ChemMedChem

Cover image for Vol. 7 Issue 6

June 2012

Volume 7, Issue 6

Pages 937–1127

  1. Cover Picture

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Review
    8. Communications
    9. Full Papers
    10. Book Reviews
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    1. Cover Picture: Hydroxamic Acids as Potent Inhibitors of FeII and MnII E. coli Methionine Aminopeptidase: Biological Activities and X-ray Structures of Oxazole Hydroxamate–EcMetAP-Mn Complexes (ChemMedChem 6/2012) (page 937)

      Dr. Florian Huguet, Dr. Armelle Melet, Dr. Rodolphe Alves de Sousa, Dr. Aurélie Lieutaud, Dr. Jacqueline Chevalier, Dr. Laure Maigre, Dr. Patrick Deschamps, Prof. Alain Tomas, Nicolas Leulliot, Dr. Jean-Marie Pages and Dr. Isabelle Artaud

      Article first published online: 25 MAY 2012 | DOI: 10.1002/cmdc.201290024

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      The cover picture shows an oxazole derivative in complex with Escherichia coli methionine aminopeptidase (MetAP) in its MnII form. The enzyme is consistently dinuclear even when crystallized with a substoichiometric ratio of MnII/apo-protein. The derivative shown is part of a new series of hydroxamic acids linked to five-membered heterocycles, such as oxazole and oxadiazole or imidazole, that are potent and specific inhibitors of both the MnII and FeII forms of E. coli MetAP. For more details, see the Full Paper by Isabelle Artaud et al. on p. 1020 ff.

  2. Inside Cover

    1. Top of page
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    5. Graphical Abstract
    6. News
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    8. Communications
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    1. Inside Cover: Pentacycloundecane-diol-Based HIV-1 Protease Inhibitors: Biological Screening, 2D NMR, and Molecular Simulation Studies (ChemMedChem 6/2012) (page 938)

      Dr. Bahareh Honarparvar, Dr. Maya M. Makatini, Sachin A. Pawar, Dr. Katja Petzold, Dr. Mahmoud E. S. Soliman, Prof. Per I. Arvidsson, Dr. Yasien Sayed, Dr. Thavendran Govender, Dr. Glenn E. M. Maguire and Prof. Hendrik G. Kruger

      Article first published online: 25 MAY 2012 | DOI: 10.1002/cmdc.201290025

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      The inside cover picture shows conserved hydrogen bonds between the pentacycloundecane (PCU) cage peptide and catalytic triad (Asp 25, Ile 26, Gly 27) of C-South African (C-SA) HIV-1 protease predicted by computational techniques. Three inhibitors identified display promising IC50 values against the target, with toxicity toward human MT-4 cells significantly lower than current therapies. For more details, see the Full Paper by Glenn E. M. Maguire, Hendrik G. Kruger et al. on p. 1009 ff.

  3. Back Cover

    1. Top of page
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    6. News
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    1. Back Cover: Discovery of 3H-Imidazo[4,5-b]pyridines as Potent c-Met Kinase Inhibitors: Design, Synthesis, and Biological Evaluation (ChemMedChem 6/2012) (page 1129)

      Dr. Danqi Chen, Ying Wang, Yuchi Ma, Dr. Bing Xiong, Dr. Jing Ai, Prof. Yi Chen, Prof. Dr. Meiyu Geng and Prof. Dr. Jingkang Shen

      Article first published online: 25 MAY 2012 | DOI: 10.1002/cmdc.201290028

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      The back cover picture shows the analysis of underexplored sequences and crystal structures of the tyrosine kinase subfamily in the human kinome, identifying the imidazolopyridine ring as a novel hinge binder scaffold for the development of c-Met inhibitors. For more details, see the Full Paper by Meiyu Geng, Jingkang Shen et al. on p. 1057 ff.

