ChemMedChem

Cover image for Vol. 8 Issue 1

January 2013

Volume 8, Issue 1

Pages 1–167

  1. Cover Pictures

    1. Top of page
    2. Cover Pictures
    3. Editorials
    4. Graphical Abstract
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. You have free access to this content
      Cover Picture: Synthesis and Evaluation of 3,4-Dihydropyrimidin-2(1H)-ones as Sodium Iodide Symporter Inhibitors (ChemMedChem 1/2013) (page 1)

      Pierre Lacotte, Celine Puente and Dr. Yves Ambroise

      Article first published online: 23 DEC 2012 | DOI: 10.1002/cmdc.201290064

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      The front cover picture shows the structure of a new dihydropyrimidin-2-one inhibitor of iodide entrapment in thyroid cells. The identification of this low-nanomolar inhibitor was achieved through an exhaustive structure–activity relationship study in which more than a hundred derivatives in this compound family were designed, synthesized and tested. This discovery opens new perspectives for the development of antithyroid drugs designed to prevent iodide overload in the thyroid gland. For more details, see the Full Paper by Yves Ambroise et al. on p. 104 ff.

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      Inside Cover: From In Situ to In Vivo: An In Situ Click-Chemistry-Derived Carbonic Anhydrase II Imaging Agent for Positron Emission Tomography (ChemMedChem 1/2013) (page 2)

      Dr. Vani P. Mocharla, Dr. Joseph C. Walsh, Dr. Henry C. Padgett, Dr. Helen Su, Dr. Barbara Fueger, Prof. Dr. Wolfgang A. Weber, Prof. Dr. Johannes Czernin and Dr. Hartmuth C. Kolb

      Article first published online: 23 DEC 2012 | DOI: 10.1002/cmdc.201290066

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      The inside cover picture shows a target-guided approach to identifying positron emission tomography (PET) imaging agents. Incubation of click-chemistry-enabled non-radioactive surrogate fragments with the target enzyme carbonic anhydrase-II generates high-affinity ligands, which can be easily modified into the corresponding radioactive PET tracer without altering its chemical and biological characteristics. For more details, see the Communication by Hartmuth C. Kolb et al. on p. 43 ff.

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      Back Cover: Small-Molecule APOBEC3G DNA Cytosine Deaminase Inhibitors Based on a 4-Amino-1,2,4-triazole-3-thiol Scaffold (ChemMedChem 1/2013) (page 172)

      Margaret E. Olson, Dr. Ming Li, Dr. Reuben S. Harris and Prof. Dr. Daniel A. Harki

      Article first published online: 23 DEC 2012 | DOI: 10.1002/cmdc.201290068

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      The back cover picture shows that APOBEC3G (A3G)-mediated cytosine deamination of single-stranded DNA oligonucleotides can be inhibited by 4-amino-1,2,4-triazole-3-thiol-based small molecules. Engagement of A3G C321, which is proximal to the active site, confers activity for this class of compounds. For more details, see the Full Paper by Daniel A. Harki et al. on p. 112 ff.

  2. Editorials

    1. Top of page
    2. Cover Pictures
    3. Editorials
    4. Graphical Abstract
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. You have free access to this content
      Editorial: Lucky Number 8! (pages 3–5)

      Dr. Scott D. Williams and Dr. Natalia Ortúzar

      Article first published online: 23 DEC 2012 | DOI: 10.1002/cmdc.201200495

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  3. Graphical Abstract

    1. Top of page
    2. Cover Pictures
    3. Editorials
    4. Graphical Abstract
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Graphical Abstract: ChemMedChem 1/2013 (pages 9–14)

      Article first published online: 23 DEC 2012 | DOI: 10.1002/cmdc.201290067

  4. News

    1. Top of page
    2. Cover Pictures
    3. Editorials
    4. Graphical Abstract
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Spotlights on our sister journals: ChemMedChem 1/2013 (pages 20–22)

      Article first published online: 23 DEC 2012 | DOI: 10.1002/cmdc.201290065

  5. Minireview

    1. Top of page
    2. Cover Pictures
    3. Editorials
    4. Graphical Abstract
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Thiadiazole—a Promising Structure in Medicinal Chemistry (pages 27–41)

