ChemMedChem

Cover image for Vol. 3 Issue 9

September 15, 2008

Volume 3, Issue 9

Pages 1285–1462

  1. Cover Picture

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Minireview
    6. Communications
    7. Full Papers
    8. Book Review
    9. Preview
    1. Cover Picture: Intracellular uptake and inhibitory activity of aromatic fluorinated amino acids in human breast cancer cells (ChemMedChem 9/2008) (page 1285)

      Christoph Giese, Sandra Lepthien, Linda Metzner, Matthias Brandsch, Nediljko Budisa and Hauke Lilie

      Version of Record online: 5 SEP 2008 | DOI: 10.1002/cmdc.200890034

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      The cover picture shows fluorinated aromatic amino acids that exhibit cytostatic activity on tumor cells. These amino acid derivatives are taken up by the cells via the amino acid transport system L. This active process results in a 70-fold accumulation of the fluorinated aromatic amino acids within the cell relative to the surrounding media, which explains why they are biologically active with quite low EC50 values. For details, see the Full Paper by N. Budisa, H. Lilie, et al. on p. 1449 ff.

  2. Graphical Abstract

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

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

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Minireview
    6. Communications
    7. Full Papers
    8. Book Review
    9. Preview
    1. Structure–Activity Relationships of Phenylalkylamines as Agonist Ligands for 5-HT2A Receptors (pages 1299–1309)

      Antoni R. Blaazer, Pieter Smid and Chris G. Kruse

      Version of Record online: 30 JUL 2008 | DOI: 10.1002/cmdc.200800133

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      Agonist activation of 5-HT2Areceptors has become therapeutically interesting. Substituted phenylalkylamines are the most suitable agonists for the study of 5-HT2A receptor activation. This minireview summarizes the structure–activity relationships of phenylalkylamines as agonist ligands for the 5-HT2A receptor.

  5. Communications

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Minireview
    6. Communications
    7. Full Papers
    8. Book Review
    9. Preview
    1. Superparamagnetic Iron Oxide Nanoparticle–Aptamer Bioconjugates for Combined Prostate Cancer Imaging and Therapy (pages 1311–1315)

      Andrew Z. Wang, Vaishali Bagalkot, Christophoros C. Vasilliou, Frank Gu, Frank Alexis, Liangfang Zhang, Mariam Shaikh, Kai Yuet, Michael J. Cima, Robert Langer, Philip W. Kantoff, Neil H. Bander, Sangyong Jon and Omid C. Farokhzad

      Version of Record online: 9 JUL 2008 | DOI: 10.1002/cmdc.200800091

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      Multifunctional superparamagnetic iron oxide nanoparticles: Herein we report a novel, targeted, iron oxide nanoparticle for combined prostate cancer imaging and therapy. By conjugating an aptamer to a thermally stable iron oxide nanoparticle, we have demonstrated that bioconjugates can detect prostate cancer cells with high sensitivity and specificity. Furthermore, the bioconjugates can be used to deliver targeted chemotherapy.

    2. Rational Design and Synthesis of 2,2-Bisheterocycle Tandem Derivatives as Non-Nucleoside Hepatitis B Virus Inhibitors (pages 1316–1321)

      Hai-Jun Chen, Wen-Long Wang, Gui-Feng Wang, Li-Ping Shi, Min Gu, Yu-Dan Ren, Li-Fei Hou, Pei-Lan He, Feng-Hua Zhu, Xian-Gen Zhong, Wei Tang, Jian-Ping Zuo and Fa-Jun Nan

      Version of Record online: 28 JUL 2008 | DOI: 10.1002/cmdc.200800136

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      Non-nucleoside tandem derivatives: Potent hepatitis B antiviral activity is established for 2,2′-bisthiazole heterocyclic derivatives. The core structure of these compounds differs from those of known non-nucleoside hepatitis B antiviral agents, constituting a new direction in hepatitis B virus drug development.

