ChemMedChem

Cover image for Vol. 8 Issue 5

May 2013

Volume 8, Issue 5

Pages 673–860

  1. Cover Pictures

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Viewpoint
    6. Review
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. You have free access to this content
      Cover Picture: tert-Butylcarbamate-Containing Histone Deacetylase Inhibitors: Apoptosis Induction, Cytodifferentiation, and Antiproliferative Activities in Cancer Cells (ChemMedChem 5/2013) (page 673)

      Dr. Sergio Valente, Dr. Daniela Trisciuoglio, Dr. Maria Tardugno, Dr. Rosaria Benedetti, Dr. Donatella Labella, Prof. Daniela Secci, Dr. Ciro Mercurio, Dr. Roberto Boggio, Dr. Stefano Tomassi, Dr. Salvatore Di Maro, Prof. Ettore Novellino, Prof. Lucia Altucci, Dr. Donatella Del Bufalo, Prof. Antonello Mai and Dr. Sandro Cosconati

      Version of Record online: 26 APR 2013 | DOI: 10.1002/cmdc.201390015

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      The front cover picture shows the 3D homology model of the second catalytic subunit CDII of HDAC6 in complex with a selective tert-butylcarbamate-containing inhibitor as predicted by docking calculations. The protein is represented as yellow ribbons while the ligand as green sticks. When tested against a wide panel of different cancer cell lines (four of them are represented as “planets” in the front cover picture), this compound and its structural congeners showed low or single-digit micromolar antiproliferative effect. Remarkably, against neuroblastoma cell lines, these HDAC inhibitors (HDACis) exerted growth inhibition at nanomolar level, suggesting an additional role for HDAC6 inhibition in neurologic diseases. For more details, see the Full Paper by Lucia Altucci, Donatella Del Bufalo, Antonello Mai, Sandro Cosconati et al. on p. 800 ff.

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      Inside Cover: Artemisinin–Polypyrrole Conjugates: Synthesis, DNA Binding Studies and Preliminary Antiproliferative Evaluation (ChemMedChem 5/2013) (page 674)

      Dr. Louise La Pensée, Dr. Sunil Sabbani, Dr. Raman Sharma, Dr. Inder Bhamra, Emma Shore, Dr. Amy E. Chadwick, Dr. Neil G. Berry, James Firman, Dr. Nuna C. Araujo, Lília Cabral, Prof. Maria L. S. Cristiano, Cerys Bateman, Dr. Omar Janneh, Adelina Gavrila, Yi Hang Wu, Afthab Hussain, Prof. Stephen A. Ward, Dr. Paul A. Stocks, Prof. Rick Cosstick and Prof. Paul M. O'Neill

      Version of Record online: 26 APR 2013 | DOI: 10.1002/cmdc.201390016

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      The inside cover picture shows a DNA-targeting artemisinin–netropsin drug conjugate docked into d(CGCGAATTCGCG) duplex DNA (PDB code: 1D86). The conjugate combines a trioxane warhead and a minor groove binder joined through a phenyl linker. For more details, see the Communication by Paul M. O'Neill et al. on p. 709 ff.

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      Back Cover: Crystal Structures of a Bioactive 6′-Hydroxy Variant of Sisomicin Bound to the Bacterial and Protozoal Ribosomal Decoding Sites (ChemMedChem 5/2013) (page 864)

      Dr. Jiro Kondo, Mai Koganei, Juan Pablo Maianti, Vu Linh Ly and Prof. Stephen Hanessian

      Version of Record online: 26 APR 2013 | DOI: 10.1002/cmdc.201390019

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      The back cover picture shows a sandfly, the insect carrying the parasite Leishmania donovani as a promastigote, which is responsible for parasitic infections in humans. The semi-synthetic 6′-hydroxysisomicin is shown bound to the A-site of the protozoal RNA, thus interfering with the protein synthesis machinery. For more details, see the Full Paper by Jiro Kondo, Stephen Hanessian et al. on p. 733 ff.

