ChemMedChem

Cover image for Vol. 7 Issue 11

November 2012

Volume 7, Issue 11

Pages 1865–2043

  1. Cover Pictures

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigenda
    5. News
    6. Review
    7. Communications
    8. Full Papers
    9. Book Reviews
    10. Preview
    1. You have free access to this content
      Cover Picture: Identification of Drugs Inducing Phospholipidosis by Novel in vitro Data (ChemMedChem 11/2012) (page 1865)

      Markus Muehlbacher, Dr. Philipp Tripal, Florian Roas and Prof. Johannes Kornhuber

      Version of Record online: 29 OCT 2012 | DOI: 10.1002/cmdc.201290053

      Thumbnail image of graphical abstract

      Drug-induced phospholipidosis may be associated with undesirable clinical side effects, and its relationship with drug toxicity remains unclear. A means to predict the phenomenon would have significant clinical utility. The front cover picture shows that drugs such as amitripyline (left panel) elevate cellular phospholipid levels significantly, even when applied in moderate concentrations. The effect on the cells can be visualized by fluorescence microscopy (right panel). In vitro experiments identified several well-known and widely used drugs that induce phospholipidosis. Based on these results, an in silico model was built in an attempt to predict whether a novel therapeutic agent might induce phospholipidosis in cells. For more details, see the Full Paper by Johannes Kornhuber et al. on p. 1925 ff. Background image: iStockphoto.com/FotografiaBasica

    2. You have free access to this content
      Inside Cover: Inhibition of Bacterial Dihydrofolate Reductase by 6-Alkyl-2,4-diaminopyrimidines (ChemMedChem 11/2012) (page 1866)

      Dr. Baskar Nammalwar, Dr. Christina R. Bourne, Prof. Richard A. Bunce, Dr. Nancy Wakeham, Dr. Philip C. Bourne, Dr. Kal Ramnarayan, Dr. Shankari Mylvaganam, Prof. K. Darrell Berlin, Dr. Esther W. Barrow and Prof. William W. Barrow

      Version of Record online: 29 OCT 2012 | DOI: 10.1002/cmdc.201290054

      Thumbnail image of graphical abstract

      The inside cover picture shows a 6-alkyl-2,4-diaminopyrimidine inhibitor (magenta) with a propyl at the C6 position of the 2,4-diaminopyrimidine ring (asterisk) bound to S. aureus dihydrofolate reductase (blue model with surface shown, PDB: 4FGG). Binding triggers movement of a leucine side chain (yellow sticks), resulting in the opening of an adjacent hydrated pocket (filled with red spheres) contiguous with the binding pocket. For more details, see the Full Paper by Christina R. Bourne, Richard A. Bunce et al. on p. 1974 ff.

    3. You have free access to this content
      Back Cover: Discovery of a New Class of Liver Receptor Homolog-1 (LRH-1) Antagonists: Virtual Screening, Synthesis and Biological Evaluation (ChemMedChem 11/2012) (page 2044)

      Dr. Jullien Rey, Dr. Haipeng Hu, Dr. Fiona Kyle, Chun-Fui Lai, Dr. Laki Buluwela, Prof. R. Charles Coombes, Prof. Eric A. Ortlund, Prof. Simak Ali, Prof. James P. Snyder and Prof. Anthony G. M. Barrett

      Version of Record online: 29 OCT 2012 | DOI: 10.1002/cmdc.201290058

      Thumbnail image of graphical abstract

      The back cover picture shows superimposed models for two successive events in liver receptor homolog-1 (LRH-1) blockade. In the apo-receptor, the binding site is capped with helix 12 (cream), but antagonist (green) binding fills the entrance and displaces H-12 (orange). Two side chains on the apo-protein H-12 are responsible for the steric clash. For more details, see the Communication by Simak Ali, James P. Snyder, Anthony G. M. Barrett et al. on p. 1909 ff.

