ChemMedChem

Cover image for Vol. 3 Issue 6

June 16, 2008

Volume 3, Issue 6

Pages 849–1006

  1. Cover Picture

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Minireview
    6. Communications
    7. Full Papers
    8. Book Reviews
    9. Preview
    1. Cover Picture: Herceptin–Platinum(II) Binding Complexes: Novel Cancer-Cell-Specific Agents (ChemMedChem 6/2008) (page 849)

      Jian Gao, Ya Guang Liu, Renbin Liu and Ralph A. Zingaro

      Version of Record online: 5 JUN 2008 | DOI: 10.1002/cmdc.200890023

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      The cover picture shows a schematic representation of the Herceptin–platinum(II) binding complex, which recognizes Her2/neu on the surface of SK-BR-3 cancer cells. The novel platinum(II)-based agents achieve their high binding affinity through Herceptin, which retains its capacity to recognize Her2/neu. The investigated binding complex, Her–nLPtII, shows remarkable cancer-cell-specific cytotoxicity toward SK-BR-3 and SK-OV-3 cancer cells. This study highlights an approach that is more practical than the preparation of mAb–drug conjugates, which can be more complex and difficult to develop as drugs. These findings will guide the development of mAb–metal-based drug-targeting entities as a means to treat human cancers and other diseases. For details, see the Full Paper by J. Gao and R. A. Zingaro, et al. on p. 954 ff.

  2. Graphical Abstract

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Minireview
    6. Communications
    7. Full Papers
    8. Book Reviews
    9. Preview
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  3. News

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Minireview
    6. Communications
    7. Full Papers
    8. Book Reviews
    9. Preview
  4. Minireview

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Minireview
    6. Communications
    7. Full Papers
    8. Book Reviews
    9. Preview
    1. Towards Small-Molecule CXCR3 Ligands with Clinical Potential (pages 861–872)

      Maikel Wijtmans, Dennis Verzijl, Rob Leurs, Iwan J. P. de Esch and Martine J. Smit

      Version of Record online: 28 APR 2008 | DOI: 10.1002/cmdc.200700365

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      This minireview highlights the postulated therapeutic roles of the CXCR3 chemokine receptor and the nonpeptidergic CXCR3 antagonists and agonists that have been developed in recent years. The use of these molecules in exploring the (patho)physiological roles and putative clinical applications of CXCR3 are discussed.

  5. Communications

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Minireview
    6. Communications
    7. Full Papers
    8. Book Reviews
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    1. A Combinatorial Approach to 2,4,6-Trisubstituted Triazines with Potent Antimalarial Activity: Combining Conventional Synthesis and Microwave-Assistance (pages 873–876)

      Sergio Melato, Davide Prosperi, Paolo Coghi, Nicoletta Basilico and Diego Monti

      Version of Record online: 22 FEB 2008 | DOI: 10.1002/cmdc.200700344

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      Managing malaria. Malaria is responsible for two million deaths per year particularly in developing countries, therefore there is great need for the development of cost effective treatment. The synthesis of a library of trisubstituted triazines with potent antimalarial in vitro activity is reported. Among them, five products may be developed as potential leads in the search for new drugs against plasmodial chloroquine-resistant strains.

    2. Discovery of VHR Phosphatase Inhibitors with Micromolar Activity based on Structure-Based Virtual Screening (pages 877–880)

      Hwangseo Park, Suk-Kyeong Jung, Dae Gwin Jeong, Seong Eon Ryu and Seung Jun Kim

      Version of Record online: 31 JAN 2008 | DOI: 10.1002/cmdc.200700348

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      Human VHR phosphatase has been shown to be involved in the regulation of cell-cycle progression and is itself modulated during the cell cycle, indicating that VHR can serve as a therapeutic target for cancer. In the present study, we identify new VHR inhibitors by means of a structure-based drug design protocol involving the virtual screening with docking simulations and in vitro enzyme assay.

    3. Discovery of a Drug-Like G-Quadruplex Binding Ligand by High-Throughput Docking (pages 881–884)

      Dik-Lung Ma, Tat-Shing Lai, Fung-Yi Chan, Wai-Hong Chung, R. Abagyan, Yun-Chung Leung and Kwok-Yin Wong

      Version of Record online: 26 MAR 2008 | DOI: 10.1002/cmdc.200700342

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      A new G-quadruplex binding ligand, namely 1H-pyrazole-3-carboxy-4-methyl-5-phenyl-(1H-indol-3-ylmethylene)hydrazide, was identified from a database of 100 000 drug-like compounds by in silico high-throughput docking. This compound was demonstrated experimentally to be an effective stabilizer of G-quadruplex DNA; it exhibits high selectivity for G-quadruplex over duplex DNA.

