ChemMedChem

Cover image for ChemMedChem

October 2013

Volume 8, Issue 10

Pages 1573–1716

  1. Cover Pictures

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Minireviews
    6. Highlights
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. You have free access to this content
      Cover Picture: Disruption of Interactions between Hydrophobic Residues on Nonpolar Faces is a Key Determinant in Decreasing Hemolysis and Increasing Antimicrobial Activities of α-Helical Amphipathic Peptides (ChemMedChem 10/2013) (page 1573)

      Mieon Son, Yuri Lee, Heeyong Hwang, Dr. Soonsil Hyun and Prof. Jaehoon Yu

      Article first published online: 2 OCT 2013 | DOI: 10.1002/cmdc.201390040

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      The front cover picture shows the modulation of hemolytic and antimicrobial activity of peptides through mutation. An amphipathic (green/black) α-helical peptide composed of leucine and lysine residues was mutated (bright green) with a variety of amino acids to decrease the hemolytic activity (top) and improve the antimicrobial activity (bottom). Disruption of the segregated hydrophobicity by incorporation of neutral hydrophilic residues (green) gave rise to peptide derivatives with significantly decreased α-helicity and hydrophobicity. One analogue (LK-L8N) exhibited a greater than 8000-fold decrease in hemolytic activity over the parent peptide and an 8-fold improvement in antimicrobial activity against E. coli, giving a 64000-fold increase in therapeutic index. This strategy is generally applicable in the design of selective antimicrobial peptides. For more details, see the Communication by Jaehoon Yu et al. on p. 1638 ff.

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      Inside Cover: CONFECT: Conformations from an Expert Collection of Torsion Patterns (ChemMedChem 10/2013) (page 1574)

      Christin Schärfer, Dr. Tanja Schulz-Gasch, Dr. Jérôme Hert, Lennart Heinzerling, Benjamin Schulz, Therese Inhester, Dr. Martin Stahl and Prof. Dr. Matthias Rarey

      Article first published online: 2 OCT 2013 | DOI: 10.1002/cmdc.201390041

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      The inside cover picture shows the conformational ensemble of AMP generated by CONFECT, a novel knowledge-based conformer generator. Conformations are generated by using lists of “usual” torsion angles derived from CSD-based frequency histograms (top left). One of the bioactive conformations of AMP is shown in the binding site of the protein from PDB complex 3TV2 (bottom right). For more details, see the Full Paper by Matthias Rarey et al. on p. 1690 ff.

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      Back Cover: In silico Optimization of a Fragment-Based Hit Yields Biologically Active, High-Efficiency Inhibitors for Glutamate Racemase (ChemMedChem 10/2013) (page 1720)

      Katie L. Whalen, Anthony C. Chau and Dr. M. Ashley Spies

      Article first published online: 2 OCT 2013 | DOI: 10.1002/cmdc.201390044

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      The back cover picture shows the molecular structure of glutamate racemase from Bacillus subtilis (ribbon) with a novel inhibitor (space-filling) bound to the active site cleft. The inhibitor was discovered via an in silico lead optimization technique, termed FERM-SMD, that combines steered molecular dynamics simulations and ensemble docking. For more details, see the Full Paper by M. Ashley Spies et al. on p. 1681 ff.

  2. Graphical Abstract

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Minireviews
    6. Highlights
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Graphical Abstract: ChemMedChem 10/2013 (pages 1575–1581)

      Article first published online: 2 OCT 2013 | DOI: 10.1002/cmdc.201390042

  3. News

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

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Minireviews
    6. Highlights
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Recent Advances in Inhibitors of Bacterial Fatty Acid Synthesis Type II (FASII) System Enzymes as Potential Antibacterial Agents (pages 1589–1608)

      Yi Wang and Prof. Shutao Ma

      Article first published online: 24 JUL 2013 | DOI: 10.1002/cmdc.201300209

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      Fast to fight infection: Bacterial infections remain a major global health concern. The fatty acid synthesis type II (FASII) pathway is a potential target used for the discovery and development of antibacterial agents with novel mechanisms of action. This review highlights recent advances in FASII inhibitors, with particular focus on their activities, structure–activity relationships, and mechanisms.