      Yijing Li, Jingkun Geng, Yang Liu, Shenghui Yu and Prof. Guisen Zhao

      Article first published online: 3 DEC 2012 | DOI: 10.1002/cmdc.201200355

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      A scaffold with potential: Thiadiazoles possess unique properties that make them useful scaffolds in medicinal chemistry. As bioisosteres of pyrimidines, their derivatives can potentially interact with DNA and RNA. As mesoionic compounds, thiadiazoles can readily cross cell membranes and interact with biological compounds in unique ways. The broad range of activities exhibited by thiadiazole-containing compounds is testimony to their utility.

  6. Communications

    1. Top of page
    2. Cover Pictures
    3. Editorials
    4. Graphical Abstract
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. From In Situ to In Vivo: An In Situ Click-Chemistry-Derived Carbonic Anhydrase II Imaging Agent for Positron Emission Tomography (pages 43–48)

      Dr. Vani P. Mocharla, Dr. Joseph C. Walsh, Dr. Henry C. Padgett, Dr. Helen Su, Dr. Barbara Fueger, Prof. Dr. Wolfgang A. Weber, Prof. Dr. Johannes Czernin and Dr. Hartmuth C. Kolb

      Article first published online: 3 DEC 2012 | DOI: 10.1002/cmdc.201200466

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      CA II makes a good PET: Discovering positron emission tomography (PET) probes with high target affinities is challenging. PET probe discovery using in situ click chemistry uses 19F-bearing fragments as 18F surrogates. This ensures that the lead hits and PET probes have equivalent chemical or biological characteristics, making PET probe discovery predictable and reliable.

    2. Combining Quantum Mechanical Ligand Conformation Analysis and Protein Modeling to Elucidate GPCR–Ligand Binding Modes (pages 49–53)

      Sabine Schultes, Harald Engelhardt, Dr. Luc Roumen, Obbe P. Zuiderveld, Prof. Dr. Eric E. J. Haaksma, Dr. Iwan J. P. de Esch, Prof. Dr. Rob Leurs and Dr. Chris de Graaf

      Article first published online: 19 NOV 2012 | DOI: 10.1002/cmdc.201200412

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      SAR beyond protein–ligand interactions: By combining structure–affinity relationships, protein–ligand modeling studies, and quantum mechanical calculations, we show that ligand conformational energies and basicity play critical roles in ligand binding to the histamine H4 receptor, a GPCR that plays a key role in inflammation.

    3. Discovery of Schaeffer’s Acid Analogues as Lead Structures of Mycobacterium tuberculosis Type II Dehydroquinase Using a Rational Drug Design Approach (pages 54–58)

      Dr. Marco F. Schmidt, Dr. Oliver Korb, Dr. Nigel I. Howard, Dr. Marcio V. B. Dias, Prof. Dr. Tom L. Blundell and Prof. Dr. Chris Abell

      Article first published online: 21 NOV 2012 | DOI: 10.1002/cmdc.201200508

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      Rational ligand design: Schaeffer′s acid analogues were identified as novel inhibitors of M. tuberculosis type II dehydroquinase, a key enzyme of the shikimate pathway. Their likely binding mode was predicted using a combination of ensemble docking and flexible active site residues. Potentially, this scaffold could provide a good starting point for the design of antitubercular agents.

    4. Reduction of Helical Content by Insertion of a Disulfide Bond Leads to an Antimicrobial Peptide with Decreased Hemolytic Activity (pages 59–62)

      Heeyong Hwang, Soonsil Hyun, Prof. Yangsoo Kim and Prof. Jaehoon Yu

      Article first published online: 13 NOV 2012 | DOI: 10.1002/cmdc.201200463

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      CAPs off to the S–S bond: Application of a strategy involving the introduction of intramolecular disulfide bonds to amphipathic cationic antimicrobial peptides (CAPs) led to decreased α-helicity and hydrophobicity. The mutant peptides were observed to have significantly increased (250-fold) minimum hemolytic concentrations while maintaining MIC values against E. coli, affording more therapeutically selective CAPs.