  6. Full Papers

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Minireview
    6. Communications
    7. Full Papers
    8. Book Review
    9. Preview
    1. Computer-Aided Design and Synthesis of Nonpeptidic Plasmepsin II and IV Inhibitors (pages 1323–1336)

      Torsten Luksch, Nan-Si Chan, Sascha Brass, Christoph A. Sotriffer, Gerhard Klebe and Wibke E. Diederich

      Version of Record online: 27 AUG 2008 | DOI: 10.1002/cmdc.200700270

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      Computer-aided inhibitor design: Nonpeptidic inhibitors of the aspartic proteases plasmepsin II and IV were developed that bear a tetrahydro-1H-azepine scaffold. Structural modifications of the initial lead in a consecutive design cycle led to inhibitors with affinities in the nanomolar range. The Ki values are generally in good agreement with the design hypothesis, thus supporting the predicted binding mode for both plasmepsins.

    2. Targeting the Open-Flap Conformation of HIV-1 Protease with Pyrrolidine-Based Inhibitors (pages 1337–1344)

      Jark Böttcher, Andreas Blum, Stefanie Dörr, Andreas Heine, Wibke E. Diederich and Gerhard Klebe

      Version of Record online: 21 AUG 2008 | DOI: 10.1002/cmdc.200800113

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      Although HIV-1 protease exhibits high flexibility, all approved drugs target virtually the same protein conformation. Herein we report novel symmetric pyrrolidine-based inhibitors addressing the open-flap conformation of the protease. The co-crystal structure of one derivative provides a valuable starting point for further development of HIV protease inhibitors.

    3. Small-Molecule Negative Modulators of Adrenomedullin: Design, Synthesis, and 3D-QSAR Study (pages 1345–1355)

      Virginia Roldós, Sonsoles Martín-Santamaría, Miguel Julián, Alfredo Martínez, Laurence Choulier, Danièle Altschuh, Beatriz de Pascual-Teresa and Ana Ramos

      Version of Record online: 29 AUG 2008 | DOI: 10.1002/cmdc.200800066

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      The synthesis of a series of adrenomedullin (AM) modulators was carried out. A competitive AM monoclonal antibody assay and SPR measurements were used to evaluate the affinity of these compounds toward AM. A 3D-QSAR study highlighted essential features for AM binding, and the derived model is a valuable tool in the design of new derivatives.

    4. A Flexible Method for the Conjugation of Aminooxy Ligands to Preformed Complexes of Nucleic Acids and Lipids (pages 1356–1361)

      James G. Hecker, Gideon O. Berger, Keith A. Scarfo, Shaomin Zou and Michael H. Nantz

      Version of Record online: 30 JUL 2008 | DOI: 10.1002/cmdc.200800084

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      Attachment of ligands to DNA or RNA delivery systems is a promising strategy for targeted applications. We report the conjugation of a ligand directly onto lipid–nucleic acid complexes using an oximation approach. Simple incubation of DMDK lipoplexes with an aminooxy reagent labeled the lipoplexes without sacrificing transfection efficiency.

    5. Synthesis and Biological Evaluation of N-Acylhydrazones as Inhibitors of MurC and MurD Ligases (pages 1362–1370)

      Roman Šink, Andreja Kovač, Tihomir Tomašić, Veronika Rupnik, Audrey Boniface, Julieanne Bostock, Ian Chopra, Didier Blanot, Lucija Peterlin Mašič, Stanislav Gobec and Anamarija Zega

      Version of Record online: 24 JUL 2008 | DOI: 10.1002/cmdc.200800087

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      Targeting pathogen resistance: There is an urgent need to improve existing compounds and to develop new antimicrobial drugs in the battle against infectious diseases because of the increase in multidrug-resistant bacteria. As Mur ligases have an essential role in the intracellular biosynthesis of bacterial peptidoglycan, they represent attractive targets for the design of novel antibacterials.

    6. Evaluation of Solvent Accessibility Epitopes for Different Dehydrogenase Inhibitors (pages 1371–1376)

      Christian Ludwig, Paulus J. A. Michiels, Alessia Lodi, John Ride, Chris Bunce and Ulrich L. Günther

      Version of Record online: 24 JUN 2008 | DOI: 10.1002/cmdc.200800110

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      Solvent accessibility mapping can be used to characterize protein–ligand interactions. Herein, we critically evaluate the applicability of solvent accessibility mapping to derive binding orientations for ligands of two dehydrogenases (AKR1C3 and HSD17β1) with very different binding pockets, including complexes in which the ligand is buried more deeply inside the protein.

