ChemMedChem

Cover image for Vol. 8 Issue 9

September 2013

Volume 8, Issue 9

Pages 1421–1568

  1. Cover Pictures

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Highlight
    6. Minireview
    7. Communications
    8. Full Papers
    1. You have free access to this content
      Cover Picture: Probing the S1′ Site for the Identification of Non-Zinc-Binding MMP-2 Inhibitors (ChemMedChem 9/2013) (page 1421)

      Dr. Antonella Di Pizio, Dr. Antonio Laghezza, Prof. Paolo Tortorella and Dr. Mariangela Agamennone

      Article first published online: 27 AUG 2013 | DOI: 10.1002/cmdc.201390035

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      The front cover picture shows a virtual screening protocol used to identify non-zinc-binding matrix metalloproteinase (MMP)-2 inhibitors. A virtual library was filtered to obtain a drug-like subset of molecules that was subsequently submitted to pharmacophore screening, followed by docking in the MMP-2 (grey protein structure) binding site. The pharmacophore model employed was inspired by a known MMP-8 inhibitor (green sticks), which was used like a probe in the MMP-2 S1′ site (top left protein structure). Finally, visual inspection of the docking poses of the virtual hits led to the selection of 20 compounds for experimental evaluation. The virtual screening protocol identified a novel MMP-2 inhibitor (orange sticks); modeling (bottom left protein structure) suggests that this compound does not bind to the zinc ion (purple sphere), but rather interacts with the target by other means, such as hydrogen bonds (dashed lines). For more details, see the Full Paper by Mariangela Agamennone et al. on p. 1475 ff.

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      Inside Cover: A Parallel Semisynthetic Approach for Structure–Activity Relationship Studies of Peptide YY (ChemMedChem 9/2013) (page 1422)

      Louise Albertsen, Dr. Søren Østergaard, Dr. Johan F. Paulsson, Dr. Jens Chr. Norrild and Prof. Kristian Strømgaard

      Article first published online: 27 AUG 2013 | DOI: 10.1002/cmdc.201390036

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      The inside cover picture shows a recombinant thioester fragment (pink tube) of the gut hormone peptide YY (PYY) used in a semisynthetic strategy for the design of C-terminally modified (blue chemical structure) PYY analogues with potential applications as antiobesity agents. Combining the native chemical ligation–desulfurization approach with a 96-well plate (background) format allowed rapid parallel generation of PYY analogues that were subsequently tested in cell-based GPCR (blue cartoon) assays. For more details, see the Full Paper by Jens Chr. Norrild, Kristian Strømgaard et al. on p. 1505 ff.

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      Back Cover: Strategic Targeting of Multiple Water-Mediated Interactions: A Concise and Rational Structure-Based Design Approach to Potent and Selective MMP-13 Inhibitors (ChemMedChem 9/2013) (page 1572)

      Thomas Fischer and Prof. Dr. Rainer Riedl

      Article first published online: 27 AUG 2013 | DOI: 10.1002/cmdc.201390039

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      The back cover picture depicts the beauty and significance of water molecules, key structural components in the architecture of living systems, for the rational design of small molecules with tailored biological activity. A potent and selective inhibitor of the therapeutically relevant target matrix metalloproteinase 13 was realized, without any screening activities, by a concise structure-based approach targeting multiple water molecules as binding partners. For more details, see the Communication by Rainer Riedl et al. on p. 1457 ff.

  2. Graphical Abstract

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Highlight
    6. Minireview
    7. Communications
    8. Full Papers
    1. Graphical Abstract: ChemMedChem 9/2013 (pages 1423–1429)

      Article first published online: 27 AUG 2013 | DOI: 10.1002/cmdc.201390037

  3. News

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

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Highlight
    6. Minireview
    7. Communications
    8. Full Papers
    1. Rise of the Selective Inhibitors of Anti-Apoptotic Bcl-2 Family Proteins (pages 1437–1440)

      Dr. Li Han and Prof. Renxiao Wang

      Article first published online: 31 JUL 2013 | DOI: 10.1002/cmdc.201300301

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      No trivial pursuit! It is not trivial to develop effective small-molecule regulators of protein–protein interactions (PPIs). Moreover, anti-apoptotic Bcl-2 family proteins share similar binding grooves, making it particularly difficult to target them selectively. Despite these challenges, potent and selective inhibitors of individual members of the Bcl-2 family have been successfully developed.

