ChemMedChem

Cover image for Vol. 8 Issue 8

August 2013

Volume 8, Issue 8

Pages 1229–1417

  1. Cover Pictures

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. You have free access to this content
      Cover Picture: Discovery of NVP-LEQ506, a Second-Generation Inhibitor of Smoothened (ChemMedChem 8/2013) (page 1229)

      Dr. Stefan Peukert, Dr. Feng He, Miao Dai, Rui Zhang, Yingchuan Sun, Dr. Karen Miller-Moslin, Michael McEwan, Dr. Bharat Lagu, Kate Wang, Dr. Naeem Yusuff, Aaron Bourret, Arun Ramamurthy, Dr. Wieslawa Maniara, Adam Amaral, Anthony Vattay, Anlai Wang, Ribo Guo, Jing Yuan, John Green, Dr. Juliet Williams, Dr. Silvia Buonamici, Dr. Joseph F. Kelleher III and Dr. Marion Dorsch

      Version of Record online: 29 JUL 2013 | DOI: 10.1002/cmdc.201390030

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      The front cover picture shows the structure of NVP-LEQ506, a new and potent inhibitor of the transmembrane receptor Smoothened. This compound, currently in clinical trials, binds to Smoothened, resulting in inhibition of the Hedgehog signaling pathway and thus preventing cell proliferation mediated by Gli transcription factors. The identification of this low-nanomolar inhibitor was achieved through systematic structure–property relationship studies in which potency, solubility, and off-target effects were optimized. This discovery opens new treatment options for patients with cancers driven by Hedgehog pathway mutations such as medulloblastoma, a malignant brain tumor. For more details, see the Communication by Stefan Peukert et al. on p. 1261 ff.

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      Inside Cover: Synthesis and Radiopharmacological Characterisation of a Fluorine-18-Labelled Azadipeptide Nitrile as a Potential PET Tracer for in vivo Imaging of Cysteine Cathepsins (ChemMedChem 8/2013) (page 1230)

      Dr. Reik Löser, Dr. Ralf Bergmann, Dr. Maxim Frizler, Dr. Birgit Mosch, Lilli Dombrowski, Manuela Kuchar, Prof. Dr. Jörg Steinbach, Prof. Dr. Michael Gütschow and Prof. Dr. Jens Pietzsch

      Version of Record online: 29 JUL 2013 | DOI: 10.1002/cmdc.201390031

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      The inside cover picture shows a 3D model of an azadipeptide nitrile labeled with fluorine-18. This compound is capable of targeting cysteine cathepsins, which are implicated in tumor invasion and metastasis, and thereby allows the visualization of these enzymes in vivo by positron emission tomography (PET). For more details, see the Full Paper by Reik Löser et al. on p. 1330 ff.

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      Back Cover: Probing the Key Interactions between Human Atg5 and Atg16 Proteins: A Prospective Application of Molecular Modeling (ChemMedChem 8/2013) (page 1420)

      Zhixiong Zhao, Zhengxi Zhang, Dr. Yan Li, Mi Zhou, Dr. Xun Li, Prof. Biao Yu and Prof. Renxiao Wang

      Version of Record online: 29 JUL 2013 | DOI: 10.1002/cmdc.201390034

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      The back cover picture shows a structural model of ATG5 (cyan) in complex with a segment of ATG16 (pink) derived through homology modeling. ATG5–ATG16 association is a key step in the formation of the pre-autophagosomal structure in autophagy. Using this model as a reference, three residues were identified in ATG16 as critical for maintaining its affinity to ATG5. A recently resolved crystal structure of the ATG12–ATG5–ATG16 complex (PDB 4GDK; blue) provides validation of this model. For more details, see the Communication by Renxiao Wang et al. on p. 1270 ff.

  2. Graphical Abstract

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. You have free access to this content
  3. Corrigendum

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. You have free access to this content
      Corrigendum: Cinnamic Acid/Chloroquinoline Conjugates as Potent Agents against Chloroquine-Resistant Plasmodium falciparum (page 1238)

      Bianca Pérez, Dr. Cátia Teixeira, Jiri Gut, Prof. Philip J. Rosenthal, Dr. José R. B. Gomes and Prof. Paula Gomes

      Version of Record online: 29 JUL 2013 | DOI: 10.1002/cmdc.201300258

      This article corrects:
  4. News

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
  5. Minireview

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Recent Developments of 19-Nor-1,25-dihydroxyvitamin D3 Analogues (pages 1249–1260)

      Can-Fei Zhang, Prof. Ren-Zhong Wan and Prof. Zhao-Peng Liu

      Version of Record online: 20 JUN 2013 | DOI: 10.1002/cmdc.201300160

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      Vital analogues: The use of 1,25(OH)2D3 for the treatment of a wide variety of diseases was limited by the parallel induction of hypercalcemic effects. There is an urgent need to find novel agents with greater selectivity. This review highlights recent advances in the research of 19-nor-1,25-dihydroxyvitamin D3 analogues, paying special attention to their activities and structure– activity relationships.

