ChemMedChem

Cover image for Vol. 2 Issue 12

December 10, 2007

Volume 2, Issue 12

Pages 1661–1838

  1. Cover Picture

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Highlight
    8. Communications
    9. Full Papers
    10. Preview
    11. Index
    1. Cover Picture: Vitamin B12 as a Carrier for the Oral Delivery of Insulin (ChemMedChem 12/2007) (page 1661)

      Amanda K. Petrus, Anthony R. Vortherms, Timothy J. Fairchild and Robert P. Doyle

      Version of Record online: 29 NOV 2007 | DOI: 10.1002/cmdc.200790041

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      The cover picture shows an orally active, glucose-lowering vitamin B12–insulin conjugate bound to the B12 uptake protein transcobalamin II (TCII). The inset shows a close-up view of the TCII binding pocket. (Insulin is in red; vitamin B12 is in bright yellow.) For details, see the Communication by T. J. Fairchild, R. P. Doyle, et al. on p. 1717 ff.

  2. Graphical Abstract

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Highlight
    8. Communications
    9. Full Papers
    10. Preview
    11. Index
    1. You have free access to this content
  3. News

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

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Highlight
    8. Communications
    9. Full Papers
    10. Preview
    11. Index
    1. Molecules that Target beta-Amyloid (pages 1674–1692)

      Cliff I. Stains, Kalyani Mondal and Indraneel Ghosh

      Version of Record online: 19 OCT 2007 | DOI: 10.1002/cmdc.200700140

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      Targeting amyloid. A review of molecules that target β-amyloid (Aβ) is presented. Particular attention is given to natural protein ligands, Aβ-derived peptides and peptidomimetics, anti-Aβ antibodies, in vitro anti-Aβ selected peptides and proteins, and small molecules that bind Aβ. Moreover, the described anti-amyloid molecular toolbox will also provide an avenue for the design of new diagnostic and therapeutic reagents.

  5. Minireview

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Highlight
    8. Communications
    9. Full Papers
    10. Preview
    11. Index
    1. The Trifluoroethylamine Function as Peptide Bond Replacement (pages 1693–1700)

      Monica Sani, Alessandro Volonterio and Matteo Zanda

      Version of Record online: 6 SEP 2007 | DOI: 10.1002/cmdc.200700156

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      3D instead of 2D. That's the main difference between the tetrahedral stereogenic trifluoroethylamine function and the planar peptide bond. This property, together with other remarkable features such as high metabolic stability and low basicity, turns out to be of great importance to allow trifluoroethylamines to be excellent peptide bond replacements.

  6. Highlight

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Highlight
    8. Communications
    9. Full Papers
    10. Preview
    11. Index
    1. Allergic Contact Dermatitis and the Endocannabinoid System: From Mechanisms to Skin Care (pages 1701–1702)

      Didier M. Lambert

      Version of Record online: 17 SEP 2007 | DOI: 10.1002/cmdc.200700168

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      A therapeutic endocannabinoid-based strategy could be useful in numerous and diverse pathological conditions, including CNS disorders, cancer, and cardiovascular diseases. However, Karsak et al. have explored a poorly investigated area: the endocannabinoid system and its abilitly to elicit a protective role in allergic contact dermatitis. Herein, the significance of this work is discussed.

  7. Communications

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Highlight
    8. Communications
    9. Full Papers
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    11. Index
    1. Biologically Stable 2-5A Analogues containing 3′-O,4′-C-bridged Adenosine as Potent RNase L Agonists (pages 1703–1707)

      Koji Morita , Masakatsu Kaneko, Satoshi Obika, Takeshi Imanishi, Yukio Kitade and Makoto Koizumi 

      Version of Record online: 1 OCT 2007 | DOI: 10.1002/cmdc.200700150

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      2′,5′-Oligoadenylate 5′-triphosphate, referred to as 2-5A, plays an important role in an interferon-regulated RNA degradation pathway with antiviral, growth-inhibitory, and apoptotic activities in mammalian cells. However, its short half-life limits its therapeutic usefulness. Herein, we describe 2-5 A analogues synthesized to be more biologically stable and therefore may be developed as chemotherapeutics for viral diseases and cancer.