  4. Graphical Abstract

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    1. Graphical Abstract: ChemMedChem 6/2012 (pages 939–945)

      Article first published online: 25 MAY 2012 | DOI: 10.1002/cmdc.201290026

  5. News

    1. Top of page
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    1. Spotlights on our sister journals: ChemMedChem 6/2012 (pages 948–950)

      Article first published online: 25 MAY 2012 | DOI: 10.1002/cmdc.201290027

  6. Review

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    1. Docetaxel Nanotechnology in Anticancer Therapy (pages 952–972)

      Pengxiang Zhao and Didier Astruc

      Article first published online: 19 APR 2012 | DOI: 10.1002/cmdc.201200052

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      A dose of docetaxel: Given the importance and vast potential of this anticancer drug, herein we review the state of the art and recently published results of various academic efforts aimed at improving specificity and bioavailability through nanotechnology-based drug-delivery systems involving nanocarriers and targeting agents for docetaxel formulations.

  7. Communications

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    1. Synthesis, Structure Analysis, and Antitumor Evaluation of 3,6-Dimethyl-1,2,4,5-tetrazine-1,4-dicarboxamide Derivatives (pages 973–976)

      Dr. Guo-Wu Rao, Yan-Mei Guo and Prof. Dr. Wei-Xiao Hu

      Article first published online: 26 APR 2012 | DOI: 10.1002/cmdc.201200109

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      Tumor downsizing: A series of tetrazine derivatives were synthesized and characterized. Their antitumor activity in vitro showed several compounds to be endowed with cytotoxicity in the low micromolar range. The activity of one compound in vivo and its acute toxicity were further evaluated. The results revealed that it has relatively low toxicity and good efficacy.

    2. Exploration and Optimization of Structure–Activity Relationships in Drug Design using the Taguchi Method (pages 977–982)

      Wee Kiang Yeo, Kheng Lin Tan, Siang Boon Koh, Dr. Matiullah Khan, Dr. Shahul Nilar and Prof. Mei Lin Go

      Article first published online: 3 MAY 2012 | DOI: 10.1002/cmdc.201200106

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      From engineering to drug design: Use of the Taguchi method to predict the optimal compound from a dataset could potentially allow the identification of the most biologically active compound without the synthesis of a full combinatorial library of derivatives. Our results show that the method achieved favorable outcomes for biological activities that are measured against specific target proteins. However, limitations were observed when the method was applied to data derived from a cell-based system.

  8. Full Papers

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Review
    8. Communications
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    10. Book Reviews
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    1. Kinase Inhibitor Scaffolds against Neurodegenerative Diseases from a Southern Australian Ascidian, Didemnum sp. (pages 983–990)

      Fabien Plisson, Melissa Conte, Zeinab Khalil, Xiao-Cong Huang, Dr. Andrew M. Piggott and Prof. Robert J. Capon

      Article first published online: 24 APR 2012 | DOI: 10.1002/cmdc.201200169

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      Chemical investigation of an Australian Didemnum species returned known ningalins B–D as the major metabolites, together with six minor metabolites, previously unknown ningalins E–G and known lamellarins Z, G and A6. These natural products were shown inhibit neurodegenerative disease kinase targets, casein kinase 1 (CK1δ), cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β).

    2. Evaluation of Bis-Alkylamidoxime O-Alkylsulfonates as Orally Available Antimalarials (pages 991–1001)

      Dr. Mélissa Degardin, Sharon Wein, Dr. Smitha Gouni, Christophe Tran Van Ba, Dr. Jean-Frédéric Duckert, Dr. Thierry Durand, Prof. Roger Escale, Dr. Henri Vial and Dr. Yen Vo-Hoang

      Article first published online: 27 APR 2012 | DOI: 10.1002/cmdc.201200112

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      Improved bioavailability: Bis-alkylamidines were originally developed as potential new antimalarial agents that target phospholipid metabolism, but these compounds are not orally bioavailable. To solve this issue, 25 sulfonates were investigated as prodrug candidates. Their antimalarial activities were evaluated in vitro and in vivo to define structure–activity relationships.

