ChemMedChem

Cover image for Vol. 8 Issue 11

November 2013

Volume 8, Issue 11

Pages 1721–1891

  1. Cover Pictures

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
    9. Conference Report
    1. You have free access to this content
      Cover Picture: X-ray Structural Analysis of Tau-Tubulin Kinase 1 and Its Interactions with Small Molecular Inhibitors (ChemMedChem 11/2013) (page 1721)

      Dr. Yafeng Xue, Dr. Paul T. Wan, Dr. Per Hillertz, Dr. Fritz Schweikart, Dr. Yanlong Zhao, Lisa Wissler and Dr. Niek Dekker

      Article first published online: 28 OCT 2013 | DOI: 10.1002/cmdc.201390045

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      The front cover picture shows structure models for human tau-tubulin kinase 1 (TTBK1). The electrostatic surface model of TTBK1 reveals two basic patches on the substrate binding face providing an explanation for the requirement for phosphorylation-primed substrates. The insert highlights the distinct backbone conformations upon binding of inhibitors. 3-[(6,7-Dimethoxyquinazolin-4-yl)amino]phenol (1) (magenta) binds with fast kinetics, with no structural change to the peptide bond L199–D200 compared with either the ATP–complex or apo structure. In contrast, binding of methyl 2-bromo-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzoate (2) (cyan) induces a flip of the peptide bond L199–D200, which coincides with slow kinetics. The analyses of TTBK1 binding to ligands with distinct characteristics could enable a fast track for structure-based ligand design of selective TTBK1 inhibitors. For more details, see the Full Paper by Yafeng Xue, Niek Dekker et al. on p. 1846 ff.

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      Inside Cover: Identification of Chiral Alkenyl- and Alkynylcarbinols as Pharmacophores for Potent Cytotoxicity (ChemMedChem 11/2013) (page 1722)

      Dr. Dounia El Arfaoui, Dymytrii Listunov, Isabelle Fabing, Mohamed Oukessou, Céline Frongia, Dr. Valérie Lobjois, Arnaud Samson, Dr. Frédéric Ausseil, Prof. Abdeslem Ben-Tama, Prof. El Mestafa El Hadrami, Prof. Remi Chauvin and Dr. Yves Génisson

      Article first published online: 28 OCT 2013 | DOI: 10.1002/cmdc.201390046

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      The inside cover picture shows how a chemistry driven study inspired by marine acetylenic lipids isolated from the sponge Cribrochalina vasculum led to the identification of chiral alkynylcarbinol pharmacophores for potent cytotoxicity against HCT116 colon cancer cells. Chirality has a pronounced effect on activity, with the non-natural (R)-like configuration giving more cytotoxic derivatives. For more details, see the Communication by Remi Chauvin, Yves Génisson et al. on p. 1779 ff.

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      Back Cover: Glucosylceramide Mimics: Highly Potent GCase Inhibitors and Selective Pharmacological Chaperones for Mutations Associated with Types 1 and 2 Gaucher Disease (ChemMedChem 11/2013) (page 1896)

      Wojciech Schönemann, Dr. Estelle Gallienne, Dr. Kyoko Ikeda-Obatake, Dr. Naoki Asano, Shinpei Nakagawa, Dr. Atsushi Kato, Dr. Isao Adachi, Dr. Marcin Górecki, Prof. Jadwiga Frelek and Prof. Olivier R. Martin

      Article first published online: 28 OCT 2013 | DOI: 10.1002/cmdc.201390049

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      The back cover picture shows the structure of glucocerebrosidase in complex with its substrate, glucosylceramide (GlcCer), and the structure of an iminoglycolipid acting as a mimic of GlcCer. This compound is a very potent inhibitor of glucocerebrosidase and exhibits significant chaperone effect on the N370S and L444P mutations, which are responsible for type 1 and type 2 Gaucher disease, respectively. For more details, see the Full Paper by Olivier R. Martin et al. on p. 1805 ff.

