ChemMedChem

Cover image for Vol. 8 Issue 12

December 2013

Volume 8, Issue 12

Pages 1897–2076

  1. Cover Pictures

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Communications
    7. Full Papers
    1. You have free access to this content
      Cover Picture: Chromophore-Linked Substrate (CLS405): Probing Metallo-β-Lactamase Activity and Inhibition (ChemMedChem 12/2013) (page 1897)

      Anne Makena, Dr. Sander S. van Berkel, Dr. Clarisse Lejeune, Dr. Raymond J. Owens, Dr. Anil Verma, Ramya Salimraj, Dr. James Spencer, Dr. Jürgen Brem and Prof. Dr. Christopher J. Schofield

      Version of Record online: 29 NOV 2013 | DOI: 10.1002/cmdc.201390050

      Thumbnail image of graphical abstract

      The front cover picture shows the hydrolysis of chromogenic substrate CLS405 (green) by NDM-1 (blue protein structure), a metallo-beta-lactamase (MBL), generating the detectable para-nitrophenolate product (yellow). Upon binding of an inhibitor (N-hydroxythiazole shown in gray), hydrolysis of the substrate is hampered, thus facilitating rapid residual activity determination. Monitoring inhibition in a concentration-dependent manner allows for straightforward IC50 value determination using chromogenic substrate CLS405. Given the threat posed by MBLs to the clinical use of beta-lactam antibiotics, the identification of MBL inhibitors is an important research goal. CLS405 represents a useful tool compound to facilitate the identification of improved MBL inhibitors with therapeutic potential against resistant strains of bacteria. For more details, see the Full Paper by Jürgen Brem, Christopher J. Schofield et al. on p. 1923 ff.

    2. You have free access to this content
      Inside Cover: Sigma-2 Receptor Agonists as Possible Antitumor Agents in Resistant Tumors: Hints for Collateral Sensitivity (ChemMedChem 12/2013) (page 1898)

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

      Version of Record online: 29 NOV 2013 | DOI: 10.1002/cmdc.201390051

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      The inside cover picture shows a carbazole (compd 25 in the article) interacting with both P-glycoprotein (P-gp) and σ2 receptors. Through these combined activities, a futile ATP cycle is activated and reactive oxygen species (ROS) are generated. Enhanced antiproliferative effects were observed in drug-resistant over standard MCF7 cells. This phenomenon, termed collateral sensitivity, is under study in multidrug- resistant tumors, and mixed σ2 agonists/P-gp substrates are promising for their treatment. For more details, see the Full Paper by Carmen Abate et al. on p. 2026 ff.

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      Back Cover: Synthesis and Biological Evaluation of Imidazopyridine–Oxindole Conjugates as Microtubule-Targeting Agents (ChemMedChem 12/2013) (page 2080)

      Dr. Ahmed Kamal, Vangala Santhosh Reddy, Santosh Karnewar, Sumit S. Chourasiya, Anver Basha Shaik, G. Bharath Kumar, Chandan Kishor, M. Kashi Reddy, M. P. Narasimha Rao, Dr. Ananthamurthy Nagabhushana, Kallaganti V. S. Ramakrishna, Dr. Anthony Addlagatta and Dr. Srigiridhar Kotamraju

      Version of Record online: 29 NOV 2013 | DOI: 10.1002/cmdc.201390054

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      The back cover picture shows the predicted interaction of an imidazopyridine–oxindole conjugate with β-chain amino acids of tubulin. A series of conjugates were designed, synthesized and evaluated as microtubule-targeting agents. Molecular modeling predicts that these conjugates bind in the colchicine binding site at the interface between the α- and β-chains of tubulin. For more details, see the Full Paper by Ahmed Kamal, Anthony Addlagatta, Srigiridhar Kotamraju, et al. on p. 2015 ff.

  2. Graphical Abstract

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Communications
    7. Full Papers
    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. Communications
    7. Full Papers
    1. You have free access to this content
      Corrigendum: Small-Molecule Modulators for Epigenetics Targets (page 1904)

      Prof. Dr. Stefan Knapp and Prof. Dr. Hilmar Weinmann

      Version of Record online: 29 NOV 2013 | DOI: 10.1002/cmdc.201300464

      This article corrects:

      Small-Molecule Modulators for Epigenetics Targets

      Vol. 8, Issue 11, 1885–1891, Version of Record online: 14 OCT 2013

  4. News

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

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Communications
    7. Full Papers
    1. Synthesis and Structure–Activity Relationship Studies of Quinoxaline Derivatives as Aldose Reductase Inhibitors (pages 1913–1917)