  2. Graphical Abstract

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

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigenda
    5. News
    6. Review
    7. Communications
    8. Full Papers
    9. Book Reviews
    10. Preview
    1. You have free access to this content
      Corrigendum: An Efficient Synthesis of a Hydroxyethylamine (HEA) Isostere and Its α-Aminophosphonate and Phosphoramidate Derivatives as Potential Anti-HIV Agents (page 1874)

      Dr. Asish K. Bhattacharya, Dr. Kalpeshkumar C. Rana, Prof. Dr. Christophe Pannecouque and Prof. Dr. Eric De Clercq

      Version of Record online: 29 OCT 2012 | DOI: 10.1002/cmdc.201200442

    2. You have free access to this content
      Corrigendum: Advances in Targeting Voltage-Gated Sodium Channels with Small Molecules (page 1874)

      Dr. Antonio Nardi, Dr. Nils Damann, Dr. Torsten Hertrampf and Dr. Achim Kless

      Version of Record online: 29 OCT 2012 | DOI: 10.1002/cmdc.201200443

      This article corrects:

      Advances in Targeting Voltage-Gated Sodium Channels with Small Molecules

      Vol. 7, Issue 10, 1712–1740, Version of Record online: 4 SEP 2012

  4. News

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigenda
    5. News
    6. Review
    7. Communications
    8. Full Papers
    9. Book Reviews
    10. Preview
  5. Review

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigenda
    5. News
    6. Review
    7. Communications
    8. Full Papers
    9. Book Reviews
    10. Preview
    1. A Case Study of Single-Pill Combination Therapy: The Ezetimibe/Simvastatin Combination for Treatment of Hyperlipidemia (pages 1882–1894)

      Dr. Xianhai Huang and Prof. Dr. David Y.-K. Chen

      Version of Record online: 20 AUG 2012 | DOI: 10.1002/cmdc.201200287

      Thumbnail image of graphical abstract

      Team players: Using the ezetimibe/simvastatin combination therapy as a case study, a comprehensive overview of the successful discovery and development of the single-pill combination, Vytorin, is presented in this review. Bioequivalency studies, clinical efficacy and safety profile studies, and the economic consequences of the single-pill combination therapy are emphasized.

  6. Communications

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigenda
    5. News
    6. Review
    7. Communications
    8. Full Papers
    9. Book Reviews
    10. Preview
    1. Synthesis and Structure–Activity Relationships of Lansine Analogues as Antileishmanial Agents (pages 1895–1900)

      Dr. Marco Pieroni, Sisay Girmay, Dr. Dianqing Sun, Rajnish Sahu, Dr. Babu L. Tekwani and Dr. Ghee T. Tan

      Version of Record online: 17 SEP 2012 | DOI: 10.1002/cmdc.201200346

      Thumbnail image of graphical abstract

      Clear and rational thinking: A series of rationally designed, lansine-derived carbazoles was synthesized and evaluated for activity against promastigotes and amastigotes of Leishmania donovani, the causative agent of leishmaniasis. Some structural modifications gave rise to compounds with enhanced activity and selectivity over lansine, allowing structure–activity relationships to be elucidated and providing a foundation for the further development of this pharmacophore.

    2. Synthesis and Antiproliferative Activity of the Ring System [1,2]Oxazolo[4,5-g]indole (pages 1901–1904)

      Prof. Paola Barraja, Dr. Libero Caracausi, Prof. Patrizia Diana, Dr. Virginia Spanò, Dr. Alessandra Montalbano, Dr. Anna Carbone, Dr. Barbara Parrino and Prof. Girolamo Cirrincione

      Version of Record online: 22 AUG 2012 | DOI: 10.1002/cmdc.201200296

      Thumbnail image of graphical abstract

      Brand new ring: A series of 27 derivatives of the new ring system [1,2]oxazolo[4,5-g]indole were conveniently prepared and tested at the NCI for antiproliferative studies. Several of them showed good inhibitory activity toward all tested cell lines, reaching GI50 values generally at the micromolar and sub- micromolar levels and in some cases at nanomolar concentrations. The mean GI50 values, calculated on the full panel, were in the range 0.25–7.08 μM.