  2. Graphical Abstract

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
    9. Conference Report
    1. Graphical Abstract: ChemMedChem 11/2013 (pages 1723–1729)

      Article first published online: 28 OCT 2013 | DOI: 10.1002/cmdc.201390047

  3. News

    1. Top of page
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    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
    9. Conference Report
  4. Review

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    4. News
    5. Review
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    7. Communications
    8. Full Papers
    9. Conference Report
    1. Kinesin Spindle Protein (KSP) Inhibitors in Combination with Chemotherapeutic Agents for Cancer Therapy (pages 1736–1749)

      Hualong Song, Dr. Shanshan Zhou, Dr. Rubing Wang and Prof. Shaoshun Li

      Article first published online: 21 AUG 2013 | DOI: 10.1002/cmdc.201300228

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      Two are better than one: Targeted therapies in the form of antibodies and small molecules have been studied in combination with kinesin spindle protein (KSP) inhibitors to enhance their efficacy against cancer in preclinical investigations. Accumulated data suggest that a combination of KSP inhibitors with various cytostatic drugs will result in a more powerful tumor-killing effect than monotherapy. Combination therapies may predominate and represent the next frontier in discovery research for KSP inhibitors as potential anticancer drugs.

  5. Minireview

    1. Top of page
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    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
    9. Conference Report
    1. Targets, Structures, and Recent Approaches in Malignant Melanoma Chemotherapy (pages 1751–1765)

      Ana Marta Matos and Dr. Ana Paula Francisco

      Article first published online: 16 AUG 2013 | DOI: 10.1002/cmdc.201300248

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      Targeting malignancies: Discovery of the pathophysiological processes behind malignant metastatic melanoma has allowed the development of novel drugs that are selective for several molecular targets. Such drugs may lead to increased survival rates and improved quality of life for cancer patients. Identifying the best molecular targets should lay the groundwork for developing new effective chemotherapies.

  6. Communications

    1. Top of page
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    3. Graphical Abstract
    4. News
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    7. Communications
    8. Full Papers
    9. Conference Report
    1. An Efficient Combinatorial Synthesis of Allocolchicine Analogues via a Triple Cascade Reaction and their Evaluation as Inhibitors of Insulin Aggregation (pages 1767–1772)

      Subhendu Bhowmik, Shruti Khanna, Dr. Kumkum Srivastava, Mohammad Hasanain, Dr. Jayanta Sarkar, Prof. Sandeep Verma and Dr. Sanjay Batra

      Article first published online: 5 SEP 2013 | DOI: 10.1002/cmdc.201300302

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      A controlled cascade: A divergent, diastereoselective and efficient one-pot synthesis of allocolchicinoids via a cascade Suzuki–Michael addition–Carbocyclization sequence is described. The utility of the compounds as possible inhibitors of insulin aggregation is also presented.

    2. Quinoline Carboxamide-Type ABCG2 Modulators: Indole and Quinoline Moieties as Anilide Replacements (pages 1773–1778)

      Stefanie Bauer, Dr. Cristian Ochoa-Puentes, Qiu Sun, Manuel Bause, Prof. Dr. Günther Bernhardt, Prof. Dr. Burkhard König and Prof. Dr. Armin Buschauer

      Article first published online: 28 AUG 2013 | DOI: 10.1002/cmdc.201300319

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      ABC, it′s easy as 1 2 3! Bioisosteric replacement of the anilide core by an indole moiety considerably increased stability and gave potent and selective ABCG2 (BCRP) inhibitors. Some compounds are superior to the reference substances fumitremorgin C and Ko143 in terms of potency and efficacy and are the most potent ABCG2 modulators reported so far.

    3. Identification of Chiral Alkenyl- and Alkynylcarbinols as Pharmacophores for Potent Cytotoxicity (pages 1779–1786)

      Dr. Dounia El Arfaoui, Dymytrii Listunov, Isabelle Fabing, Mohamed Oukessou, Céline Frongia, Dr. Valérie Lobjois, Arnaud Samson, Dr. Frédéric Ausseil, Prof. Abdeslem Ben-Tama, Prof. El Mestafa El Hadrami, Prof. Remi Chauvin and Dr. Yves Génisson

      Article first published online: 6 SEP 2013 | DOI: 10.1002/cmdc.201300230

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      Illumination by acetylene: Systematic structural variations in a series of archetypal acetylenic lipids derived from the naturally occurring (S,E)-icos-4-en-1-yn-3-ol allowed the discovery of a series of 3R-like 1,4-di-unsaturated carbinol units with a significant and systematic enantiomeric effect on cytotoxicity.

  7. Full Papers

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
    9. Conference Report
    1. Development and in vitro Evaluation of Antigen-Loaded Poly(amidoamine) Nanoparticles for Respiratory Epithelium Applications (pages 1787–1794)

      Dr. Grégory Coué, Dr. Iris Hermanns, Dr. Ronald E. Unger, Prof. C. James Kirkpatrick and Prof. Johan F. J. Engbersen

      Article first published online: 5 SEP 2013 | DOI: 10.1002/cmdc.201300307

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      A nose for good transport: Nanoparticles were prepared by self-assembly of a biodegradable poly(amidoamine), using p24 or ovalbumin as model antigens and CpG as the adjuvant, with the goal of developing therapeutic protein formulations for improved delivery of antigen via the intranasal route. The nanoparticles are nontoxic and stable for at least 10 days at room temperature. Their capacity to pass through epithelial and endothelial cell layers was evaluated in vitro by using a respiratory mucosa-like barrier model.

