ChemMedChem

Cover image for Vol. 9 Issue 3

Special Issue: Epigenetics & Drug Discovery

March 2014

Volume 9, Issue 3

Pages 413–670

  1. Cover Pictures

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. News
    6. Concept
    7. Reviews
    8. Minireviews
    9. Communications
    10. Full Papers
    1. You have free access to this content
      Cover Picture: A Chimeric SERM–Histone Deacetylase Inhibitor Approach to Breast Cancer Therapy (ChemMedChem 3/2014) (page 413)

      Hitisha K. Patel, Marton I. Siklos, Hazem Abdelkarim, Emma L. Mendonca, Aditya Vaidya, Dr. Pavel A. Petukhov and Dr. Gregory R. J. Thatcher

      Version of Record online: 25 FEB 2014 | DOI: 10.1002/cmdc.201490005

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      The front cover picture shows a novel hybrid SERMostat that acts as both a class I histone deacetylase (HDAC) inhibitor and a selective estrogen receptor modulator (SERM). A combinatorial therapy using an HDAC inhibitor and antiestrogen drug is currently being tested in clinical trials for the treatment of ER([BOND]) breast cancer, since HDAC inhibitors are proposed to increase transcription of ER (blue arrow). Based on this concept, SERMostats were designed with computational guidance and evaluated for their activity against ER([BOND]) breast cancer cells. The SERMostats showed increased efficacy compared with the combinatorial treatment using the parent SERM and HDAC inhibitor. For further details, see the Full Paper by Gregory R. J. Thatcher et al. on p. 602 ff.

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      Inside Cover: A Chemical Tool for In Vitro and In Vivo Precipitation of Lysine Methyltransferase G9a (ChemMedChem 3/2014) (page 414)

      Kyle D. Konze, Dr. Samantha G. Pattenden, Dr. Feng Liu, Dr. Dalia Barsyte-Lovejoy, Dr. Fengling Li, Dr. Jeremy M. Simon, Prof. Dr. Ian J. Davis, Prof. Dr. Masoud Vedadi and Prof. Dr. Jian Jin

      Version of Record online: 25 FEB 2014 | DOI: 10.1002/cmdc.201490006

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      The inside cover picture shows chem-ChIP, a method to examine occupancy of the lysine methyltranferase G9a on chromatin. UNC0965 (green) bridges streptavidin-coupled magnetic beads (blue and yellow) and G9a (magenta). UNC0965 is cell permeable, which gives chem-ChIP a distinct advantage over traditional in vitro antibody ChIP. For further details, see the Communication by Jian Jin et al. on p. 549 ff.

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      Back Cover: The Effect of Various Zinc Binding Groups on Inhibition of Histone Deacetylases 1–11 (ChemMedChem 3/2014) (page 672)

      Dr. Andreas S. Madsen, Helle M. E. Kristensen, Gyrithe Lanz and Prof. Christian A. Olsen

      Version of Record online: 25 FEB 2014 | DOI: 10.1002/cmdc.201490009

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      The back cover picture shows coordination of a novel silanediol histone deacetylase (HDAC) inhibitor to a Zn2+ atom in the active site of a human HDAC enzyme. The equilibrium between keto and hydrated forms of a structurally related trifluoromethyl-ketone-containing inhibitor is also shown. The compounds are part of an array of inhibitors, which was synthesized and profiled for their potencies against recombinant human HDACs 1[BOND]11. For further details, see the Full Paper by Christian A. Olsen et al. on p. 614 ff.