    3. The Importance of the trans-Enamine Intermediate as a β-Lactamase Inhibition Strategy Probed in Inhibitor-Resistant SHV β-Lactamase Variants (pages 1002–1008)

      Wei Ke, Elizabeth A. Rodkey, Jared M. Sampson, Marion J. Skalweit, Anjaneyulu Sheri, Dr. Sundar Ram Reddy Pagadala, Michael D. Nottingham, Prof. John D. Buynak, Prof. Robert A. Bonomo and Prof. Focco van den Akker

      Article first published online: 21 MAR 2012 | DOI: 10.1002/cmdc.201200006

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      Beating that bug! A novel mechanism of class A β-lactamase inhibition entails stabilization of an inhibitory trans-enamine intermediate. Here, the effectiveness of such a mode of inhibition is crystallographically probed for two mutants of SHV-1 β-lactamase that have an inhibitor-resistant phenotype.

    4. Pentacycloundecane-diol-Based HIV-1 Protease Inhibitors: Biological Screening, 2D NMR, and Molecular Simulation Studies (pages 1009–1019)

      Dr. Bahareh Honarparvar, Dr. Maya M. Makatini, Sachin A. Pawar, Dr. Katja Petzold, Dr. Mahmoud E. S. Soliman, Prof. Per I. Arvidsson, Dr. Yasien Sayed, Dr. Thavendran Govender, Dr. Glenn E. M. Maguire and Prof. Hendrik G. Kruger

      Article first published online: 27 APR 2012 | DOI: 10.1002/cmdc.201100512

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      Cage peptides unleashed: The combination of drug design with in vitro assays, NMR techniques, and molecular modeling has enabled us to rationalize the observed inhibitory activities toward HIV protease by the various cage peptides in this series. EASY-ROESY NMR data show that the entire range of inhibitors exhibit a relatively stable interaction between the cage side chain and the cage protons.

    5. Hydroxamic Acids as Potent Inhibitors of FeII and MnII E. coli Methionine Aminopeptidase: Biological Activities and X-ray Structures of Oxazole Hydroxamate–EcMetAP-Mn Complexes (pages 1020–1030)

      Dr. Florian Huguet, Dr. Armelle Melet, Dr. Rodolphe Alves de Sousa, Dr. Aurélie Lieutaud, Dr. Jacqueline Chevalier, Dr. Laure Maigre, Dr. Patrick Deschamps, Prof. Alain Tomas, Nicolas Leulliot, Dr. Jean-Marie Pages and Dr. Isabelle Artaud

      Article first published online: 4 APR 2012 | DOI: 10.1002/cmdc.201200076

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      Great rings of five! New hydroxamic acids linked to furan, oxazole, oxadiazole, imidazole, and indole heterocycles were prepared and assayed against E. coli methionine aminopeptidase (EcMetAP). They showed selectivity for MnII and FeII metalloforms. Two X-ray crystal structures of oxazole hydroxamic acid–EcMetAP-Mn complexes were solved, and a molecular model of the indole derivative–EcMetAP-Mn complex was built.

    6. Elucidation of Mycobacterium tuberculosis Type II Dehydroquinase Inhibitors using a Fragment Elaboration Strategy (pages 1031–1043)

      Anh Thu Tran, Dr. Nicholas P. West, Prof. Warwick J. Britton and Dr. Richard J. Payne

      Article first published online: 27 MAR 2012 | DOI: 10.1002/cmdc.201100606

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      Extend to improve: Novel inhibitors of Mycobacterium tuberculosis type II dehydroquinase were discovered through a fragment elaboration approach. A number of low-micromolar inhibitors of the enzyme were elucidated which possess significant activity against M. tuberculosis in vitro.

    7. Synthesis, Anti-HIV Activity Studies, and in silico Rationalization of Cyclobutane-Fused Nucleosides (pages 1044–1056)

      Antoni Figueras, Rosa Miralles-Llumà, Dr. Ramon Flores, Dr. Albert Rustullet, Dr. Félix Busqué, Dr. Marta Figueredo, Dr. Josep Font, Dr. Ramon Alibés and Dr. Jean-Didier Maréchal

      Article first published online: 13 APR 2012 | DOI: 10.1002/cmdc.201200059

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      Sweet insight: Nucleoside analogues of d4T built on a 3-oxabicyclo[3.2.0]heptane scaffold bearing various functionalities were prepared and evaluated as anti-HIV agents. This synthetic work is complemented by an extensive molecular modeling study on the entire activation process of these compounds and on their interaction with HIV reverse transcriptase.