    5. C3′/C4′-Stereochemical Effects of Digitoxigenin α-L-/α-D-Glycoside in Cancer Cytotoxicity (pages 63–69)

      John W. Hinds, Sean B. McKenna, Ehesan U. Sharif, Dr. Hua-Yu L. Wang, Dr. Novruz G. Akhmedov and Prof. George A. O'Doherty

      Article first published online: 8 NOV 2012 | DOI: 10.1002/cmdc.201200465

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      Sweet′n low in stereo: A Wharton reaction was employed along with a diastereoselective palladium-catalyzed glycosylation and other post-glycosylation transformations to synthesize digitoxin analogues. Cytotoxic evaluation against a panel of cancer cell lines uncovered the stereochemical and substitutional limits of the C3′/C4′-hydroxy functionality in digitoxin monosaccharide.

    6. Cyclopropyl-tryptamine Analogues: Synthesis and Biological Evaluation as 5-HT6 Receptor Ligands (pages 70–73)

      Dr. Claude Szalata, Prof. Jan Szymoniak, Prof. Frédéric Fabis, Sabrina Butt-Gueulle, Prof. Sylvain Rault, Prof. Philippe Bertus, Dr. Stéphane Gérard and Prof. Janos Sapi

      Article first published online: 5 NOV 2012 | DOI: 10.1002/cmdc.201200396

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      Conformational restrictions: Based on the pharmacophore model for 5-HT6 receptor ligands (shown), tryptamine analogues bearing a cyclopropyl ring on the α-position of the tryptamine side chain were synthesized and evaluated against 5-HT receptors. N,N-Dimethyl-1-arylsulfonyltryptamine derivatives exhibited promising selectivity for 5-HT6 over 5-HT1a and 5-HT4 receptors and interesting activity against 5-HT6 (Ki=∼0.15 μM; IC50=∼0.20 μM).

  7. Full Papers

    1. Top of page
    2. Cover Pictures
    3. Editorials
    4. Graphical Abstract
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Development of a Metabolically Stable Neurotensin Receptor 2 (NTS2) Ligand (pages 75–81)

      Cornelia Held, Manuel Plomer, Dr. Harald Hübner, Dr. Jasmin Meltretter, Prof. Dr. Monika Pischetsrieder and Prof. Dr. Peter Gmeiner

      Article first published online: 24 OCT 2012 | DOI: 10.1002/cmdc.201200376

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      No pain, no pain: Second-generation peptide–peptoid hybrids are more metabolically stable than their predecessor compounds. Hybrid 2 b showed excellent NTS2 binding affinity (Ki=2.8 nM) and 22 000-fold selectivity over NTS1 along with metabolic stability over 32 h in a serum degradation assay. As NTS2 is widely distributed in the brain and is involved in modulation of tonic pain sensitivity, selective NTS2 ligands could be useful analgesics without the side effects of opioid-mediated antinociception.

    2. Exploring the Polyamine Regulatory Site of the NMDA Receptor: a Parallel Synthesis Approach (pages 82–94)

      Dr. Michael L. Berger, Dr. Thomas Pöhler, Dr. Oliver Schadt, Maximilian Stanger, Patrick Rebernik, Dr. Petra Scholze and Prof. Dr. Christian R. Noe

      Article first published online: 6 DEC 2012 | DOI: 10.1002/cmdc.201200470

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      The long arm of the asymmetric thieno diamine N4T8N was resolved into a dipeptidic structure by a combinatorial synthesis approach. The obtained small libraries were tested at the NMDA receptor and exhibited stimulatory and inhibitory properties, the latter depending on spermine and pH.

    3. How is 68Ga Labeling of Macrocyclic Chelators Influenced by Metal Ion Contaminants in 68Ge/68Ga Generator Eluates? (pages 95–103)

      Jakub Šimeček, Prof. Dr. Petr Hermann, Prof. Dr. Hans-Jürgen Wester and Dr. Johannes Notni

      Article first published online: 7 NOV 2012 | DOI: 10.1002/cmdc.201200471

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      Gallium preferred: 68Ga labeling of triazacyclononane-triphosphinate chelators is comparably insensitive to the presence of contaminants such as Zn2+, Cu2+, Fe3+, Al3+, TiIV, and SnIV in the eluate of 68Ge/68Ga generators compared with a selection of other pendant-arm azamacrocycles. Their ZnII complexes undergo transmetallation with 68Ga3+, which is uncommon for this type of ligand.