    2. Blocking the Peroxisome Proliferator-Activated Receptor (PPAR): An Overview (pages 1609–1616)

      Dr. Alessandra Ammazzalorso, Dr. Barbara De Filippis, Dr. Letizia Giampietro and Prof. Rosa Amoroso

      Article first published online: 12 AUG 2013 | DOI: 10.1002/cmdc.201300250

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      Right on target: Peroxisome proliferator-activated receptors (PPARs) have been studied extensively in recent decades and assessed as molecular targets for the development of drugs against metabolic disorders. Herein we present an overview of the various chemical structures that are able to block the PPAR subtypes, through different mechanisms, with a focus on promising therapeutic applications.

  5. Highlights

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Minireviews
    6. Highlights
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Tafamidis (Vyndaqel): A Light for FAP Patients (pages 1617–1619)

      Dr. Susanna Nencetti, Prof. Armando Rossello and Prof. Elisabetta Orlandini

      Article first published online: 2 SEP 2013 | DOI: 10.1002/cmdc.201300245

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      Slowing FAP progression: Tafamidis meglumine is a small molecule capable of stabilizing the transthyretin (TTR) tetramer. Tafamidis acts in a similar way to the natural hormone T4, prevents TTR amyloid fibril formation, and offers a potential alternative to liver transplantation for the treatment of patients with TTR familial amyloid polyneuropathies (TTR-FAP).

    2. Targeting the K-Ras/PDEδ Protein–Protein Interaction: The Solution for Ras-Driven Cancers or Just Another Therapeutic Mirage? (pages 1620–1622)

      Brendan Frett, Dr. Yuanxiang Wang and Prof. Dr. Hong-yu Li

      Article first published online: 12 AUG 2013 | DOI: 10.1002/cmdc.201300311

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      The holy grail, finally? After years of unsuccessful attempts at drugging the Ras oncogene, a recent paper by Zimmerman et al. has revealed the possibility of inhibiting Ras signaling on a clinically relevant level by blocking the K-Ras/PDEδ protein–protein interaction. The results, reported in Nature, are highlighted herein with future implications and directions to evaluate the full clinical potential of this research.

  6. Communications

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Minireviews
    6. Highlights
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. N-Substituted 1,2-Dihydroquinolines as Anticancer Agents: Electronic Control of Redox Stability, Assessment of Antiproliferative Effects, and Mechanistic Insights (pages 1623–1628)

      Napoleon John Victor, Ramasamy Sakthivel, Dr. Kannoth Manheri Muraleedharan and Prof. Devarajan Karunagaran

      Article first published online: 5 AUG 2013 | DOI: 10.1002/cmdc.201300210

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      Redox chemotherapy: Antiproliferative activities of a series of N-substituted 1,2-dihydroquinolines capable of causing redox imbalance in cancer cells are presented. Detailed studies showed that these derivatives arrest the cell cycle in the G2/M phase and induce apoptosis through an intrinsic pathway characterized by loss of mitochondrial membrane potential, DNA fragmentation, cytochrome c release, and activation of caspases 9 and 3.

    2. Identification of the Binding Site of an Allosteric Ligand Using STD-NMR, Docking, and CORCEMA-ST Calculations (pages 1629–1633)

      Dr. Wei Zhang, Rongbao Li, Dr. Ronald Shin, Dr. Yimin Wang, Dr. Indira Padmalayam, Dr. Ling Zhai and Prof. Dr. N. Rama Krishna

      Article first published online: 25 JUL 2013 | DOI: 10.1002/cmdc.201300267

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      Singling out the truth: A combined application of STD-NMR, molecular docking, and CORCEMA-ST calculations is described as an attractive, easily applicable tool for the identification and validation of the binding site for allosteric ligands, with potential application as an aid in drug discovery research.

    3. Metal-Based Compounds as Prospective Antileishmanial Agents: Inhibition of Trypanothione Reductase by Selected Gold Complexes (pages 1634–1637)

      Dr. Gianni Colotti, Dr. Andrea Ilari, Dr. Annarita Fiorillo, Dr. Paola Baiocco, Prof. Maria Agostina Cinellu, Dr. Laura Maiore, Federica Scaletti, Dr. Chiara Gabbiani and Prof. Luigi Messori

      Article first published online: 23 AUG 2013 | DOI: 10.1002/cmdc.201300276

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      Picking a fight with parasites! Trypanothione reductase (TR) is a validated drug target for the development of antileishmanial agents. A group of structurally diverse gold-containing compounds was evaluated in vitro for TR inhibition. A number of compounds exhibited potent activity and deserve further pharmacological evaluation.