    7. Solid-State Forms of Sodium Valproate, Active Component of the Anticonvulsant Drug Epilim (pages 1377–1386)

      Gjorgi Petruševski, Panče Naumov, Gligor Jovanovski, Gordana Bogoeva-Gaceva and Seik Weng Ng

      Version of Record online: 9 JUL 2008 | DOI: 10.1002/cmdc.200800112

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      Sodium valproate, the active ingredient of a group of valproate-based anticonvulsants, can be present in eight forms in the solid state, including four solvates with valproic acid. The pronounced hygroscopicity of some of the forms is inherent to the loose crystal packing, which is directed by the symmetric shape of the compound. Partial or complete stabilization can be achieved by thermal/evacuation treatment and crystallization with valproic acid.

    8. Targeting the Folate Receptor (FR): Imaging and Cytotoxicity of ReI Conjugates in FR-Overexpressing Cancer Cells (pages 1387–1394)

      Nerissa Viola-Villegas, Amy E. Rabideau, Justin Cesnavicious, Jon Zubieta and Robert P. Doyle

      Version of Record online: 23 JUL 2008 | DOI: 10.1002/cmdc.200800125

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      Lighting the way: A new folic acid based bioconjugate selectively delivers ReI to the folate-receptor-positive ovarian tumor cell line A2780/AD (shown). The compounds have significant cytotoxicity, and this is explored in terms of DNA interactions and is contrasted with cisplatin controls.

    9. The First Step into the Brain: Uptake of NIO-PBCA Nanoparticles by Endothelial Cells in vitro and in vivo, and Direct Evidence for their Blood–Brain Barrier Permeation (pages 1395–1403)

      Clemens K. Weiss, Maria-Verena Kohnle, Katharina Landfester, Thomas Hauk, Dietmar Fischer, Julia Schmitz-Wienke and Volker Mailänder

      Version of Record online: 9 JUL 2008 | DOI: 10.1002/cmdc.200800130

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      Enter the brain. Fluorescent polysorbate 80 coated PBCA nanoparticles, prepared in miniemulsion, were investigated for their capacity to permeate blood–tissue barriers in vivo and in vitro. Direct evidence for a concentration-dependent permeation of the blood–brain barrier as well as the blood–retina barrier was obtained.

    10. Stimulus Dependence of the Action of Small-Molecule Inhibitors in the CD3/CD28 Signalling Network (pages 1404–1411)

      Karsten Köhler, Alexander Ganser, Thomas André, Günter Roth, Ludger Grosse-Hovest, Gundram Jung and Roland Brock

      Version of Record online: 4 JUL 2008 | DOI: 10.1002/cmdc.200800134

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      2+2≠4. Inside the body, cells are simultaneously exposed to a multitude of various stimuli. To address the relevance of cellular signalling networks for drug design, cells were exposed to a matrix of combinations of two stimuli, and the cellular responses were recorded in the absence and presence of pharmacological inhibitors.

    11. Substrate-Induced Stable Enzyme–Inhibitor Complex Formation Allows Tight Binding of Novel 2-Aminopyrimidin-4(3H)-ones to Drug-Resistant HIV-1 Reverse Transcriptase Mutants (pages 1412–1418)

      Alberta Samuele, Marcella Facchini, Dante Rotili, Antonello Mai, Marino Artico, Mercedes Armand-Ugón, José A. Esté and Giovanni Maga

      Version of Record online: 8 MAY 2008 | DOI: 10.1002/cmdc.200800051

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      Fast on, slow off: In addition to their greatly improved association rates to HIV-1 RT wild-type and mutated forms, 2-Cl-6-F-N,N-DABOs preferentially associate with mutated RT forms in the unbound (free enzyme) state or in binary complex with the nucleic acid substrate. Their interaction with mutated RT is highly stabilized by nucleotide binding to the enzyme, resulting in very slow inhibitor dissociation rates. These unique properties can be exploited to design NNRTIs that specifically target drug-resistant forms of HIV-1 RT.

