ChemMedChem

Cover image for ChemMedChem

February 2013

Volume 8, Issue 2

Pages 173–339

  1. Cover Pictures

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. You have free access to this content
      Cover Picture: Development and Characterization of New Peptidomimetic Inhibitors of the West Nile Virus NS2B–NS3 Protease (ChemMedChem 2/2013) (page 173)

      M. Zouhir Hammamy, Caroline Haase, Dr. Maya Hammami, Prof. Dr. Rolf Hilgenfeld and Prof. Dr. Torsten Steinmetzer

      Article first published online: 28 JAN 2013 | DOI: 10.1002/cmdc.201390000

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      The front cover picture shows the crystal structure of a new substrate-analogue inhibitor in complex with the West Nile virus (WNV) NS2B-NS3 protease, which has emerged as a potential and specific target for the treatment of WNV infections. Together with other cellular host proteases, it is involved in the processing of the WNV polyprotein, which is a prerequisite for virus propagation. The NS3 domain of the protease (gray) is surrounded and stabilized by the NS2B chain (green). The inset provides a detailed view of the amino acid residues surrounding the inhibitor within the active site of the WNV protease. For more details see the Full Paper by Torsten Steinmetzer et al. on p. 231 ff.

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      Inside Cover: Synthesis and Biological Evaluation of Diaryl-Substituted Carboranes as Inhibitors of Hypoxia Inducible Factor (HIF)-1 Transcriptional Activity (ChemMedChem 2/2013) (page 174)

      Hidemitsu Minegishi, Takuya Matsukawa and Prof. Dr. Hiroyuki Nakamura

      Article first published online: 28 JAN 2013 | DOI: 10.1002/cmdc.201390001

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      The inside cover picture shows diaromatic-substituted icosahedral carborane, a mimic of manassantin A, which induces hypoxia inducible factor (HIF)-1α protein degradation via the proteasome pathway, leading to inhibition of hypoxia-induced HIF-1 transcriptional activity and suppression of angiogenesis necessary for tumor growth. For more details, see the Full Paper by Hiroyuki Nakamura et al. on p. 265 ff.

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      Back Cover: A Combined Bioinformatics and Chemoinformatics Approach for Developing Asymmetric Bivalent AMPA Receptor Positive Allosteric Modulators as Neuroprotective Agents (ChemMedChem 2/2013) (page 344)

      Dr. Haijun Chen, Dr. Cheng Z. Wang, Dr. Chunyong Ding, Christopher Wild, Dr. Bryan Copits, Prof. Geoffrey T. Swanson, Prof. Kenneth M. Johnson and Prof. Jia Zhou

      Article first published online: 28 JAN 2013 | DOI: 10.1002/cmdc.201390004

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      The back cover picture shows the rational design of asymmetric bivalent positive allosteric modulators (PAMs) of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor by using an effective, combined bio- and chemoinformatic approach. These ligands display marked potency in vitro and efficacy in vivo for preventing neuroapoptosis. For more details, see the Communication by Jia Zhou et al. on p. 226 ff.

  2. Graphical Abstract

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Graphical Abstract: ChemMedChem 2/2013 (page 175181)

      Article first published online: 28 JAN 2013 | DOI: 10.1002/cmdc.201390002

  3. News

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Spotlights on our sister journals: ChemMedChem 2/2013 (pages 186–189)

      Article first published online: 28 JAN 2013 | DOI: 10.1002/cmdc.201390003

  4. Review

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Synthetic Strategies for the Biotinylation of Bioactive Small Molecules (pages 190–203)

      Prof. Dr. Paul C. Trippier

      Article first published online: 9 JAN 2013 | DOI: 10.1002/cmdc.201200498

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      Biotinylation in the crosshairs: Methods to synthesize biotinylated derivatives of active small molecules for subsequent use as chemical probes to determine binding partners and biological modes of action are reviewed. Amide bond formation, click chemistry, Staudinger ligation, thioether formation, Diels–Alder reaction, palladium-catalyzed cross-coupling reactions and others are presented.

  5. Minireview

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Heterocycles as Nonclassical Bioisosteres of α-Amino Acids (pages 205–215)

      Christian B. M. Poulie and Prof. Lennart Bunch

      Article first published online: 15 JAN 2013 | DOI: 10.1002/cmdc.201200436

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      The sincerest form of flattery: In drug design, bioisosteres are used to optimize properties such as target selectivity, potency, and pharmacokinetic properties. For α-amino acids, while α-carboxylate can be substituted with carboxylic acid bioisosteres, mimicking of the whole α-amino acid moiety can be accomplished with heterocyclic bioisosteres that often display an acidic functionality, and the different classes are reviewed here.

