ChemMedChem

Cover image for Vol. 6 Issue 1

January 3, 2011

Volume 6, Issue 1

Pages 1–207

  1. Cover Picture

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Minireviews
    9. Communications
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. Cover Picture: Characterization of C-Alkyl Amidines as Bioavailable Covalent Reversible Inhibitors of Human DDAH-1 (ChemMedChem 1/2011) (page 1)

      Dr. Matthew Lluis, Dr. Yun Wang, Dr. Arthur F. Monzingo, Prof. Dr. Walter Fast and Prof. Dr. Jon D. Robertus

      Article first published online: 27 DEC 2010 | DOI: 10.1002/cmdc.201090059

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      The cover picture showsN5-(1-iminopentyl)-L-ornithine bound to dimethylarginine dimethylaminohydrolase-1 (DDAH-1). This inhibitory amidine is a bioavailable dual-targeted inhibitor of both DDAH-1 and nitric oxide (NO) synthase, designed to more effectively block biological NO production. An unusual covalent, reversible mode of inhibition is illustrated by the covalent bond formed with wild-type DDAH-1 (in blue; PDB code: 3P8E) but not with the C274S variant (in white; PDB code: 3P8P). For more details, see the Full Paper by Walter Fast, Jon D. Robertus et al. on p. 81 ff.

  2. Inside Cover

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Minireviews
    9. Communications
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. Inside Cover: 1-Cyclohexyl-4-(4-arylcyclohexyl)piperazines: Mixed σ and Human Δ8–Δ7 Sterol Isomerase Ligands with Antiproliferative and P-Glycoprotein Inhibitory Activity (ChemMedChem 1/2011) (page 2)

      Dr. Carmen Abate, Dr. Mauro Niso, Dr. Marialessandra Contino, Prof. Dr. Nicola Antonio Colabufo, Prof. Savina Ferorelli, Prof. Dr. Roberto Perrone and Prof. Dr. Francesco Berardi

      Article first published online: 27 DEC 2010 | DOI: 10.1002/cmdc.201090062

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      The inside cover picture shows a cis-cyclohexylpiperazine (cis-11) reverting P-glycoprotein (P-gp)-mediated drug resistance towards doxorubicin. Upon co-administration with cis-11, doxorubicin can enter cells and reduce cell viability. Alone, cis-11 exerts an antiproliferative effect mediated by σ receptors and human Δ87 sterol isomerase. Cis-11 could potentially be used alone or in combination with classic chemotherapeutics against drug-resistant cancer. For more information, see the Full Paper by Carmen Abate et al. on p. 73 ff.

  3. Editorial

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Minireviews
    9. Communications
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. You have free access to this content
      The Winds of Change (pages 3–6)

      Dr. Natalia Ortúzar

      Article first published online: 27 DEC 2010 | DOI: 10.1002/cmdc.200000493

  4. Graphical Abstract

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Minireviews
    9. Communications
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. You have free access to this content
      Graphical Abstract: ChemMedChem 1/2011 (pages 8–13)

      Article first published online: 27 DEC 2010 | DOI: 10.1002/cmdc.201090063

  5. News

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Minireviews
    9. Communications
    10. Full Papers
    11. Book Reviews
    12. Preview
  6. Author Profile

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Minireviews
    9. Communications
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. Authors Profile (page 21)

      Alan P. Kozikowski

      Article first published online: 27 DEC 2010 | DOI: 10.1002/cmdc.201000497

  7. Minireviews

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Minireviews
    9. Communications
    10. Full Papers
    11. Book Reviews
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    1. Synthesis and Bioactivity of Carbohydrate Derivatives of Indigo, Its Isomers and Heteroanalogues (pages 25–37)

      Dr. Gnuni Karapetyan, Dr. Kuheli Chakrabarty, Dr. Martin Hein and Prof. Dr. Peter Langer

      Article first published online: 24 NOV 2010 | DOI: 10.1002/cmdc.201000374

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      Go indigo: Carbohydrate derivatives of indigoid bis-indoles are effective inhibitors of several kinases, such as CDKs and GSK-3β. Recent studies have shown that thia analogues of glycosylated indirubins are good candidates for the treatment of malignant melanoma. Herein we review the progress made in synthesis and biological screening of various carbohydrate derivatives of indigo, its isomers, and their heteroanalogues with special focus on synthetic issues.

