ChemMedChem

Cover image for Vol. 7 Issue 7

July 2012

Volume 7, Issue 7

Pages 1129–1299

  1. Cover Picture

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Review
    9. Minireview
    10. Communications
    11. Full Papers
    12. Book Reviews
    13. Preview
    1. Cover Picture: Bicyclic Peptides with Optimized Ring Size Inhibit Human Plasma Kallikrein and its Orthologues While Sparing Paralogous Proteases (ChemMedChem 7/2012) (page 1129)

      Dr. Vanessa Baeriswyl, Dr. Helen Rapley, Lisa Pollaro, Dr. Catherine Stace, Dr. Dan Teufel, Dr. Edward Walker, Shiyu Chen, Sir Greg Winter, Dr. John Tite and Prof. Christian Heinis

      Article first published online: 25 JUN 2012 | DOI: 10.1002/cmdc.201290029

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      The cover picture shows a novel bicyclic peptide inhibitor of the serine protease plasma kallikrein identified by phage display. By modulating the loop size of the peptide macrocycles, inhibitors with sub-nanomolar potency and an optimal specificity profile could be generated. For more details, see the Communication by Greg Winter, John Tite, Christian Heinis et al. on p. 1173 ff.

  2. Inside Cover

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Review
    9. Minireview
    10. Communications
    11. Full Papers
    12. Book Reviews
    13. Preview
    1. Inside Cover: Structural Characterization and Computer-Aided Optimization of a Small-Molecule Inhibitor of the Arp2/3 Complex, a Key Regulator of the Actin Cytoskeleton (ChemMedChem 7/2012) (page 1130)

      Andrew W. Baggett, Dr. Zoe Cournia, Min Suk Han, Dr. George Patargias, Dr. Adam C. Glass, Prof. Shih-Yuan Liu and Prof. Brad J. Nolen

      Article first published online: 25 JUN 2012 | DOI: 10.1002/cmdc.201290030

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      The inside cover picture shows the optimization of a small-molecule inhibitor of Arp2/3 complex, a seven-subunit 225 kD protein that nucleates branched actin filaments. The X-ray structure of the complex bound to a known inhibitor, CK-666, was solved, and computational, synthetic, and biochemical methods were used to generate a novel inhibitor with improved potency—an important tool compound for dissecting the cellular functions of Arp2/3 complex. For more details, see the Full Paper by Brad J. Nolen et al. on p. 1286 ff.

  3. Back Cover

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Review
    9. Minireview
    10. Communications
    11. Full Papers
    12. Book Reviews
    13. Preview
    1. Back Cover: Design, Synthesis, and in vitro Antibacterial Activity of Fluoroquinolone Derivatives Containing a Chiral 3-(Alkoxyimino)-2-(aminomethyl)azetidine Moiety (ChemMedChem 7/2012) (page 1300)

      Dr. Kai Lv, Yexin Sun, Lanyin Sun, Zengquan Wei, Prof. Huiyuan Guo, Jinwei Wu and Prof. Mingliang Liu

      Article first published online: 25 JUN 2012 | DOI: 10.1002/cmdc.201290034

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      The back cover picture shows the structural evolution of fluroqinolone-derived antibacterial agents—particularly the C-7 nitrogen heterocycle, which influences the potency, activity spectrum and safety, from piperazine to pyrrolidine and azetidine. Now, derivatives containing a chiral 3-(alkoxyimino)-2-(aminomethyl)azetidine show promise against Gram-positive strains including methicillin-resistant Staphylococcus aureus (MRSA). For more details, see the Full Paper by Mingliang Liu et al. on p. 1230 ff.

  4. Graphical Abstract

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Review
    9. Minireview
    10. Communications
    11. Full Papers
    12. Book Reviews
    13. Preview
    1. Graphical Abstract: ChemMedChem 7/2012 (pages 1131–1137)

      Article first published online: 25 JUN 2012 | DOI: 10.1002/cmdc.201290031

  5. News

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

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Review
    9. Minireview
    10. Communications
    11. Full Papers
    12. Book Reviews
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    1. Joaquín M. Campos (page 1145)

      Article first published online: 5 JUN 2012 | DOI: 10.1002/cmdc.201200218

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      “The part of my job which I enjoy the most is writing up papers and scientific projects—communication is one of the raisons d'être of science, without it, there is no science!” This and more from Prof. Joaquín M. Campos can be found on page 1145.