    3. Carprofen Analogues as Sirtuin Inhibitors: Enzyme and Cellular Studies (pages 1905–1908)

      Dr. Paolo Mellini, Dr. Vincenzo Carafa, Dr. Barbara Di Rienzo, Dr. Dante Rotili, Dr. Daniela De Vita, Dr. Roberto Cirilli, Dr. Bruno Gallinella, Dr. Donatella Paola Provvisiero, Dr. Salvatore Di Maro, Prof. Ettore Novellino, Prof. Lucia Altucci and Prof. Antonello Mai

      Version of Record online: 25 SEP 2012 | DOI: 10.1002/cmdc.201200318

      Thumbnail image of graphical abstract

      The best of both: SIRT1/2 inhibitors were developed by combining chemical features of selisistat (SIRT1-selective inhibitor; blue) and carprofen (anti-inflammatory drug; red). The most potent compound (shown) increased acetyl-p53 and acetyl-α-tubulin levels, and induced slight apoptosis at 50 μM in U937 cells, differently from selisistat and carprofen.

    4. Discovery of a New Class of Liver Receptor Homolog-1 (LRH-1) Antagonists: Virtual Screening, Synthesis and Biological Evaluation (pages 1909–1914)

      Dr. Jullien Rey, Dr. Haipeng Hu, Dr. Fiona Kyle, Chun-Fui Lai, Dr. Laki Buluwela, Prof. R. Charles Coombes, Prof. Eric A. Ortlund, Prof. Simak Ali, Prof. James P. Snyder and Prof. Anthony G. M. Barrett

      Version of Record online: 7 SEP 2012 | DOI: 10.1002/cmdc.201200307

      Thumbnail image of graphical abstract

      Targeting LRH-1: Virtual screening and molecular modeling were used to identify novel antagonists of liver receptor homolog-1 (LRH-1), an emerging therapeutic target for breast cancer. Hit compounds were synthesized and biologically assayed, and the preliminary results suggest that raloxifene-based analogues, substituted at the position C-7 of the benzothiophene ring, might generate an inactive protein conformation through binding and thus antagonize this nuclear receptor.

    5. A Facile Synthesis of Novel Bis-(indolyl)-1,3,4-oxadiazoles as Potent Cytotoxic Agents (pages 1915–1920)

      Prof. Dalip Kumar, V. Arun, N. Maruthi Kumar, Glen Acosta, Brett Noel and Prof. Kavita Shah

      Version of Record online: 20 SEP 2012 | DOI: 10.1002/cmdc.201200363

      Thumbnail image of graphical abstract

      A recipe for potency: A novel series of bis(indolyl)-1,3,4-oxadiazoles was prepared from the corresponding hydrazide-hydrazones via iodobenzene diacetate-promoted oxidative cyclization. Evaluation against a panel of human cancer cell lines revealed that some derivatives possess potent cytotoxicity with tunable selectivity for different cancer types.

    6. Partial Inhibition of Aldose Reductase by Nitazoxanide and Its Molecular Basis (pages 1921–1923)

      Dr. Xuehua Zheng, Liping Zhang, Weijia Chen, Yunyun Chen, Prof. Wei Xie and Prof. Xiaopeng Hu

      Version of Record online: 13 AUG 2012 | DOI: 10.1002/cmdc.201200333

      Thumbnail image of graphical abstract

      A little is more than enough: Aldose reductase (AR) is a potential target in a wide range of diseases but its utility may be limited by the side effects caused by complete inhibition. Furthermore, known inhibitors of AR have suffered in clinical evaluation due to poor bioavailability. Here, the clinically used antiprotozoal drug nitazoxanide with proven bioavailability has been shown to partially inhibit AR, potentially circumventing the negatives effects of complete enzyme inhibition.

  7. Full Papers

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigenda
    5. News
    6. Review
    7. Communications
    8. Full Papers
    9. Book Reviews
    10. Preview
    1. You have full text access to this OnlineOpen article
      Identification of Drugs Inducing Phospholipidosis by Novel in vitro Data (pages 1925–1934)

      Markus Muehlbacher, Dr. Philipp Tripal, Florian Roas and Prof. Johannes Kornhuber

      Version of Record online: 3 SEP 2012 | DOI: 10.1002/cmdc.201200306

      Thumbnail image of graphical abstract

      Supercalifragilistic phospholipidosis! Drug-induced phospholipidosis (PLD) is a lysosomal storage disorder characterized by the accumulation of phospholipids within the lysosome. We tested 297 drug-like compounds at two different concentrations (2.5 μM and 5.0 μM), identifying 28 previously unknown PLD-inducing agents. We also developed a binary classification model to predict PLD-inducing agents based on their molecular properties and discuss associations to other related activities.