  6. Communications

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Discovery of NVP-LEQ506, a Second-Generation Inhibitor of Smoothened (pages 1261–1265)

      Dr. Stefan Peukert, Dr. Feng He, Miao Dai, Rui Zhang, Yingchuan Sun, Dr. Karen Miller-Moslin, Michael McEwan, Dr. Bharat Lagu, Kate Wang, Dr. Naeem Yusuff, Aaron Bourret, Arun Ramamurthy, Dr. Wieslawa Maniara, Adam Amaral, Anthony Vattay, Anlai Wang, Ribo Guo, Jing Yuan, John Green, Dr. Juliet Williams, Dr. Silvia Buonamici, Dr. Joseph F. Kelleher III and Dr. Marion Dorsch

      Version of Record online: 2 JUL 2013 | DOI: 10.1002/cmdc.201300217

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      First disclosure: Continued optimization provided a novel type of Smoothened (Smo) antagonist based on a pyridazine core. The compound, NVP-LEQ506, currently in phase I clinical trials, combines high intrinsic potency and good pharmacokinetic properties resulting in excellent efficacy in rodent tumor models of medulloblastoma. Activity against a Smo mutant conferring resistance observed in a previous clinical trial with a competitor compound suggests additional therapeutic potential.

    2. Antiproliferative Activity, Cell Cycle, and Apoptosis Studies of a Series of 6-Substituted 9H-Purin-9-yl-pyridinium Derivatives on a Human Cervical Carcinoma Cell Line (pages 1266–1269)

      Dr. Belén Rubio-Ruiz, Javier Ramos-Torrecillas, Fermín Capitán-Cañadas, Dr. Rosario Sánchez-Martín, Prof. Miguel Ángel Gallo, Prof. Antonio Espinosa, Prof. Concepción Ruiz, Dr. Ana Conejo-García and Prof. Antonio Entrena

      Version of Record online: 14 JUN 2013 | DOI: 10.1002/cmdc.201300171

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      Better by benzylthio: A series of 6-substituted 9H-purin-9-yl-pyridinium derivatives was synthesized and evaluated for their antitumor activity. Compounds included in this study elicit variations in cell-cycle progression and an increase of apoptotic cells in a caspase-3-dependent process.

    3. Probing the Key Interactions between Human Atg5 and Atg16 Proteins: A Prospective Application of Molecular Modeling (pages 1270–1275)

      Zhixiong Zhao, Zhengxi Zhang, Dr. Yan Li, Mi Zhou, Dr. Xun Li, Prof. Biao Yu and Prof. Renxiao Wang

      Version of Record online: 26 JUN 2013 | DOI: 10.1002/cmdc.201300256

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      Breaking things down: Disruption of the Atg5–Atg16 protein–protein interaction is a potential strategy for the development of effective inhibitors of autophagy. Using a structural model of the human Atg5–Atg16 complex, a total of 30 Atg16-based peptides were designed and tested for their binding affinity to Atg5. A number of these peptides exhibited binding affinities in the low micromolar range. Furthermore, three Atg16 residues were identified as the key factors in Atg5 binding.

    4. The Bivalent Ligand Approach as a Tool for Improving the in vitro Anti-Alzheimer Multitarget Profile of Dimebon (pages 1276–1281)

      Dr. Michela Rosini, Dr. Elena Simoni, Dr. Manuela Bartolini, Dr. Elena Soriano, Prof. José Marco-Contelles, Prof. Vincenza Andrisano, Dr. Barbara Monti, Dr. Manfred Windisch, Dr. Birgit Hutter-Paier, Dr. David W. McClymont, Dr. Ian R. Mellor and Prof. Maria Laura Bolognesi

      Version of Record online: 3 JUL 2013 | DOI: 10.1002/cmdc.201300263

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      Inspired by the concept of bivalent ligands, we prepared a small set of analogues of the drug candidate dimebon. They were shown to inhibit AChE, Aβ42 aggregation, and NMDA receptor activation to a greater extent than dimebon. Some of these compounds also enhanced the survival of chicken neurons under apoptosis-inducing conditions.