  2. Editorial

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. News
    6. Concept
    7. Reviews
    8. Minireviews
    9. Communications
    10. Full Papers
    1. You have free access to this content
      Targeting Epigenetics in Drug Discovery (pages 415–417)

      Prof. Antonello Mai

      Version of Record online: 25 FEB 2014 | DOI: 10.1002/cmdc.201400084

  3. Graphical Abstract

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. News
    6. Concept
    7. Reviews
    8. Minireviews
    9. Communications
    10. Full Papers
    1. You have free access to this content
  4. News

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. News
    6. Concept
    7. Reviews
    8. Minireviews
    9. Communications
    10. Full Papers
  5. Concept

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. News
    6. Concept
    7. Reviews
    8. Minireviews
    9. Communications
    10. Full Papers
    1. An Update on Lysine Deacylases Targeting the Expanding “Acylome” (pages 434–437)

      Prof. Christian A. Olsen

      Version of Record online: 20 DEC 2013 | DOI: 10.1002/cmdc.201300421

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      The updated concept! Recently, novel acyl groups have been identified as post-translational modifications to lysine side chains in diverse proteins. Some of these marks appear to be regulated by HDACs and/or sirtuins. Here, these new developments are summarized and discussed with emphasis on the connection to lysine deacylase enzymes including new assays and inhibitors.

  6. Reviews

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. News
    6. Concept
    7. Reviews
    8. Minireviews
    9. Communications
    10. Full Papers
    1. Bromodomains and Their Pharmacological Inhibitors (pages 438–464)

      Dr. Daniel Gallenkamp, Dr. Kathy A. Gelato, Dr. Bernard Haendler and Dr. Hilmar Weinmann

      Version of Record online: 4 FEB 2014 | DOI: 10.1002/cmdc.201300434

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      A safe BET: Bromodomains are an exciting target class for therapeutic intervention. Highly potent and selective small-molecule modulators with drug-like properties have been identified recently for several bromodomains. Herein we provide an overview of the most recent developments in this field, with a focus on the biology of selected bromodomain proteins on the one hand, and on reported pharmacological inhibitors on the other, including recent examples from the patent literature.

    2. Mind the Methyl: Methyllysine Binding Proteins in Epigenetic Regulation (pages 466–483)

      Tobias Wagner, Dr. Dina Robaa, Prof. Dr. Wolfgang Sippl and Prof. Dr. Manfred Jung

      Version of Record online: 21 JAN 2014 | DOI: 10.1002/cmdc.201300422

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      Avid readers: Methyllysine binding proteins recognize different levels of lysine methylation in histones and mediate the signaling events induced by histone methylation. These binding proteins are therefore called readers of the epigenetic code. Herein we review the current literature on the structure and biology of methyllysine binding proteins, especially with regard to their potential as drug targets. Available inhibitors that block the interaction of methylated histones with their binding proteins are presented.

    3. Epigenetic Molecular Recognition: A Biomolecular Modeling Perspective (pages 484–494)

      Nadeem A. Vellore and Prof. Riccardo Baron

      Version of Record online: 12 FEB 2014 | DOI: 10.1002/cmdc.201300510

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      Epigenetic research has progressed rapidly, and epigenetic processes are known to be crucial to the modulation of various diseases. However, knowledge of the molecular mechanisms that underlie epigenetic regulation remains in its infancy, and is currently too limited to allow rapid development of molecular probes. Computational studies hold great promise to aid drug development. Given the steady increase in supercomputing power and algorithm accuracy, modeling and molecular simulations are now becoming an integral part of drug development.

  7. Minireviews

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. News
    6. Concept
    7. Reviews
    8. Minireviews
    9. Communications
    10. Full Papers
    1. Synthetic Chromatin Approaches To Probe the Writing and Erasing of Histone Modifications (pages 495–504)

      Beat Fierz

      Version of Record online: 4 FEB 2014 | DOI: 10.1002/cmdc.201300487

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      How the editors tick: Enzymes that write and erase histone modifications are key for chromatin regulation and are involved in diseases, rendering them as promising drug targets. Recently, several strategies for the production of synthetic chromatin were developed. Herein examples are highlighted where the use of synthetic chromatin has provided unprecedented insight into the enzymatic and regulatory mechanisms of writer and eraser enzymes.