    2. Characterization of Telmisartan-Derived PPARγ Agonists: Importance of Moiety Shift from Position 6 to 5 on Potency, Efficacy and Cofactor Recruitment (pages 1935–1942)

      Dr. Lena Herbst, Dr. Matthias Goebel, Sebastian Bandholtz, Prof. Dr. Ronald Gust and Prof. Dr. Ulrich Kintscher

      Version of Record online: 25 SEP 2012 | DOI: 10.1002/cmdc.201200337

      Thumbnail image of graphical abstract

      Changes to the core: The AT1-receptor blocker telmisartan is a partial PPARγ agonist with promising in vitro and in vivo properties for the treatment of insulin resistance. However, potency and efficacy need to be optimized to accomplish sufficient plasma levels for PPARγ activation. Therefore, we performed modifications at position 2, 5 and 6 in order to increase potency, but also to analyze the structure–activity relationship and its influence on cofactor recruitment.

    3. Systematic Structure–Activity Study on Potential Chaperone Lead Compounds for Acid α-Glucosidase (pages 1943–1953)

      Dr. Chiara Bruckmann, Heidi Repo, Dr. Elina Kuokkanen, Dr. Henri Xhaard and Prof. Pirkko Heikinheimo

      Version of Record online: 11 SEP 2012 | DOI: 10.1002/cmdc.201200309

      Thumbnail image of graphical abstract

      Stabilising acid α-glucosidase (GAA): An emerging treatment for lysosomal defects is the use of pharmacological chaperones to enhance the total cellular activity of the target enzyme. We evaluated 13 GAA inhibitors for their ability to stabilise recombinant human GAA and their capacity to increase lysosomal localisation of GAA variants, and rationalised our observations by molecular modelling. Our study creates a firm basis for chaperone design on acid α-glucosidase and for the treatment of Pompe disease.

    4. MT1-Selective Melatonin Receptor Ligands: Synthesis, Pharmacological Evaluation, and Molecular Dynamics Investigation of N-{[(3-O-Substituted)anilino]alkyl}amides (pages 1954–1964)

      Prof. Silvia Rivara, Dr. Daniele Pala, Dr. Alessio Lodola, Prof. Marco Mor, Dr. Valeria Lucini, Dr. Silvana Dugnani, Prof. Francesco Scaglione, Dr. Annalida Bedini, Dr. Simone Lucarini, Prof. Giorgio Tarzia and Prof. Gilberto Spadoni

      Version of Record online: 27 AUG 2012 | DOI: 10.1002/cmdc.201200303

      Thumbnail image of graphical abstract

      Focusing on selectivity: A new series of MT1-selective agonists was synthesized by modulating the versatile N-anilinoethylamide scaffold through introduction of lipophilic (aryl)alkyl substituents on the ether oxygen atom. A combination of molecular modeling studies and ligand-based information provided hypotheses for ligand–receptor interactions and for MT1 subtype selectivity.

    5. Beyond Heparinization: Design of Highly Potent Thrombin Inhibitors Suitable for Surface Coupling (pages 1965–1973)

      Prof. Dr. Torsten Steinmetzer, Dr. Bernhard Baum, Dr. Adam Biela, Prof. Dr. Gerhard Klebe, Prof. Dr. Götz Nowak and Dr. Elke Bucha

      Version of Record online: 20 AUG 2012 | DOI: 10.1002/cmdc.201200292

      Thumbnail image of graphical abstract

      To affinity and beyond! A series of potent thrombin inhibitors with high selectivity over related trypsin-like serine proteases was developed. The experimentally determined structure of a thrombin/inhibitor complex reveals that the P3 side chain of these inhibitors is directed into the solvent and therefore could serve as an anchor point for further modification. Such compounds might be suitable candidates for anticoagulant surface coating.