  6. Communications

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. N-Cyano Sulfoximines: COX Inhibition, Anticancer Activity, Cellular Toxicity, and Mutagenicity (pages 217–220)

      Seong Jun Park, Hannah Baars, Stefanie Mersmann, Dr. Helmut Buschmann, Prof. Dr. Jens Malte Baron, Dr. Philipp M. Amann, Katharina Czaja, Prof. Dr. Henner Hollert, Kerstin Bluhm, Regine Redelstein and Prof. Dr. Carsten Bolm

      Article first published online: 6 DEC 2012 | DOI: 10.1002/cmdc.201200403

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      From insects to cancer: N-Cyano sulfoximines were evaluated for COX inhibition and antiproliferative activity against a panel of cancer cell lines. The most active compound exhibited potent COX-2 inhibition, some selectivity for COX-2 over COX-1, only slight cytotoxicity towards healthy cells (HaCaT skin cells), and no mutagenic potential (as determined by an Ames assay).

    2. Synthesis of a Potent Antimalarial Agent through Natural Products Conjugation (pages 221–225)

      Dr. Michela Bruno, Dr. Beatrice Trucchi, Dr. Diego Monti, Prof. Sergio Romeo, Dr. Marcel Kaiser and Prof. Luisella Verotta

      Article first published online: 10 JAN 2013 | DOI: 10.1002/cmdc.201200503

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      Au naturel! (+)-Usnic acid (green) is a weak antimalarial agent, however, in conjugation with known antimalarial scaffolds and drugs, such as dihydroartemisinin (blue), potent activity against the blood-stage parasite can be seen both in vitro and in vivo. The compound shown exhibits an IC50 value of 1.4 nM against Plasmodium falciparum in vitro and proved nearly as efficacious as artesunate in a mouse model of infection.

    3. A Combined Bioinformatics and Chemoinformatics Approach for Developing Asymmetric Bivalent AMPA Receptor Positive Allosteric Modulators as Neuroprotective Agents (pages 226–230)

      Dr. Haijun Chen, Dr. Cheng Z. Wang, Dr. Chunyong Ding, Christopher Wild, Dr. Bryan Copits, Prof. Geoffrey T. Swanson, Prof. Kenneth M. Johnson and Prof. Jia Zhou

      Article first published online: 20 DEC 2012 | DOI: 10.1002/cmdc.201200554

      Thumbnail image of graphical abstract

      PAMs new in town! An effective, combined bioinformatics and chemoinformatics approach was applied to the design of novel asymmetric bivalent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators (PAMs) with marked potency in vitro and efficacy in vivo for preventing neuroapoptosis. The novel chemotype could provide pharmacological probes and potential therapeutic agents for glutamatergic hypofunction and its related neurological and psychiatric disorders.

  7. Full Papers

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Development and Characterization of New Peptidomimetic Inhibitors of the West Nile Virus NS2B–NS3 Protease (pages 231–241)

      M. Zouhir Hammamy, Caroline Haase, Dr. Maya Hammami, Prof. Dr. Rolf Hilgenfeld and Prof. Dr. Torsten Steinmetzer

      Article first published online: 10 JAN 2013 | DOI: 10.1002/cmdc.201200497

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      Crystal clear: A series of new substrate analogue inhibitors of the WNV NS2B–NS3 protease with an improved selectivity profile was developed, which contain decarboxylated arginine mimetics at the P1 position. For one of the most potent inhibitors, a crystal structure in complex with the WNV protease was determined.

    2. A Chemogenomic Analysis of Ionization Constants—Implications for Drug Discovery (pages 242–255)

      Dr. David T. Manallack, Dr. Richard J. Prankerd, Gemma C. Nassta, Dr. Oleg Ursu, Prof. Tudor I. Oprea and Dr. David K. Chalmers

      Article first published online: 9 JAN 2013 | DOI: 10.1002/cmdc.201200507

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      Road to success: A breakdown of acid/base classes for small-molecule drugs approved for use in humans is shown. The compound classes include always ionized, neutral, single acids, single bases, diacids, dibases, simple ampholytes and complex compounds. Including specific acid/base information in filtering protocols, may improve the success rate of chemogenomic primary screens.

    3. Butyltin(IV) Benzoates: Inhibition of Thioredoxin Reductase, Tumor Cell Growth Inhibition, and Interactions with Proteins (pages 256–264)

      Dr. Kely Navakoski de Oliveira, Vincent Andermark, Susanne von Grafenstein, Liliane A. Onambele, Gregor Dahl, Riccardo Rubbiani, Prof. Dr. Gerhard Wolber, Dr. Chiara Gabbiani, Prof. Dr. Luigi Messori, Prof. Dr. Aram Prokop and Prof. Dr. Ingo Ott

      Article first published online: 23 DEC 2012 | DOI: 10.1002/cmdc.201200505

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      Metal masterpieces: The mode of action of cytotoxic tin organometallics is largely unknown. Virtual screening suggested inhibition of thioredoxin reductase (TrxR) as a contributing factor for organotin biochemistry. Its relevance was confirmed in an interdisciplinary pilot study of a series of tin(IV) complexes with benzoate ligands.