    2. The Role of Long Noncoding RNAs in the Epigenetic Control of Gene Expression (pages 505–510)

      Dr. Mariangela Morlando, Dr. Monica Ballarino, Prof. Alessandro Fatica and Prof. Irene Bozzoni

      Version of Record online: 2 FEB 2014 | DOI: 10.1002/cmdc.201300569

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      Long noncoding RNAs (lncRNAs) are a newly identified class of transcripts that regulate gene expression. In particular, many of these lncRNAs are involved in epigenetic regulation, acting as guides for activating or repressing chromatin modifier complexes towards specific genomic loci, and these roles are reviewed here.

    3. Lysine Deacetylase (KDAC) Regulatory Pathways: an Alternative Approach to Selective Modulation (pages 511–522)

      Prof. Michael W. Van Dyke

      Version of Record online: 21 JAN 2014 | DOI: 10.1002/cmdc.201300444

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      Target acquired: Protein lysine deacetylases (KDACs) are valid therapeutic targets for several human diseases, including diabetes, neurodegenerative disorders and cancer. However, achieving KDAC isoform specificity with small molecules directed against enzyme active sites has proven difficult. An alternative approach, utilizing endogenous regulatory pathways, offers the promise of not only isoform but also context and cell type specificity for the pharmacologic modulation of KDAC activity.

    4. Towards Selective Inhibition of Histone Deacetylase Isoforms: What Has Been Achieved, Where We Are and What Will Be Next (pages 523–536)

      Dr. Florian Thaler and Dr. Ciro Mercurio

      Version of Record online: 16 DEC 2013 | DOI: 10.1002/cmdc.201300413

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      Finding the differences: Histone deacetylases (HDACs) have been intensively studied targets for the treatment of cancer or other diseases for almost two decades, resulting in over 20 inhibitors in clinical studies and two compounds with market approval. However, the development of isoform-selective compounds has proven to be a difficult task, and several insights were gained only recently. This Minireview focuses on these recent biology and medicinal chemistry efforts.

  8. Communications

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. News
    6. Concept
    7. Reviews
    8. Minireviews
    9. Communications
    10. Full Papers
    1. Rational Design of Substrate-Based Multivalent Inhibitors of the Histone Acetyltransferase Tip60 (pages 537–541)

      Dr. Chao Yang, Liza Ngo and Prof. Dr. Y. George Zheng

      Version of Record online: 20 JAN 2014 | DOI: 10.1002/cmdc.201300478

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      Tipping your HAT! Substrate-based multivalent inhibitors of the histone acetyltransferase Tip60 were designed with the incorporation of multiple binding motifs. The catalytic domain of Tip60 was shown to recognize methyl-lysine marks. The designed inhibitors are useful probes for mechanistic investigation of this potential drug target.

    2. Quinoline-Based p300 Histone Acetyltransferase Inhibitors with Pro-apoptotic Activity in Human Leukemia U937 Cells (pages 542–548)

      Dr. Alessia Lenoci, Dr. Stefano Tomassi, Dr. Mariarosaria Conte, Dr. Rosaria Benedetti, Dr. Veronica Rodriguez, Dr. Simone Carradori, Prof. Daniela Secci, Dr. Sabrina Castellano, Prof. Gianluca Sbardella, Dr. Patrizia Filetici, Prof. Ettore Novellino, Prof. Lucia Altucci, Dr. Dante Rotili and Prof. Antonello Mai

      Version of Record online: 6 FEB 2014 | DOI: 10.1002/cmdc.201300536

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      Chemical space exploration! Preliminary exploration of the chemical space around the quinoline scaffold previously reported by us as HAT inhibitor acting as pro-apoptotic agent in human leukemia U937 cells at 0.5-1 mM, allowed us to obtain C2- or C6-substituted quinolines with improved potencies of >3-fold in enzyme assays and >10-fold at cellular level. Next investigation of the quinoline chemical space is required to obtain more efficient compounds.

