ChemMedChem

Cover image for Vol. 2 Issue 11

November 12, 2007

Volume 2, Issue 11

Pages 1541–1658

  1. Cover Picture

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
    9. Preview
    1. Cover Picture: Light-Directed Activation of Human T-Cells / Light Activation of Anti-CD3 in vivo Reduces the Growth of an Aggressive Ovarian Carcinoma (ChemMedChem 11/2007) (page 1541)

      Colin H. Self, Alexander C. Self, Jacqueline A. Smith, David J. Self, Stephen Thompson and Robert Stewart

      Article first published online: 2 NOV 2007 | DOI: 10.1002/cmdc.200790037

      Thumbnail image of graphical abstract

      The cover picture shows an impression of a photoactivatable bispecific antibody bound to a tumour. Only the antitumour portion is initially active, allowing tumour cell binding. On irradiation with UV light the T-cell binding site is reactivated, allowing T-cell binding and activation. As anti-T-cell activity is not reactivated outside of the illuminated treatment area, immune activation is highly specific targeted to tumour tissues. For details, see the two back-to-back Communications by C. H. Self, S. Thompson, et al. on pp. 1587 and 1591 ff. (BioTransformations Ltd. Image courtesy of the Centre for Design Research.)

  2. Graphical Abstract

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
    9. Preview
    1. You have free access to this content
      Graphical Abstract: ChemMedChem 11/2007 (pages 1543–1547)

      Article first published online: 2 NOV 2007 | DOI: 10.1002/cmdc.200790038

  3. News

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
    9. Preview
  4. Review

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
    9. Preview
    1. Mu Opioid Receptor Antagonists: Recent Developments (pages 1552–1570)

      Allan J. Goodman, Bertrand Le Bourdonnec and Roland E. Dolle

      Article first published online: 8 OCT 2007 | DOI: 10.1002/cmdc.200700143

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      Modifying morphine. There has been an extensive amount of research performed during the last ten years on mu opioid receptor antagonists. The positive clinical data generated with N-methylnaltrexone and alvimopan has greatly contributed to a renewed interest in this field. In this article we review various chemical classes of mu opioid receptor antagonists and the clinical applications for this class of agents.

  5. Minireview

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
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    1. Novel Inhibitors of Checkpoint Kinase 1 (pages 1571–1585)

      Kenneth L. Arrington and Vadim Y. Dudkin

      Article first published online: 13 SEP 2007 | DOI: 10.1002/cmdc.200700131

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      Inhibition of Chk1 kinase has garnered attention as a possible complement to DNA-damaging chemotherapeutic agents, widening their therapeutic window. As a result, several distinct classes of Chk1 inhibitors have been recently identified with selected compound advancing to clinical trials stage. This review focuses on the challenges and recent progress achieved in this area from a medicinal chemistry perspective.

  6. Communications

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
    9. Preview
    1. Light-Directed Activation of Human T-Cells (pages 1587–1590)

      Colin H. Self, Alexander C. Self, Jacqueline A. Smith, David J. Self and Stephen Thompson

      Article first published online: 2 NOV 2007 | DOI: 10.1002/cmdc.200700200

      Thumbnail image of graphical abstract

      Anti-human CD3 antibodies are rendered inert with a coating of photolabile 2-nitrobenzyl groups until their activity is restored by irradiation with UVA light, at which point the antibodies are free to bind and activate T-cells. Such antibodies should enable the regulation of cytotoxic T-cell activity at required times and locations in the body. This would have widespread medical application, particularly in the treatment of cancer.

    2. Light Activation of Anti-CD3 in vivo Reduces the Growth of an Aggressive Ovarian Carcinoma (pages 1591–1593)

      Stephen Thompson, Robert Stewart, Jacqueline A. Smith and Colin H. Self

      Article first published online: 2 NOV 2007 | DOI: 10.1002/cmdc.200700116

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      A photoactivatable anti-murine CD3 antibody was constructed. When reactivated in vivo in the presence of tumour pieces it markedly reduces the growth of ovarian carcinoma. Such antibodies provide a means to target T-cells with a much higher degree of specificity to tumours, whilst minimising side effects in other non-illuminated areas of the body.

    3. Rapid Synthesis of Iminosugar Derivatives for Cell-Based In Situ Screening: Discovery of “Hit” Compounds with Anticancer Activity (pages 1594–1597)

      Lei Zhang, Fang Sun, Yingxia Li, Xue Sun, Xiaomin Liu, Yingshen Huang, Li-He Zhang, Xin-Shan Ye and Junjun Xiao

      Article first published online: 19 JUL 2007 | DOI: 10.1002/cmdc.200700120

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      Effective and efficacious drug screening methods are imperative in the drug discovery process. A library has been constructed efficiently and followed by in situ cell-based screening without product purification. This method led to discovery of several iminosugar derivatives with anticancer activity.

    4. Semisynthesis and Cytotoxicity of Hypothemycin Analogues (pages 1598–1600)

      Brian R. Hearn, Kurt Sundermann, Jonah Cannoy and Daniel V. Santi

      Article first published online: 9 AUG 2007 | DOI: 10.1002/cmdc.200700128

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      Evaluation of the hypothemycin cytotoxicity SAR identifies the C4′–C8′ region of the macrocyclic lactone as relatively intolerant of structural modifications. Manipulation of the 4-position of the resorcylic acid, however, provides new opportunities to improve solubility and pharmacokinetic properties as this site may be modified without negatively impacting cytotoxicity.