    8. Discovery of 3H-Imidazo[4,5-b]pyridines as Potent c-Met Kinase Inhibitors: Design, Synthesis, and Biological Evaluation (pages 1057–1070)

      Dr. Danqi Chen, Ying Wang, Yuchi Ma, Dr. Bing Xiong, Dr. Jing Ai, Prof. Yi Chen, Prof. Dr. Meiyu Geng and Prof. Dr. Jingkang Shen

      Article first published online: 13 MAY 2012 | DOI: 10.1002/cmdc.201200120

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      Amazing imidazolopyridines: By screening crystal structures of members of the human kinome and analyzing hinge binders, we designed a novel scaffold for inhibitors of c-Met. A series of derivatives were prepared and their SARs were studied; among them, compound 41 showed good in vitro and in vivo activities and proved to be a promising lead compound for further investigation.

    9. Structure–Activity Relationships and Mechanism of Action of Eph–ephrin Antagonists: Interaction of Cholanic Acid with the EphA2 Receptor (pages 1071–1083)

      Dr. Massimiliano Tognolini, Dr. Matteo Incerti, Iftiin Hassan-Mohamed, Dr. Carmine Giorgio, Simonetta Russo, Dr. Renato Bruni, Dr. Barbara Lelli, Prof. Luisa Bracci, Dr. Roberta Noberini, Prof. Elena B. Pasquale, Prof. Elisabetta Barocelli, Prof. Paola Vicini, Prof. Marco Mor and Dr. Alessio Lodola

      Article first published online: 23 APR 2012 | DOI: 10.1002/cmdc.201200102

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      Well worth the Ephort! A combined application of computational and experimental techniques led to the identification of (5α)-cholan-24-oic acid derivatives that disrupt the ephrinA1–EphA2 complex by specific interaction with the ligand binding domain of the EphA2 receptor. SAR studies provide a detailed analysis of the requirements for small molecules able to disrupt the Eph–ephrin interaction. As this system plays a critical role in tumor and vascular functions during carcinogenesis, these compounds could provide leads for therapeutic agents.

    10. Synthesis of Gd and 68Ga Complexes in Conjugation with a Conformationally Optimized RGD Sequence as Potential MRI and PET Tumor-Imaging Probes (pages 1084–1093)

      Dr. Leonardo Manzoni, Dr. Laura Belvisi, Dr. Daniela Arosio, Dr. Maria Paola Bartolomeo, Dr. Aldo Bianchi, Dr. Chiara Brioschi, Dr. Federica Buonsanti, Dr. Claudia Cabella, Prof. Cesare Casagrande, Dr. Monica Civera, Dr. Marilenia De Matteo, Dr. Lorenza Fugazza, Dr. Luciano Lattuada, Dr. Federico Maisano, Luigi Miragoli, Dr. Cristina Neira, Dr. Michael Pilkington-Miksa and Prof. Carlo Scolastico

      Article first published online: 5 APR 2012 | DOI: 10.1002/cmdc.201200043

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      Persistence pays: Novel Gd and 68Ga chelates conjugated with a cyclic RGD peptidomimetic integrin ligand were prepared. Preliminary in vivo evaluation of the first integrin-targeted AAZTA(68Ga) complex showed good uptake and persistence in a xenograft mouse model of human glioblastoma (U-87 MG) cells.