    12. Facile Biocatalytic Access to 9-Fluorenylmethyl Polyglycosides: Evaluation of Antiviral Activity on Immunocompetent Cells (pages 1419–1426)

      Annabella Tramice, Adriana Arena, Ambra De Gregorio, Rosaria Ottanà, Rosanna Maccari, Bernadette Pavone, Nicoletta Arena, Daniela Iannello, Maria Gabriella Vigorita and Antonio Trincone

      Version of Record online: 23 JUN 2008 | DOI: 10.1002/cmdc.200800086

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      Biocatalytic routes that circumvent difficult chemical procedures for the production of a series of various polyglycosides using marine glycosidases from A. fasciata (α-glucosides) and T. neapolitana (β-xylosides) are described. Easy access to these polyglycosides permits the discovery of antiviral activity, possibly exerted by influencing the balance of cytokines in the environment of peripheral blood mononuclear cells.

    13. Phenanthroline Derivatives with Improved Selectivity as DNA-Targeting Anticancer or Antimicrobial Drugs (pages 1427–1434)

      Sudeshna Roy, Katharine D. Hagen, Palanisamy Uma Maheswari, Martin Lutz, Anthony L. Spek, Jan Reedijk and Gilles P. van Wezel

      Version of Record online: 9 JUN 2008 | DOI: 10.1002/cmdc.200800097

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      Leading a double life: The dual action of DNA-targeting drugs as both antineoplastic and antimicrobial agents is exemplified by the phenanthroline derivatives and then resolved through their complexation with Pt leading to greater specificity and hence improved therapeutic utility.

    14. Synthesis of Benzamides Related to Anacardic Acid and Their Histone Acetyltransferase (HAT) Inhibitory Activities (pages 1435–1442)

      José A. Souto, Mariarosaria Conte, Rosana Álvarez, Angela Nebbioso, Vincenzo Carafa, Lucia Altucci and Angel R. de Lera

      Version of Record online: 9 JUN 2008 | DOI: 10.1002/cmdc.200800096

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      HATs off: 4-Cyano-3-trifluoromethylphenylbenzamides 8 ab and 8 bb exhibit activities similar to anacardic acid (AA) as human p300 inhibitors. They induce a decrease in histone acetylation levels in immortalized HEK cells and counteract the action of the HDAC inhibitor SAHA in MCF7 breast cancer cells.

    15. Structure–Antioxidant Activity Relationships in a Series of NO-Donor Phenols (pages 1443–1448)

      Paolo Tosco, Elisabetta Marini, Barbara Rolando, Loretta Lazzarato, Clara Cena, Massimo Bertinaria, Roberta Fruttero, Marianne Reist, Pierre-Alain Carrupt and Alberto Gasco

      Version of Record online: 14 JUL 2008 | DOI: 10.1002/cmdc.200800101

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      Antioxidants have attracted a great deal of attention as therapeutic agents for a number of pathologies. The relationships between reactivity descriptors, lipophilicity, and antioxidant activity have been explored on a recently reported series of NO-donor phenols. QSAR equations have been derived which shed light on the possible mechanisms of reaction with radicals in different environments.

    16. Intracellular uptake and inhibitory activity of aromatic fluorinated amino acids in human breast cancer cells (pages 1449–1456)

      Christoph Giese, Sandra Lepthien, Linda Metzner, Matthias Brandsch, Nediljko Budisa and Hauke Lilie

      Version of Record online: 27 AUG 2008 | DOI: 10.1002/cmdc.200800108

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      Fluorinated aromatic amino acids as antitumor agents: The cellular uptake of fluorinated derivatives of tryptophan, tyrosine and phenylalanine via the active amino acid transport system L resulted in a 70-fold intracellular accumulation. These analogues effectively and irreversibly inhibited MCF-7 tumor cell culture growth with IC50 values in the low micromolar range, indicating that these substances might represent new cytostatic drugs for certain tumor types.

  7. Book Review

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

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Minireview
    6. Communications
    7. Full Papers
    8. Book Review
    9. Preview
    1. Preview: ChemMedChem 10/2008 (page 1462)

      Version of Record online: 5 SEP 2008 | DOI: 10.1002/cmdc.200890037

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