ChemMedChem

Cover image for ChemMedChem

March 7, 2011

Volume 6, Issue 3

Pages 381–571

  1. Cover Picture

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. News
    6. Author Profile
    7. Minireview
    8. Essay
    9. Communications
    10. Full Papers
    11. Book Review
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    1. Cover Picture: Revealing Atropisomer Axial Chirality in Drug Discovery (ChemMedChem 3/2011) (page 381)

      Dr. Steven R. LaPlante, Dr. Paul J. Edwards, Dr. Lee D. Fader, Dr. Araz Jakalian and Dr. Oliver Hucke

      Article first published online: 1 MAR 2011 | DOI: 10.1002/cmdc.201190005

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      The cover picture shows that an atropisomeric drug dosed as a single enantiomer can racemize as a result of axial rotation along a hindered bond. Atropisomerism is an often overlooked source of chirality that has the potential to complicate the drug discovery process and cause late-stage attrition from clinical development. However, if detected early and managed properly, atropisomeric compounds can be developed as drugs. For more details, see the Full Paper by Steven R. LaPlante, Oliver Hucke, et al. on p. 505 ff. Background: Vitruvian Man by Leonardo da Vinci (pen and ink on paper; ca. 1487), stored at the Gallerie dell'Accademia (Venice, Italy).

  2. Inside Cover

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. News
    6. Author Profile
    7. Minireview
    8. Essay
    9. Communications
    10. Full Papers
    11. Book Review
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    1. Inside Cover: A Fragmenting Hybrid Approach for Targeted Delivery of Multiple Therapeutic Agents to the Malaria Parasite (ChemMedChem 3/2011) (page 382)

      Dr. Sumit S. Mahajan, Dr. Edgar Deu, Dr. Erica M. W. Lauterwasser, Melissa J. Leyva, Prof. Dr. Jonathan A. Ellman, Prof. Dr. Matthew Bogyo and Prof. Dr. Adam R. Renslo

      Article first published online: 1 MAR 2011 | DOI: 10.1002/cmdc.201190006

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      The inside cover picture shows release of a Plasmodium falciparum DPAP1 inhibitor from a fragmenting hybrid. Iron(II)-promoted scission of a 1,2,4-trioxolane ring in the hybrid produces an initial cytotoxic effect while simultaneously precipitating release of the free DPAP1 inhibitor. Thus, two antiparasitic activities are conferred to the parasite in an iron(II)-dependent fashion. For more information, see the Communication by Matthew Bogyo, Adam R. Renslo, et al. on p. 415 ff.

  3. Graphical Abstract

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. News
    6. Author Profile
    7. Minireview
    8. Essay
    9. Communications
    10. Full Papers
    11. Book Review
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      Graphical Abstract: ChemMedChem 3/2011 (pages 383–390)

      Article first published online: 1 MAR 2011 | DOI: 10.1002/cmdc.201190007

  4. News

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

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. News
    6. Author Profile
    7. Minireview
    8. Essay
    9. Communications
    10. Full Papers
    11. Book Review
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    1. Barry V. L. Potter (page 397)

      Article first published online: 14 FEB 2011 | DOI: 10.1002/cmdc.201000542

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      "I am waiting for the day when someone will discover an infallible method of predicting ligand–protein affinity computationally. My science 'heroes' are Richard Dawkins, Dorothy Hodgkin and Lord Alexander Todd ..." This and more about Barry Potter can be found on page 397.

  6. Minireview

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    1. The Medicinal Potential of Promising Marine Macrolides with Anticancer Activity (pages 399–409)

      Yunkun Qi and Prof. Shutao Ma

      Article first published online: 7 FEB 2011 | DOI: 10.1002/cmdc.201000534

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      From the deep blue sea: Cancer is the second-leading cause of death in developed countries, and marine macrolides offer continued promise for breakthroughs in anticancer research. This review summarizes some recent studies of marine macrolides with particular attention to their discovery, anticancer activities, mechanisms of action, synthesis, and representative analogues.

  7. Essay

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    1. Effective Collaborations: How to Protect Yourself, Your Collaborators, and Your Data (pages 411–414)

      Alan P. Kozikowski and Joseph H. Neale

      Article first published online: 27 JAN 2011 | DOI: 10.1002/cmdc.201000529

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      Scientific self-defense! Two long-time collaborators share their experiences and discuss the best and worst of scientific collaborations, how to protect you and your data.