    2. Synthesis and Anti-Plasmodium Activity of Benzimidazole Analogues Structurally Related to Astemizole (pages 1795–1804)

      Dr. Gheorghe Roman, Dr. Ian E. Crandall and Prof. Walter A. Szarek

      Article first published online: 10 SEP 2013 | DOI: 10.1002/cmdc.201300172

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      Derivatization iteration: Several modifications of astemizole were considered in order to better define the optimal structure for anti-Plasmodium activity in a series of structurally related astemizole derivatives. The presence of a secondary cyclic amine at position 2 and substitution with chlorine at positions 4 and 5 of the benzimidazole moiety resulted in potent activity.

    3. Glucosylceramide Mimics: Highly Potent GCase Inhibitors and Selective Pharmacological Chaperones for Mutations Associated with Types 1 and 2 Gaucher Disease (pages 1805–1817)

      Wojciech Schönemann, Dr. Estelle Gallienne, Dr. Kyoko Ikeda-Obatake, Dr. Naoki Asano, Shinpei Nakagawa, Dr. Atsushi Kato, Dr. Isao Adachi, Dr. Marcin Górecki, Prof. Jadwiga Frelek and Prof. Olivier R. Martin

      Article first published online: 2 OCT 2013 | DOI: 10.1002/cmdc.201300327

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      The sincerest form of flattery: Glucosylceramide mimics based on an iminoxylitol C-linked to a di-O-acyl or di-O-alkyl glyceryl group were prepared, and all of them were shown to be nanomolar inhibitors of lysosomal β-glucosidase (glucocerebrosidase, GCase). One diester was identified as a potent chaperone for the L444P GCase in human fibroblasts. These structures provide leads for the development of therapeutic agents for Gaucher disease.

    4. A Glutathione Derivative with Chelating and in vitro Neuroprotective Activities: Synthesis, Physicochemical Properties, and Biological Evaluation (pages 1818–1829)

      Dr. Ivana Cacciatore, Dr. Catia Cornacchia, Dr. Erika Fornasari, Dr. Leonardo Baldassarre, Prof.  Francesco Pinnen, Dr. Piera Sozio, Prof. Antonio Di Stefano, Dr. Lisa Marinelli, Dr. Annalisa Dean, Prof. Stefania Fulle, Dr. Ester Sara Di Filippo, Dr. Rita Maria Laura La Rovere, Dr. Antonia Patruno, Dr. Alessio Ferrone and Dr. Valerio Di Marco

      Article first published online: 17 SEP 2013 | DOI: 10.1002/cmdc.201300295

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      Multi-target multitasking: We report the synthesis of a novel and chemically stable S-hydroxyquinoline glutathione derivative. This compound was shown to prevent H2O2- and 6-OHDA-mediated oxidative stress in in vitro models and to partially and quantitatively remove CuII and ZnII, respectively, from the Aβ peptide.

    5. Synthesis and Pharmacological Evaluation of a series of the Agomelatine Analogues as Melatonin MT1/MT2 Agonist and 5-HT2C Antagonist (pages 1830–1845)

      Dr. Mohamed Ettaoussi, Dr. Ahmed Sabaouni, Dr. Basile Pérès, Elodie Landagaray, Dr. Olivier Nosjean, Dr. Jean A. Boutin, Dr. Daniel-Henri Caignard, Dr. Philippe Delagrange, Prof. Pascal Berthelot and Dr. Saïd Yous

      Article first published online: 12 SEP 2013 | DOI: 10.1002/cmdc.201300294

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      Selectively seeking subtypes: A series of agomelatine analogues were synthesized and biologically evaluated. Most of the prepared compounds exhibited good binding affinity at melatonin MT1 and MT2 receptor subtypes. Compounds 21 a and 21 e showed good binding affinities and behaved as agonists at melatonin (MT1/MT2) receptors and as antagonists at serotonin 5-HT2C receptor subtypes.