  5. Minireview

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    2. Cover Pictures
    3. Graphical Abstract
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    7. Communications
    8. Full Papers
    1. The Cell’s Nucleolus: an Emerging Target for Chemotherapeutic Intervention (pages 1441–1449)

      Amanda J. Pickard and Prof. Ulrich Bierbach

      Article first published online: 23 JUL 2013 | DOI: 10.1002/cmdc.201300262

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      Getting to the core: The cell's nucleolus is emerging as a promising anticancer target. Herein we review a broad range of molecular entities that have been shown to interact with the nucleolus. Molecules that interfere with this sub-nuclear structure have the potential to trigger cancer cell death by mechanisms such as inhibition of ribosomal RNA transcription, thereby producing a selective therapeutic effect while sparing normal tissue.

  6. Communications

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Highlight
    6. Minireview
    7. Communications
    8. Full Papers
    1. You have full text access to this OnlineOpen article
      Overcoming the Limitations of Fragment Merging: Rescuing a Strained Merged Fragment Series Targeting Mycobacterium tuberculosis CYP121 (pages 1451–1456)

      Dr. Sean A. Hudson, Dr. Sachin Surade, Dr. Anthony G. Coyne, Dr. Kirsty J. McLean, Prof. David Leys, Prof. Andrew W. Munro and Prof. Chris Abell

      Article first published online: 20 JUN 2013 | DOI: 10.1002/cmdc.201300219

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      Freedom to merge: A combination of crystal structure examination and in silico predictions made it possible to overcome the conformational limitations of fragment merging and escape the internal strain in a series of weakly binding merged fragments that target M. tuberculosis CYP121. The insights attained provide a new perspective and guide for prioritizing synthetic efforts toward fragment merging in future and ongoing fragment-based ligand discovery campaigns.

    2. You have full text access to this OnlineOpen article
      Strategic Targeting of Multiple Water-Mediated Interactions: A Concise and Rational Structure-Based Design Approach to Potent and Selective MMP-13 Inhibitors (pages 1457–1461)

      Thomas Fischer and Prof. Dr. Rainer Riedl

      Article first published online: 26 JUL 2013 | DOI: 10.1002/cmdc.201300278

      Thumbnail image of graphical abstract

      Water in the architecture of life: Potent and selective matrix metalloproteinase-13 (MMP-13) inhibitors were rationally designed by targeting multiple water-mediated interactions between the target protein and small-molecule inhibitors. This structure-based design concept offers tremendous opportunities for the discovery of unique small molecules with tailored biological activity.

    3. Zopolrestat as a Human Glyoxalase I Inhibitor and Its Structural Basis (pages 1462–1464)

      Jing Zhai, Hong Zhang, Ligping Zhang, Yining Zhao, Dr. Sangke Chen, Yunyun Chen, Xinyu Peng, Prof. Qing Li, Dr. Minggui Yuan and Prof. Xiaopeng Hu

      Article first published online: 15 JUL 2013 | DOI: 10.1002/cmdc.201300243

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      Old drugs new tricks: Zopolrestat, an aldose reductase inhibitor developed by Pfizer for the treatment of diabetic complications, is a potent competition inhibitor of human glyoxalase I (GLOI) in vitro. Crystal structures of GLOI in complex with zopolrestat and indomethacin, a nonsteroidal anti-inflammatory drug and moderate inhibitor of GLOI, provide a structural basis for the development of novel GLOI inhibitors with excellent pharmacokinetics profiles.

    4. cis-[PtII(1R,2R-DACH)(3-acetoxy-1,1-cyclobutanedicarboxylato)], a Water-Soluble, Oxalate-Free and Stable Analogue of Oxaliplatin: Synthesis, Characterization, and Biological Evaluations (pages 1465–1467)

      Prof. Dr. Weiping Liu, Dr. Qingsong Ye, Dr. Jing Jiang, Prof. Dr. Liguang Lou, Dr. Yongping Xu, Dr. Chengying Xie and Prof. Dr. Mingjin Xie

      Article first published online: 3 JUL 2013 | DOI: 10.1002/cmdc.201300249

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      Strong, like ox! A new oxaliplatin derivative that features 3-acetoxy-1,1-cyclobutanedicarboxylate as the leaving group has good aqueous solubility and stability. It exhibits higher antitumor activity and greater tolerability than oxaliplatin.

    5. Synthesis and Biological Evaluation of 2-Arylamino-5- (3′-Indolyl)-1,3,4-Oxadiazoles as Potent Cytotoxic Agents (pages 1468–1474)

      Mukund P Tantak, Anil Kumar, Brett Noel, Prof. Kavita Shah and Prof. Dalip Kumar

      Article first published online: 11 JUL 2013 | DOI: 10.1002/cmdc.201300221

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      Rationally simple: Coupling of two key scaffolds in medicinal chemistry, the indole and 1,3,4-oxadiazole ring systems, gave rise to 2-arylamino-5-(3′-indolyl)-1,3,4-oxadiazoles with IC50 values in the nanomolar range against a panel of tumor cell lines. Preliminary structure–activity relationship studies indicate potential for improved selectivity through further manipulation of the oxadiazole C-2 and C-5 positions.

