ChemMedChem

Cover image for Vol. 4 Issue 3

March 16, 2009

Volume 4, Issue 3

Pages 297–479

  1. Cover Picture

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. News
    6. Review
    7. Communications
    8. Full Papers
    9. Book Reviews
    10. Preview
    1. Cover Picture: Exploring the Implications of Vitamin B12 Conjugation to Insulin on Insulin Receptor Binding (ChemMedChem 3/2009) (page 297)

      Amanda K. Petrus, Damian G. Allis, Robert P. Smith, Timothy J. Fairchild and Robert P. Doyle

      Version of Record online: 11 MAR 2009 | DOI: 10.1002/cmdc.200990010

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      The cover picture shows three views of a vitamin B12–insulin conjugate bound to transcobalamin II, docked in the insulin receptor (IR). This study reveals how the structure of an orally deliverable insulin changes in solution after vitamin B12 conjugation and its effect on IR binding capacity. The results demonstrate that chemical modification of insulin by linking relatively large pendant groups does not interfere with IR recognition. For more details, see the Full Paper by T. J. Fairchild, R. P. Doyle, et al. on p. 421 ff.

  2. Inside Cover

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. News
    6. Review
    7. Communications
    8. Full Papers
    9. Book Reviews
    10. Preview
    1. Inside Cover: Cytotoxicities and Structure–Activity Relationships of Natural and Unnatural Lamellarins toward Cancer Cell Lines (ChemMedChem 3/2009) (page 298)

      Montakarn Chittchang, Paratchata Batsomboon, Somsak Ruchirawat and Poonsakdi Ploypradith

      Version of Record online: 11 MAR 2009 | DOI: 10.1002/cmdc.200990011

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      The inside cover picture shows the structure of lamellarin N as a representative of cytotoxic marine lamellarin alkaloids, together with a potential molecular target, the topoisomerase I–DNA complex. Systematic SAR studies revealed the importance of the substituents for potent cytotoxicity. For more details, see the Full Paper by P. Ploypradith et al. on p. 457 ff.

  3. Graphical Abstract

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

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

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. News
    6. Review
    7. Communications
    8. Full Papers
    9. Book Reviews
    10. Preview
    1. Recent Approaches to Antifungal Therapy for Invasive Mycoses (pages 310–323)

      Bijoy P. Mathew and Mahendra Nath

      Version of Record online: 23 JAN 2009 | DOI: 10.1002/cmdc.200800353

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      Antimycotic agents: Diverse classes of antimycotic drugs have been developed over the past decades with the goal of improving selectivity and efficacy. This review discusses both conventional and novel targets for antifungal agents and the possibility of vaccination in the treatment of invasive fungal infections.

  6. Communications

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. News
    6. Review
    7. Communications
    8. Full Papers
    9. Book Reviews
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    1. The Azulene Framework as a Novel Arene Bioisostere: Design of Potent Dopamine D4 Receptor Ligands Inducing Penile Erection (pages 325–328)

      Stefan Löber, Nuska Tschammer, Harald Hübner, Maria Rosaria Melis, Antonio Argiolas and Peter Gmeiner

      Version of Record online: 2 FEB 2009 | DOI: 10.1002/cmdc.200800395

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      Blue makes it happen: The non-uniform charge distribution of the blue colored azulene framework is highly suitable for the bioisosteric replacement of bicyclic heteroarene moieties. Showing an analogous binding mode as heterocyclic dopamine D4 receptor-selective lead compounds, the induction of penile erection in rats over a greater range of doses indicates a putative advantage of the rationally developed azulene derivative 2 b over apomorphine.

    2. The Synthesis and in vivo Evaluation of 2′,2′-Difluoro KRN7000 (pages 329–334)

      Leo Leung, Cyrille Tomassi, Katrien Van Beneden, Tine Decruy, Matthias Trappeniers, Dirk Elewaut, Yifang Gao, Tim Elliott, Aymen Al-Shamkhani, Christian Ottensmeier, Jörn M. Werner, Anthony Williams, Serge Van Calenbergh and Bruno Linclau

      Version of Record online: 9 JAN 2009 | DOI: 10.1002/cmdc.200800348

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      The synthesis of 2′,2′-difluoro KRN7000 is described. In vivo evaluation demonstrates that this fluorinated glycolipid induces CD1d-dependent TCR activation of NKT cells, with a bias towards Th2 cytokine production.