    2. Small-Molecule Inhibitors of the ERK Signaling Pathway: Towards Novel Anticancer Therapeutics (pages 38–48)

      Jeremy L. Yap, Dr. Shilpa Worlikar, Prof. Dr. Alexander D. MacKerell Jr., Prof. Dr. Paul Shapiro and Prof. Dr. Steven Fletcher

      Article first published online: 25 NOV 2010 | DOI: 10.1002/cmdc.201000354

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      David and Goliath: Small-molecule inhibitors of the ERK signaling pathway (shown) and their potential as novel antitumor agents are discussed in detail within this Minireview. Specifically, the direct and indirect inhibition of ERK through ATP-competitive and non-ATP-competitive modes of action is highlighted.

  8. Communications

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Minireviews
    9. Communications
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. Chemotherapeutic Evaluation of a Synthetic Tubulysin Analogue–Dendrimer Conjugate in C26 Tumor Bearing Mice (pages 49–53)

      William C. Floyd III, Dr. Gopal K. Datta, Dr. Shinichi Imamura, Heidi M. Kieler-Ferguson, Katherine Jerger, Dr. Andrew W. Patterson, Megan E. Fox, Prof. Francis C. Szoka, Prof. Jean M. J. Fréchet and Prof. Jonathan A. Ellman

      Article first published online: 25 OCT 2010 | DOI: 10.1002/cmdc.201000377

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      Conjugate to ameliorate! Polymeric drug delivery using a synthetic tubulysin analogue in C26 tumor bearing mice is described. A single dose of this conjugate (shown) resulted in a 90 % increase in the average lifespan of the mice as compared to groups given a phosphate-buffered saline control or the free tubulysin analogue. Moreover, 37 % of the mice given the polymeric formulation were tumor free at the conclusion of the study.

    2. The Legumain Protease-Activated Auristatin Prodrugs Suppress Tumor Growth and Metastasis without Toxicity (pages 54–59)

      Dr. Krishna Mohan Bajjuri , Dr. Yuan Liu , Prof. Dr. Cheng Liu and Prof. Dr. Subhash C. Sinha

      Article first published online: 10 DEC 2010 | DOI: 10.1002/cmdc.201000478

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      Tumor exploitation: Novel monomethylauristatin E and didesmethylauristatin E prodrugs were prepared, and in vitro and in vivo evaluations of the prodrugs using human and mouse cancer cell lines showed that they are less toxic and more efficacious than the parent cytotoxins, as their activation was catalyzed selectively by the cysteine protease, legumain, which is overexpressed in the active form in tumor microenvironments.

    3. Solid-State Perturbation for Solubility Improvement: A Proof of Concept (pages 60–62)

      Dr. Lars-Erik Briggner, Dr. Ramon Hendrickx, Prof. Lars Kloo, Dr. Jan Rosdahl and Prof. Per H. Svensson

      Article first published online: 29 NOV 2010 | DOI: 10.1002/cmdc.201000405

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      Simple and rational: The intrinsic solubility of a compound can be systematically improved by perturbing key interactions in its crystal structure. By carefully choosing the perturbation, the end result will be a molecule similar to the original one, but with significantly higher solubility. This methodology is demonstrated on a subset of benzodiazepines, resulting in significant improvement of their solubility.

  9. Full Papers

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Minireviews
    9. Communications
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. Discovery of 4-Benzylamino-Substituted α-Carbolines as a Novel Class of Receptor Tyrosine Kinase Inhibitors (pages 63–72)

      Dr. Martin Krug, Dr. Kanin Wichapong, German Erlenkamp, Prof. Dr. Wolfgang Sippl, Dr. Christoph Schächtele, Dr. Frank Totzke and Priv.-Doz. Dr. Andreas Hilgeroth

      Article first published online: 7 DEC 2010 | DOI: 10.1002/cmdc.201000384

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      Resisting resistance: Novel 4-benzylamino-α-carbolines show nanomolar binding affinities to the receptor tyrosine kinases EGFR and VEGFR2 and 3. Docking studies suggest these compounds bind to the active conformation of EGFR through the α-carboline amino functions to the amide group of Met793. Members of this compound class show promise in combating drug-resistant cancer cells.