    2. Betraying the Parasite’s Redox System: Diaryl Sulfide-Based Inhibitors of Trypanothione Reductase: Subversive Substrates and Antitrypanosomal Properties (pages 1708–1712)

      Bernhard Stump, Marcel Kaiser, Reto Brun, R. Luise Krauth-Siegel and François Diederich

      Version of Record online: 8 OCT 2007 | DOI: 10.1002/cmdc.200700172

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      Subversive substrates. Replacing the 3,4-dichlorophenyl entity of diphenyl sulfide-based trypanothione reductase (TR) inhibitors for a nitrofuran moiety led to a new class of inhibitors with a distinctively changed inhibition mode. These ligands do not only undergo mixed competitive–uncompetitive inhibition but additionally act as subversive substrates for TR.

    3. On the Absolute Configuration in 1,4-Dihydrothiazepine Covalent Complexes Derived from Inhibition of Class A and C β-Lactamases with 6-Methylidene Penems (pages 1713–1716)

      Tarek S. Mansour, Atul Agarwal, Aranapakam Venkatesan, Takao Abe, Ado Mihira, Tsuyoshi Takasaki, Koichi Sato, Hideki Ushirogochi, Itsuki Yamamura, Takeshi Isoda, Zhong Li, Youjun Yang and Toshio Kumagai

      Version of Record online: 17 SEP 2007 | DOI: 10.1002/cmdc.200700144

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      Bacterial resistance is addressed clinically by combining a β-lactamase inhibitors with a β-lactam antibiotic. Whereas this strategy is effective with the class A β-lactamase inhibitors, there is an urgent need to extend the spectrum of activity to the other classes of serine β-lactamases. Interaction energies and modeling studies on penem inhibitors described herein, show that β-lactamases of the different classes prefer different stereochemistries.

    4. Vitamin B12 as a Carrier for the Oral Delivery of Insulin (pages 1717–1721)

      Amanda K. Petrus, Anthony R. Vortherms, Timothy J. Fairchild and Robert P. Doyle

      Version of Record online: 25 SEP 2007 | DOI: 10.1002/cmdc.200700239

      Thumbnail image of graphical abstract

      The noninvasive delivery of insulin continues to be a major goal for the treatment of diabetes mellitus. Oral–enteric administration would make insulin delivery easier and more effective, as higher patient compliance and improved glycemic control are likely; yet the oral–enteric pathway has been unfeasible owing to insulin's susceptibility to proteolytic degradation and inefficient enteric uptake. Herein we show that a noninvasive oral delivery route for insulin is possible through the vitamin B12 uptake pathway. In diabetic rat models, insulin–B12 conjugates can significantly lower blood glucose levels when administered orally.

  8. Full Papers

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Highlight
    8. Communications
    9. Full Papers
    10. Preview
    11. Index
    1. Chiral Salicyl Diamines: Potent Anticancer Molecules (pages 1723–1729)

      Jian Gao , Ya-Guang Liu, Yaqing Zhou and Ralph A. Zingaro

      Version of Record online: 17 OCT 2007 | DOI: 10.1002/cmdc.200700049

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      A grand challenge for chemical biologists involves the identification of small molecules that can effectively manipulate the transcription of encoded genes in cancer cells. Chiral N,N′-bis-salicyl diamino compounds have now been identified as an effective anticancer agent in the downregulation of Bcl-2 family gene expression in human breast cancer cells.

    2. Stereochemical and Steric Control of the UDP-Glucuronosyltransferase-Catalyzed Conjugation Reaction: A Rational Approach for the Design of Inhibitors for the Human UGT2B7 (pages 1730–1740)

      Ingo Bichlmaier, Moshe Finel, Wolfgang Sippl and Jari Yli-Kauhaluoma

      Version of Record online: 17 OCT 2007 | DOI: 10.1002/cmdc.200700122

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      Detailed structure–activity relationships for the design of potent inhibitors for UGT isoforms have not been reported to date. This study provides a rational approach for the design of potent inhibitors for the UGT-isoform 2B7 based on the analysis of functional, stereochemical, and steric properties of a large set of tricyclic sesquiterpenoid derivatives.