  7. Review

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Review
    9. Minireview
    10. Communications
    11. Full Papers
    12. Book Reviews
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    1. Activity-Based Probes for the Study of Proteases: Recent Advances and Developments (pages 1146–1159)

      Sevnur Serim, Ute Haedke and Dr. Steven H. L. Verhelst

      Article first published online: 19 MAR 2012 | DOI: 10.1002/cmdc.201200057

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      Lots of activity! In the last decade, the use of activity-based probes has had a significant impact on the study of proteases in complex systems. With a variety of applications ranging from imaging to high-throughput screening and functional proteomics, activity-based probes will aid future target discovery and drug design.

  8. Minireview

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Review
    9. Minireview
    10. Communications
    11. Full Papers
    12. Book Reviews
    13. Preview
    1. The Development of FtsZ Inhibitors as Potential Antibacterial Agents (pages 1161–1172)

      Siti Ma and Prof. Shutao Ma

      Article first published online: 25 MAY 2012 | DOI: 10.1002/cmdc.201200156

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      Stopping division and multiplication: Bacterial infection is a serious and ongoing threat to human health. FtsZ, an essential cell-division protein, is a very promising potential target for the development of antibacterial agents. This review introduces the role of FtsZ in bacterial cytokinesis and discusses recent studies into various FtsZ inhibitors.

  9. Communications

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Review
    9. Minireview
    10. Communications
    11. Full Papers
    12. Book Reviews
    13. Preview
    1. Bicyclic Peptides with Optimized Ring Size Inhibit Human Plasma Kallikrein and its Orthologues While Sparing Paralogous Proteases (pages 1173–1176)

      Dr. Vanessa Baeriswyl, Dr. Helen Rapley, Lisa Pollaro, Dr. Catherine Stace, Dr. Dan Teufel, Dr. Edward Walker, Shiyu Chen, Sir Greg Winter, Dr. John Tite and Prof. Christian Heinis

      Article first published online: 11 APR 2012 | DOI: 10.1002/cmdc.201200071

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      Picky push-bikes! Bicyclic peptides with low to sub-nanomolar inhibitory activities towards the serine protease plasma kallikrein were developed. By modulating the size of the macrocyclic rings, inhibitors with the desired specificity profile could be generated.

    2. 6-Halogenochromones Bearing Tryptamine: One-Step Access to Potent and Highly Selective Inhibitors of Breast Cancer Resistance Protein (pages 1177–1180)

      Glaucio Valdameri, Dr. Estelle Genoux-Bastide, Charlotte Gauthier, Basile Peres, Dr. Raphaël Terreux, Prof. Sheila M. B. Winnischofer, Prof. Maria E. M. Rocha, Dr. Attilio Di Pietro and Prof. Ahcène Boumendjel

      Article first published online: 21 MAY 2012 | DOI: 10.1002/cmdc.201200154

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      Easy as A B C! 6-Halochromone derivatives bearing a tryptamine moiety were evaluated as inhibitors of the breast cancer resistance protein (BCRP)/ABCG2. The 6-bromo analogue has been identified as a highly potent, selective and nontoxic inhibitor of BCRP. The facile synthesis from commercial starting materials makes this inhibitor an ideal candidate for preclinical investigations.

    3. Identification of a 17β-Hydroxysteroid Dehydrogenase Type 10 Steroidal Inhibitor: A Tool to Investigate the Role of Type 10 in Alzheimer’s Disease and Prostate Cancer (pages 1181–1184)

      Diana Ayan, Dr. René Maltais and Prof. Donald Poirier

      Article first published online: 6 JUN 2012 | DOI: 10.1002/cmdc.201200129

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      Ten out of ten! Androsterone derivatives inhibit 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), a versatile mitochondrial NAD+-dependent enzyme with potential roles in both Alzheimer's disease and prostate cancer. These androsterone derivatives could be useful tool compounds to help elucidate the role of 17β-HSD10 in these important diseases.