    2. 1-Cyclohexyl-4-(4-arylcyclohexyl)piperazines: Mixed σ and Human Δ8–Δ7 Sterol Isomerase Ligands with Antiproliferative and P-Glycoprotein Inhibitory Activity (pages 73–80)

      Dr. Carmen Abate, Dr. Mauro Niso, Dr. Marialessandra Contino, Prof. Dr. Nicola Antonio Colabufo, Prof. Savina Ferorelli, Prof. Dr. Roberto Perrone and Prof. Dr. Francesco Berardi

      Article first published online: 10 NOV 2010 | DOI: 10.1002/cmdc.201000371

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      Synergistic mixed activity: A series of cyclohexylpiperazines with mixed σ and HSI affinities and P-gp inhibitory activity were synthesized. Their antiproliferative activity, combined with P-gp inhibitory activity, shows the potential of these compounds to be used as antitumor agents devoid of P-gp-mediated resistance, or in association with classic antitumor agents susceptible to P-gp activity.

    3. Characterization of C-Alkyl Amidines as Bioavailable Covalent Reversible Inhibitors of Human DDAH-1 (pages 81–88)

      Dr. Matthew Lluis, Dr. Yun Wang, Dr. Arthur F. Monzingo, Prof. Dr. Walter Fast and Prof. Dr. Jon D. Robertus

      Article first published online: 26 OCT 2010 | DOI: 10.1002/cmdc.201000392

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      Inhibition, interrupted: A series of dual-targeted DDAH-1/NO synthase inhibitors were ranked for potency within cells, and the most potent compound was characterized in detail. X-ray crystallography and isothermal titration calorimetry were used to compare binding to wild-type and mutant DDAH-1 to dissect the contribution of reversible covalent bond formation to the potency of these C-alkyl amidine inhibitors.

    4. Asborin Inhibits Aldo/Keto Reductase 1A1 (pages 89–93)

      Matthias Scholz, Max Steinhagen, Dr. John T. Heiker, Prof. Dr. Annette G. Beck-Sickinger and Prof. Dr. Evamarie Hey-Hawkins

      Article first published online: 21 OCT 2010 | DOI: 10.1002/cmdc.201000368

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      Never a dull moment with borane! Substitution of the phenyl ring in aspirin for an ortho-carbaborane to give asborin led to a loss in inhibitory potency against cyclooxygenases (COX); however, asborin inhibits aldo/keto reductase (AKR) instead. This change in drug target can be attributed to both the geometry and the unique electronic properties of the ortho-carbaborane pharmacophore.

    5. A Combined Ligand- and Structure-Based Virtual Screening Protocol Identifies Submicromolar PPARγ Partial Agonists (pages 94–103)

      Dr. Dušica Vidović, Dr. Scott A. Busby, Prof. Dr. Patrick R. Griffin and Prof. Dr. Stephan C. Schürer

      Article first published online: 15 DEC 2010 | DOI: 10.1002/cmdc.201000428

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      Two heads are better than one! Nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) regulates numerous genes involved in obesity and diabetes. PPARγ activated by partial agonists displays desired pharmacological behavior but without the severe side effects associated with the use of known full agonist drugs for the treatment of type 2 diabetes. Virtual screening based on three-dimensional ligand shape similarity and docking identified novel submicromolar PPARγ partial agonists.