  6. Full Papers

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Minireview
    6. Communications
    7. Full Papers
    8. Book Reviews
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    1. Towards an Integrated Description of Hydrogen Bonding and Dehydration: Decreasing False Positives in Virtual Screening with the HYDE Scoring Function (pages 885–897)

      Ingo Reulecke, Gudrun Lange, Jürgen Albrecht, Robert Klein and Matthias Rarey

      Version of Record online: 2 APR 2008 | DOI: 10.1002/cmdc.200700319

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      HYDE is a new empirical scoring function for the evaluation of protein–ligand complexes that estimates binding free energy based on two terms for dehydration and hydrogen bonding only. In contrast to other scoring functions, HYDE accounts for destabilizing dehydration effects in a consistent manner, thereby decreasing the rate of false positive hits in virtual screening.

    2. Substituted Pyrazolo[3,4-b]pyridines as Potent A1 Adenosine Antagonists: Synthesis, Biological Evaluation, and Development of an A1 Bovine Receptor Model (pages 898–913)

      Tiziano Tuccinardi, Silvia Schenone, Francesco Bondavalli, Chiara Brullo, Olga Bruno, Luisa Mosti, Alessandra Tania Zizzari, Cristina Tintori, Fabrizio Manetti, Osele Ciampi, Maria Letizia Trincavelli, Claudia Martini, Adriano Martinelli and Maurizio Botta

      Version of Record online: 13 MAR 2008 | DOI: 10.1002/cmdc.200700355

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      Healthy antagonism: A1 adenosine receptor (A1AR) affinity evaluations of purified enantiomers of the most active compound among the series reported (scaffold shown) indicate that the absolute stereochemical configuration affects the species-subtype selectivity of these antagonists, in agreement with a hypothesized larger cavity for bovine A1AR with respect to the human A1AR receptor.

    3. On the Way to Selective PARP-2 Inhibitors. Design, Synthesis, and Preliminary Evaluation of a Series of Isoquinolinone Derivatives (pages 914–923)

      Roberto Pellicciari, Emidio Camaioni, Gabriele Costantino, Laura Formentini, Paola Sabbatini, Francesco Venturoni, Gökçen Eren, Daniele Bellocchi, Alberto Chiarugi and Flavio Moroni

      Version of Record online: 11 APR 2008 | DOI: 10.1002/cmdc.200800010

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      Selective PARP-2 inhibitors: A series of isoquinolinone derivatives were synthesized and pharmacologically evaluated as PARP-1/PARP-2 inhibitors. Among them, we identified the 5-benzoyloxyisoquinolin-1(2H)-one derivative (shown here) as the most selective PARP-2 inhibitor reported so far, with a PARP-2/PARP-1 selectivity index greater than 60.

    4. Inhibitors of Inducible NO Synthase Expression: Total Synthesis of (S)-Curvularin and Its Ring Homologues (pages 924–939)

      Stephan Elzner, Denise Schmidt, Dieter Schollmeyer, Gerhard Erkel, Timm Anke, Hartmut Kleinert, Ulrich Förstermann and Horst Kunz

      Version of Record online: 25 MAR 2008 | DOI: 10.1002/cmdc.200800022

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      Nonsteroidal anti-inflammatory drugs: (S)-Curvularin and its 13-, 14-, and 16-membered homologues were synthesized by a uniform strategy based on Kochi oxidative decarboxylation and ring-closing metathesis. The 5,7-di-O-acetyl and 4-chloro derivatives of (S)-curvularin show improved downregulation of iNOS expression and almost no negative effects on eNOS expression, as is desirable for anti-inflammatory drugs.

    5. Targeted RNA Interference of Cyclin A2 Mediated by Functionalized Single-Walled Carbon Nanotubes Induces Proliferation Arrest and Apoptosis in Chronic Myelogenous Leukemia K562 Cells (pages 940–945)

      Xiaohui Wang, Jinsong Ren and Xiaogang Qu

      Version of Record online: 19 FEB 2008 | DOI: 10.1002/cmdc.200700329

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      Carbon-nanotube vectors. Cyclin A2 plays critical role in DNA replication, transcription, and cell cycle regulation. SWNTs can facilitate the coupling of siRNA specifically targeting human cyclin A2 in chronic myelogenous leukemia K562 cells. Depletion of cyclin A2 in this manner inhibits cell proliferation and promotes apoptosis demonstrating that cyclin A2 can serve as a novel therapeutic target.

    6. Synthesis and Biological Activity of a Novel Inhibitor of Dihydroceramide Desaturase (pages 946–953)

      Jose M. Munoz-Olaya, Xavier Matabosch, Carmen Bedia, Meritxell Egido-Gabás, Josefina Casas, Amadeu Llebaria, Antonio Delgado and Gemma Fabriàs

      Version of Record online: 31 JAN 2008 | DOI: 10.1002/cmdc.200700325

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      Rational design considering both mechanistic aspects of enzymatic desaturation and structural features of reported fatty acyl-CoA desaturase inhibitors led to the dihydroceramide desaturase inhibitor XM462. The design, synthesis, and biological activity of this compound both in vitro and in Jurkat A3 human leukemia cells are reported.