    3. A Chemical Tool for In Vitro and In Vivo Precipitation of Lysine Methyltransferase G9a (pages 549–553)

      Kyle D. Konze, Dr. Samantha G. Pattenden, Dr. Feng Liu, Dr. Dalia Barsyte-Lovejoy, Dr. Fengling Li, Dr. Jeremy M. Simon, Prof. Dr. Ian J. Davis, Prof. Dr. Masoud Vedadi and Prof. Dr. Jian Jin

      Version of Record online: 17 JAN 2014 | DOI: 10.1002/cmdc.201300450

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      Pull it down! A biotinylated inhibitor of lysine methyltransferase G9a (UNC0965, green) is conjugated to immobilized streptavidin (blue) for “chemiprecipitation” of G9a protein (purple) cross-linked to chromatin. This chemical inhibitor-based chromatin immunoprecipitation (chem-ChIP) method is useful for the determination of G9a occupancy on chromatin in an in vivo setting.

    4. Non-radioactive Protein Lysine Methyltransferase Microplate Assay Based on Reading Domains (pages 554–559)

      Dr. Srikanth Kudithipudi, Denis Kusevic and Prof. Dr. Albert Jeltsch

      Version of Record online: 13 MAY 2013 | DOI: 10.1002/cmdc.201300111

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      Readout with reading domains: We describe a novel non-radioactive protein lysine methyltransferase microplate assay that uses reading domains for the detection of peptide methylation and demonstrate its application in the investigation of SUV39H1 inhibition by chaetocin.

    5. Toward Drug Repurposing in Epigenetics: Olsalazine as a Hypomethylating Compound Active in a Cellular Context (pages 560–565)

      Oscar Méndez-Lucio, Jeremy Tran, Dr. José L. Medina-Franco, Dr. Nathalie Meurice and Dr. Mark Muller

      Version of Record online: 31 JAN 2014 | DOI: 10.1002/cmdc.201300555

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      A bold new direction: Using a novel DNA methylation reprogramming system that operates in the context of living cells, we report the characterization of olsalazine, an anti-inflammatory drug, as a new DNA hypomethylating agent. The results come from cell-based assays that monitor the activity of DNA methyltransferase (DNMT) in living cells.

    6. You have full text access to this OnlineOpen article
      A Cell-Permeable Ester Derivative of the JmjC Histone Demethylase Inhibitor IOX1 (pages 566–571)

      Rachel Schiller, Dr. Giuseppe Scozzafava, Dr. Anthony Tumber, Dr. James R. Wickens, Jacob T. Bush, Dr. Ganesha Rai, Dr. Clarisse Lejeune, Dr. Hwanho Choi, Dr. Tzu-Lan Yeh, Mun Chiang Chan, Dr. Bryan T. Mott, Dr. James S. O. McCullagh, Dr. David J. Maloney, Prof. Christopher J. Schofield and Dr. Akane Kawamura

      Version of Record online: 6 FEB 2014 | DOI: 10.1002/cmdc.201300428

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      A new tool in epigenetics: Ester derivatives of 5-carboxy-8-hydroxyquinoline (IOX1), a broad-spectrum inhibitor of 2OG oxygenases, including the JmjC demethylases, were evaluated for their in vitro activity against enzymes and in cell-based assays. Results showed a dependence of JmjC inhibition on the aliphatic chain length, with the n-octyl ester showing both enhanced cellular potency (30-fold) and improved selectivity over the parent IOX1.

  9. Full Papers

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. News
    6. Concept
    7. Reviews
    8. Minireviews
    9. Communications
    10. Full Papers
    1. Structured Water Molecules in the Binding Site of Bromodomains Can Be Displaced by Cosolvent (pages 573–579)

      Danzhi Huang, Emanuele Rossini, Sandra Steiner and Prof. Amedeo Caflisch

      Version of Record online: 26 JUN 2013 | DOI: 10.1002/cmdc.201300156

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      Virtual domains! Using molecular dynamics (MD) simulations, the importance of structured water molecules in bromodomains, an important class of emerging drug targets, was investigated. The results show that structured water molecules in the acetyl-lysine binding site can be replaced by co- solvent molecules. This result has important implications for the design of selective drugs against bromodomain targets.