    3. Synthesis, Enantiomeric Resolution, and Structure–Activity Relationship Study of a Series of 10,11-Dihydro-5H-Dibenzo[a,d]cycloheptene MT2 Receptor Antagonists (pages 1741–1749)

      Gilberto Spadoni, Annalida Bedini, Giuseppe Diamantini, Giorgio Tarzia, Silvia Rivara, Simone Lorenzi, Alessio Lodola, Marco Mor, Valeria Lucini, Marilou Pannacci, Alessia Caronno and Franco Fraschini

      Version of Record online: 28 SEP 2007 | DOI: 10.1002/cmdc.200700141

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      Tricyclic melatonin receptor antagonists: a series of MT2 melatonin receptor antagonists, characterized by a 10,11-dihydro-5H-dibenzo[a,d]cycloheptene scaffold, were synthesized, and SARs were investigated. Enantiomeric resolution by MPLC allowed the testing of enantiomer selectivity, and docking studies with the MT2 receptor suggested possible binding modes.

    4. Combining Computational and Biochemical Studies for a Rationale on the Anti-Aromatase Activity of Natural Polyphenols (pages 1750–1762)

      Marco A. C. Neves, Teresa C. P. Dinis, Giorgio Colombo and M. Luisa Sá e Melo

      Version of Record online: 1 OCT 2007 | DOI: 10.1002/cmdc.200700149

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      New strong aromatase inhibitors were identified experimentally. The physicochemical determinants for their productive binding to the active site of the enzyme were characterized through a combination of molecular modeling techniques based on grid-independent descriptors, molecular interaction fields and docking into the 3D homology model structure of the enzyme.

    5. Virtual Screening for Selective Allosteric mGluR1 Antagonists and Structure–Activity Relationship Investigations for Coumarine Derivatives (pages 1763–1773)

      Tobias Noeske, Aigars Jirgensons, Igors Starchenkovs, Steffen Renner, Ieva Jaunzeme, Dina Trifanova, Mirko Hechenberger, Tanja Bauer, Valerjans Kauss, Christopher G. Parsons, Gisbert Schneider and Tanja Weil

      Version of Record online: 17 SEP 2007 | DOI: 10.1002/cmdc.200700151

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      Courmarine mGluR1 antagonists. The important role of allosteric antagonists of metabotropic glutamate receptors (mGluRs) in diseases involving neurodegeneration, anxiety, pain, epilepsy, neuroprotection, and schizophrenia has been investigated. A virtual screening study and activity optimization program of a series of coumarine derivatives facilitated the discovery of novel and subtype selective noncompetitive antagonists of the mGluR1.

    6. Analysis of System Structure–Function Relationships (pages 1774–1782)

      Anton F. Fliri, William T. Loging and Robert A. Volkmann

      Version of Record online: 19 OCT 2007 | DOI: 10.1002/cmdc.200700153

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      Improving success rates of new medicines in clinical trials requires the capture, standardization, and comparison of vast amounts of heterogeneous structure–effect information. Herein we describe an approach for relating the molecular structure of medicines to the corresponding “system-wide” effects observed at the cellular and organism levels.

    7. Multispecificity of Drug Transporters: Probing Inhibitor Selectivity for the Human Drug Efflux Transporters ABCB1 and ABCG2 (pages 1783–1788)

      Joerg Cramer, Stephan Kopp, Susan E. Bates, Peter Chiba and Gerhard F. Ecker

      Version of Record online: 12 NOV 2007 | DOI: 10.1002/cmdc.200700160

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      Multidrug resistance transporters ABCB1 and ABCG2 demonstrate broad and partly overlapping ligand specificity. Herein we show that within the chemical scaffold of propafenone-type efflux pump inhibitors, selectivity indices up to 1000 can be obtained by triggering hydrophobicity, number of rotatable bonds, and the number of H-bond acceptors.