    4. Synthesis and Evaluation of 3,4-Dihydropyrimidin-2(1H)-ones as Sodium Iodide Symporter Inhibitors (pages 104–111)

      Pierre Lacotte, Celine Puente and Dr. Yves Ambroise

      Article first published online: 6 NOV 2012 | DOI: 10.1002/cmdc.201200417

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      Ain′t NIS-behavin′: The effect of structure modification at five key positions on the dihydropyrimidone core is reported against iodide transport in rat thyroid-derived cells. This work describes extensive structure–activity relationships and identifies the most potent inhibitor reported to date.

    5. Small-Molecule APOBEC3G DNA Cytosine Deaminase Inhibitors Based on a 4-Amino-1,2,4-triazole-3-thiol Scaffold (pages 112–117)

      Margaret E. Olson, Dr. Ming Li, Dr. Reuben S. Harris and Prof. Dr. Daniel A. Harki

      Article first published online: 23 NOV 2012 | DOI: 10.1002/cmdc.201200411

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      A gift from C to U: A small library of 4-amino-1,2,4-triazole-3-thiol inhibitors of the DNA cytosine deaminase APOBEC3G (A3G) was developed based on leads from HTS. Analogues with pendent sulfhydryl groups potently inhibit A3G activity (IC50: 3.9–8.2 μM) and show remarkable selectivity over the related deaminase APOBEC3A. Sulfhydryl group alkylation abolished inhibitory activity by blocking disulfide formation with Cys 321 on A3G, as verified by the resistance of the A3G C321A mutant protein to molecules of this class.

    6. Low-Molecular-Weight CXCR4 Ligands with Variable Spacers (pages 118–124)

      Dr. Tetsuo Narumi, Dr. Haruo Aikawa, Dr. Tomohiro Tanaka, Chie Hashimoto, Dr. Nami Ohashi, Dr. Wataru Nomura, Takuya Kobayakawa, Hikaru Takano, Yuki Hirota, Dr. Tsutomu Murakami, Prof. Naoki Yamamoto and Prof. Hirokazu Tamamura

      Article first published online: 19 OCT 2012 | DOI: 10.1002/cmdc.201200390

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      Keeping it light: Low-molecular-weight CXCR4 ligands were synthesized. Three types of aromatic spacers were used to build four pharmacophore groups; 2-pyridylmethyl and 1-naphthylmethyl groups are present in all of the compounds, and an aromatic group and a cationic group from 1-propylguanidine and 1,1,3,3-tetramethyl-2-propylguanidine were adopted. Several compounds show significant CXCR4 binding affinity. Zinc(II) complexation of bis(pyridin-2-ylmethyl)amine moieties resulted in a remarkable increase in CXCR4 binding affinity.

    7. Synthesis and Quantitative Structure–Activity Relationships of Selective BCRP Inhibitors (pages 125–135)

      Federico Marighetti, Dr. Kerstin Steggemann, Markus Hanl and Prof. Dr. Michael Wiese

      Article first published online: 13 NOV 2012 | DOI: 10.1002/cmdc.201200377

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      ABC: easy as rings 2, 3: The breast cancer resistance protein (BCRP/ABCG2) plays a crucial role in protecting the body from xenobiotics, but its overexpression in certain tumors causes resistance against various chemotherapeutics. We synthesized 25 compounds of a new class of selective BCRP inhibitors. A QSAR model for the second and third aromatic ring was established. The results show the importance of the electron density on the third aromatic ring and of steric hindrance on the second aromatic ring.