  7. Full Papers

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Design of a Highly Selective and Potent Class of Non-planar Estrogen Receptor β Agonists (pages 1283–1294)

      Dr. Henrik Sundén, Dr. Jian-Nong Ma, Prof. Lars K. Hansen, Dr. Anna-Lena Gustavsson, Dr. Ethan S. Burstein and Prof. Roger Olsson

      Version of Record online: 19 JUN 2013 | DOI: 10.1002/cmdc.201300175

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      Nothing flat about it: A T-shaped trans-SS diastereomer of 4-{3-fluoro-8-oxatricyclo[7.5.0.02,7]tetradeca-2,4,6-trien-1-yl}phenol (10) was found to be 1000-fold selective for ERβ over ERα. This compound exhibits ∼10 nM potency and appears to be the first to take advantage of both conservative amino acid differences found in the α- and β-faces of the binding cavities of ERα and ERβ.

    2. Selective and Brain-Permeable Polo-like Kinase-2 (Plk-2) Inhibitors That Reduce α-Synuclein Phosphorylation in Rat Brain (pages 1295–1313)

      Dr. Danielle L. Aubele, Dr. Roy K. Hom, Dr. Marc Adler, Dr. Robert A. Galemmo Jr., Dr. Simeon Bowers, Dr. Anh P. Truong, Dr. Hu Pan, Dr. Paul Beroza, Dr. R. Jeffrey Neitz, Dr. Nanhua Yao, May Lin, Dr. George Tonn, Heather Zhang, Dr. Michael P. Bova, Dr. Zhao Ren, Danny Tam, Lany Ruslim, Dr. Jeanne Baker, Linnea Diep, Dr. Kent Fitzgerald, Jennifer Hoffman, Ruth Motter, Donald Fauss, Pearl Tanaka, Dr. Michael Dappen, Dr. Jacek Jagodzinski, Wayman Chan, Dr. Andrei W. Konradi, Dr. Lee Latimer, Dr. Yong L. Zhu, Dr. Hing L. Sham, Dr. John P. Anderson, Dr. Marcelle Bergeron and Dr. Dean R. Artis

      Version of Record online: 21 JUN 2013 | DOI: 10.1002/cmdc.201300166

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      Gets into your head: By using a structure-guided drug discovery approach, highly selective brain-penetrant Plk-2 inhibitors were designed with the use of an interesting aromatic edge–face interaction as a potency–selectivity determinant. An analogue from this work lowered phosphorylated α-synuclein levels in vivo on oral dosing, demonstrating successful target engagement in the rat brain and paving the way for proof-of-concept studies in rodent models of Parkinson's disease.

    3. E-64c-Hydrazide: A Lead Structure for the Development of Irreversible Cathepsin C Inhibitors (pages 1314–1321)

      Hanna Radzey, Markus Rethmeier, Dennis Klimpel, Maresa Grundhuber, Prof. Dr. Christian P. Sommerhoff and Priv.-Doz. Dr. Norbert Schaschke

      Version of Record online: 18 JUN 2013 | DOI: 10.1002/cmdc.201300093

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      Hitting the spot! Converting the carboxylic acid function of (2S,3S)-trans- epoxysuccinyl-L-leucylamido-3-methylbutane (E-64c), a synthetic broad-spectrum cysteine peptidase inhibitor, into the corresponding alkylhydrazide was identified as a key step to obtain potent irreversible cathepsin C inhibitors.

    4. Structure-Based Design of Small-Molecule Ligands of Phosphofructokinase-2 Activating or Inhibiting Glycolysis (pages 1322–1329)

      Dr. Timothy V. Pyrkov, Dr. Irina A. Sevostyanova, Dr. Elena V. Schmalhausen, Dr. Andrei N. Shkoporov, Dr. Andrei A. Vinnik, Prof. Vladimir I. Muronetz, Prof. Fedor F. Severin and Dr. Peter O. Fedichev

      Version of Record online: 28 JUN 2013 | DOI: 10.1002/cmdc.201300154

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      Fruct-o so good! Using a structure-based approach, potential small-molecule regulators of phosphofructokinase-2, a bifunctional enzyme and regulator of glycolytic flux, were discovered. The most potent inhibitors of kinase activity in the series also inhibited the proliferation of HeLa, lung adenocarcinoma, colon adenocarcinoma, and breast cancer cells at concentrations in the low micromolar range.