  8. Communications

    1. Top of page
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    3. Inside Cover
    4. Graphical Abstract
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    7. Minireview
    8. Essay
    9. Communications
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    11. Book Review
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      A Fragmenting Hybrid Approach for Targeted Delivery of Multiple Therapeutic Agents to the Malaria Parasite (pages 415–419)

      Dr. Sumit S. Mahajan, Dr. Edgar Deu, Dr. Erica M. W. Lauterwasser, Melissa J. Leyva, Prof. Dr. Jonathan A. Ellman, Prof. Dr. Matthew Bogyo and Prof. Dr. Adam R. Renslo

      Article first published online: 24 JAN 2011 | DOI: 10.1002/cmdc.201100002

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      Hybrid drugs with a twist: The coupling of iron(II)-promoted trioxolane ring scission with a β-elimination reaction enables the targeted delivery of multiple drug activities to the malaria parasite. A prototypical fragmenting hybrid (shown) comprises an iron(II)-reactive 1,2,4-trioxolane ring (red) joined via a masked retro-Michael linker (blue) to a partner drug—in this case a protease inhibitor (green). Successful delivery of the protease inhibitor to intra-erythrocytic Plasmodium falciparum parasites is demonstrated using a chemical–biological approach.

    2. Chemical Synthesis and Biological Evaluation of the Englerin Analogues (pages 420–423)

      Dr. Kok Ping Chan and Prof. Dr. David Y.-K. Chen

      Article first published online: 18 JAN 2011 | DOI: 10.1002/cmdc.201000544

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      Improving on nature: The synthesis and biological evaluation of englerin analogues is reported. Structure–activity relationships concerning the cinnamate and glycolic acid domains of englerin A were investigated, revealing insightful information and thereby enabling further diversification of the englerin parent structure.

    3. High-Yielding, Two-Step 18F Labeling Strategy for 18F-PARP1 Inhibitors (pages 424–427)

      Dr. Edmund J. Keliher, Dr. Thomas Reiner, Anna Turetsky, Dr. Scott A. Hilderbrand and Prof. Dr. Ralph Weissleder

      Article first published online: 4 JAN 2011 | DOI: 10.1002/cmdc.201000426

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      Speedy and easy! An 18F-labeled PARP1 imaging agent, based on AZD2281, was prepared via an inverse electron demand Diels–Alder cycloaddition in high radiochemical yield for positron emission tomography (PET) imaging. This strain-promoted ‘bioorthogonal’ reaction is envisioned to be a widely applicable 18F-labeling strategy for repeat and on-demand synthesis of small molecules for PET imaging.

  9. Full Papers

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. News
    6. Author Profile
    7. Minireview
    8. Essay
    9. Communications
    10. Full Papers
    11. Book Review
    12. Preview
    1. Cellular Selectivity and Biological Impact of Cytotoxic Rhodium(III) and Iridium(III) Complexes Containing Methyl-Substituted Phenanthroline Ligands (pages 429–439)

      Dr. Yvonne Geldmacher, Dr. Igor Kitanovic, Hamed Alborzinia, Katharina Bergerhoff, Riccardo Rubbiani, Pascal Wefelmeier, Dr. Aram Prokop, Prof. Ronald Gust, Prof. Ingo Ott, Prof. Stefan Wölfl and Prof. William S. Sheldrick

      Article first published online: 17 FEB 2011 | DOI: 10.1002/cmdc.201000517

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      A complex situation: Trichlorido Ir and Rh complexes with methyl-substituted phenanthroline ligands represent a novel class of potent anticancer agents with pronounced selectivity toward adherent cancer cells and lymphoma relative to normal cells. Their distinct pharmacodynamic profile includes high ROS levels, apoptosis induction, and inhibition of cell respiration.