  2. Graphical Abstract

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

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

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

    1. Top of page
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    4. News
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    6. Review
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Small-Molecule Regulators of Autophagy and Their Potential Therapeutic Applications (pages 694–707)

      Mi Zhou and Prof. Renxiao Wang

      Version of Record online: 8 APR 2013 | DOI: 10.1002/cmdc.201200560

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      Self-consumption: Autophagy plays an important role in maintaining normal cellular homeostasis. Growing evidence indicates that autophagy is associated with a variety of diseases such as cancer, making genes in autophagic pathways potential drug targets. However, given the dual role of autophagy in tumorigenesis, whether to induce or inhibit autophagy as a cancer treatment is a complicated issue that depends on tumor genotype, stage of tumor progression, and types of stress.

  6. Communications

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Viewpoint
    6. Review
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Artemisinin–Polypyrrole Conjugates: Synthesis, DNA Binding Studies and Preliminary Antiproliferative Evaluation (pages 709–718)

      Dr. Louise La Pensée, Dr. Sunil Sabbani, Dr. Raman Sharma, Dr. Inder Bhamra, Emma Shore, Dr. Amy E. Chadwick, Dr. Neil G. Berry, James Firman, Dr. Nuna C. Araujo, Lília Cabral, Prof. Maria L. S. Cristiano, Cerys Bateman, Dr. Omar Janneh, Adelina Gavrila, Yi Hang Wu, Afthab Hussain, Prof. Stephen A. Ward, Dr. Paul A. Stocks, Prof. Rick Cosstick and Prof. Paul M. O'Neill

      Version of Record online: 11 MAR 2013 | DOI: 10.1002/cmdc.201200536

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      Greater than the sum of its parts: Artemisinins are currently in phase I–II clinical trials against breast, colorectal and non-small-cell lung cancers. In an attempt to offer increased specificity, a series of hybrid artemisinin–polypyrrole minor groove binder conjugates are described. DNA binding/modelling studies and preliminary biological evaluation give insights into their mechanism of action and the potential of this strategy.

    2. Enhanced Replication of R5 HIV-1 Isolates in vitro by a Small-Molecule Reagent Targeting HIV-1 Protease (pages 719–721)

      Dr. Nick J. Wardle, Prof. Harry R. Hudson, Prof. Ray W. Matthews, Dr. Christine M. Nunn, Dr. Cherelyn Vella and Prof. S. W. Annie Bligh

      Version of Record online: 18 MAR 2013 | DOI: 10.1002/cmdc.201300051

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      Chemical enhancement: Designed to target HIV-1 protease, a novel γ-hydroxyphosphonate has been found to significantly enhance viral replication in a panel of clinically relevant R5 HIV-1 isolates. This unexpected result constitutes the first instance of a small molecule capable of doing this, and it has implications for the preparation and use of R5 isolates in vaccine and drug development.

    3. Synthesis and Hepatitis C Antiviral Activity of 1-Aminobenzyl-1H-indazole-3-carboxamide Analogues (pages 722–725)

      Jing-Jing Shi, Fei-Hong Ji, Pei-Lan He, Ya-xi Yang, Wei Tang, Prof. Jian-Ping Zuo and Prof. Yuan-Chao Li

      Version of Record online: 19 MAR 2013 | DOI: 10.1002/cmdc.201300083

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      Fighting HCV: Two potent antiviral analogues were developed from a previously identified lead as novel agents against hepatitis C virus. Their potency and selectivity (5 n: IC50=0.013 μM and EC50=0.018 μM; 5 t: IC50=0.007 μM and EC50=0.024 μM) make them good candidates for further development as antiviral agents.