  7. Full Papers

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Highlight
    6. Minireview
    7. Communications
    8. Full Papers
    1. Probing the S1′ Site for the Identification of Non-Zinc-Binding MMP-2 Inhibitors (pages 1475–1482)

      Dr. Antonella Di Pizio, Dr. Antonio Laghezza, Prof. Paolo Tortorella and Dr. Mariangela Agamennone

      Article first published online: 19 JUL 2013 | DOI: 10.1002/cmdc.201300186

      Thumbnail image of graphical abstract

      Leave the Zn alone: This work reports the first attempt to identify non-zinc-binding MMP-2 inhibitors through a virtual screening protocol established expressly to take advantage of unexplored interactions in the S1' site. The identified active compounds should ensure lower toxicity and higher selectivity than traditional ligands.

    2. Rational Design of Resorcylic Acid Lactone Analogues as Covalent MNK1/2 Kinase Inhibitors by Tuning the Reactivity of an Enamide Michael Acceptor (pages 1483–1494)

      Jin Xu, Dr. Anqi Chen, Dr. Joma Joy, Vanessa Joanne Xavier, Esther H. Q. Ong, Dr. Jeffrey Hill and Prof. Christina L. L. Chai

      Article first published online: 8 AUG 2013 | DOI: 10.1002/cmdc.201300231

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      Reactivity-tunable Michael acceptor: Enamide analogues of resorcylic acid lactone (RAL) as novel covalent inhibitors of MNK1/2 kinases were developed in this study. The covalent binding ability of such enamides can be tuned by attaching an electron-withdrawing motif to enhance its reactivity toward the cysteine residues at the MNK1/2 binding sites.

    3. 6-Aryl and Heterocycle Quinazoline Derivatives as Potent EGFR Inhibitors with Improved Activity toward Gefitinib-Sensitive and -Resistant Tumor Cell Lines (pages 1495–1504)

      Mostafa M. Hamed, Prof. Dr. Dalal A. Abou El Ella, Dr. Adam B. Keeton, Prof. Dr. Gary A. Piazza, Prof. Dr. Ashraf H. Abadi, Prof. Dr. Rolf W. Hartmann and Dr. Matthias Engel

      Article first published online: 11 JUL 2013 | DOI: 10.1002/cmdc.201300147

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      Hits out for EGFR: Gefitinib increases survival time for many cancer patients, but there is room for improvement, especially regarding less sensitive and resistant cancer cells. The introduction of aryl and heteroaryl substituents through different linkers at position 6 of an anilinoquinazoline nucleus significantly enhanced activity toward EGFR-wild-type and -mutant cancer cells. The inhibition of mutant EGFR kinase was also significantly improved.

    4. A Parallel Semisynthetic Approach for Structure–Activity Relationship Studies of Peptide YY (pages 1505–1513)

      Louise Albertsen, Dr. Søren Østergaard, Dr. Johan F. Paulsson, Dr. Jens Chr. Norrild and Prof. Kristian Strømgaard

      Article first published online: 31 JUL 2013 | DOI: 10.1002/cmdc.201300290

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      It's all parallel: A semisynthetic approach was used to study the effect of C-terminal modifications of the appetite-reducing gut hormone peptide YY on interaction with its receptor. The approach involved ligation of a recombinant thioester building block with a suite of synthetic cysteine-containing peptides followed by desulfurization; this was performed in a parallel one-pot fashion.

    5. Chemical, Pharmacological, and in vitro Metabolic Stability Studies on Enantiomerically Pure RC-33 Compounds: Promising Neuroprotective Agents Acting as σ1 Receptor Agonists (pages 1514–1527)

      Dr. Daniela Rossi, Dr. Alice Pedrali, Dr. Raffaella Gaggeri, Dr. Annamaria Marra, Dr. Luca Pignataro, Dr. Erik Laurini, Dr. Valentina Dal Col, Prof. Maurizio Fermeglia, Prof. Sabrina Pricl, Dr. Dirk Schepmann, Prof. Bernhard Wünsch, Dr. Marco Peviani, Dr. Daniela Curti and Prof. Simona Collina

      Article first published online: 5 JUL 2013 | DOI: 10.1002/cmdc.201300218

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      A tale of two enantiomers: (S)- and (R)-RC-33, recently identified σ1 receptor agonists, were thoroughly investigated. (R)-RC-33 emerged as the optimal candidate for in vivo investigations, being a potent and selective σ1 agonist with higher in vitro hepatic metabolic stability than (S)-RC-33.