    6. Fluorine–Protein Interactions and 19F NMR Isotropic Chemical Shifts: An Empirical Correlation with Implications for Drug Design (pages 104–114)

      Dr. Claudio Dalvit and Dr. Anna Vulpetti

      Article first published online: 29 NOV 2010 | DOI: 10.1002/cmdc.201000412

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      NMR for guided fluorine chemistry: An empirical correlation between 19F NMR chemical shifts and the type of fluorine–protein interactions observed in crystal structures is presented. A relationship between the 19F NMR chemical shifts and experimental and computed hydrogen bond distances is also shown. The proposed “rule of shielding” provides guidelines for the application of selective fluorine chemistry in the field of lead optimization.

    7. Structure–Activity Relationship Refinement and Further Assessment of Indole-3-glyoxylamides as a Lead Series against Prion Disease (pages 115–130)

      Dr. Mark J. Thompson, Jennifer C. Louth, Steven Ferrara, Fiona J. Sorrell, Benjamin J. Irving, Edward J. Cochrane, Dr. Anthony J. H. M. Meijer and Dr. Beining Chen

      Article first published online: 8 DEC 2010 | DOI: 10.1002/cmdc.201000383

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      Making mad cows a myth! The indole-3-glyoxylamide series of antiprion agents has been further optimised, and characteristics contributing to their activity have been identified by computational studies. Varying the glyoxylamide motif or introducing substitution at N-1 gave analogues with lower efficacy.

    8. Integrated Synthetic, Pharmacological, and Computational Investigation of cis-2-(3,5-Dichlorophenylcarbamoyl)cyclohexanecarboxylic Acid Enantiomers As Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 4 (pages 131–140)

      Dr. Christo Christov, Dr. Patricia González-Bulnes, Dr. Fanny Malhaire, Dr. Tatyana Karabencheva, Dr. Cyril Goudet, Dr. Jean-Philippe Pin, Dr. Amadeu Llebaria and Dr. Jesús Giraldo

      Article first published online: 5 DEC 2010 | DOI: 10.1002/cmdc.201000378

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      A helping handedness: Pharmacological assays revealed that the 1R,2S enantiomer of cis-2-(3,5-dichlorophenylcarbamoyl)cyclohexanecarboxylic acid possesses significantly higher potency than its molecular mirror image, thereby emphasizing the role that ligand chirality may have in mGluR4 allosteric modulation.

    9. New cis-Configured Aziridine-2-carboxylates as Aspartic Acid Protease Inhibitors (pages 141–152)

      Dr. Christian Büchold, Yasmin Hemberger, Cornelia Heindl, Armin Welker, Dr. Björn Degel, Dr. Thomas Pfeuffer, Dr. Peter Staib, Sabrina Schneider, Prof. Dr. Philip J. Rosenthal, Dr. Jiri Gut, Prof. Dr. Joachim Morschhäuser, Prof. Dr. Gerhard Bringmann and Prof. Dr. Tanja Schirmeister

      Article first published online: 16 NOV 2010 | DOI: 10.1002/cmdc.201000370

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      Sapping SAP activity:N-Alkyl-3-phenylaziridine-2-carboxylates are highly active inhibitors of cathepsin D and secreted aspartic acid protease 2 (SAP2). Syntheses, biological activity, and determination of the absolute configurations of the stereocenters by experimental circular dichroism (CD) and computational quantum chemical CD are presented herein.

    10. Polyphosphates and Pyrophosphates of Hexopyranoses as Allosteric Effectors of Human Hemoglobin: Synthesis, Molecular Recognition, and Effect on Oxygen Release (pages 153–168)

      Prof. Konstantina C. Fylaktakidou, Dr. Carolina D. Duarte, Prof. Alexandros E. Koumbis, Prof. Claude Nicolau and Prof. Jean-Marie Lehn

      Article first published online: 24 NOV 2010 | DOI: 10.1002/cmdc.201000366

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      To bind or not to bind: The synthesis of polyphosphate and pyrophosphate derivatives of hexopyranoses provides a range of compounds that bind to hemoglobin and induce enhanced oxygen release. Analysis of the effects observed gives insight into structure–activity relationships. Potential medicinal applications involve the numerous diseases that display hypoxic conditions.