    5. Synthesis and Radiopharmacological Characterisation of a Fluorine-18-Labelled Azadipeptide Nitrile as a Potential PET Tracer for in vivo Imaging of Cysteine Cathepsins (pages 1330–1344)

      Dr. Reik Löser, Dr. Ralf Bergmann, Dr. Maxim Frizler, Dr. Birgit Mosch, Lilli Dombrowski, Manuela Kuchar, Prof. Dr. Jörg Steinbach, Prof. Dr. Michael Gütschow and Prof. Dr. Jens Pietzsch

      Version of Record online: 19 JUN 2013 | DOI: 10.1002/cmdc.201300135

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      Visualising cathepsins in tumours: Cysteine cathepsins are key players in tumour pathology. An azadipeptide nitrile with high affinity for cathepsins L, S, B, and K was labelled with fluorine-18 and investigated for its pharmacokinetic properties. PET imaging studies with tumour-bearing mice indicate the tumour accumulation of the probe and the potential of tumour targeting for this inhibitor class.

    6. Characterization of the Stereochemical Structures of 2H-Thiazolo[3,2-a]pyrimidine Compounds and Their Binding Affinities for Anti-apoptotic Bcl-2 Family Proteins (pages 1345–1352)

      Yaochun Xu, Mi Zhou, Yan Li, Chengke Li, Zhengxi Zhang, Prof. Biao Yu and Prof. Renxiao Wang

      Version of Record online: 21 JUN 2013 | DOI: 10.1002/cmdc.201300159

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      Ambidexterity! The compounds reported herein were characterized as inhibitors of anti-apoptotic Bcl-2 family proteins. Structures in this compound class contain a chiral center (C4 atom) on the pyrimidine ring. Interestingly, our study revealed that the R and S enantiomers of this compound class have similar binding affinities for Bcl-xL, Bcl-2, and Mcl-1.

    7. Identification of Hck Inhibitors As Hits for the Development of Antileukemia and Anti-HIV Agents (pages 1353–1360)

      Dr. Cristina Tintori, Ilaria Laurenzana, Francesco La Rocca, Dr. Federico Falchi, Prof. Fabio Carraro, Alba Ruiz, Prof. José A. Esté, Miroslava Kissova, Dr. Emmanuele Crespan, Prof. Giovanni Maga, Prof. Mariangela Biava, Dr. Chiara Brullo, Prof. Silvia Schenone and Prof. Maurizio Botta

      Version of Record online: 28 JUN 2013 | DOI: 10.1002/cmdc.201300204

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      Rational design: Virtual screening by cross-docking identified various small molecules as hematopoietic cell kinase (Hck) inhibitors. Evaluation of the virtual hits in a cell-free assay revealed that some compounds inhibit Hck at sub- micromolar concentrations. Simulations allowed the identification of key interactions in the inhibitor–kinase complexes.

    8. Synergistic Inhibitor Binding to the Papain-Like Protease of Human SARS Coronavirus: Mechanistic and Inhibitor Design Implications (pages 1361–1372)

      Dr. Hyun Lee, Shuyi Cao, Prof. Kirk E. Hevener, Lena Truong, Joseph L. Gatuz, Kavankumar Patel, Prof. Arun K. Ghosh and Prof. Michael E. Johnson

      Version of Record online: 20 JUN 2013 | DOI: 10.1002/cmdc.201300134

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      Synergistic fragment merging: To improve the potency of previously developed SARS-PLpro inhibitors, synergistic small fragments were identified by enzymatic assay and confirmed by SPR. Merged compounds are proposed based on enzymatic mode of inhibition, mutual exclusivity, computational solvent mapping, and molecular docking studies.

    9. Discovery of an Acyclic Nucleoside Phosphonate that Inhibits Mycobacterium tuberculosis ThyX Based on the Binding Mode of a 5-Alkynyl Substrate Analogue (pages 1373–1383)

      Anastasia Parchina, Prof. Dr. Matheus Froeyen, Lia Margamuljana, Prof. Dr. Jef Rozenski, Dr. Steven De Jonghe, Dr. Yves Briers, Prof. Dr. Rob Lavigne, Prof. Dr. Piet Herdewijn and Prof. Dr. Eveline Lescrinier

      Version of Record online: 8 JUL 2013 | DOI: 10.1002/cmdc.201300146

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      Rational design: The selective ThyX inhibitor 5-alkynyl 2'-deoxyuridine 5'-monophosphate was modeled in its target active site, and NMR was used to support the predicted binding mode. To increase the stability of the lead compound, some acyclic nucleoside phosphonate (ANP) derivatives were synthesized and tested in vitro for ThyX inhibition. A modestly active inhibitor was identified, further optimization of which could lead to antibacterial thymidylate synthase inhibitors.