    3. Efficient Synthesis of Highly Active Phospha-Isosteres of the Influenza Neuraminidase Inhibitor Oseltamivir (pages 335–337)

      Benoit Carbain, Patrick J. Collins, Lori Callum, Stephen R. Martin, Alan J. Hay, John McCauley and Hansjörg Streicher

      Version of Record online: 20 JAN 2009 | DOI: 10.1002/cmdc.200800379

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      With a Hunsdiecker–Barton iododecarboxylation strategy, we converted the carboxylate group of the oseltamivir precursor into exemplary phosphonate monoesters. In all cases, Ki values towards influenza virus sialidase remained in the sub-nanomolar range. We have thus made valuable structural space available for the design of novel oseltamivir-based tools for influenza virus research.

  7. Full Papers

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. News
    6. Review
    7. Communications
    8. Full Papers
    9. Book Reviews
    10. Preview
    1. Unsaturated Mannich Bases Active Against Multidrug-Resistant Trypanosoma brucei brucei Strains (pages 339–351)

      I. Nicole Wenzel, Pui E. Wong, Louis Maes, Thomas J. J. Müller, R. Luise Krauth-Siegel, Michael P. Barrett and Elisabeth Davioud-Charvet

      Version of Record online: 13 FEB 2009 | DOI: 10.1002/cmdc.200800360

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      Unsaturated Mannich bases with potent antitrypanosomal action against multidrug-resistant strains of T. brucei brucei were identified. Their observed activities correlated well with their high Michael acceptor properties but not with their affinities to the P2 purine transporter.

    2. Synthesis, SAR, and Biological Evaluation of α-Sulfonylphosphonic Acids as Selective Matrix Metalloproteinase Inhibitors (pages 352–362)

      Maria Teresa Rubino, Mariangela Agamennone, Cristina Campestre, Giuseppe Fracchiolla, Antonio Laghezza, Fulvio Loiodice, Elisa Nuti, Armando Rossello and Paolo Tortorella

      Version of Record online: 9 FEB 2009 | DOI: 10.1002/cmdc.200800324

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      Selective MMP inhibitors: Eleven α-sulfonylphosphonates were synthesized and tested as MMP inhibitors. The IC50 values for most of them are in the nanomolar range against MMP-2, -8, -13, and -14, with an interesting selectivity profile versus MMP-9.

    3. DNA Binding Ellipticine Analogues: Synthesis, Biological Evaluation, and Structure–Activity Relationships (pages 363–377)

      Maria Grazia Ferlin, Christine Marzano, Valentina Gandin, Stefano Dall'Acqua and Lisa Dalla Via

      Version of Record online: 5 FEB 2009 | DOI: 10.1002/cmdc.200800368

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      Novel angular and branched ellipticine-correlated anticancer agents were developed. In particular, compound 24, with two basic side chains on opposite sides of the molecule, exhibits cytotoxicity in the nanomolar range, acting as a DNA intercalator and topoisomerase II inhibitor. SAR studies with pyridocarbazole derivatives in comparison with corresponding smaller pyrroloquinolines are discussed.

    4. Design, Synthesis, and Biological Evaluation of Enantiomeric β-N-Acetylhexosaminidase Inhibitors LABNAc and DABNAc as Potential Agents against Tay-Sachs and Sandhoff Disease (pages 378–392)

      J. S. Shane Rountree, Terry D. Butters, Mark R. Wormald, Stephanie D. Boomkamp, Raymond A. Dwek, Naoki Asano, Kyoko Ikeda, Emma L. Evinson, Robert J. Nash and George W. J. Fleet

      Version of Record online: 14 JAN 2009 | DOI: 10.1002/cmdc.200800350

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      Combating glycolipid storage disorders: LABNAc was prepared in an efficient 11-step procedure from D-lyxonolactone. The enantiomer DABNAc was also prepared from L-lyxonolactone. Preliminary cellular studies indicate that these compounds may find utility as chemical chaperones for the treatment of Tay-Sachs and Sandhoff diseases.