    11. Development of Selective Estrogen Receptor Modulator (SERM)-Like Activity Through an Indirect Mechanism of Estrogen Receptor Antagonism: Defining the Binding Mode of 7-Oxabicyclo[2.2.1]hept-5-ene Scaffold Core Ligands (pages 1094–1100)

      Yangfan Zheng, Manghong Zhu, Dr. Sathish Srinivasan, Dr. Jerome C. Nwachukwu, Valerie Cavett, Jian Min, Kathryn E. Carlson, Pengcheng Wang, Prof. Dr. Chune Dong, Prof. Dr. John A. Katzenellenbogen, Prof. Dr. Kendall W. Nettles and Prof. Dr. Hai-Bing Zhou

      Article first published online: 19 APR 2012 | DOI: 10.1002/cmdc.201200048

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      A set of estrogen receptor ligands with a novel phenyl 2,3-diaryl-7-oxabicyclo[2.2.1]hept-7-ene-5-sulfonate core structure with various substituents on the phenyl sulfonate have been prepared (5,6-bis-(4-hydroxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonic acid phenyl ester (OBHS), shown). Evaluation of these OBHS derivatives showed a distinctive pattern of affinity and transcriptional activity, and the tolerance for ortho substituents can be understood from a new X-ray crystal structure.

    12. You have full text access to this OnlineOpen article
      Comparative Molecular Profiling of the PPARα/γ Activator Aleglitazar: PPAR Selectivity, Activity and Interaction with Cofactors (pages 1101–1111)

      Michel Dietz, Dr. Peter Mohr, Dr. Bernd Kuhn, Dr. Hans Peter Maerki, Dr. Peter Hartman, Dr. Armin Ruf, Dr. Jörg Benz, Dr. Uwe Grether and Dr. Matthew B. Wright

      Article first published online: 4 APR 2012 | DOI: 10.1002/cmdc.201100598

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      The perfect balance: Detailed transactivation and cofactor recruitment profiles of aleglitazar in comparison with other peroxisome proliferator-activated receptor (PPAR) agonists, including pioglitazone and fenofibric acid, reveal that aleglitazar is a balanced and potent agonist of PPARα and PPARγ.

    13. Molecular Recognition of T:G Mismatched Base Pairs in DNA as Studied by Electrospray Ionization Mass Spectrometry (pages 1112–1122)

      Dr. Federico Riccardi Sirtori, Prof. Giancarlo Aldini, Dr. Maristella Colombo, Dr. Nicoletta Colombo, Dr. Jan Malyszko, Prof. Giulio Vistoli and Dr. Roberto D'Alessio

      Article first published online: 4 APR 2012 | DOI: 10.1002/cmdc.201100526

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      A perfect (mis)match: An ESI-MS method for the identification of small molecules able to recognize T:G mismatched base pairs in DNA targets is described. T:G pairing is one of the common mutations that lead to tumorigenesis and resistance to several chemotherapeutic agents. Among the compounds prepared, one derivative (NMS-057) showed a higher affinity for T:G mismatched DNA sequences.

  9. Book Reviews

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    1. Peptide Drug Discovery and Development: Translational Research in Academia and Industry. Edited by Miguel Castanho and Nuno C. Santos. (page 1123)

      Prof. Dr. Bernd Groner

      Article first published online: 19 APR 2012 | DOI: 10.1002/cmdc.201200178

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      Wiley-VCH, Weinheim 2011. 390 pp., hardcover $ 149.95.—ISBN 978-3-52732-891-8

    2. Medicinal Chemistry of Nucleic Acids. Edited by Li He Zhang, Zhen Xi and Jyoti Chattopadhyaya. (pages 1124–1125)

      Prof. Dr. Joachim W. Engels

      Article first published online: 13 FEB 2012 | DOI: 10.1002/cmdc.201200073

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      John Wiley & Sons, Hoboken 2011. 456 pp., hardcover $ 149.95.—ISBN 978-0-470-59668-5

    3. Therapeutic Oligonucleotides: Methods and Protocols. Edited by John Goodchild. (page 1125)

      Dr. Yashveer Singh

      Article first published online: 13 FEB 2012 | DOI: 10.1002/cmdc.201200072

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      Humana Press, Totowa 2011. xi+340 pp., hardcover $ 139.00.—ISBN 978-1-61779-187-1

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    1. You have free access to this content
      Preview: ChemMedChem 7/2012 (page 1127)

      Article first published online: 25 MAY 2012 | DOI: 10.1002/cmdc.201290023

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