    2. Comparison of a Pair of Synthetic Tea-Catechin-Derived Epimers: Synthesis, Antifolate Activity, and Tyrosinase-Mediated Activation in Melanoma (pages 440–449)

      Magalí Sáez-Ayala, Dr. Luis Sánchez-del-Campo, Dr. María F. Montenegro, Dr. Soledad Chazarra, Prof. Alberto Tárraga, Dr. Juan Cabezas-Herrera and Dr. José Neptuno Rodríguez-López

      Article first published online: 7 FEB 2011 | DOI: 10.1002/cmdc.201000482

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      One small but important difference: Herein we report the synthesis and biological evaluation of two epimeric compounds derived from the structure of tea catechins. The catechin epimer was more effective than the epicatechin epimer as an antitumor drug against various cancer cell systems. These epimeric differences could be due to greater inhibition of dihydrofolate reductase by the catechin derivative and more efficient oxidation of this derivative by tyrosinase in melanoma cells.

    3. 2-Amino-3,4,5-Trimethoxybenzophenones as Potent Tubulin Polymerization Inhibitors (pages 450–456)

      Hsun-Yueh Chuang, Dr. Jang-Yang Chang, Dr. Mei-Jung Lai, Dr. Ching-Chuan Kuo, Dr. Hsueh-Yun Lee, Dr. Hsing-Pang Hsieh, Ying-Jen Chen, Dr. Li-Tzong Chen, Wen-Yu Pan and Dr. Jing-Ping Liou

      Article first published online: 4 JAN 2011 | DOI: 10.1002/cmdc.201000479

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      A major problem for microtubules: A series of novel 2-amino-3,4,5-trimethoxybenzophenone analogues displayed potent microtubule destabilizing activities. Lead compound 17 exhibited an IC50 value of 1.6 μM, similar to that of combretastatin A-4 (IC50=1.9 μM).

    4. Combinatorial Pharmacologic Effects of Gemcitabine and its Metabolite dFdU (pages 457–464)

      Prof. Alexey Benyumov, Prof. Vadim J. Gurvich, Dr. Lev G. Lis, Brent W. Williams and Prof. Mark N. Kirstein

      Article first published online: 30 JAN 2011 | DOI: 10.1002/cmdc.201000447

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      Conditional pharmacology: An improved synthetic and purification strategy was implemented to produce dFdU (80 % yield; >95 % purity). The biological activity of dFdU (alone and in combination with gemcitabine to mimic concurrent pharmacokinetic exposure) was tested using zebrafish embryo screens and human breast and lung cancer cell lines. The data demonstrate that the anticancer activity of dFdU is cell-type dependent.

    5. Biodistribution and Photodynamic Efficacy of a Water-Soluble, Stable, Halogenated Bacteriochlorin against Melanoma (pages 465–475)

      Dr. Janusz M. Dąbrowski, Prof. Krystyna Urbanska, Prof. Luis G. Arnaut, Prof. Mariette M. Pereira, Dr. Artur R. Abreu, Prof. Sérgio Simões and Prof. Grażyna Stochel

      Article first published online: 24 JAN 2011 | DOI: 10.1002/cmdc.201000524

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      Light relief: The extraordinary spectroscopic and photochemical properties of a water-soluble, stable, NIR absorbing, chlorinated bacteriochlorin and its high ROS yields are associated with melanoma tumor selectivity. Additionally, the favorable biodistribution contributes to a remarkable PDT against melanoma.

    6. Bicyclic Substituted Hydroxyphenylmethanone Type Inhibitors of 17 β-Hydroxysteroid Dehydrogenase Type 1 (17 β-HSD1): The Role of the Bicyclic Moiety (pages 476–487)

      Alexander Oster, Tobias Klein, Claudia Henn, Ruth Werth, Dr. Sandrine Marchais-Oberwinkler, Dr. Martin Frotscher and Prof. Dr. Rolf W. Hartmann

      Article first published online: 17 FEB 2011 | DOI: 10.1002/cmdc.201000457

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      17 β-HSD1 inhibition is a promising strategy for the treatment of estrogen-dependent diseases like breast cancer and endometriosis. Modifications on the bicyclic moiety in bicyclic substituted hydroxyphenylmethanones led to sulphonamide derivatives with high inhibitory activity (IC50=12 nM), remarkable selectivity, and good metabolic stability.