    6. An Endoperoxide-Based Hybrid Approach to Deliver Falcipain Inhibitors Inside Malaria Parasites (pages 1528–1536)

      Rudi Oliveira, Ana S. Newton, Dr. Rita C. Guedes, Daniela Miranda, Dr. Richard K. Amewu, Dr. Abhishek Srivastava, Dr. Jiri Gut, Prof. Philip J. Rosenthal, Prof. Paul M. O'Neill, Prof. Stephen A. Ward, Dr. Francisca Lopes and Prof. Rui Moreira

      Article first published online: 12 JUL 2013 | DOI: 10.1002/cmdc.201300202

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      Parasite fighters: A series of tetraoxane–vinyl sulfone hybrids generate toxic radicals once activated inside malaria parasites, releasing highly active falcipain-2 (FP-2) inhibitors in situ. These hybrids are active within the low nanomolar range against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains and may present alternatives to current antimalarial chemotherapeutics.

    7. You have full text access to this OnlineOpen article
      Structure–Activity Relationship Studies of Pyrrolone Antimalarial Agents (pages 1537–1544)

      Dr. Dinakaran Murugesan, Dr. Marcel Kaiser, Dr. Karen L. White, Suzanne Norval, Jennifer Riley, Prof. Paul G. Wyatt, Prof. Susan A. Charman, Dr. Kevin D. Read, Dr. Clive Yeates and Prof. Ian H. Gilbert

      Article first published online: 5 AUG 2013 | DOI: 10.1002/cmdc.201300177

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      Molecular fine-tuning: Previously reported pyrrolones (e.g., TDR32570) exhibited potent antimalarial activity but suffered from poor aqueous solubility and metabolic instability. Further structure–activity relationship studies are reported that aimed to improve these properties and to generate optimised leads. Modifications to the lead pyrrolone involved replacement of a phenyl ring with a piperidine and removal of the ester.

    8. Synthesis and Biological Evaluation of N-Substituted Sophocarpinic Acid Derivatives as Coxsackievirus B3 Inhibitors (pages 1545–1553)

      Li-Mei Gao, Dr. Sheng Tang, Dr. Yan-Xiang Wang, Dr. Rong-Mei Gao, Dr. Xin Zhang, Dr. Zong-Gen Peng, Jian-Rui Li, Prof. Jian-Dong Jiang, Prof. Yu-Huan Li and Prof. Dan-Qing Song

      Article first published online: 23 JUL 2013 | DOI: 10.1002/cmdc.201300224

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      Double-bond drugs: N-Substituted sophocarpinic acid derivatives were designed, synthesized, and evaluated for their activities against coxsackieviruses B3 (CVB3) and B6 (CVB6). Compound 11 m exhibited the most potent anti-CVB3 effect, with an IC50 value of 2.5 μM (selectivity index: 107), which is much better than that of ribavirin.

    9. Synthesis and in vitro Evaluation of West Nile Virus Protease Inhibitors Based on the 1,3,4,5-Tetrasubstituted 1H-Pyrrol-2(5H)-one Scaffold (pages 1554–1560)

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

      Article first published online: 18 JUL 2013 | DOI: 10.1002/cmdc.201300244

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      Conquering the Nile: An in vitro assay for West Nile virus (WNV) NS2B–NS3 protease resulted in the discovery of 1,3,4,5-tetrasubstituted 1H-pyrrol-2(5H)-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 2.2±0.7 μM.

    10. Thiuram Disulfides as Pseudo-irreversible Inhibitors of Lymphoid Tyrosine Phosphatase (pages 1561–1568)

      Dr. Rhushikesh A. Kulkarni, Dr. Stephanie M. Stanford, Dr. Nadeem A. Vellore, Dr. Divya Krishnamurthy, Matthew R. Bliss, Prof. Riccardo Baron, Prof. Nunzio Bottini and Prof. Amy M. Barrios

      Article first published online: 19 JUL 2013 | DOI: 10.1002/cmdc.201300215

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      Not just LYP service: In conjunction with the discovery that disulfiram inhibits the activity of lymphoid tyrosine phosphatase (LYP), a series of thiuram disulfides were investigated as LYP inhibitors. The most potent among these was found to be a time-dependent pseudo-irreversible inhibitor with a Ki value of 1.1 μM and a kinact value of 0.004 s−1.

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