    7. Herceptin–Platinum(II) Binding Complexes: Novel Cancer-Cell-Specific Agents (pages 954–962)

      Jian Gao, Ya Guang Liu, Renbin Liu and Ralph A. Zingaro

      Version of Record online: 25 MAR 2008 | DOI: 10.1002/cmdc.200700349

      Thumbnail image of graphical abstract

      Specificity and toxicity. A new series of Herceptin–platinum(II) binding complexes, Her–nLPtII, were investigated and show remarkable cancer-cell-specific cytotoxicity toward Her2/neu-overexpressing cancer cells (SK-BR-3 and SK-OV-3). This study suggests a new approach for the development of mAb–platinum(II)-based targeting agents for the treatment of human cancers.

    8. Investigating Amine Derivatives of Ambruticin VS-5 and VS-4 (pages 963–969)

      Zong-Qiang Tian, Zhan Wang, Yuan Xu, Chau Q. Tran, David C. Myles, Ziyang Zhong, Jessica Simmons, Leandro Vetcher, Leonard Katz, Yong Li and Simon J. Shaw

      Version of Record online: 28 FEB 2008 | DOI: 10.1002/cmdc.200800008

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      Potent antifungals: A study of the amine region of the ambruticin VS series resulted in compound KOS-2079, which has excellent potency and oral bioavailability, and which showed efficacy in an in vivo mouse model.

    9. Dipeptide Derivatives of AZT: Synthesis, Chemical Stability, Activation in Human Plasma, hPEPT1 Affinity, and Antiviral Activity (pages 970–978)

      Cledir Santos, José Morais, Luís Gouveia, Erik de Clercq, Christophe Pannecouque, Carsten Uhd Nielsen, Bente Steffansen, Rui Moreira and Paula Gomes

      Version of Record online: 3 APR 2008 | DOI: 10.1002/cmdc.200800012

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      5′-O-Dipeptide ester prodrugs of AZT were prepared and found to be good substrates for hPEPT1. They exhibit anti-HIV activity similar to that of AZT, yet are less cytotoxic. The prodrugs release AZT through an elimination–cyclization pathway in aqueous buffer and by the action of amino- and diaminopeptidases in human plasma, as shown in the scheme.

    10. Conformationally Restricted Hydantoin-Based Peptidomimetics as Inhibitors of Caspase-3 with Basic Groups Allowed at the S3 Enzyme Subsite (pages 979–985)

      Jesús Vázquez, Alicia García-Jareño, Laura Mondragón, Jaime Rubio-Martinez, Enrique Pérez-Payá and Fernando Albericio

      Version of Record online: 4 APR 2008 | DOI: 10.1002/cmdc.200800020

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      Apoptosis induction: Novel scaffold molecules for the inhibition of caspase-3 have been developed. These compounds have an overall attenuated negative charge and show similar IC50 values for both recombinant and human endogenous caspase-3. This could provide the basis for a new strategy for the discovery of potent and more druglike inhibitors of caspase-3.

    11. Naphthoxazepine Inhibitors of HIV-1 Integrase: Synthesis and Biological Evaluation (pages 986–990)

      Antonio Garofalo, Fedora Grande, Antonella Brizzi, Francesca Aiello, Raveendra Dayam and Nouri Neamati

      Version of Record online: 26 MAR 2008 | DOI: 10.1002/cmdc.200800026

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      Taking IN out: Herein we report the preparation and preliminary biological evaluation of two series of tetracyclic analogues resulting from the fusion of a diversely annulated naphthoxazepinedione system with 1,3-thiazole and 1,3-oxazole. To understand their mode of interaction with the HIV-1 integrase (IN) active site, we docked the compounds into the X-ray crystal structure of the core domain of IN.

    12. Molecular Recognition of Small-Cell Lung Cancer Cells Using Aptamers (pages 991–1001)

      Hui William Chen, Colin D. Medley, Kwame Sefah, Dihua Shangguan, Zhiwen Tang, Ling Meng, Josh E. Smith and Weihong Tan

      Version of Record online: 13 MAR 2008 | DOI: 10.1002/cmdc.200800030

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      Early diagnosis is the key for lung cancer survival. Novel aptamer-based molecular probes were developed for the recognition of specific small-cell lung cancer (SCLC) cell-surface molecular markers. They show high affinity and specificity in various assay formats. This approach shows the potential for early lung cancer detection.

  7. Book Reviews

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Minireview
    6. Communications
    7. Full Papers
    8. Book Reviews
    9. Preview
    1. The Art of Drug Synthesis. Edited by Douglas S. Johnson and Jie Jack Li. (page 1002)

      Stefan Peukert and Branko Radetich

      Version of Record online: 5 JUN 2008 | DOI: 10.1002/cmdc.200800015

  8. Preview

    1. Top of page
    2. Cover Picture
    3. Graphical Abstract
    4. News
    5. Minireview
    6. Communications
    7. Full Papers
    8. Book Reviews
    9. Preview
    1. Preview: ChemMedChem 7/2008 (page 1006)

      Version of Record online: 5 JUN 2008 | DOI: 10.1002/cmdc.200890022

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