    4. Synthesis and Biological Evaluation of Diaryl-Substituted Carboranes as Inhibitors of Hypoxia Inducible Factor (HIF)-1 Transcriptional Activity (pages 265–271)

      Hidemitsu Minegishi, Takuya Matsukawa and Prof. Dr. Hiroyuki Nakamura

      Article first published online: 23 DEC 2012 | DOI: 10.1002/cmdc.201200502

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      Icosahedral scaffolds: Diaryl-substituted carboranes 1 and 2 were found to suppress hypoxia-induced HIF-1α protein accumulation without affecting the expression levels of HIF-1α mRNA. They also inhibit the translocation of HIF-1α into nuclei, thereby preventing HIF-1 transcriptional activity under hypoxic conditions.

    5. Discovery of Pyridone-Based Histone Deacetylase Inhibitors: Approaches for Metabolic Stability (pages 272–279)

      Misun Cho, Dr. Eunhyun Choi, Dr. Jee Sun Yang, Dr. Chulho Lee, Jeong Jea Seo, Beom Seok Kim, Dr. Soo Jin Oh, Prof. Hwan Mook Kim, Prof. Kiho Lee, Prof. Song-Kyu Park, Prof. Ho Jeong Kwon and Prof. Gyoonhee Han

      Article first published online: 4 JAN 2013 | DOI: 10.1002/cmdc.201200529

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      Conjugation to avoid deacetylation: δ-Lactam- and γ-lactam-based HDAC inhibitors showed potent biological activity in a previous study. However, they were metabolically unstable in the presence of liver microsomes. After adding a conjugation system, newly designed pyridone-based HDAC inhibitors now exhibit more potent biological activity in vitro and improved metabolic stability.

    6. The Discovery of Phenylbenzamide Derivatives as Grb7-Based Antitumor Agents (pages 280–288)

      Dr. Nigus D. Ambaye, Dr. Menachem J. Gunzburg, Dr. Reece C. C. Lim, Dr. John T. Price, Prof. Matthew C. J. Wilce and Prof. Jacqueline A. Wilce

      Article first published online: 17 DEC 2012 | DOI: 10.1002/cmdc.201200400

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      Stopping tumor progression: Virtual screening involving a shape-based similarity search, molecular docking, and 2D-similarity searches complemented by experimental binding studies resulted in the discovery of phenylbenzamide ligands that are able to interact with the Grb7 SH2 domain and inhibit the growth of MDA-MB-468 cancer cells. The NSC 104999 lead is shown along with its predicted binding mode at the surface of Grb7.

    7. Hydrosoluble Benzo[e]pyridoindolones as Potent Inhibitors of Aurora Kinases (pages 289–296)

      Ly-Thuy-Tram Le, Dr. Hong-Lien Vu, Delphine Naud-Martin, Marianne Bombled, Dr. Chi-Hung Nguyen and Dr. Annie Molla

      Article first published online: 28 DEC 2012 | DOI: 10.1002/cmdc.201200479

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      Northern lights, western blot! A series of hydrosoluble benzo[e]pyridoindolones were synthesized and evaluated as aurora kinase inhibitors. Several of these compounds were shown to exhibit potent antiproliferative activity in cell-based studies, and the most active derivative ranks among the top 10 inhibitors of aurora kinase identified to date, warranting further preclinical investigation.

    8. You have full text access to this OnlineOpen article
      Structure–Activity Relationship Study Reveals ML240 and ML241 as Potent and Selective Inhibitors of p97 ATPase (pages 297–312)

      Prof. Dr. Tsui-Fen Chou, Dr. Kelin Li, Dr. Kevin J. Frankowski, Dr. Frank J. Schoenen and Prof. Dr. Raymond J. Deshaies

      Article first published online: 11 JAN 2013 | DOI: 10.1002/cmdc.201200520

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      AAA ATPase inhibitors: To discover more potent p97 inhibitors, we carried out a SAR study of the quinazoline scaffold (DBeQ) identified from our previous HTS campaigns. Two improved and functionally complementary inhibitors, ML240 and ML241, inhibit p97 ATPase with IC50 values of 100 nM. Our studies provide a rationale for developing pathway-specific inhibitors.