    4. Disruption of Interactions between Hydrophobic Residues on Nonpolar Faces is a Key Determinant in Decreasing Hemolysis and Increasing Antimicrobial Activities of α-Helical Amphipathic Peptides (pages 1638–1642)

      Mieon Son, Yuri Lee, Heeyong Hwang, Dr. Soonsil Hyun and Prof. Jaehoon Yu

      Article first published online: 25 JUL 2013 | DOI: 10.1002/cmdc.201300264

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      To design antimicrobial peptides with decrease pore-forming activity in eukaryotic (host) membranes, an amphipathic α-helical model peptide composed of Leu and Lys was modified to probe the balance in antimicrobial and hemolytic activities. Among analogues with broken hydrophobic interactions, L8N derivative exhibited an 8000-fold decrease in hemolytic activity and an eightfold improvement in antimicrobial activity, affording a 64 000-fold increase in therapeutic index against E. coli.

  7. Full Papers

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Minireviews
    6. Highlights
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Inhibition of Human α-Methylacyl CoA Racemase (AMACR): a Target for Prostate Cancer (pages 1643–1647)

      Dr. Andrew J. Carnell, Ralph Kirk, Matthew Smith, Shane McKenna, Prof. Lu-Yun Lian and Dr. Robert Gibson

      Article first published online: 8 AUG 2013 | DOI: 10.1002/cmdc.201300179

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      Enolate mimicry: A range of inhibitors were designed and synthesized to determine the structural requirements for inhibition of the prostate cancer target racemase AMACR using the recently available human enzyme from HEK293 kidney cell cultures. An N-methylthiocarbamate (Ki=98 nM), designed to mimic the proposed enzyme-bound enolate, is the most potent AMACR inhibitor reported to date.

    2. You have full text access to this OnlineOpen article
      Synthesis, G-Quadruplex Stabilisation, Docking Studies, and Effect on Cancer Cells of Indolo[3,2-b]quinolines with One, Two, or Three Basic Side Chains (pages 1648–1661)

      Dr. João Lavrado, Dr. Pedro M. Borralho, Dr. Stephan A. Ohnmacht, Dr. Rui E. Castro, Prof. Cecília M. P. Rodrigues, Prof. Rui Moreira, Dr. Daniel J. V. A. dos Santos, Prof. Stephen Neidle and Dr. Alexandra Paulo

      Article first published online: 19 AUG 2013 | DOI: 10.1002/cmdc.201300288

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      Three is better: Novel trisubstituted indolo[3,2-b]quinolines bearing a 7-(aminoalkyl)carboxylate side chain stand as the most promising anticancer compounds, showing good G4 thermal stabilising effects, good selectivity for G4 over duplex DNA, and good selectivity toward the HCT116 cancer cell line.

    3. Evaluating Prodrug Strategies for Esterase-Triggered Release of Alcohols (pages 1662–1667)

      Christian Perez, Kevin B. Daniel and Prof. Seth M. Cohen

      Article first published online: 8 AUG 2013 | DOI: 10.1002/cmdc.201300255

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      Probing alcohol release: Esterase-responsive prodrug strategies were evaluated for release of alcohol groups. This work highlights the advantages of installing the ester-based promoiety trigger with a benzylic linker, which affords improved aqueous stability and fast rates of conversion. The syntheses of the promoieties studied here are facile, making this strategy particularly attractive for further prodrug development.

    4. Anti-HIV-1 Peptide Derivatives Based on the HIV-1 Co-receptor CXCR4 (pages 1668–1672)

      Dr. Chie Hashimoto, Dr. Wataru Nomura, Dr. Tetsuo Narumi, Dr. Masayuki Fujino, Dr. Hiroshi Tsutsumi, Masaki Haseyama, Prof. Naoki Yamamoto, Dr. Tsutomu Murakami and Prof. Hirokazu Tamamura

      Article first published online: 23 AUG 2013 | DOI: 10.1002/cmdc.201300289

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      Several peptide derivatives of CXCR4 extracellular domains were synthesized and evaluated for anti-HIV-1 activity. The 39-mer N-terminal region (NT) was divided into three fragments with 10-mer overlapping sites, and these linear peptides were synthesized. The peptide containing Met 1–Asp 20 shows significant anti-HIV-1 activity. Extracellular loops 1 and 2 (ECL1 and 2) were mimicked by cyclic peptides, synthesized by chemoselective cyclization. Both show higher anti-HIV-1 activity than their linear counterparts. These results show that Met 1–Asp 20 on the NT and cyclic peptides of ECL1 and ECL2 are potent anti-HIV-1 drug candidates.