      Bobin Wu, Dr. Yanchun Yang, Dr. Xiangyu Qin, Dr. Shuzhen Zhang, Dr. Chaojun Jing, Prof. Dr. Changjin Zhu and Dr. Bing Ma

      Version of Record online: 2 OCT 2013 | DOI: 10.1002/cmdc.201300324

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      ARIs for diabetes: A series of 2-(3-benzyl-2-oxoquinoxalin-1(2H)-yl)acetic acid derivatives were designed and synthesized as inhibitors of aldose reductase (AR), a novel target for the treatment of diabetes complications. Most of the derivatives proved to be potent and selective, with IC50 values in the low nanomolar to micromolar range.

    2. A Template-Based Approach to Inhibitors of Calpain 2, 20S Proteasome, and HIV-1 Protease (pages 1918–1921)

      Dr. Seth A. Jones, Dr. Paul M. Neilsen, Limei Siew, Prof. David F. Callen, Dr. Nathan E. Goldfarb, Prof. Ben M. Dunn and Prof. Andrew D. Abell

      Version of Record online: 15 OCT 2013 | DOI: 10.1002/cmdc.201300387

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      Specificity counts: A template-based approach to protease inhibitors is presented using a core macrocycle that presents a generic β-strand template for binding to protease active sites. This is then specifically functionalized at P2, and the C and N termini to give inhibitors of calpain 2, 20S proteasome, and HIV-1 protease.

  6. Full Papers

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. Corrigendum
    5. News
    6. Communications
    7. Full Papers
    1. Chromophore-Linked Substrate (CLS405): Probing Metallo-β-Lactamase Activity and Inhibition (pages 1923–1929)

      Anne Makena, Dr. Sander S. van Berkel, Dr. Clarisse Lejeune, Dr. Raymond J. Owens, Dr. Anil Verma, Ramya Salimraj, Dr. James Spencer, Dr. Jürgen Brem and Prof. Dr. Christopher J. Schofield

      Version of Record online: 25 OCT 2013 | DOI: 10.1002/cmdc.201300350

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      Monitoring MBLs! Resistance to β-lactam antibiotics, mediated by metallo-β-lactamases (MBLs), is an increasing clinical problem. While compounds that target MBLs could be useful antibacterial agents, their identification is hampered by the lack of suitable assay platforms. To this end, CLS405, a chromophore-linked MBL substrate, was developed and its applicability demonstrated by the identification of N-hydroxythiazoles as potential inhibitors against a panel of clinically relevant MBLs.

    2. Discovery of MK-8742: An HCV NS5A Inhibitor with Broad Genotype Activity (pages 1930–1940)

      Dr. Craig A. Coburn, Dr. Peter T. Meinke, Wei Chang, Dr. Christine M. Fandozzi, Donald J. Graham, Dr. Bin Hu, Qian Huang, Dr. Stacia Kargman, Dr. Joseph Kozlowski, Dr. Rong Liu, Dr. John A. McCauley, Dr. Amin A. Nomeir, Dr. Richard M. Soll, Dr. Joseph P. Vacca, Dr. Dahai Wang, Dr. Hao Wu, Dr. Bin Zhong, Dr. David B. Olsen and Dr. Steven W. Ludmerer

      Version of Record online: 14 OCT 2013 | DOI: 10.1002/cmdc.201300343

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      Effective treatment of chronic hepatitis C with direct-acting antivirals will require combination therapy with multiple agents that target different steps in the viral replication cycle and impose a high barrier to resistance. MK-8742 is a potent inhibitor of hepatitis C virus non-structural protein 5A (HCV NS5A) that is being developed as a component of an once-daily, all-oral, interferon-free regimen for the treatment of chronic HCV infection.

    3. Computer-Aided Design, Synthesis and Validation of 2-Phenylquinazolinone Fragments as CDK9 Inhibitors with Anti-HIV-1 Tat-Mediated Transcription Activity (pages 1941–1953)

      Dr. Luca Sancineto, Dr. Nunzio Iraci, Dr. Serena Massari, Dr. Vanessa Attanasio, Dr. Gianmarco Corazza, Dr. Maria Letizia Barreca, Dr. Stefano Sabatini, Dr. Giuseppe Manfroni, Dr. Nilla Roberta Avanzi, Prof. Violetta Cecchetti, Prof. Christophe Pannecouque, Prof. Alessandro Marcello and Dr. Oriana Tabarrini

      Version of Record online: 21 OCT 2013 | DOI: 10.1002/cmdc.201300287

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      Potent fragments! A 2-phenylquinazolinone fragment was initially identified by computational study, which after a first optimization evolved into a series of compounds capable of inhibiting cyclin-dependent kinase 9 (CDK9) activity at micromolar concentrations. The anti-kinase activity translated well into the ability to inhibit Tat-mediated transcription and HIV-1 infectivity in latently infected cells.