    11. Tetrakisphosphates and Bispyrophosphates of myo-Inositol Derivatives as Allosteric Effectors of Human Hemoglobin: Synthesis, Molecular Recognition, and Oxygen Release (pages 169–180)

      Prof. Alexandros E. Koumbis, Dr. Carolina D. Duarte, Prof. Claude Nicolau and Prof. Jean-Marie Lehn

      Article first published online: 10 DEC 2010 | DOI: 10.1002/cmdc.201000421

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      Winning hemoglobin's heart: The synthesis of myo-inositol tetrakisphosphates and bispyrophosphates yields a number of compounds that bind to hemoglobin and induce enhanced oxygen release. These effects were analyzed in order to gain insight into structure–activity relationships. Potential medicinal applications include the numerous diseases in which hypoxic conditions are encountered.

    12. Symmetry Complementarity-Guided Design of Anthrax Toxin Inhibitors Based on β-Cyclodextrin: Synthesis and Relative Activities of Face-Selective Functionalized Polycationic Clusters (pages 181–192)

      Dr. Alejandro Díaz-Moscoso, Alejandro Méndez-Ardoy, Dr. Fernando Ortega-Caballero, Dr. Juan M. Benito, Prof. Carmen Ortiz Mellet, Dr. Jacques Defaye, Tanisha M. Robinson, Adiamseged Yohannes, Dr. Vladimir A. Karginov and Prof. José M. García Fernández

      Article first published online: 7 DEC 2010 | DOI: 10.1002/cmdc.201000419

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      Molecular disarmament: The heptameric pore formed by the anthrax toxin protective antigen (PA) plays a decisive role in infection. Pore blockage was investigated by using size, charge, and C7 symmetry complementary β-cyclodextrin scaffolds. Toxin inhibitor candidates with potency in the low micromolar range were identified, and intimate structure–activity relationships were inferred.

    13. Palmitoylated SDF1 α Shows Increased Resistance against Proteolytic Degradation in Liver Homogenates (pages 193–200)

      Kathrin Bellmann-Sickert and Prof. Dr. Annette G. Beck-Sickinger

      Article first published online: 7 DEC 2010 | DOI: 10.1002/cmdc.201000403

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      Regenerative Medicine: The stromal cell-derived factor-1 α (SDF1 α) is heavily involved in organogenesis, as well as inflammation and tissue repair, making it a compound of interest for drug development in regenerative medicine. SDF1 α was C-terminally palmitoylated by native chemical ligation. While activation of the CXCR4 receptor was not affected, the modification led to a sevenfold increase in half time after incubation in porcine liver homogenates.

  10. Book Reviews

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Minireviews
    9. Communications
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. BACE: Lead Target for Orchestrated Therapy of Alzheimer's Disease. Edited by Varghese John. (pages 201–202)

      Dr. Andrew Stamford

      Article first published online: 19 OCT 2010 | DOI: 10.1002/cmdc.201000427

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      Wiley, Hoboken 2010. 266 pp., hardcover $ 99.95.—ISBN 978-0-470-29342-3

    2. Monoclonal Antibody and Peptide-Targeted Radiotherapy of Cancer. Edited by Raymond M. Reilly. (page 202)

      Prof. Dr. Thomas L. Mindt and Priv.-Doz. Dr. Dr. med. Flavio Forrer

      Article first published online: 27 DEC 2010 | DOI: 10.1002/cmdc.201000400

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      Wiley, Hoboken 2010. 632 pp., hardcover $ 149.95.—ISBN 978-0-470-24372-5

    3. Modern Drug Synthesis. Edited by Jie Jack Li and Douglas S. Johnson. (pages 202–203)

      Dr. Andreas Schall and Dr. Helmut Haning

      Article first published online: 7 OCT 2010 | DOI: 10.1002/cmdc.201000394

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      Wiley, Hoboken 2010. 355+xiv pp., hardcover $ 110.00.—ISBN 978-0-470-52583-8

  11. Preview

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Minireviews
    9. Communications
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. You have free access to this content
      Preview: ChemMedChem 2/2011 (page 207)

      Article first published online: 27 DEC 2010 | DOI: 10.1002/cmdc.201090061

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