    9. You have full text access to this OnlineOpen article
      Fueling Open-Source Drug Discovery: 177 Small-Molecule Leads against Tuberculosis (pages 313–321)

      Dr. Lluís Ballell, Dr. Robert H. Bates, Dr. Rob J. Young, Daniel Alvarez-Gomez, Dr. Emilio Alvarez-Ruiz, Vanessa Barroso, Delia Blanco, Benigno Crespo, Dr. Jaime Escribano, Rubén González, Sonia Lozano, Dr. Sophie Huss, Angel Santos-Villarejo, Dr. José Julio Martín-Plaza, Dr. Alfonso Mendoza, Dr. María José Rebollo-Lopez, Dr. Modesto Remuiñan-Blanco, Dr. José Luis Lavandera, Dr. Esther Pérez-Herran, Dr. Francisco Javier Gamo-Benito, Dr. José Francisco García-Bustos, Dr. David Barros, Dr. Julia P. Castro and Dr. Nicholas Cammack

      Article first published online: 10 JAN 2013 | DOI: 10.1002/cmdc.201200428

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      Needles from the haystack: As part of GlaxoSmithKline's commitment to open innovation research against neglected diseases such as TB, herein we report the results of a high-throughput phenotypic screen of two million compounds. A set of 177 potent, non-cytotoxic hits against Mycobacterium tuberculosis H37Rv are described. Samples of these compounds will be made available in an effort to promote further research against this critical disease.

    10. Non-natural Peptide Triazole Antagonists of HIV-1 Envelope gp120 (pages 322–328)

      Dr. Kantharaju Kamanna, Dr. Rachna Aneja, Caitlin Duffy, Pamela Kubinski, Dr. Diogo Rodrigo Moreira, Lauren D. Bailey, Dr. Karyn McFadden, Dr. Arne Schön, Andrew Holmes, Dr. Ferit Tuzer, Dr. Mark Contarino, Prof. Ernesto Freire and Prof. Irwin M. Chaiken

      Article first published online: 13 DEC 2012 | DOI: 10.1002/cmdc.201200422

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      Antivirals turning Pro: Shown is a tripartite model of ferrocenyl peptide triazoles, highlighting key domains around the central proline: the hydrophobic triazole substituent, the hydrophobic side chain C-terminal to Pro, and the N-terminal extension from Pro. An analogue with the critical “hot spot” Trp 6 residue replaced with L-3-benzothienylalanine (Bta) (KR-41), as well as a non-natural analogue with D-amino acid substitutions outside the central cluster (KR-42), were shown to retain dual receptor site antagonism and antiviral activity.

    11. 2-Carbaborane-3-phenyl-1H-indoles—Synthesis via McMurry Reaction and Cyclooxygenase (COX) Inhibition Activity (pages 329–335)

      Markus Laube, Wilma Neumann, Dr. Matthias Scholz, Dr. Peter Lönnecke, Brenda Crews, Prof. Dr. Lawrence J. Marnett, Prof. Dr. Jens Pietzsch, Dr. Torsten Kniess and Prof. Dr. Evamarie Hey-Hawkins

      Article first published online: 9 JAN 2013 | DOI: 10.1002/cmdc.201200455

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      Three-dimensional aromaticity: This report presents carbaboranyl derivatives of COX-2-selective 2,3-disubstituted indoles synthesized by McMurry cyclization. Although the meta-carbaboranyl-substituted derivatives 3 ac lacked COX inhibitory activity, the ortho-carbaboranyl analogue 3 d was active, but showed a selectivity shift toward COX-1.

  8. Book Reviews

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Dendrimer-Based Drug Delivery Systems: From Theory to Practice. Edited by Yiyun Cheng (page 336)

      Dr. Christine Dufès

      Article first published online: 4 JAN 2013 | DOI: 10.1002/cmdc.201200556

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      Wiley, Hoboken 2012. 542 pp., hardcover, $ 175.00.—ISBN 978-0-470-46005-4

    2. Drug Repositioning: Bringing New Life to Shelved Assets and Existing Drugs. Edited by Michael J. Barratt and Donald E. Frail (pages 336–337)

      Dr. Raúl Insa

      Article first published online: 19 DEC 2012 | DOI: 10.1002/cmdc.201200552

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      Wiley, Hoboken 2012. 498 pp., hardcover, $ 125.00.—ISBN 978-0-470-87827-9

    3. Plant Bioactives and Drug Discovery: Principles, Practice, and Perspectives. Edited by Valdir Cechinel-Filho (page 337)

      Prof. Orazio Taglialatela-Scafati

      Article first published online: 27 NOV 2012 | DOI: 10.1002/cmdc.201200526

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      Wiley, Hoboken 2012. 586 pp., hardcover, $ 175.00.—ISBN 978-0-470-58226-8

    4. Applications of Ion Chromatography in the Analysis of Pharmaceutical and Biological Products. Edited by Lokesh Bhattacharyya and Jeffrey S. Rohrer (pages 338–339)

      Prof. Dr. Andreas Seubert

      Article first published online: 12 DEC 2012 | DOI: 10.1002/cmdc.201200553

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      Wiley, Hoboken 2012. 476 pp., hardcover, $ 125.00.—ISBN 978-0-470-46709-1

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