    7. Discovery of Isoerianin Analogues as Promising Anticancer Agents (pages 488–497)

      Dr. Samir Messaoudi, Dr. Abdallah Hamze, Dr. Olivier Provot, Bret Tréguier, Dr. Jordi Rodrigo De Losada, Dr. Jérôme Bignon, Dr. Jian-Miao Liu, Dr. Joanna Wdzieczak-Bakala, Sylviane Thoret, Dr. Joëlle Dubois, Prof. Jean-Daniel Brion and Dr. Mouad Alami

      Article first published online: 14 JAN 2011 | DOI: 10.1002/cmdc.201000456

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      Breaking the cell cycle: We studied the anticancer activity of a series of new isoerianin derivatives bearing modifications at the A and B rings. Isoerianin was selected as a lead compound for its high antitumor activity.

    8. Rational Design, Synthesis and Pharmacological Evaluation of the (2R)- and (2S)-Stereoisomers of 3-(2-Carboxypyrrolidinyl)-2-methyl Acetic Acid as Ligands for the Ionotropic Glutamate Receptors (pages 498–504)

      Julie L. Rasmussen, Dr. Morten Storgaard, Prof. Darryl S. Pickering and Prof. Lennart Bunch

      Article first published online: 25 JAN 2011 | DOI: 10.1002/cmdc.201000543

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      Mind blowing! Glutamate analogues (shown in yellow and orange) were designed as hybrid structures of kainic acid, CPAA (type code) and SYM2081 (green). Pharmacological evaluation revealed that one stereoisomer showed a subtype selectivity profile with low micromolar affinity for GluK1 and GluK3 and a 10- to 15-fold lower affinity for GluK2. The other stereoisomer displayed full selectivity for the KA over AMPA and NMDA receptors.

    9. Revealing Atropisomer Axial Chirality in Drug Discovery (pages 505–513)

      Dr. Steven R. LaPlante, Dr. Paul J. Edwards, Dr. Lee D. Fader, Dr. Araz Jakalian and Dr. Oliver Hucke

      Article first published online: 5 JAN 2011 | DOI: 10.1002/cmdc.201000485

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      Uncovering stealth chirality: An often overlooked source of chirality is atropisomerism, which results from slow rotation along a bond axis as a result of steric hindrance and/or electronic factors. A combination of strategies is introduced to flag compounds with atropisomeric properties, and a categorization scheme helps to foresee potential development plans.

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      Thiazolidinedione-Based PI3Kα Inhibitors: An Analysis of Biochemical and Virtual Screening Methods (pages 514–522)

      Jo-Anne Pinson, Dr. Oleg Schmidt-Kittler, Dr. Jiuxiang Zhu, Dr. Ian G. Jennings, Prof. Kenneth W. Kinzler, Prof. Bert Vogelstein, Dr. David K. Chalmers and Prof. Philip E. Thompson

      Article first published online: 4 JAN 2011 | DOI: 10.1002/cmdc.201000467

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      The power of computers: A series of compounds were assessed as PI3Kα inhibitors and the results compared to binding calculated in silico. Using reported PI3Kγ and PI3Kδ structures as a template, docking was able to identify the majority of potent inhibitors from a decoy set of 1000 compounds. The apo-form of PI3Kα gave poor results, but a homology model of PI3Kα built from PI3Kδ and incorporating induced-fit optimization yielded better results.

    11. Nitrooxyacyl Derivatives of Salicylic Acid: Aspirin-Like Molecules that Covalently Inactivate Cyclooxygenase-1 (pages 523–530)

      Prof. Dr. Clara Cena, Dr. Paolo Tosco, Dr. Elisabetta Marini, Dr. Loretta Lazzarato, Prof. Dr. Marco Piccinini, Dr. Cristina Ramondetti, Dr. Elisa Lupino, Prof. Roberta Fruttero and Prof. Alberto Gasco

      Article first published online: 5 JAN 2011 | DOI: 10.1002/cmdc.201000397

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      Blocks for COX: A recently described series of gastrosparing nitrooxyacyl derivatives of salicylic acid, endowed with aspirin-like anti-inflammatory and platelet anti-aggregatory properties, have been proven to act as covalent, irreversible inhibitors of cyclooxygenase-1 (COX-1).