    2. Naphthyridines as Novel BET Family Bromodomain Inhibitors (pages 580–589)

      Dr. Olivier Mirguet, Yann Lamotte, Chun-wa Chung, Dr. Paul Bamborough, Delphine Delannée, Dr. Anne Bouillot, Dr. Françoise Gellibert, Gael Krysa, Antonia Lewis, Dr. Jason Witherington, Pascal Huet, Yann Dudit, Dr. Lionel Trottet and Dr. Edwige Nicodeme

      Version of Record online: 2 SEP 2013 | DOI: 10.1002/cmdc.201300259

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      Place your BET! Naphthyridine derivatives were designed and synthesized as potent inhibitors of the BET bromodomain family with good cell activity and oral pharmacokinetic parameters. X-ray crystal structures were solved and quantum mechanical calculations were used to explain the higher affinity of the 1,5-isomer over the others. The best compounds were progressed in a mice model of inflammation and exhibited dose-dependent anti-inflammatory pharmacology.

    3. You have full text access to this OnlineOpen article
      Design, Synthesis and Biological Evaluation of 4-Amino-N-(4-aminophenyl)benzamide Analogues of Quinoline-Based SGI-1027 as Inhibitors of DNA Methylation (pages 590–601)

      Elodie Rilova, Alexandre Erdmann, Christina Gros, Véronique Masson, Yannick Aussagues, Valérie Poughon-Cassabois, Arumugam Rajavelu, Prof. Albert Jeltsch, Yoann Menon, Natacha Novosad, Dr. Jean-Marc Gregoire, Dr. Stéphane Vispé, Philippe Schambel, Dr. Fréderic Ausseil, François Sautel, Dr. Paola B. Arimondo and Dr. Frédéric Cantagrel

      Version of Record online: 13 FEB 2014 | DOI: 10.1002/cmdc.201300420

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      Ep–(igenet)–ic! Guided by modeling studies, derivatives of the known DNA methyltransferase (DNMT) inhibitor SGI-1027 were designed, synthesized and evaluated. Structure–activity relationships were derived from the results, leading to the identification of derivatives with improved potency and potential for further development.

    4. A Chimeric SERM–Histone Deacetylase Inhibitor Approach to Breast Cancer Therapy (pages 602–613)

      Hitisha K. Patel, Marton I. Siklos, Hazem Abdelkarim, Emma L. Mendonca, Aditya Vaidya, Dr. Pavel A. Petukhov and Dr. Gregory R. J. Thatcher

      Version of Record online: 16 AUG 2013 | DOI: 10.1002/cmdc.201300270

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      Two in one: The combination of HDAC inhibition and selective estrogen receptor modulation caused time-dependent killing of breast cancer cells. A hybrid molecule, acting as HDAC inhibitor and selective estrogen receptor modulator (SERM), has potential, but can both activities be retained in killing ER (−) breast cancer cells?

    5. The Effect of Various Zinc Binding Groups on Inhibition of Histone Deacetylases 1–11 (pages 614–626)

      Dr. Andreas S. Madsen, Helle M. E. Kristensen, Gyrithe Lanz and Prof. Christian A. Olsen

      Version of Record online: 27 DEC 2013 | DOI: 10.1002/cmdc.201300433

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      Zinc about it: We synthesized a series of compounds containing diverse zinc binding motifs and profiled their inhibitory activity against the 11 human histone deacetylases (HDAC1–11). From the results, we discovered silanediol to be a novel functionality with potential as a suitable design element in the preparation of new HDAC inhibitors. Compounds of this type show promise as future drug leads.

    6. Discovery of Potent HDAC Inhibitors Based on Chlamydocin with Inhibitory Effects on Cell Migration (pages 627–637)

      Shimiao Wang, Dr. Xiaohui Li, Yingdong Wei, Zhilong Xiu and Dr. Norikazu Nishino

      Version of Record online: 27 NOV 2013 | DOI: 10.1002/cmdc.201300372

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      Keeping cells in their place: Inhibition of cell migration by improved HDAC inhibitory activity was realized by the design and synthesis of highly effective HDAC inhibitors. The interactions between target compounds and HDAC4 were predicted by docking analyses. Cell migration was completely inhibited after treatment with compound 1 b.

