biological Evaluation of N-Substituted Noscapine Analogues (pages 2122–2133)

      Aaron J. DeBono, Jin Han Xie, Dr. Sabatino Ventura, Prof. Colin W. Pouton, Dr. Ben Capuano and Prof. Peter J. Scammells

      Article first published online: 10 OCT 2012 | DOI: 10.1002/cmdc.201200365

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      Problem cells under arrest: The synthesis and biological evaluation of a number of N-nornoscapine derivatives is described. More specifically, N-alkyl, N-acyl, N-carbamoyl, N-thiocarbamoyl, and N-carbamate cyclic ether analogues were prepared, and their effect on cell-cycle arrest was assessed in three cell lines. The cytotoxicity of the most active compounds was assessed in prostate cancer (PC3) cells.

    5. Camptothecin-7-yl-methanthiole: Semisynthesis and Biological Evaluation (pages 2134–2143)

      Dr. Michael S. Christodoulou, Dr. Franco Zunino, Dr. Valentina Zuco, Dr. Stella Borrelli, Dr. Daniela Comi, Dr. Gabriele Fontana, Dr. Marisa Martinelli, Prof. Dr. James B. Lorens, Dr. Lasse Evensen, Prof. Dr. Maurizio Sironi, Dr. Stefano Pieraccini, Prof. Dr. Lisa Dalla Via, Prof. Dr. Ornella Maria Gia and Prof. Dr. Daniele Passarella

      Article first published online: 19 OCT 2012 | DOI: 10.1002/cmdc.201200322

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      Substitution prevails! The introduction of a methylenthiol group at position 7 of camptothecin (CPT) was carried out in four steps, along with the corresponding disulfide prodrug. Antiproliferation assays, mechanism of action studies, and molecular modeling analysis indicate that these 7-modified CPT derivatives maintain the biological activity and drug–target interaction characteristics of the parent compound.

    6. Aromatic Core Extension in the Series of N-Cyclic Bay-Substituted Perylene G-Quadruplex Ligands: Increased Telomere Damage, Antitumor Activity, and Strong Selectivity for Neoplastic over Healthy Cells (pages 2144–2154)

      Dr. Marco Franceschin, Dr. Angela Rizzo, Dr. Valentina Casagrande, Dr. Erica Salvati, Dr. Antonello Alvino, Dr. Alessandro Altieri, Dr. Alina Ciammaichella, Dr. Sara Iachettini, Dr. Carlo Leonetti, Prof. Giancarlo Ortaggi, Dr. Manuela Porru, Prof. Armandodoriano Bianco and Dr. Annamaria Biroccio

      Article first published online: 24 OCT 2012 | DOI: 10.1002/cmdc.201200348

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      Selective damage control: G-quadruplex ligands are thought to play a role in key biological processes including telomere maintenance. A “chimera” molecule, EMICORON (3), was designed as a new promising G-quadruplex ligand with potent antitumor activity, typical of the hydrosoluble coronene derivatives (2), and an intriguing selectivity toward tumor cells, characteristic of the perylene derivatives (1).

    7. Stable Synthetic Bacteriochlorins for Photodynamic Therapy: Role of Dicyano Peripheral Groups, Central Metal Substitution (2H, Zn, Pd), and Cremophor EL Delivery (pages 2155–2167)

      Dr. Ying-Ying Huang, Dr. Thiagarajan Balasubramanian, Dr. Eunkyung Yang, Dr. Dianzhong Luo, Dr. James R. Diers, Prof. David F. Bocian, Prof. Jonathan S. Lindsey, Prof. Dewey Holten and Dr. Michael R. Hamblin

      Article first published online: 12 OCT 2012 | DOI: 10.1002/cmdc.201200351

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      Metalation & Encapsulation: The photostability of bacteriochlorins was improved by including peripheral dicyano groups. Palladium chelation was found to increase hydroxyl radical generation and phototoxicity, while zinc chelation increased singlet oxygen generation but decreased phototoxicity. Finally, micellar delivery improved intracellular localization in mitochondria and increased phototoxicity. Taken together, these findings lead to increasingly promising bacteriochlorin-derived PDT agents.

    8. Receptor-Based Virtual Screening and Biological Characterization of Human Apurinic/Apyrimidinic Endonuclease (Ape1) Inhibitors (pages 2168–2178)

      Dr. Federico M. Ruiz, Sandrea M. Francis, Maria Tintoré, Rubén Ferreira, Dr. Rubén Gil-Redondo, Dr. Antonio Morreale, Prof. Ángel R. Ortiz, Prof. Ramon Eritja and Dr. Carmen Fàbrega

      Article first published online: 25 OCT 2012 | DOI: 10.1002/cmdc.201200372

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      Rational design: Six compounds were identified as potential human apurinic/apyrimidinic endonuclease inhibitors by the use of docking-based virtual screening. The compounds show in vitro inhibitory activity in the low-to-medium micromolar range and also potentiate the cytotoxicity of methyl methanesulfonate in fibrosarcoma cells. This study opens the door to the development of a new generation of Ape1 inhibitors.