    12. Synthesis, Receptor Binding, and CNS Pharmacological Studies of New Thyrotropin-Releasing Hormone (TRH) Analogues (pages 531–543)

      Dr. Vikramdeep Monga, Chhuttan L. Meena, Satyendra Rajput, Chandrashekhar Pawar, Dr. Shyam S. Sharma, Dr. Xinping Lu, Dr. Marvin C. Gershengorn and Prof. Rahul Jain

      Article first published online: 7 FEB 2011 | DOI: 10.1002/cmdc.201000481

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      Neuroprotective peptides: Four new series of thyrotropin-releasing hormone (TRH) analogues with modifications at the N-terminus pGlu and central His residues were synthesized using solid- and solution-phase peptide synthesis protocols. The analogues were evaluated in cells as agonists at TRH-R1 and TRH-R2 and in mice for analeptic and anticonvulsant activities.

    13. 1-(3-Biaryloxy-2-oxopropyl)indole-5-carboxylic Acids and Related Compounds as Dual Inhibitors of Human Cytosolic Phospholipase A2α and Fatty Acid Amide Hydrolase (pages 544–549)

      Stefan Zahov, Dr. Andreas Drews, Dr. Mark Hess, Alwine Schulze Elfringhoff and Prof. Dr. Matthias Lehr

      Article first published online: 21 JAN 2011 | DOI: 10.1002/cmdc.201000473

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      Dual inhibitors: Cytosolic phospholipase A2α (cPLA2α) and fatty acid amide hydrolase (FAAH) have both emerged as attractive targets for the development of analgesic and anti-inflammatory drugs. Herein we describe the inhibition data for a series of heteroaryl-substituted propane-2-ones against these two enzymes.

    14. Design and Synthesis of Novel Cyclooxygenase-1 Inhibitors as Analgesics: 5-Amino-2-ethoxy-N-(substituted-phenyl)benzamides (pages 550–560)

      Ryosuke Fukai, Xiaoxia Zheng, Kazunori Motoshima, Dr. Akihiro Tai, Dr. Futoshi Yazama and Dr. Hiroki Kakuta

      Article first published online: 7 JAN 2011 | DOI: 10.1002/cmdc.201000462

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      COX-1 blockers of a different color: N-(4-Aminophenyl)-4-trifluoromethylbenzamide (TFAP), a COX-1 inhibitor, exhibits an analgesic effect without causing gastric damage. However, this compound causes reddish purple coloration of urine, and has an analgesic effect less potent than that of indomethacin. Herein we describe our study of 4- and 5-amino-2-alkoxy-N-phenylbenzamide scaffolds, designed from the structures of TFAP and parsalmide, known analgesic COX-1 inhibitors.

    15. Synthesis and Radioprotective Properties of Pulvinic Acid Derivatives (pages 561–569)

      Dr. Antoine Le Roux, Dr. Stéphane Meunier, Dr. Thierry Le Gall, Jean-Marc Denis, Dr. Pierre Bischoff and Dr. Alain Wagner

      Article first published online: 18 JAN 2011 | DOI: 10.1002/cmdc.201000391

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      In pulvinic we trust? Norbadione A, a naturally occurring pulvinic acid, is known to exhibit radioprotective activity. We synthesized several hydrophilic derivatives and tested their radioprotective efficacy in cell cultures. Excellent protection and cell proliferation was observed several days following strong X-ray irradiation, which suggests that pulvinic acid derivatives are a novel class of radioprotecting agents worth further evaluation.

  10. Book Review

    1. Top of page
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    3. Inside Cover
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    6. Author Profile
    7. Minireview
    8. Essay
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    1. Multi-Drug Resistance in Cancer. Edited by Jun Zhou. (page 570)

      Prof. Dr. Rolf W. Hartmann

      Article first published online: 7 DEC 2010 | DOI: 10.1002/cmdc.201000501

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      Humana Press, New York 2010. xii+492 pp., hardcover $ 110.00.—ISBN 978-1-60761-415-9

  11. Preview

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Graphical Abstract
    5. News
    6. Author Profile
    7. Minireview
    8. Essay
    9. Communications
    10. Full Papers
    11. Book Review
    12. Preview
    1. Preview: ChemMedChem 4/2011 (page 571)

      Article first published online: 1 MAR 2011 | DOI: 10.1002/cmdc.201190009

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