    7. Histone Deacetylase Inhibitors with Enhanced Enzymatic Inhibition Effects and Potent in vitro and in vivo Antitumor Activities (pages 638–648)

      Dr. Lei Zhang, Dr. Yingjie Zhang, Prof. C. James Chou, Dr. Elizabeth S. Inks, Dr. Xuejian Wang, Xiaoguang Li, Jinning Hou and Prof. Wenfang Xu

      Version of Record online: 12 NOV 2013 | DOI: 10.1002/cmdc.201300297

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      Lead the way! A series of potent histone deacetylase inhibitors were developed based on structural modification of a previously reported lead compound. Aromatic R groups were introduced to interact with hydrophobic residues in a of the active site of HDAC2. These modifications gave rise to compounds with improved activities in an enzymatic inhibition assay. Moreover, several representative derivatives displayed potent antitumor activities in the in vitro and in vivo studies.

    8. Lactam-Based HDAC Inhibitors for Anticancer Chemotherapy: Restoration of RUNX3 by Posttranslational Modification and Epigenetic Control (pages 649–656)

      Dr. Misun Cho, Dr. Eunhyun Choi, Jae Hyun Kim, Dr. Hwan Kim, Prof. Hwan Mook Kim, Prof. Jang Ik Lee, Prof. Ki-Chul Hwang, Dr. Hyun-Jung Kim and Prof. Gyoonhee Han

      Version of Record online: 2 DEC 2013 | DOI: 10.1002/cmdc.201300393

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      Keep it RUNning! Epigenetic and posttranslational stabilization of RUNX3 is regulated by HDACs, leading to cancer suppression. Our γ-lactam-based HDAC inhibitors restored RUNX3 stability by epigenetic and posttranslational regulation. We set selection criteria for identifying potent HDAC inhibitors and found a novel therapeutic agent for gastric cancer.

    9. Design, Synthesis, and Biological Activity of NCC149 Derivatives as Histone Deacetylase 8-Selective Inhibitors (pages 657–664)

      Prof. Takayoshi Suzuki, Nobusuke Muto, Dr. Masashige Bando, Dr. Yukihiro Itoh, Ayako Masaki, Dr. Masaki Ri, Yosuke Ota, Prof. Hidehiko Nakagawa, Prof. Shinsuke Iida, Prof. Katsuhiko Shirahige and Prof. Naoki Miyata

      Version of Record online: 8 JAN 2014 | DOI: 10.1002/cmdc.201300414

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      Better and better: A series of NCC149 derivatives bearing various aromatic linkers were designed and synthesized as histone deacetylase 8 (HDAC8)-selective inhibitors. Four compounds showed HDAC8 inhibitory activity similar to that of NCC149, one displayed HDAC8 selectivity superior to NCC149, and another suppressed the growth of T-cell lymphoma cells more potently than NCC149. These findings are useful for further development of HDAC8-selective inhibitors.

    10. Synthesis, Antimalarial Properties, and SAR Studies of Alkoxyurea-Based HDAC Inhibitors (pages 665–670)

      Dr. Finn K. Hansen, Dr. Tina S. Skinner-Adams, Sandra Duffy, Linda Marek, Subathdrage D. M. Sumanadasa, Krystina Kuna, Dr. Jana Held, Prof. Dr. Vicky M. Avery, Assoc. Prof. Dr. Katherine T. Andrews and Prof. Dr. Thomas Kurz

      Version of Record online: 4 FEB 2014 | DOI: 10.1002/cmdc.201300469

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      Antimalarial sweet sixteen: A mini-library of 16 HDAC inhibitors containing an alkoxyurea connecting-unit linker region was evaluated for antiplasmodial activity. Some compounds revealed potent activity against asexual blood stages and moderate activity against sexual-stage parasites. Selected compounds were shown to cause hyperacetylation of P. falciparum histones.

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