    4. Design of Libraries Targeting Protein–Protein Interfaces (pages 726–732)

      Dr. David Fry, Dr. Kuo-Sen Huang, Dr. Paola Di Lello, Dr. Peter Mohr, Prof. Klaus Müller, Dr. Sung-Sau So, Dr. Takeo Harada, Dr. Martin Stahl, Dr. Binh Vu and Dr. Harald Mauser

      Version of Record online: 21 FEB 2013 | DOI: 10.1002/cmdc.201200540

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      Targeting PPIs: A novel strategy for designing libraries targeting protein–protein interfaces enabled us to identify diverse chemical entry points to interact with therapeutic targets for which conventional screening libraries delivered no or only few hit structures. The concept was experimentally validated by early hit evaluation in biochemical screens and early ADMET profiling.

  7. Full Papers

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Viewpoint
    6. Review
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Crystal Structures of a Bioactive 6′-Hydroxy Variant of Sisomicin Bound to the Bacterial and Protozoal Ribosomal Decoding Sites (pages 733–739)

      Dr. Jiro Kondo, Mai Koganei, Juan Pablo Maianti, Vu Linh Ly and Prof. Stephen Hanessian

      Version of Record online: 21 FEB 2013 | DOI: 10.1002/cmdc.201200579

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      Activity explained: The crystal structure of 6′-hydroxysisomicin bound to the protozoal ribosomal A-site provides structural insight into the molecular mechanisms through which it derives its antiprotozoal activity. The key interactions for specific binding are a pseudo pair and a stacking from the unsaturated ring I of the aminoglycoside to G1408 and G1491 of the ribosomal RNA, respectively. These interactions are distinct to those with bacterial rRNA.

    2. Comparative Binding Energy (COMBINE) Analysis for Understanding the Binding Determinants of Type II Dehydroquinase Inhibitors (pages 740–747)

      Antonio Peón, Dr. Claire Coderch, Prof. Federico Gago and Prof. Concepción González-Bello

      Version of Record online: 1 MAR 2013 | DOI: 10.1002/cmdc.201300013

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      Interactions driving inhibition: QSAR studies conducted with type II dehydroquinase (DHQ2) inhibitors from H. pylori and M. tuberculosis support the importance of H-bonding interactions between the inhibitors and the water molecule involved in the DHQ2 reaction mechanism. These studies identified important differences in ligand interactions with the interface pocket close to the active site for both DHQ2 enzymes.

    3. Protein Contacts and Ligand Binding in the Inward-Facing Model of Human P-Glycoprotein (pages 748–762)

      Prof. Dr. Ilza K. Pajeva, Markus Hanl and Prof. Dr. Michael Wiese

      Version of Record online: 5 APR 2013 | DOI: 10.1002/cmdc.201200491

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      Building networks: Contacts were analyzed between residues in the nucleotide binding domains (NBDs) and at the NBD–transmembrane domain (TMD) interfaces in the inward-facing structural model of human P-glycoprotein. The results reveal possible ways of communication between NBDs and TMDs through the intracellular, X-, and Q-loops and point to differences between both NBDs in the way of networking. Several binding pockets involving residues important for interdomain communication were identified, and binding sites were proposed for rhodamine 123 (R-site) and prazosin (regulatory site), in agreement with experimental data.

    4. Potent Agonists of a Hematopoietic Stem Cell Cytokine Receptor, c-Mpl (pages 763–771)

      Dr. Anna Tarasova, Prof. David N. Haylock, Dr. Laurence Meagher, Cheang Ly Be, Jacinta White, Prof. Susan K. Nilsson, Dr. Jessica Andrade, Kellie Cartledge and Prof. David A. Winkler

      Version of Record online: 28 MAR 2013 | DOI: 10.1002/cmdc.201300089

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      Boosting TPO effects: Through sequence analysis, mutation experiments, and computational studies, we developed a series of peptides with very high c-Mpl agonist activity and high efficacy relative to recombinant human thrombopoietin. One of our peptides potently stimulates megakaryocyte differentiation of primary hematopoietic stem cells in vitro. It is also highly active in vivo, resulting in an increase in megakaryocyte ploidy and platelet counts in mice.