    4. Amythiamicin D and Related Thiopeptides as Inhibitors of the Bacterial Elongation Factor EF-Tu: Modification of the Amino Acid at Carbon Atom C2 of Ring C Dramatically Influences Activity (pages 1954–1962)

      Dr. Stefan Gross, Fabian Nguyen, Matthias Bierschenk, Daniel Sohmen, Dr. Thomas Menzel, Prof. Dr. Iris Antes, Dr. Daniel N. Wilson and Prof. Dr. Thorsten Bach

      Version of Record online: 17 SEP 2013 | DOI: 10.1002/cmdc.201300323

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      Virtue in the sinister: Binding of amythiamicin D related thiopeptides 1 to the bacterial elongation factor Tu (EF-Tu) is very sensitive to minor modifications at the indicated (- - - - -, red) site. An S-configured hydroxymethyl-substituted analogue (R1=CH2OH) showed better translation inhibition than amythiamicin D, whereas its R isomer was inactive, as was the respective BOM derivative (R1=CH2OCH2OBn). Molecular modeling and docking experiments corroborate these experimental results.

    5. Probing Binding and Cellular Activity of Pyrrolidinone and Piperidinone Small Molecules Targeting the Urokinase Receptor (pages 1963–1977)

      Dr. Timmy Mani, Dr. Degang Liu, Dr. Donghui Zhou, Dr. Liwei Li, Dr. William Eric Knabe, Fang Wang, Prof. Kyungsoo Oh and Prof. Samy O. Meroueh

      Version of Record online: 2 OCT 2013 | DOI: 10.1002/cmdc.201300340

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      Optimization through computation: Pyrazole-, propylamine-, pyrrolidinone- and piperidinone-containing compounds were designed, synthesized and evaluated as inhibitors of urokinase receptor (uPAR), a cell-surface protein known to be involved in cancer cell invasion and metastasis.

    6. para-Substituted 2-Phenyl-3,4-dihydroquinazolin-4-ones As Potent and Selective Tankyrase Inhibitors (pages 1978–1985)

      Dr. Teemu Haikarainen, Dr. Jarkko Koivunen, Mohit Narwal, Harikanth Venkannagari, Ezeogo Obaji, Päivi Joensuu, Prof. Taina Pihlajaniemi and Dr. Lari Lehtiö

      Version of Record online: 15 OCT 2013 | DOI: 10.1002/cmdc.201300337

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      TNKS for the inhibitors: A tankyrase inhibitor scaffold was identified, and a set of analogues were assayed for tankyrase inhibition. As a result, several highly potent and isoenzyme-selective inhibitors were discovered. Crystal structures of the compounds in complex with tankyrase 2 allowed us to rationalize inhibitor design using this and other similar scaffolds.

    7. De Novo Design, Synthesis and Evaluation of Benzylpiperazine Derivatives as Highly Selective Binders of Mcl-1 (pages 1986–2014)

      Dr. Xiao Ding, Dr. Yan Li, Li Lv, Mi Zhou, Dr. Li Han, Zhengxi Zhang, Dr. Qian Ba, Dr. Jingquan Li, Prof. Hui Wang, Prof. Hong Liu and Prof. Renxiao Wang

      Version of Record online: 9 OCT 2013 | DOI: 10.1002/cmdc.201300316

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      Selecting the fragments: Four series of benzylpiperazine derivatives were synthesized and tested as B-cell lymphoma 2 (Bcl-2) family protein inhibitors. They were designed using a fragment-based strategy on the basis of the outcomes of a computational algorithm. A num- ber of compounds exhibited binding affinities in the micromolar range (Ki <20 μM) to at least one target protein. Some compounds were selective binders to Mcl-1 with no detectable binding to Bcl-2 or Bcl-xL.

