ChemMedChem

Cover image for Vol. 7 Issue 2

February 6, 2012

Volume 7, Issue 2

Pages 177–335

  1. Cover Picture

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Review
    9. Communications
    10. Full Papers
    11. Book Review
    12. Preview
    1. Cover Picture: Engineering and Functionalization of the Disulfide-Constrained Miniprotein Min-23 as a Scaffold for Diagnostic Application (ChemMedChem 2/2012) (page 177)

      Frederic Zoller, Thimon Schwaebel, Dr. Annette Markert, Prof. Dr. Uwe Haberkorn and Dr. Walter Mier

      Version of Record online: 27 JAN 2012 | DOI: 10.1002/cmdc.201290000

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      The cover picture shows the concept of disulfide-constrained miniproteins as alternatives to antibodies for the development of new chemical entities. Their structural characteristics and beneficial pharmacokinetic profile highlight this peptide format for the engineering of novel diagnostic imaging agents. Here, the chemical synthesis of the scaffold Min-23 and its functionalization for in vitro and in vivo applications are described. For more details, see the Full Paper by Walter Mier et al. on p. 237 ff.

  2. Inside Cover

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Review
    9. Communications
    10. Full Papers
    11. Book Review
    12. Preview
    1. Inside Cover: RAFT-Derived Polymer–Drug Conjugates: Poly(hydroxypropyl methacrylamide) (HPMA)–7-Ethyl-10-hydroxycamptothecin (SN-38) Conjugates (ChemMedChem 2/2012) (page 178)

      Dr. Charlotte C. Williams, Dr. San H. Thang, Tina Hantke, Uwe Vogel, Prof. Dr. Peter H. Seeberger, Dr. John Tsanaktsidis and Dr. Bernd Lepenies

      Version of Record online: 27 JAN 2012 | DOI: 10.1002/cmdc.201290001

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      The inside cover picture shows how RAFT polymerisation technology can be used to construct well- defined drug–polymer conjugates by growing a polymer of desired length, composition and architecture from a specific point of the drug molecule. RAFT is a powerful alternative to PEGylation that provides medicinal chemists with a “second chance” to adjust the solubility and bioavailability of bioactive molecules. For more details, see the Full Paper by J. Tsanaktsidis, B. Lepenies et al. on p. 281 ff.

  3. Back Cover

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Review
    9. Communications
    10. Full Papers
    11. Book Review
    12. Preview
    1. Back Cover: Discovery of Novel Stem Cell Mobilizers That Target the CXCR4 Receptor (ChemMedChem 2/2012) (page 336)

      Dr. Chien-Huang Wu, Dr. Chun-Ping Chang, Dr. Jen-Shin Song, Jiing-Jyh Jan, Ming-Chen Chou, Szu-Huei Wu, Kai-Chia Yeh, Dr. Ying-Chieh Wong, Chieh-Jui Hsieh, Dr. Chiung-Tong Chen, Tzu-Ting Kao, Dr. Su-Ying Wu, Ching-Fang Yeh, Dr. Chen-Tso Tseng, Dr. Yu-Sheng Chao and Dr. Kak-Shan Shia

      Version of Record online: 27 JAN 2012 | DOI: 10.1002/cmdc.201290005

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      The back cover picture shows a novel CXCR4-targeted antagonist blocking the SDF-1/CXCR4 interaction, resulting in mobilization of various stem cells, particularly the CD34+ cell type, from the bone marrow to the peripheral blood circulating system. Hematopoietic stem cells thus collected can be potentially applied to autologous transplantation to help cancer patients restore their immune system rapidly after undergoing chemo- or radiotherapy. For more details, see the Communication by Kak-Shan Shia et al. on p. 209 ff.

  4. Graphical Abstract

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Review
    9. Communications
    10. Full Papers
    11. Book Review
    12. Preview
    1. You have free access to this content
  5. News

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

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Review
    9. Communications
    10. Full Papers
    11. Book Review
    12. Preview
    1. M. Alami (page 193)

      Version of Record online: 13 DEC 2011 | DOI: 10.1002/cmdc.201100495

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      “When I was eighteen, I wanted to be … a doctor: “Where there is love of mankind, there is also love of the art of medicine” (Hippocrates).” This and more from Prof. Mouâd Alami can be found on page 193.

  7. Review

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Review
    9. Communications
    10. Full Papers
    11. Book Review
    12. Preview
    1. A Decade of the Human Genome Sequence—How Does the Medicinal Chemist Benefit? (pages 194–203)

      Dr. Andreas Brunschweiger and Prof. Jonathan Hall

      Version of Record online: 13 DEC 2011 | DOI: 10.1002/cmdc.201100498

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      Where are we now? Today genomics technologies are firmly embedded in the drug discovery process. Here, we describe how approaches, such as structural genomics and family-wide screening, which derived from the human genome sequencing project are being applied by medicinal chemists to discover potent and selective new drugs.