    5. A Conformational Mimetic Approach for the Synthesis of Carbocyclic Nucleosides as Anti-HCV Leads (pages 1673–1680)

      Mohan Kasula, Tuniki Balaraju, Dr. Massaki Toyama, Anandarajan Thiyagarajan, Dr. Chandralata Bal, Dr. Masanori Baba and Dr. Ashoke Sharon

      Article first published online: 13 AUG 2013 | DOI: 10.1002/cmdc.201300277

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      A well-defined shape analysis is needed for correlating conformation with biological activity. Our nucleoside mimetic design process involves conformational cluster analysis to evaluate the preferred “anti” conformation of the base with respect to the 6-position hydrogen bond donor and 2′-exo conformations for anti-HCV activity. In neplanocin A, the adenine base shows 80 % syn with only 20 % in the preferred anti conformation in carbocyclic nucleosides.

    6. In silico Optimization of a Fragment-Based Hit Yields Biologically Active, High-Efficiency Inhibitors for Glutamate Racemase (pages 1681–1689)

      Katie L. Whalen, Anthony C. Chau and Dr. M. Ashley Spies

      Article first published online: 8 AUG 2013 | DOI: 10.1002/cmdc.201300271

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      FERM conclusions: A novel lead compound for inhibition of the antibacterial drug target, glutamate racemase, was optimized for both potency and lipophilic efficiency. A hybrid MD–docking and scoring scheme, FERM-SMD, was used to predict the relative potencies of potential derivatives prior to chemical synthesis.

    7. CONFECT: Conformations from an Expert Collection of Torsion Patterns (pages 1690–1700)

      Christin Schärfer, Dr. Tanja Schulz-Gasch, Dr. Jérôme Hert, Lennart Heinzerling, Benjamin Schulz, Therese Inhester, Dr. Martin Stahl and Prof. Dr. Matthias Rarey

      Article first published online: 8 AUG 2013 | DOI: 10.1002/cmdc.201300242

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      We can generate low-energy conformational ensembles based on an expert-driven collection of torsion angle preferences derived from an experimental crystal structure database of small molecules (CSD). This allows us to decrease the ensemble size relative to current state-of-the-art conformation generators while still exhaustively covering the conformational space that is energetically relevant to the drug design process.

    8. Interactions of the Multidrug Resistance Modulators Tariquidar and Elacridar and their Analogues with P-glycoprotein (pages 1701–1713)

      Prof. Dr. Ilza K. Pajeva, Dr. Katja Sterz, Matthias Christlieb, Dr. Kerstin Steggemann, Federico Marighetti and Prof. Dr. Michael Wiese

      Article first published online: 13 AUG 2013 | DOI: 10.1002/cmdc.201300233

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      How do they do it? Tariquidar (magenta) and elacridar (green) are two of the most potent known inhibitors of P-glycoprotein (P-gp), but the way in which they interact with this target has not been determined. We pursued structure–activity relationship analyses of tariquidar and elacridar analogues and evaluated their effects on cellular P-gp substrate accumulation to produce results useful for the future design of selective P-gp inhibitors.

  8. Book Reviews

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Minireviews
    6. Highlights
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Drug Discovery: Practices, Processes, and Perspectives. Edited by Jie Jack Li and E. J. Corey (pages 1714–1715)

      Dr. Christoph Boss

      Article first published online: 12 AUG 2013 | DOI: 10.1002/cmdc.201300318

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      Wiley, Hoboken 2013. 570 pp., hardcover, $ 125.00.—ISBN 978-0-470-94235-2

    2. Devalued and Distrusted: Can the Pharmaceutical Industry Restore its Broken Image?. By John L. LaMattina (pages 1715–1716)

      Dr. Mike Hann

      Article first published online: 19 JUL 2013 | DOI: 10.1002/cmdc.201300279

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      Wiley, Hoboken 2013. 136 pp., softcover, $29.95.—ISBN 978-1-11848-747-1

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