    8. Synthesis and Biological Evaluation of Imidazopyridine–Oxindole Conjugates as Microtubule-Targeting Agents (pages 2015–2025)

      Dr. Ahmed Kamal, Vangala Santhosh Reddy, Santosh Karnewar, Sumit S. Chourasiya, Anver Basha Shaik, G. Bharath Kumar, Chandan Kishor, M. Kashi Reddy, M. P. Narasimha Rao, Dr. Ananthamurthy Nagabhushana, Kallaganti V. S. Ramakrishna, Dr. Anthony Addlagatta and Dr. Srigiridhar Kotamraju

      Version of Record online: 23 SEP 2013 | DOI: 10.1002/cmdc.201300308

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      Arrested development: A library of imidazopyridine–oxindole conjugates was synthesised and investigated for anticancer activity against various human cancer cell lines. Some of the tested compounds, such as 10 a, 10 e, 10 f, and 10 k, exhibited promising antiproliferative activity.

    9. Sigma-2 Receptor Agonists as Possible Antitumor Agents in Resistant Tumors: Hints for Collateral Sensitivity (pages 2026–2035)

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

      Version of Record online: 19 SEP 2013 | DOI: 10.1002/cmdc.201300291

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      Collateral damage: We developed promising σ2 ligands for alternative strategies against multidrug-resistant cancer. New high-affinity σ2 agonists display antiproliferative activity in breast tumor cells; their interaction with P-gp generates higher activity in resistant than in parent cells (collateral sensitivity). Compounds co-administered with doxorubicin revert P-gp-mediated resistance.

    10. Effect of Linker Length and Composition on Heterobivalent Ligand-Mediated Receptor Cross-Talk between the A1 Adenosine and β2 Adrenergic Receptors (pages 2036–2046)

      Nicholas Barlow, Prof. Stephen P. Baker and Prof. Peter J. Scammells

      Version of Record online: 18 SEP 2013 | DOI: 10.1002/cmdc.201300286

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      A molecular double date: Heterobivalent ligands containing pharmacophores designed to interact with both the A1 adenosine receptor (A1AR) and the β2 adrenergic receptor (β2AR) were prepared. The affinity and potency of these ligands at both receptors were found to be dependent upon the linker length and composition. The data suggest that heterobivalent ligands for receptors mediating opposite responses might be useful for investigating the regulation of receptor cross-talk in health and disease.

    11. Synthesis, Characterization, and Metabolism Studies of Fluspidine Enantiomers (pages 2047–2056)

      Dr. Katharina Holl, Dr. Evamaria Falck, Dr. Jens Köhler, Dr. Dirk Schepmann, Prof. Dr. Hans-Ulrich Humpf, Prof. Dr. Peter Brust and Prof. Dr. Bernhard Wünsch

      Version of Record online: 15 OCT 2013 | DOI: 10.1002/cmdc.201300322

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      Enantiomeric excitement! To develop a PET tracer for human studies, enantiomers of the potent σ1 ligand fluspidine were prepared and biologically evaluated. (R)-Fluspidine is the eutomer, with a σ1 affinity of 0.57 nM. During incubation with rat liver microsomes, (S)-fluspidine is metabolically more stable than its R-configured enantiomer. Eight metabolites of (S)-fluspidine and seven metabolites of (R)-fluspidine were identified.

    12. Design and Generation of Highly Diverse Fluorinated Fragment Libraries and their Efficient Screening with Improved 19F NMR Methodology (pages 2057–2069)

      Dr. Anna Vulpetti and Dr. Claudio Dalvit

      Version of Record online: 11 OCT 2013 | DOI: 10.1002/cmdc.201300351

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      Fluorine-powered screening! A versatile 19F NMR screening methodology was developed that can be efficiently applied in laboratories with a limited NMR setup. A mono- and poly-fluorinated fragment library with high chemical diversity was designed, and improved pulse sequences were developed for 19F NMR screening and deconvolution of the mixtures with known or unknown composition.

    13. Development of Rhodesain Inhibitors with a 3-Bromoisoxazoline Warhead (pages 2070–2076)

      Dr. Roberta Ettari, Dr. Lucia Tamborini, Dr. Ilenia C. Angelo, Prof. Silvana Grasso, Prof. Tanja Schirmeister, Dr. Leonardo Lo Presti, Prof. Carlo De Micheli, Dr. Andrea Pinto and Prof. Paola Conti

      Version of Record online: 15 NOV 2013 | DOI: 10.1002/cmdc.201300390

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      Awakened by the warhead: Novel rhodesain inhibitors with antitrypanosomal activity were developed by coupling a 3-bromoisoxazoline warhead to a suitable peptidomimetic recognition moiety.

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