  8. Communications

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Review
    9. Communications
    10. Full Papers
    11. Book Review
    12. Preview
    1. A Synthetic C34 Trimer of HIV-1 gp41 Shows Significant Increase in Inhibition Potency (pages 205–208)

      Dr. Wataru Nomura, Chie Hashimoto, Aki Ohya, Dr. Kosuke Miyauchi, Dr. Emiko Urano, Dr. Tomohiro Tanaka, Dr. Tetsuo Narumi, Toru Nakahara, Dr. Jun A. Komano, Prof. Dr. Naoki Yamamoto and Prof. Dr. Hirokazu Tamamura

      Version of Record online: 13 JAN 2012 | DOI: 10.1002/cmdc.201100542

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      Supramolecular interference: A synthetic peptide mimetic of the trimeric form of gp41 showed significantly increased inhibitory activity against the HIV-1 fusion mechanism. This study demonstrates a useful strategy for the design of effective inhibitors against viral infections that proceed by membrane fusion with host cells.

      Corrected by:

      Corrigendum: Corrigendum: A Synthetic C34 Trimer of HIV-1 gp41 Shows Significant Increase in Inhibition Potency

      Vol. 7, Issue 4, 546, Version of Record online: 27 MAR 2012

    2. Discovery of Novel Stem Cell Mobilizers That Target the CXCR4 Receptor (pages 209–212)

      Dr. Chien-Huang Wu, Dr. Chun-Ping Chang, Dr. Jen-Shin Song, Jiing-Jyh Jan, Ming-Chen Chou, Szu-Huei Wu, Kai-Chia Yeh, Dr. Ying-Chieh Wong, Chieh-Jui Hsieh, Dr. Chiung-Tong Chen, Tzu-Ting Kao, Dr. Su-Ying Wu, Ching-Fang Yeh, Dr. Chen-Tso Tseng, Dr. Yu-Sheng Chao and Dr. Kak-Shan Shia

      Version of Record online: 20 DEC 2011 | DOI: 10.1002/cmdc.201100525

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      Going mobile: Based on screening hit 1, a novel class of polyamine compounds, as represented by compound 8, were identified as potent and selective CXCR4 antagonists. CXCR4-targeted molecules, as demonstrated by the marketed AMD3100 and 8, are able to mobilize stem cells from bone marrow effectively and are expected to have broad utility in cell therapy and regenerative medicine.

    3. A Synthetic Lipid A Mimetic Modulates Human TLR4 Activity (pages 213–217)

      Dr. Matteo Piazza, Dr. Valentina Calabrese, Gaetana Damore, Roberto Cighetti, Prof. Theresa Gioannini, Prof. Jerrold Weiss and Prof. Francesco Peri

      Version of Record online: 2 DEC 2011 | DOI: 10.1002/cmdc.201100494

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      The sincerest form of flattery! A novel, symmetric lipid A mimetic (D1) formed by two glucose units linked through a 6-6' succinic diamide linker is active in modulating the activity of human TLR4. D1 inhibits endotoxin-stimulated TLR4 activation by inhibiting interaction of endotoxin with both receptors CD14 and MD-2 (associated to TLR4). D1 also has weak TLR4 agonist activity that makes it a promising lead compound for development as a vaccine adjuvant.

    4. Immunosuppressive Effects of Subglutinol Derivatives (pages 218–222)

      Won-Gil Lee, Woo-Seok Kim, Prof. Dr. Sung-Gyoo Park, Prof. Dr. Hyoungsu Kim, Prof. Dr. Jiyong Hong, Dr. Hyojin Ko and Prof. Dr. Yong-Chul Kim

      Version of Record online: 24 NOV 2011 | DOI: 10.1002/cmdc.201100409

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      More than herbal remedies: Subglutinols A and B, natural diterpenoid pyrone immunosuppressive agents, and their synthetic intermediates were assayed to assess their functional mechanisms of immune modulation. Subglutinol A and its methyl-γ-pyrone derivative (10) significantly suppressed interleukin-2 production (IC50) by different T cells, and also efficiently inhibited the T cell expression of activation markers, CD25 and CD69. These preliminary results suggest the subglutinol structure as a lead for the design of novel immunosuppressive agents.