    5. Impact of the Proline Residue on Ligand Binding of Neurotensin Receptor 2 (NTS2)-Selective Peptide–Peptoid Hybrids (pages 772–778)

      Dr. Cornelia Held, Dr. Harald Hübner, Ralf Kling, Dr. Yvonne A. Nagel, Prof. Dr. Helma Wennemers and Prof. Dr. Peter Gmeiner

      Version of Record online: 26 MAR 2013 | DOI: 10.1002/cmdc.201300054

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      Proline surrogates: Peptide–peptoid hybrids 2 d, 3 a,b showed substantial NTS2 binding affinity (Ki=8.1–16 nM) and 2400–8600-fold selectivity along with constitutive activity exceeding 1.7–2.0 times the activity of NT(8–13) in an IP accumulation assay. As NTS2 is involved in modulation of tonic pain sensitivity, selective NTS2 ligands could be useful antinociceptives that avoid the side effects of opioid-mediated analgesia.

    6. You have full text access to this OnlineOpen article
      Synthesis and Structure–Activity Relationship Studies of Derivatives of the Dual Aromatase–Sulfatase Inhibitor 4-{[(4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl}phenyl sulfamate (pages 779–799)

      L. W. Lawrence Woo, Paul M. Wood, Christian Bubert, Mark P. Thomas, Atul Purohit and Barry V. L. Potter

      Version of Record online: 11 MAR 2013 | DOI: 10.1002/cmdc.201300015

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      A new head! Derivatives of dual steroid sulfatase and aromatase inhibitor 4-{[(4-cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl}phenyl sulfamate were prepared, leading to a range of SAR information and a highly potent (in vitro) imidazole congener which can be further developed for potential use in treating hormone-dependent diseases.

    7. tert-Butylcarbamate-Containing Histone Deacetylase Inhibitors: Apoptosis Induction, Cytodifferentiation, and Antiproliferative Activities in Cancer Cells (pages 800–811)

      Dr. Sergio Valente, Dr. Daniela Trisciuoglio, Dr. Maria Tardugno, Dr. Rosaria Benedetti, Dr. Donatella Labella, Prof. Daniela Secci, Dr. Ciro Mercurio, Dr. Roberto Boggio, Dr. Stefano Tomassi, Dr. Salvatore Di Maro, Prof. Ettore Novellino, Prof. Lucia Altucci, Dr. Donatella Del Bufalo, Prof. Antonello Mai and Dr. Sandro Cosconati

      Version of Record online: 25 MAR 2013 | DOI: 10.1002/cmdc.201300005

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      Cell-cycle arrest warrant: Novel pyrrole- and benzene-based hydroxamates and 2′-aminoanilides bearing the tert-butylcarbamate group at the CAP moiety are shown to be HDAC inhibitors. Two compounds, 8 b and 10 c, selectively inhibit HDAC6 at nanomolar levels and display high levels of apoptosis induction in human leukemia U937 cells. In tests against a panel of cancer cells, 10 c showed inhibition of cell proliferation at sub- to low-micromolar concentrations; further studies are needed to assess its anticancer value in vivo.

    8. Library Construction and Biological Evaluation of Enmein-Type Diterpenoid Analogues as Potential Anticancer Agents (pages 812–818)

      Dr. Dahong Li, Dr. Shengtao Xu, Hao Cai, Lingling Pei, Dr. Lei Wang, Prof. Xiaoming Wu, Prof. Hequan Yao, Prof. Jieyun Jiang, Yijun Sun and Prof. Jinyi Xu

      Version of Record online: 20 MAR 2013 | DOI: 10.1002/cmdc.201200559

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      Dosing with diterpenoids: A synthetic library of enmein-type diterpenoid derivatives with potent antitumor activities was constructed by using commercially available starting materials. The analogue shown here exhibits potent in vitro and in vivo activities and suitable chemical properties similar to or exceeding those of the parent compound, warranting further preclinical investigations for potential diterpenoid-based anticancer agents.