    6. Inhibition of Bacterial Dihydrofolate Reductase by 6-Alkyl-2,4-diaminopyrimidines (pages 1974–1982)

      Dr. Baskar Nammalwar, Dr. Christina R. Bourne, Prof. Richard A. Bunce, Dr. Nancy Wakeham, Dr. Philip C. Bourne, Dr. Kal Ramnarayan, Dr. Shankari Mylvaganam, Prof. K. Darrell Berlin, Dr. Esther W. Barrow and Prof. William W. Barrow

      Version of Record online: 28 AUG 2012 | DOI: 10.1002/cmdc.201200291

      Thumbnail image of graphical abstract

      From resistance to terrorism: A series of (±)-6-alkyl-2,4-diaminopyrimidines was synthesized and evaluated for inhibition of bacterial dihydrofolate reductase (DHFR). Biological studies revealed slightly attenuated activity relative to structures lacking C6 alkyl substitution. This arises from a conformational change of the protein resulting in exposure of a hydrated pocket contiguous with the existing binding site.

    7. Discovery of Tyrosine Kinase Inhibitors by Docking into an Inactive Kinase Conformation Generated by Molecular Dynamics (pages 1983–1990)

      Hongtao Zhao, Dr. Danzhi Huang and Prof. Amedeo Caflisch

      Version of Record online: 13 SEP 2012 | DOI: 10.1002/cmdc.201200331

      Thumbnail image of graphical abstract

      An induced fit! The phenomenon of induced fit where the ligand binding site alters upon binding to become very specific for the given ligand limits the use of the crystal structure in virtual screening campaigns. To circumvent this issue and identify inhibitors of tyrosine kinases in their inactive form (DFG-out), a molecular dynamics approach was taken. The computation approach identified a novel chemotype for type II kinase inhibitors, which also inhibits the therapeutically relevant T315I mutant of Abl1.

    8. Fluorine-18 Radiolabeling and Radiopharmacological Characterization of a Benzodioxolylpyrimidine-based Radiotracer Targeting the Receptor Tyrosine Kinase EphB4 (pages 1991–2003)

      Dr. Constantin Mamat, Dr. Birgit Mosch, Christin Neuber, Prof. Dr. Martin Köckerling, Dr. Ralf Bergmann and Prof. Dr. Jens Pietzsch

      Version of Record online: 5 OCT 2012 | DOI: 10.1002/cmdc.201200264

      Thumbnail image of graphical abstract

      Small-animal PETs: We developed radiochemical access to a novel PET radiotracer derived from potent inhibitors that target the EphB4 kinase domain and which bear a benzodioxolylpyrimidine structural motif. EphB4-overexpressing human melanoma cells were used as an in vitro model, and NMRI nu/nu mice bearing both EphB4-overexpressing tumors and control tumors were used in vivo for radiopharmacological characterization.

    9. Synthesis, Cytotoxicity, Induction of Apoptosis, and Interaction with DNA of Dinuclear Platinum(II) Complexes (pages 2004–2009)

      Gang Xu, Chuanzhu Gao, Prof. Shaohua Gou and Zhe Cao

      Version of Record online: 27 SEP 2012 | DOI: 10.1002/cmdc.201200332

      Thumbnail image of graphical abstract

      The bridge club: Six dinuclear platinum(II) complexes of a chiral ligand, 2-{[(1R,2R)-2-aminocyclohexyl]amino}propanoic acid, were synthesized. Complexes S3, S4, and S5, with succinate and its derivatives as bridges, exhibited better activity than the positive controls. The compounds inhibit tumor cell growth by inducing apoptosis, and they can prompt pET22b plasmid DNA degradation in nearly the same manner as oxaliplatin.