    8. Alkoxymethylenephosphonate Analogues of (Lyso)phosphatidic Acid Stimulate Signaling Networks Coupled to the LPA2 Receptor (pages 1789–1798)

      Joanna Gajewiak, Ryoko Tsukahara, Tamotsu Tsukahara, Shuanxing Yu, Yiling Lu, Mandi Murph, Gordon B. Mills, Gabor Tigyi and Glenn D. Prestwich

      Version of Record online: 19 OCT 2007 | DOI: 10.1002/cmdc.200700111

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      Surprising subtype selectivity is observed with alkoxymethylenephosphonate (MP) analogues of lysophosphatidic acid (LPA) and phosphatidic acid (PA) that possess a stabilized phosphonate group, the glyceryl 3-oxygen atom, and the dianionic head group. The MP analogues selectively activate signaling via the LPA2 receptor subtype, while simultaneously suppressing signaling through the LPA1 and LPA3 subtypes.

      Corrected by:

      Corrigendum: Alkoxymethylenephosphonate Analogues of (Lyso)phosphatidic Acid Stimulate Signaling Networks Coupled to the LPA2 Receptor

      Vol. 3, Issue 2, 200, Version of Record online: 8 FEB 2008

    9. Organometallic Ruthenium Inhibitors of Glutathione-S-Transferase P1-1 as Anticancer Drugs (pages 1799–1806)

      Wee Han Ang, Anastasia De Luca, Catherine Chapuis-Bernasconi, Lucienne Juillerat-Jeanneret, Mario Lo Bello and Paul J. Dyson

      Version of Record online: 8 OCT 2007 | DOI: 10.1002/cmdc.200700209

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      Two-pronged attack: By combining organometallic ruthenium fragments with ethacrynic acid, novel inhibitors of glutathione-S-transferase (GST) P1-1 were obtained. The complexes exhibit greater reactivity towards the enzyme and also represent potent anticancer compounds.

    10. 20-(S)-Camptothecin Analogues as DNA Topoisomerase I Inhibitors: A QSAR Study (pages 1807–1813)

      Corwin Hansch and Rajeshwar P. Verma

      Version of Record online: 20 SEP 2007 | DOI: 10.1002/cmdc.200700138

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      Revealing relationships: Quantitative structure–activity relationships were developed for two series of camptothecin derivatives with respect to their DNA topo I inhibition. The results show that these activities of camptothecin derivatives are largely dependent on the hydrophobic (and steric) properties of the molecules/substituents.

    11. Antiproliferative Activity, Cell-Cycle Dysregulation, and Cellular Differentiation: Salicyl- and Catechol-Derived Acyclic 5-Fluorouracil O,N-Acetals against Breast Cancer Cells (pages 1814–1821)

      Juan A. Marchal, Fernando Rodríguez-Serrano, Octavio Caba, Antonia Aránega, Miguel A. Gallo, Antonio Espinosa and Joaquín M. Campos

      Version of Record online: 30 OCT 2007 | DOI: 10.1002/cmdc.200700142

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      Looking for a differentiating agent. The concept of differentiation therapy is based on the conversion of malignant cells to a more benign phenotype using chemical substances. Compounds represented by the formula shown may be useful for differentiation therapy against the MCF-7 human breast cancer cell line.

  9. Preview

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Highlight
    8. Communications
    9. Full Papers
    10. Preview
    11. Index
    1. You have free access to this content
      Preview: ChemMedChem 1/2008 (page 1824)

      Version of Record online: 29 NOV 2007 | DOI: 10.1002/cmdc.200790044

  10. Index

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Highlight
    8. Communications
    9. Full Papers
    10. Preview
    11. Index
    1. Index: ChemMedChem 2007 (pages 1825–1838)

      Version of Record online: 29 NOV 2007 | DOI: 10.1002/cmdc.200790045

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