    9. An Array of Bengamide E Analogues Modified at the Terminal Olefinic Position: Synthesis and Antitumor Properties (pages 819–831)

      Dr. Francisca Martín-Gálvez, Cristina García-Ruiz, Dr. Antonio Sánchez-Ruiz, Dr. Frederick A. Valeriote and Prof. Dr. Francisco Sarabia

      Version of Record online: 19 MAR 2013 | DOI: 10.1002/cmdc.201300033

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      Better than the real thing: A small library of bengamide E analogues was synthesized and evaluated for cytotoxicity against various tumor cell lines. This led to the identification of an analogue more potent than natural bengamide E, in which the isopropyl group, located at the terminal olefinic position, is replaced by a cyclopentyl group.

    10. Synthesis and Cytostatic and Antiviral Activities of 2′-Deoxy-2′,2′-difluororibo- and 2′-Deoxy-2′-fluororibonucleosides Derived from 7-(Het)aryl-7-deazaadenines (pages 832–846)

      Dr. Pavla Perlíková, Ludovic Eberlin, Petra Ménová, Veronika Raindlová, Dr. Lenka Slavětínská, Eva Tloušťová, Dr. Gina Bahador, Dr. Yu-Jen Lee and Prof. Dr. Michal Hocek

      Version of Record online: 4 APR 2013 | DOI: 10.1002/cmdc.201300047

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      Sugar modified: Fluorinated analogues of 7-(het)aryl-7-deazaadenines were synthesized, and these nucleosides showed micromolar cytostatic activity against cancer cell lines and moderate anti-HCV activity. The corresponding nucleoside 5′-O-triphosphates were found to be good substrates for bacterial DNA polymerases, but are inhibitors of human polymerase α.

    11. 2-Aminothiazoles with Improved Pharmacotherapeutic Properties for Treatment of Prion Disease (pages 847–857)

      Prof. Dr. Zhe Li, Prof. Dr. B. Michael Silber, Prof. Dr. Satish Rao, Prof. Dr. Joel R. Gever, Clifford Bryant, Dr. Alejandra Gallardo-Godoy, Dr. Elena Dolghih, Kartika Widjaja, Manuel Elepano, Prof. Dr. Matthew P. Jacobson, Prof. Dr. Stanley B. Prusiner and Prof. Dr. Adam R. Renslo

      Version of Record online: 18 MAR 2013 | DOI: 10.1002/cmdc.201300007

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      Fighting a bad fold: 2-Aminothiazoles are orally available small molecules with antiprion activity in neuroblastoma cell lines. Herein we describe the optimization of potency and in vivo pharmacokinetic properties for this compound series. We identified analogues such as 15, which exhibit excellent antiprion potency in ScN2a-cl3 cells and high brain exposure in mice following oral administration. Compounds such as 15 represent excellent candidates for evaluation in animal models of prion disease.

  8. Book Reviews

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Viewpoint
    6. Review
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. ADME-Enabling Technologies in Drug Design and Development. Edited by Donglu Zhang and Sekhar Surapaneni (page 858)

      Prof. Dr. Jos H. Beijnen

      Version of Record online: 10 FEB 2013 | DOI: 10.1002/cmdc.201300038

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      Wiley, Hoboken 2012. 622 pp., hardcover, $175.00.—ISBN 978-0-470-54278-1

    2. Organic Chemistry of Drug Degradation. Authored by Min Li (pages 858–859)

      Prof. Dr. Mario Thevis

      Version of Record online: 19 MAR 2013 | DOI: 10.1002/cmdc.201300109

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      RSC, Cambridge 2012. 336 pp., hardcover, £153.99.—ISBN 978-1-84973-421-9

    3. Therapeutic Targets: Modulation, Inhibition, and Activation. Edited by Luis M. Botana and Mabel Loza (pages 859–860)

      Dr. Ian Churcher

      Version of Record online: 19 MAR 2013 | DOI: 10.1002/cmdc.201300110

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      Wiley, Hoboken 2012. 502 pp., hardcover, $149.95.—ISBN 978-0-470-58719-5

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