    4. Synthesis, Structure–Activity Relationship and Docking Studies of Substituted Aryl Thiazolyl Phenylsulfonamides as Potential Protein Tyrosine Phosphatase 1B Inhibitors (pages 1185–1190)

      Kanika Varshney, Swati Gupta, Neha Rahuja, Arun K. Rawat, Nagendra Singh, Dr. Akhilesh K. Tamarkar, Dr. Arvind K. Srivastava and Dr. Anil K. Saxena

      Article first published online: 21 MAY 2012 | DOI: 10.1002/cmdc.201200197

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      28 to 1—not bad odds: Protein tyrosine phosphatase 1B (PTP1B) is a promising target for the treatment of type 2 diabetes. Aryl thiazolyl phenylsulfonamides were synthesized and screened against PTP1B in vitro. Compounds exhibiting >48 % inhibition were then evaluated in a streptozotocin-induced (STZ) rat model of diabetes, identifying one compound with efficacy comparable to that of metformin. Finally, docking studies were used to explain the observed structure–activity relationships.

  10. Full Papers

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Review
    9. Minireview
    10. Communications
    11. Full Papers
    12. Book Reviews
    13. Preview
    1. Synthesis and Biological Evaluation of Adenosines with Heterobicyclic and Polycyclic N6-Substituents as Adenosine A1 Receptor Agonists (pages 1191–1201)

      Joshua I. Gosling, Prof. Stephen P. Baker, Dr. John M. Haynes, Prof. Michael Kassiou, Prof. Colin W. Pouton, Lyndon Warfe, Dr. Paul J. White and Prof. Peter J. Scammells

      Article first published online: 8 JUN 2012 | DOI: 10.1002/cmdc.201200208

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      Chemical polyfiller! A series of adenosines with heterobicyclic and polycyclic N6-substituents were synthesised and evaluated as A1 adenosine receptor agonists. Highly potent and selective agents were identified, and the cardioprotective effects of the most promising compounds were further evaluated in a simulated ischaemia model.

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      Predicting Drug Metabolism by Cytochrome P450 2C9: Comparison with the 2D6 and 3A4 Isoforms (pages 1202–1209)

      Prof. Patrik Rydberg and Prof. Lars Olsen

      Article first published online: 16 MAY 2012 | DOI: 10.1002/cmdc.201200160

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      Foreseeing the breakdown: We developed a ligand-based model for predicting the site of drug metabolism mediated by cytochrome P450 2C9. The model is compared with two commercial models for two data sets. Because this model is constructed from only three descriptors and does not require 3D structures or electronic calculations, it is extremely rapid.

    3. Discovery, Synthesis, and in vitro Evaluation of West Nile Virus Protease Inhibitors Based on the 9,10-Dihydro-3H,4aH-1,3,9,10a-tetraazaphenanthren-4-one Scaffold (pages 1210–1216)

      Sanjay Samanta, Dr. Taian Cui and Prof. Yulin Lam

      Article first published online: 30 APR 2012 | DOI: 10.1002/cmdc.201200136

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      Running cofactor interference: In vitro assays with West Nile virus (WNV) NS2B–NS3 protease resulted in the discovery of 9,10-dihydro-3H,4aH-1,3,9,10a-tetraazaphenanthren-4-ones as a new class of inhibitors of this enzyme. Optimization of the lead compound led to an uncompetitive WNV NS2B–NS3 inhibitor with an IC50 value of 5.41±0.45 μM.

    4. Synthesis and Structure–Activity Relationship Studies of HIV-1 Virion Infectivity Factor (Vif) Inhibitors that Block Viral Replication (pages 1217–1229)

      Dr. Akbar Ali, Dr. Jinhua Wang, Robin S. Nathans, Dr. Hong Cao, Dr. Natalia Sharova, Prof. Dr. Mario Stevenson and Prof. Dr. Tariq M. Rana

      Article first published online: 3 MAY 2012 | DOI: 10.1002/cmdc.201200079

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      Coupling up! N-(2-Methoxyphenyl)-2-((4-nitrophenyl)thio)benzamide (RN-18) is a small molecule that selectively inhibits Vif–APOBEC interactions and HIV-1 replication. Structure–activity relationship studies define key structural requirements for Vif-specific antiviral activity, and new compounds with improved antiviral potency and specificity were identified, providing leads for the further exploration of these compounds as new antiviral therapeutics.