    9. Effect of Oxime Ether Incorporation in Acyl Indole Derivatives on PPAR Subtype Selectivity (pages 2179–2193)

      Dr. Morgan Le Naour, Dr. Veronique Leclerc, Dr. Amaury Farce, Dr. Daniel-Henri Caignard, Dr. Nathalie Hennuyer, Prof. Bart Staels, Dr. Valérie Audinot-Bouchez, Dr. Jean-Albert Boutin, Dr. Michel Lonchampt, Dr. Catherine Dacquet, Prof. Alain Ktorza, Prof. Pascal Berthelot and Dr. Nicolas Lebegue

      Article first published online: 9 OCT 2012 | DOI: 10.1002/cmdc.201200316

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      A balanced ratio: Incorporation of oxime ethers in a novel series of α-ethoxyphenylpropionic acid bearing substituted indoles is reported. This brought the PPARα/γ selectivity ratio equal to or slightly greater than one. The synthesized compounds were characterized by determining their binding affinity for PPARγ, their functional activity at PPARα/γ, and their capacity to lower glucose, triglyceride, and insulin levels as well as body weight in an ob/ob mouse model.

    10. Two-Photon Fluorescent Imaging of Myelination in the Spinal Cord (pages 2194–2203)

      Allison G. Condie, Prof. Stanton L. Gerson, Prof. Robert H. Miller and Prof. Yanming Wang

      Article first published online: 7 NOV 2012 | DOI: 10.1002/cmdc.201200343

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      An illuminating Case: Myelin imaging compound CIC (shown) was synthesized via an improved route and evaluated for its ability to visualize myelin in the spinal cords of mice. In vivo imaging was conducted using two-photon fluorescence microscopy. CIC could distinguish myelin content between healthy and pathological mouse models, indicating its potential as a useful probe in multiple sclerosis drug discovery.

    11. Interactions between Artemisinins and other Antimalarial Drugs in Relation to the Cofactor Model—A Unifying Proposal for Drug Action (pages 2204–2226)

      Prof. Dr. Richard K. Haynes, Kwan-Wing Cheu, Dr. Ho-Wai Chan, Dr. Ho-Ning Wong, Ka-Yan Li, Maggie Mei-Ki Tang, Min-Jiao Chen, Dr. Zu-Feng Guo, Prof. Dr. Zhi-Hong Guo, Prof. Dr. Kumar Sinniah, Amanda B. Witte, Dr. Paolo Coghi and Prof. Dr. Diego Monti

      Article first published online: 30 OCT 2012 | DOI: 10.1002/cmdc.201200383

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      Defense mechanism: The antagonism exerted by 4-aminoquinolines (e.g. piperaquine) and the additivity/synergism exerted by arylmethanols (e.g. quinine) on the antimalarial activities of MB, riboflavin, and artemisinins correlates with the inhibition of oxidation by artemisinins of LMB, reduced flavins by the quinolines, and lack of any effect on the oxidation by arylmethanols; it further allows proposal for a unifying mechanism of action.

    12. Identification of Small Molecules that Interfere with H1N1 Influenza A Viral Replication (pages 2227–2235)

      Angel Bottini, Dr. Surya K. De, Dr. Bas J. G. Baaten, Dr. Bainan Wu, Dr. Elisa Barile, Stephen Soonthornvacharin, Dr. John L. Stebbins, Prof. Linda M. Bradley, Prof. Sumit K. Chanda and Prof. Maurizio Pellecchia

      Article first published online: 8 NOV 2012 | DOI: 10.1002/cmdc.201200453

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      Flu fighters: A series of quinolinone-containing small molecules that inhibit influenza replication were identified in a fluorescence-based cellular assay. Herein we report the synthesis, characterization, and preliminary SAR studies of the most potent hit, compound 7, which demonstrated the capacity to rescue high-dose influenza infection in an animal model.

  8. Conference Report

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Conference Report
    10. Book Review
    1. Alpine Drug Discovery Summit: 10th Swiss Course on Medicinal Chemistry (pages 2237–2240)

      Dr. Gerhard Müller and Prof. Dr. Beat Ernst

      Article first published online: 23 NOV 2012 | DOI: 10.1002/cmdc.201200501

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      Alpine fresh! Aimed at instructing young scientists at the beginning of their careers in industry, this medicinal chemistry course provides an overview of the state of the art techniques and current approaches to drug discovery and development.

  9. Book Review

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Conference Report
    10. Book Review
    1. Protein and Peptide Mass Spectrometry in Drug Discovery. Edited by Michael L. Gross, Guodong Chen and Birendra N. Pramanik (pages 2241–2242)

      Dr. Peter R. Jungblut

      Article first published online: 23 OCT 2012 | DOI: 10.1002/cmdc.201200441

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      Wiley, Hoboken 2011. 492 pp., hardcover, $ 135.00.—ISBN 978-0-470-25817-0

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