    10. Design, Synthesis and Biological Evaluation of Rose Bengal Analogues as SecA Inhibitors (pages 1384–1393)

      Dr. Jianmei Cui, Dr. Jinshan Jin, Dr. Ying-Hsin Hsieh, Dr. Hsiuchin Yang, Dr. Bowen Ke, Dr. Krishna Damera, Dr. Phang C. Tai and Dr. Binghe Wang

      Version of Record online: 21 JUN 2013 | DOI: 10.1002/cmdc.201300216

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      The simpler the better: We report the synthesis and structure–activity relationship (SAR) studies of 23 rose bengal analogues that were designed by systematical dissections. Evaluation of these analogues allowed us to establish an initial SAR for SecA inhibition. The antimicrobial effects of these SecA inhibitors are confirmed in experiments using E. coli and B. subtilis.

    11. Effect of Ester to Amide or N-Methylamide Substitution on Bacterial Membrane Depolarization and Antibacterial Activity of Novel Cyclic Lipopeptides (pages 1394–1402)

      Dr. Nina Bionda, Renee M. Fleeman, Dr. Lindsey N. Shaw and Dr. Predrag Cudic

      Version of Record online: 18 JUN 2013 | DOI: 10.1002/cmdc.201300173

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      To be or not to be active: A cyclic lipodepsipeptide and its amide analogue can depolarize the cytoplasmic membranes of Gram-positive bacteria, whereas the N-methylamide analogue is inactive. Membrane depolarization does not correlate with bacterial cell lethality, suggesting that membrane-targeting activity is not the main mode of action for this class of antibacterial peptides.

    12. Design, Synthesis, and Evaluation of WC5 Analogues as Inhibitors of Human Cytomegalovirus Immediate-Early 2 Protein, a Promising Target for Anti-HCMV Treatment (pages 1403–1414)

      Dr. Serena Massari, Dr. Beatrice Mercorelli, Dr. Luca Sancineto, Dr. Stefano Sabatini, Prof. Violetta Cecchetti, Prof. Giorgio Gribaudo, Prof. Giorgio Palù, Prof. Christophe Pannecouque, Prof. Arianna Loregian and Prof. Oriana Tabarrini

      Version of Record online: 11 JUN 2013 | DOI: 10.1002/cmdc.201300106

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      Immediate, early effects: The quinolone scaffold of the potent and selective anti-HCMV compound WC5 was investigated in depth, furnishing new SAR insight and identifying novel potent analogues, the anti-HCMV activity of which is brought about by inhibition of IE2-mediated transactivation. These quinolone derivatives are therefore particularly well suited for treating patients that do not respond to the DNA polymerase inhibitors in current use.

  8. Book Reviews

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Minireview
    7. Communications
    8. Full Papers
    9. Book Reviews
    1. Understanding Diabetes: A Biochemical Perspective. Richard F. Dods (page 1415)

      Prof. Dr. Eugen J. Verspohl

      Version of Record online: 2 JUL 2013 | DOI: 10.1002/cmdc.201300266

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      Wiley, Hoboken 2013. 426 pp., softcover, $99.95.—ISBN 978-1-118-35009-6

    2. New Therapeutic Strategies for Type 2 Diabetes. Edited by Robert M. Jones (pages 1415–1416)

      Dr. Sofiya Gancheva and Prof. Dr. Michael Roden

      Version of Record online: 10 JUN 2013 | DOI: 10.1002/cmdc.201300206

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      RSC, Cambridge 2012. 532 pp., hardcover, £159.99.—ISBN 978-1-84973-414-1

    3. Drug Discovery from Natural Products. Edited by Olga Genilloud and Francisca Vicente (pages 1416–1417)

      Dr. Sabine Amslinger

      Version of Record online: 24 APR 2013 | DOI: 10.1002/cmdc.201300158

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      RSC Publishing, Cambridge 2012. 436 pp., hardcover, £159.99.—ISBN 978-1-84973-495-0

    4. Efficient Preparations of Fluorine Compounds. Edited by Herbert W. Roesky (page 1417)

      Prof. Graham Sandford

      Version of Record online: 9 APR 2013 | DOI: 10.1002/cmdc.201300126

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      Wiley, Hoboken 2013. 484 pp., hardcover, $125.00.—ISBN 978-1-1180-7856-3

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