    5. Design, Synthesis, and in vitro Antibacterial Activity of Fluoroquinolone Derivatives Containing a Chiral 3-(Alkoxyimino)-2-(aminomethyl)azetidine Moiety (pages 1230–1236)

      Dr. Kai Lv, Yexin Sun, Lanyin Sun, Zengquan Wei, Prof. Huiyuan Guo, Jinwei Wu and Prof. Mingliang Liu

      Article first published online: 25 MAY 2012 | DOI: 10.1002/cmdc.201200210

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      De-bugging agents: A series of novel (R)/(S)-7-(3-alkoxyimino-2-aminomethyl-1-azetidinyl)fluoroquinolone derivatives were synthesized and evaluated for their in vitro antibacterial activity against representative strains. Some of the target compounds show generally better activity than gemifloxacin against the Gram-positive strains tested, including MRSA and MRSE.

    6. Selectively Guanidinylated Aminoglycosides as Antibiotics (pages 1237–1244)

      Richard J. Fair, Dr. Mary E. Hensler, Wdee Thienphrapa, Quang N. Dam, Prof. Dr. Victor Nizet and Prof. Dr. Yitzhak Tor

      Article first published online: 25 MAY 2012 | DOI: 10.1002/cmdc.201200150

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      Debugging! A focused library of guanidino-aminoglycosides was synthesized and evaluated in a FRET-based assay. Most analogues were found to have superior affinity for A-site RNA than the parent antibiotics. Certain mono-guanidinylated aminoglycosides show enhanced potency against methicillin- resistant Staphylococcus aureus (MRSA) and a panel of clinically relevant, drug-resistant Gram-negative bacteria.

    7. Development of an (S)-1-{2-[Tris(4-methoxyphenyl)methoxy]ethyl}piperidine-3-carboxylic acid [(S)-SNAP-5114] Carba Analogue Inhibitor for Murine γ-Aminobutyric Acid Transporter Type 4 (pages 1245–1255)

      Dr. Jörg Pabel, Dr. Mark Faust, Dr. Cornelia Prehn, Dr. Babette Wörlein, Dr. Lars Allmendinger, Dr. Georg Höfner and Prof. Dr. Klaus T. Wanner

      Article first published online: 27 APR 2012 | DOI: 10.1002/cmdc.201200126

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      Stability is a snap! We developed a series of analogues of (S)-SNAP-5114, the most potent inhibitor of murine γ-aminobutyric acid transporter type 4 (mGAT4) known thus far. These analogues have potencies that are similar to or slightly higher than that of (S)-SNAP-5114 toward mGAT4 (DDPM-1457: pIC50=5.87), but with distinctly improved chemical stability.

    8. Design, Synthesis, and Biological Evaluation of 2-Aminobenzanilide Derivatives as Potent and Selective HDAC Inhibitors (pages 1256–1266)

      Dr. Diana A. Stolfa, Dr. Angela Stefanachi, Dr. Julia M. Gajer, Dr. Angela Nebbioso, Prof. Lucia Altucci, Prof. Saverio Cellamare, Prof. Dr. Manfred Jung and Prof. Angelo Carotti

      Article first published online: 24 MAY 2012 | DOI: 10.1002/cmdc.201200193

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      Going for number 1: HDAC1 and HDAC4 inhibition data for rationally designed 2-aminobenzanilides highlight a number of highly potent and selective HDAC1 inhibitors. Selectivity against class IIb HDAC, explored for a selected group of compounds by immunoblot assays, was confirmed by a lack of α-tubulin hyperacetylation, resulting from the absence of, or weak, HDAC6 inhibition.