    5. 1,3-Dioxolane-Based Ligands as Rigid Analogues of Naftopidil: Structure–Affinity/Activity Relationships at α1 and 5-HT1A Receptors (pages 393–399)

      Claudia Sorbi, Silvia Franchini, Annalisa Tait, Adolfo Prandi, Rossella Gallesi, Piero Angeli, Gabriella Marucci, Lorenza Pirona, Elena Poggesi and Livio Brasili

      Version of Record online: 16 JAN 2009 | DOI: 10.1002/cmdc.200800277

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      Conformational restriction of naftopidil led to the discovery of a new class of ligands with a 1,3-dioxolane (1,3-oxathiolane, 1,3-dithiolane) structure that bind to α1 adrenoceptor subtypes and 5-HT1A receptors. Adequate structural modifications address the selectivity toward one or the other receptor system.

    6. Glycosylated Neurotensin Analogues Exhibit Sub-picomolar Anticonvulsant Potency in a Pharmacoresistant Model of Epilepsy (pages 400–405)

      Hee-Kyoung Lee, Liuyin Zhang, Misty D. Smith, H. Steve White and Grzegorz Bulaj

      Version of Record online: 27 JAN 2009 | DOI: 10.1002/cmdc.200800421

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      The glycosylation of neuroactive peptides is a promising strategy to treat neurological and psychiatric disorders. Herein we investigated the effects of site-specific glycosylation of neurotensin (NT). The glycosylated analogues have low-nanomolar affinities and agonist activities toward NTS1, and suppress seizures with sub-picomolar potency. Our work points to a new research direction of exploring BBB-permeable NT analogues as potential first-in-class antiepileptic drugs.

    7. Structurally Minimized μ-Conotoxin Analogues as Sodium Channel Blockers: Implications for Designing Conopeptide-Based Therapeutics (pages 406–414)

      Tiffany S. Han, Min-Min Zhang, Aleksandra Walewska, Pawel Gruszczynski, Charles R. Robertson, Thomas E. Cheatham III, Doju Yoshikami, Baldomero M. Olivera and Grzegorz Bulaj

      Version of Record online: 23 DEC 2008 | DOI: 10.1002/cmdc.200800292

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      Transforming the neuroactive toxins of cone snails into small-size compounds poses a challenge due to the presence of multiple disulfide bridges. Herein we describe our successful efforts in minimizing the size of μ-conotoxin while retaining its biological activity.

    8. Synthesis, Chiral Resolution and Pharmacological Evaluation of a 2,3-Benzodiazepine-Derived Noncompetitive AMPA Receptor Antagonist (pages 415–420)

      Maria Luisa Calabrò, Daniela Raneri, Paola Ficarra, Tiziana Mennini, Simona Colleoni, Giovanni Grazioso, Nicola Micale, Maria Zappalà and Silvana Grasso

      Version of Record online: 9 JAN 2009 | DOI: 10.1002/cmdc.200800341

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      2,3-Benzodiazepine derivatives: 1-(4-Aminophenyl)-3,5-dihydro-3-N-ethylcarbamoyl-5-methyl-7,8-methylenedioxy-4H-2,3-benzodiazepin-4-one was synthesized, and its enantiomers were separated by chiral HPLC. Pharmacological evaluation of each enantiomer showed that (S)-(−)-5 appears to be more potent than its optical antipode (R)-(+)-5 in an AMPA receptor binding assay.

    9. Exploring the Implications of Vitamin B12 Conjugation to Insulin on Insulin Receptor Binding (pages 421–426)

      Amanda K. Petrus, Damian G. Allis, Robert P. Smith, Timothy J. Fairchild and Robert P. Doyle

      Version of Record online: 19 DEC 2008 | DOI: 10.1002/cmdc.200800346

      Thumbnail image of graphical abstract

      The dynamic behavior of insulin in solution and its binding geometry with the insulin receptor (IR) have been the focus of experimental and computational studies. We investigated how the structure of an orally deliverable insulin changes in solution after vitamin B12 conjugation and its effect on IR binding capacity. In vitro immunoelectron microscopy confirms conjugate activity, IR binding, and cellular uptake.