    10. Arene–RuII Complexes of Curcumin Exert Antitumor Activity via Proteasome Inhibition and Apoptosis Induction (pages 2010–2020)

      Dr. Laura Bonfili, Dr. Riccardo Pettinari, Dr. Massimiliano Cuccioloni, Dr. Valentina Cecarini, Dr. Matteo Mozzicafreddo, Prof. Mauro Angeletti, Prof. Giulio Lupidi, Prof. Fabio Marchetti, Prof. Claudio Pettinari and Prof. Anna Maria Eleuteri

      Version of Record online: 20 SEP 2012 | DOI: 10.1002/cmdc.201200341

      Thumbnail image of graphical abstract

      Ru ready for apoptosis? Three organometallic ruthenium(II) complexes of the general formula [(η6-arene)Ru(curcuminato)Cl] were synthesized and studied for their antitumor effects. The DNA binding ability and the influence on the oxidative status of HCT116 cells were evaluated. The compounds differently inhibited isolated and cellular proteasomes, consequently triggering apoptosis.

    11. (R)-α-Lipoyl-Glycyl-L-Prolyl-L-Glutamyl Dimethyl Ester Codrug as a Multifunctional Agent with Potential Neuroprotective Activities (pages 2021–2029)

      Dr. Ivana Cacciatore, Dr. Leonardo Baldassarre, Dr. Erika Fornasari, Dr. Catia Cornacchia, Prof. Antonio Di Stefano, Dr. Piera Sozio, Dr. Laura Serafina Cerasa, Prof. Antonella Fontana, Prof. Stefania Fulle, Dr. Ester Sara Di Filippo, Dr. Rita Maria Laura La Rovere and Prof. Francesco Pinnen

      Version of Record online: 13 SEP 2012 | DOI: 10.1002/cmdc.201200320

      Thumbnail image of graphical abstract

      Efficacy through synergy: We report the synthesis, along with pharmacokinetic and neuroprotective profiles of a novel GPE codrug as a potential candidate for the multi-target therapy of neurodegenerative diseases. The codrug shows good pharmacokinetic, potential antioxidant, and neuroprotective properties.

    12. Structural Studies on 4,5-Disubstituted 2-Aminoimidazole-Based Biofilm Modulators that Suppress Bacterial Resistance to β-Lactams (pages 2030–2039)

      Zhaoming Su, Dr. Andrew A. Yeagley, Rui Su, Dr. Lingling Peng and Dr. Christian Melander

      Version of Record online: 25 SEP 2012 | DOI: 10.1002/cmdc.201200350

      Thumbnail image of graphical abstract

      Modulating resistance: 4,5-Disubstituted 2-aminoimidazole triazole amide (2-AITA) conjugates were discovered as MRSA and MDRAB biofilm modulators, which also suppress MRSA resistance to oxacillin. Further structure–activity relationship studies identified a 2-aminoimidazole diamide (2-AIDA) conjugate with significantly increased resensitization activity without compromising the anti-biofilm activity.

  8. Book Reviews

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigenda
    5. News
    6. Review
    7. Communications
    8. Full Papers
    9. Book Reviews
    10. Preview
    1. HPLC Methods for Clinical Pharmaceutical Analysis: A User's Guide. By Herrmann Mascher. (page 2040)

      Prof. Dr. Thomas Jira

      Version of Record online: 24 AUG 2012 | DOI: 10.1002/cmdc.201200374

      Thumbnail image of graphical abstract

      Wiley-VCH, Weinheim 2012. 247 pp., hardcover € 59.00.—ISBN 978-3-527-33129-1

    2. Proteinases as Drug Targets. Edited by Ben M. Dunn. (pages 2040–2041)

      Dr. Richard Sedrani

      Version of Record online: 19 APR 2012 | DOI: 10.1002/cmdc.201200179

      Thumbnail image of graphical abstract

      RSC, Cambridge 2012. 292 pp., hardcover £132.99.—ISBN 978-1-84973-049-5

  9. Preview

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigenda
    5. News
    6. Review
    7. Communications
    8. Full Papers
    9. Book Reviews
    10. Preview
    1. You have free access to this content
      Preview: ChemMedChem 12/2012 (page 2043)

      Version of Record online: 29 OCT 2012 | DOI: 10.1002/cmdc.201290057

SEARCH

SEARCH BY CITATION