  7. Full Papers

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
    9. Preview
    1. Octa-O-bis-(R,R)-Tartarate Ditellurane (SAS)—a Novel Bioactive Organotellurium(IV) Compound: Synthesis, Characterization, and Protease Inhibitory Activity (pages 1601–1606)

      Sigal Yosef, Miri Brodsky, Benjamin Sredni, Amnon Albeck and Michael Albeck

      Article first published online: 6 AUG 2007 | DOI: 10.1002/cmdc.200700155

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      Synthetic tellurium compounds have protective effects in models of parasitic and viral diseases, autoimmune diseases, kidney diseases, and in protecting dopaminergic neurons and enhancing their function in animal models of Parkinson's disease. This wealth of biological activities prompted us to further develop additional organotellurium compounds with different activity profiles, such as Octa-O-bis-(R,R)-tartarate ditellurane (SAS) described herein.

    2. Amelioration of Hyperglycemia and Metabolic Syndromes in Type 2 Diabetic KKAy Mice by Poly(γ-glutamic acid)oxovanadium(IV) Complex (pages 1607–1612)

      Subarna Karmaker, Tapan K. Saha, Yutaka Yoshikawa and Hiromu Sakurai

      Article first published online: 4 SEP 2007 | DOI: 10.1002/cmdc.200700132

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      Dodging diabetes. Poly(γ-glutamic acid)oxovanadium(IV) complex (VO(γ-pga)) is the first example of orally active oxovanadium(IV)-polymer complex with a VO(O4) coordination environment that is efficacious in the treatment of type 2 diabetes in mice. It has also holds promise for improved treatment of a range of other metabolic disorders.

    3. Designed Amyloid β Peptide Fibril—A Tool for High-Throughput Screening of Fibril Inhibitors (pages 1613–1623)

      Gunnar T. Dolphin, Myriam Ouberai, Pascal Dumy and Julian Garcia

      Article first published online: 17 SEP 2007 | DOI: 10.1002/cmdc.200700103

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      An engineered fibril model associated with Alzheimer's disease, comprising a covalent assembly of four amyloid β peptide (Aβ) fragments, displays important properties for high-throughput screening of compounds that inhibit Aβ fibril formation. With this tool, screening studies are complete within one hour instead of a matter of days, as with native Aβ.

    4. Design, Synthesis, and Pharmacological Evaluation of Mefloquine-Based Ligands as Novel Antituberculosis Agents (pages 1624–1630)

      Jialin Mao, Yuehong Wang, Baojie Wan, Alan P. Kozikowski and Scott G. Franzblau

      Article first published online: 6 AUG 2007 | DOI: 10.1002/cmdc.200700112

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      Tuberculosis is among the top five deadly diseases in developing countries. The current TB chemotherapy regimen requires patients to take three to four drugs for a minimum of six months. The key to shortening the current long regimen lies in effectively targeting this NRP-TB. To this end, we report herein the design and synthesis of mefloquine-based analogues and the evaluation of their activity against R-TB and NRP-TB.

    5. Crystal Structure of the Bacterial Ribosomal Decoding Site Complexed with a Synthetic Doubly Functionalized Paromomycin Derivative: a New Specific Binding Mode to an A-Minor Motif Enhances in vitro Antibacterial Activity (pages 1631–1638)

      Jiro Kondo, Kandasamy Pachamuthu, Boris François, Janek Szychowski, Stephen Hanessian and Eric Westhof

      Article first published online: 27 AUG 2007 | DOI: 10.1002/cmdc.200700113

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      The synthetic paromomycin analogue with the L-haba group and an ether chain with an O-phenethylaminoethyl group could specifically bind to ribosomes in two different modes: 1) the classical binding to the A site and 2) binding to an A-minor motif participating in the recognition of the codon–anticodon helix or in the intersubunit bridges.

    6. Synthesis of Conformationally Constrained Glutamic Acid Homologues and Investigation of Their Pharmacological Profiles (pages 1639–1647)

      Paola Conti, Andrea Pinto, Lucia Tamborini, Giovanni Grazioso, Giovambattista De Sarro, Hans Bräuner-Osborne, Geza Szabo, László Gábor Hársing and Carlo De Micheli

      Article first published online: 11 SEP 2007 | DOI: 10.1002/cmdc.200700118

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      Structurally constrained homologues of glutamic acid were prepared and tested against iGluRs and mGluRs. Amino acid (±)-5 (shown at right, R=CO2H) emerged as a selective group I mGluR antagonist capable of protecting DBA/2 mice from audiogenic seizures after i.c.v. administration.

    7. Fragment Docking to S100 Proteins Reveals a Wide Diversity of Weak Interaction Sites (pages 1648–1654)

      Yvonne Arendt, Anusarka Bhaumik, Rebecca Del Conte, Claudio Luchinat, Mattia Mori and Marco Porcu

      Article first published online: 20 AUG 2007 | DOI: 10.1002/cmdc.200700096

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      NMR screening of two S100 proteins which are potential drug targets has been performed with a fragment library. A relatively large variety of interaction regions for various ligands for the two S100 proteins were identified even applying computer-aided drug design. Our results show that they have only few ligands in common, suggesting that selective leads could be developed starting from the different hits identified in the present work.

  8. Preview

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
    9. Preview
    1. You have free access to this content
      Preview: ChemMedChem 12/2007 (page 1658)

      Article first published online: 2 NOV 2007 | DOI: 10.1002/cmdc.200790040

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