    8. 3D-QSAR-Assisted Drug Design: Identification of a Potent Quinazoline-Based Aurora Kinase Inhibitor (pages 136–148)

      Dr. Yi-Yu Ke, Dr. Hui-Yi Shiao, Dr. Yung Chang Hsu, Dr. Chang-Ying Chu, Dr. Wen-Chieh Wang, Yen-Chun Lee, Dr. Wen-Hsing Lin, Chun-Hwa Chen, Dr. John T. A. Hsu, Chun-Wei Chang, Dr. Cheng-Wei Lin, Dr. Teng-Kuang Yeh, Dr. Yu-Sheng Chao, Dr. Mohane Selvaraj Coumar and Dr. Hsing-Pang Hsieh

      Article first published online: 22 NOV 2012 | DOI: 10.1002/cmdc.201200464

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      Amazing Aurora displays: Through insight obtained from 3D-QSAR modeling of pyrazoles 119 and furanopyrimdines 2066 as Aurora kinase inhibitors, a potent quinazoline inhibitor was designed and synthesized. In vitro and in vivo experiments revealed that quinazoline 67 has the potential for further development.

    9. Highly Ligand Efficient and Selective N-2-(Thioethyl)picolinamide Histone Deacetylase Inhibitors Inspired by the Natural Product Psammaplin A (pages 149–156)

      Matthias G. J. Baud, Patricia Haus, Thomas Leiser, Prof. Dr. Franz-Josef Meyer-Almes and Dr. Matthew J. Fuchter

      Article first published online: 26 NOV 2012 | DOI: 10.1002/cmdc.201200450

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      Replace the oxime: New picolinamide-based HDAC inhibitors were developed by drawing inspiration from the natural product psammaplin A. These compounds display very high potency and isoform selectivity among the HDAC family, in addition to excellent ligand efficiency relative to previously reported HDAC inhibitors.

    10. Identification of LasR Ligands through a Virtual Screening Approach (pages 157–163)

      Dr. Søren Skovstrup, Dr. Sebastian Thordal Le Quement, Dr. Thomas Hansen, Dr. Tim Holm Jakobsen, Dr. Morten Harmsen, Prof. Tim Tolker-Nielsen, Prof. Thomas E. Nielsen, Prof. Michael Givskov and Prof. Olivier Taboureau

      Article first published online: 30 NOV 2012 | DOI: 10.1002/cmdc.201200434

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      A quorum of eight compounds that modulate the activity of LasR, a transcription factor that controls quorum sensing in P. aeruginosa, were identified. Five new inducers and three inhibitors of LasR activity were validated experimentally by cell-based assays. Interestingly, these compounds are structurally distinct from N-3-oxododecanoyl-L-homoserine lactone, the native signal molecule for LasR, and thus may be suitable lead structures for the design of new drugs.

  8. Book Reviews

    1. Top of page
    2. Cover Pictures
    3. Editorials
    4. Graphical Abstract
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Introduction to Strategies for Organic Synthesis. By Laurie S. Starkey. (page 164)

      Prof. Mark G. Moloney

      Article first published online: 12 OCT 2012 | DOI: 10.1002/cmdc.201200440

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      Wiley, Hoboken 2012. 360 pp., softcover $ 49.95.—ISBN 978-0-470-48409-8

    2. Drug Discovery in Infectious Diseases, Volume 3: Parasitic Helminths: Targets, Screens, Drugs and Vaccines. Edited by Conor R. Caffrey (pages 164–166)

      Dr. Elisabeth Davioud-Charvet

      Article first published online: 23 NOV 2012 | DOI: 10.1002/cmdc.201200515

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      Wiley-Blackwell, Weinheim 2012. 500 pp., hardcover, € 119.—ISBN 978-3-527-33059-1

    3. Designing Multi-Target Drugs. Edited by J. Richard Morphy and C. John Harris. (pages 166–167)

      Dr. Jens-Uwe Peters

      Article first published online: 26 SEP 2012 | DOI: 10.1002/cmdc.201200420

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      RSC, Cambridge 2012. 394 pp., hardcover £ 153.99.—ISBN 978-1-84973-362-5

    4. Nanoparticles in Biology and Medicine: Methods and Protocols. Edited by Mikhail Soloviev. (page 167)

      Prof. Dr. Eleonore Fröhlich

      Article first published online: 2 OCT 2012 | DOI: 10.1002/cmdc.201200430

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      Humana Press, New York 2012. xvii+555 pp., hardcover $ 159.00.—ISBN 978-1-61779-952-5

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