    9. Synthesis of a Heparan Sulfate Mimetic Library Targeting FGF and VEGF via Click Chemistry on a Monosaccharide Template (pages 1267–1275)

      Dr. Ligong Liu, Dr. Caiping Li, Dr. Siska Cochran, Shane Jimmink and Dr. Vito Ferro

      Article first published online: 21 MAY 2012 | DOI: 10.1002/cmdc.201200151

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      Library of science: A disulfated mannoside template was derivatized—by click chemistry or sequential click, Swern oxidation, and Wittig olefination—for binding to FGF-1 and/or VEGF. A lead compound was identified with micromolar binding affinity toward both FGF-1 and VEGF (Kd=84 and 49 μM, respectively) and good selectivity over FGF-2 (29- and 51-fold, respectively).

    10. O-Linked Triazolotriazines: Potent and Selective c-Met Inhibitors (pages 1276–1285)

      Fang Chen, Ying Wang, Dr. Jing Ai, Zhengsheng Zhan, Yongcong Lv, Zhongjie Liang, Dr. Cheng Luo, Dr. Desheng Mei, Prof. Meiyu Geng and Prof. Wenhu Duan

      Article first published online: 26 APR 2012 | DOI: 10.1002/cmdc.201200145

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      Highly selective c-Met inhibitor: c-Met is considered one of the most promising therapeutic targets for anticancer drug discovery. Herein we report a series of O-linked triazolotriazines that inhibit c-Met at sub-nanomolar concentrations. Compound 6 a exhibits high c-Met inhibitory potency in both enzymatic and cellular assays with great selectivity.

    11. Structural Characterization and Computer-Aided Optimization of a Small-Molecule Inhibitor of the Arp2/3 Complex, a Key Regulator of the Actin Cytoskeleton (pages 1286–1294)

      Andrew W. Baggett, Dr. Zoe Cournia, Min Suk Han, Dr. George Patargias, Dr. Adam C. Glass, Prof. Shih-Yuan Liu and Prof. Brad J. Nolen

      Article first published online: 23 MAY 2012 | DOI: 10.1002/cmdc.201200104

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      Acting on actin: The Arp2/3 complex is a macromolecular assembly that nucleates branched actin filaments. Small-molecule inhibitors that block Arp2/3 complex function provide powerful tools for studying the cytoskeleton and could eventually see clinical use. Herein we report the crystal structure of the inhibitor CK-666 bound to Arp2/3 complex and use computer-aided optimization to alter CK-666, increasing its potency threefold.

  11. Book Reviews

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Review
    9. Minireview
    10. Communications
    11. Full Papers
    12. Book Reviews
    13. Preview
    1. Drug Design Strategies: Quantitative Approaches. Edited by David J. Livingstone and Andrew M. Davis. (pages 1295–1296)

      Dr. Hans Matter

      Article first published online: 19 APR 2012 | DOI: 10.1002/cmdc.201200168

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      RSC, Cambridge 2012. xviii+498 pp., hardcover £ 144.99.—ISBN 978-1-84973-166-9

    2. New Synthetic Technologies in Medicinal Chemistry. Edited by Elizabeth Farrant. (pages 1296–1297)

      Prof. Andreas Kirschning

      Article first published online: 25 APR 2012 | DOI: 10.1002/cmdc.201200177

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      RSC, Cambridge 2012. xii, 164 pp., hardcover £99.99.—ISBN 978-1-84973-017-4

    3. Chemical Genomics and Proteomics: Reviews and Protocols. Edited by Edward D. Zanders. (pages 1297–1298)

      Prof. Luc Brunsveld

      Article first published online: 19 APR 2012 | DOI: 10.1002/cmdc.201200170

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      Humana Press, New York 2012. xi+243 pp., hardcover € 94.95.—ISBN 978-1-61779-348-6

  12. Preview

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Review
    9. Minireview
    10. Communications
    11. Full Papers
    12. Book Reviews
    13. Preview
    1. You have free access to this content
      Preview: ChemMedChem 8/2012 (page 1299)

      Article first published online: 25 JUN 2012 | DOI: 10.1002/cmdc.201290033

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