    10. SHOP: A Method For Structure-Based Fragment and Scaffold Hopping (pages 427–439)

      Fabien Fontaine, Simon Cross, Guillem Plasencia, Manuel Pastor and Ismael Zamora

      Version of Record online: 16 JAN 2009 | DOI: 10.1002/cmdc.200800355

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      We present a method for fragment/scaffold substitution based on protein–ligand interactions. This concept goes beyond bioisosteric replacement, which only uses the structure of the fragment to replace as query. The methodology is validated with more than 10 biological targets relevant for drug discovery.

    11. In Silico Screening for PTPN22 Inhibitors: Active Hits from an Inactive Phosphatase Conformation (pages 440–444)

      Shuangding Wu, Massimo Bottini, Robert C. Rickert, Tomas Mustelin and Lutz Tautz

      Version of Record online: 28 JAN 2009 | DOI: 10.1002/cmdc.200800375

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      2-Benzamidobenzoic acids seem to stabilize PTPN22 phosphatase in its inactive 'open' conformation with the WPD loop locked in a distal position. In silico screening using both 3D structures in open and closed conformations yielded potent inhibitors of this potential drug target for autoimmunity that specifically dock into its open form. Tryptophan fluorescence measurements support the proposed binding mode.

    12. Characterization of New PPARγ Agonists: Analysis of Telmisartan’s Structural Components (pages 445–456)

      Matthias Goebel, Markus Clemenz, Bart Staels, Thomas Unger, Ulrich Kintscher and Ronald Gust

      Version of Record online: 5 FEB 2009 | DOI: 10.1002/cmdc.200800285

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      Telmisartan was originally designed as an AT1 antagonist but was later also characterized as a selective PPARγ modulator. This study focused on the identification of the essential structural motifs of telmisartan for PPARγ activation activity, elucidating the individual SAR of each different component (shown).

    13. Cytotoxicities and Structure–Activity Relationships of Natural and Unnatural Lamellarins toward Cancer Cell Lines (pages 457–465)

      Montakarn Chittchang, Paratchata Batsomboon, Somsak Ruchirawat and Poonsakdi Ploypradith

      Version of Record online: 16 JAN 2009 | DOI: 10.1002/cmdc.200800339

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      Shedding light on the lamellarins: Structural determinants for potent cytotoxic activity toward various cancer cell lines were systematically investigated to establish SARs for the marine alkaloids in the lamellarin family. The C5[DOUBLE BOND]C6 double bond ensures not only the planarity of the D-ring, but also proper alignment of the substituents on the E-ring with their respective moieties of the target. The importance of the C7 OH group is also revealed for the first time.

    14. Fluorescent Benzofurazan–Cholic Acid Conjugates for in vitro Assessment of Bile Acid Uptake and Its Modulation by Drugs (pages 466–472)

      Jana Rohacova, M. Luisa Marín, Alicia Martinez-Romero, Laura Diaz, José-Enrique O'Connor, M. Jose Gomez-Lechon, M. Teresa Donato, José V. Castell and Miguel A. Miranda

      Version of Record online: 27 JAN 2009 | DOI: 10.1002/cmdc.200800383

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      Fluorescent synthetic 7-nitrobenzo-2-oxa-1,3-diazole (NBD) conjugates of cholic acid were prepared and characterized. Their photophysical properties make them suitable for monitoring uptake in freshly isolated rat hepatocytes using flow cytometry. This technique makes it possible to screen drug candidates for cholestatic (and thus hepatotoxic) liability.

  8. Book Reviews

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

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. News
    6. Review
    7. Communications
    8. Full Papers
    9. Book Reviews
    10. Preview
    1. Preview: ChemMedChem 4/2009 (page 479)

      Version of Record online: 11 MAR 2009 | DOI: 10.1002/cmdc.200990014

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