    6. X-ray Structural Analysis of Tau-Tubulin Kinase 1 and Its Interactions with Small Molecular Inhibitors (pages 1846–1854)

      Dr. Yafeng Xue, Dr. Paul T. Wan, Dr. Per Hillertz, Dr. Fritz Schweikart, Dr. Yanlong Zhao, Lisa Wissler and Dr. Niek Dekker

      Article first published online: 13 SEP 2013 | DOI: 10.1002/cmdc.201300274

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      Flipped into place! The tau-tubulin kinase 1 (TTBK1) structure revealed two clear basic patches near the ATP pocket providing an explanation for phosphorylation-primed substrates. The structure in complex with compound 2 revealed a reorganization of the L199–D200 peptide backbone conformation together with altered hydrogen bonding. The analyses of TTBK1 binding to ligands with distinct characteristics could enable a fast track for structure-based ligand design of selective TTBK1 inhibitors.

    7. Aryl Biphenyl-3-ylmethylpiperazines as 5-HT7 Receptor Antagonists (pages 1855–1864)

      Jeeyeon Kim, Youngjae Kim, Prof. Jinsung Tae, Miyoung Yeom, Prof. Bongjin Moon, Dr. Xi-Ping Huang, Prof. Bryan L. Roth, Kangho Lee, Dr. Hyewhon Rhim, Prof. Il Han Choo, Prof. Youhoon Chong, Dr. Gyochang Keum, Dr. Ghilsoo Nam and Prof. Hyunah Choo

      Article first published online: 3 SEP 2013 | DOI: 10.1002/cmdc.201300240

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      Vacancies filled: 2′-Methoxybiphenyl-3-ylmethyl(2-methoxyphenyl)piperazine (28) is shown to serve as a selective 5-HT7 receptor antagonist. From a comparison with the docking modes of other known 5-HT7 receptor agonists and antagonists, it is suggested that occupancy of both hydrophobic ligand binding sites of the 5-HT7 receptor by the ligand is crucial for its antagonistic property.

    8. Dissociation of Antimicrobial and Hemolytic Activities of Gramicidin S through N-Methylation Modification (pages 1865–1872)

      Dr. Yangmei Li, Dr. Nina Bionda, Dr. Austin Yongye, Phaedra Geer, Dr. Maciej Stawikowski, Dr. Predrag Cudic, Dr. Karina Martinez and Dr. Richard A. Houghten

      Article first published online: 10 SEP 2013 | DOI: 10.1002/cmdc.201300232

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      Out of order! Disruption of the internal hydrogen bond(s) of β-sheet antimicrobial peptides by N-methylation could improve their selectivity for microbial cells over erythrocytes. We investigated a model β-sheet antimicrobial peptide, gramicidin S, for the N-methylation effects on antimicrobial and hemolytic activities. 1H NMR and circular dichroism spectroscopy results show that N-methylation of the internal hydrogen bond-forming amide affected the conformation, backbone shape, and side chain orientation.

    9. Structural Elaboration of a Natural Product: Identification of 3,3′-Diindolylmethane Aminophosphonate and Urea Derivatives as Potent Anticancer Agents (pages 1873–1884)

      Somnath Kandekar, Ranjan Preet, Maneesh Kashyap, Renu Prasad M. U., Purusottam Mohapatra, Dipon Das, Shakti Ranjan Satapathy, Sumit Siddharth, Vaibhav Jain, Maitrayee Choudhuri, Dr. Chanakya N. Kundu, Dr. Sankar K. Guchhait and Prof. Prasad V. Bharatam

      Article first published online: 28 AUG 2013 | DOI: 10.1002/cmdc.201300273

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      DIM the lights: A rational approach toward structural elaboration of a bioactive natural product, diindolylmethane (DIM), led to our exploration of novel DIM aminophosphonate and urea derivatives as potent NF-κB p65-down-regulating apoptotic anticancer agents that possess enhanced activities over the parent DIM.

  8. Conference Report

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Review
    6. Minireview
    7. Communications
    8. Full Papers
    9. Conference Report
    1. Epigenetic Targets

      Small-Molecule Modulators for Epigenetics Targets (pages 1885–1891)

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

      Article first published online: 14 OCT 2013 | DOI: 10.1002/cmdc.201300344

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      A capital conference: Influencing epigenetic mechanisms may be highly relevant for future therapies of various diseases such as cancer, inflammation, and metabolic disorders. Leading experts in the field gathered in Berlin on June 5–6, 2013 at a Bayer HealthCare Life Science Workshop to share recent success stories and to discuss future trends.

      Corrected by:

      Corrigendum: Corrigendum: Small-Molecule Modulators for Epigenetics Targets

      Vol. 8, Issue 12, 1904, Article first published online: 29 NOV 2013

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