    5. Design, Synthesis and Biological Evaluation of Noncovalent Inhibitors of Human CD38 NADase (pages 223–228)

      Dr. Yi Zhou, Kai Yiu Ting, Connie Mo Ching Lam, Anna Ka Yee Kwong, Jie Xia, Dr. Hongwei Jin, Dr. Zhenming Liu, Prof. Liangren Zhang, Prof. Hon Cheung Lee and Prof. Lihe Zhang

      Version of Record online: 3 JAN 2012 | DOI: 10.1002/cmdc.201100487

      Thumbnail image of graphical abstract

      Shoot the messenger! CD38 is a multifunctional enzyme responsible for the generation of calcium ion messengers. A structural optimization was carried out to develop noncovalent CD38 inhibitors based on hit compound S125 (top) (IC50=86 μM). The best compound inhibited CD38 NADase with an IC50 value of 4.7 μM (bottom). Molecular modeling was used to predict potentially important interactions between the inhibitor and enzyme.

    6. Remarkable Stability and Cytostatic Effect of a Quercetin Conjugate, 3,7-Bis-O-Pivaloxymethyl (POM) Quercetin (pages 229–232)

      Mi Kyoung Kim, Kwang-Su Park and Prof. Youhoon Chong

      Version of Record online: 18 NOV 2011 | DOI: 10.1002/cmdc.201100478

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      Stable conjugates: Two pivaloxymethyl (POM) groups were introduced at the 3- and 7-hydroxy groups of quercetin to provide a 3,7-bis-O-POM derivative (shown) with exceptional stability in cell culture media and efficient cellular uptake. Hydrolyzed to the 3-O-POM derivative in cytoplasm, the quercetin conjugate exhibits a significant cytostatic effect in various cancer cell lines.

    7. Application of Barluenga Boronic Coupling (BBC) to the Parallel Synthesis of Drug-like and Drug Fragment-like Molecules (pages 233–236)

      Shoko Nakagawa, Katie A. Bainbridge, Ken Butcher, Dr. Dave Ellis, Dr. Wolfgang Klute and Dr. Thomas Ryckmans

      Version of Record online: 7 NOV 2011 | DOI: 10.1002/cmdc.201100339

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      BBC news: C[BOND]C bond formation reactions are underused by medicinal chemists for the preparation of libraries of compounds with good drug-like (“rule-of-five”) and drug fragment-like (“rule-of-three”) properties. Herein we demonstrate the versatility of the Barluenga boronic coupling (BBC) for the preparation of small drug-like and drug fragment-like compounds in parallel.

  9. Full Papers

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Review
    9. Communications
    10. Full Papers
    11. Book Review
    12. Preview
    1. Engineering and Functionalization of the Disulfide-Constrained Miniprotein Min-23 as a Scaffold for Diagnostic Application (pages 237–247)

      Frederic Zoller, Thimon Schwaebel, Dr. Annette Markert, Prof. Dr. Uwe Haberkorn and Dr. Walter Mier

      Version of Record online: 23 DEC 2011 | DOI: 10.1002/cmdc.201100497

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      Small but smart: Miniproteins are scaffolds for the development of alternative non-immunoglobin binding entities. Their structural characteristics and excellent stability support the use of this peptide format for the engineering of novel diagnostic agents. Herein we present the total chemical synthesis of the disulfide-constrained scaffold Min-23 and its functionalization for in vitro and in vivo application.

    2. Experimental and Computational Active Site Mapping as a Starting Point to Fragment-Based Lead Discovery (pages 248–261)

      Dr. Jürgen Behnen, Helene Köster, Gerd Neudert, Dr. Tobias Craan, Dr. Andreas Heine and Prof. Gerhard Klebe

      Version of Record online: 23 DEC 2011 | DOI: 10.1002/cmdc.201100490

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      Small highly soluble molecules were soaked into various protein crystals to detect binding hot spots with respect to hydrophobic and hydrophilic properties. These hot spots were subjected to computational active site mapping with an approach using knowledge-based pair potentials to detect favorable binding positions for various atom types. Our findings confirm the central hypothesis of fragment-based lead discovery: binding poses, even of small probes, do not strongly deviate once a ligand is grown further into a binding site.

    3. Intermolecular and Intramolecular Hydrogen Bonds Involving Fluorine Atoms: Implications for Recognition, Selectivity, and Chemical Properties (pages 262–272)

      Dr. Claudio Dalvit and Dr. Anna Vulpetti

      Version of Record online: 19 JAN 2012 | DOI: 10.1002/cmdc.201100483

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      Analysis of hydrogen bonds involving fluorine found in small molecules listed in the Cambridge Structural Database (CSD) and in fluorinated natural products listed in the Protein Data Bank (PDB) identified a correlation between 19F NMR isotropic chemical shift and close F⋅⋅⋅H[BOND]X contacts (with X=N or O), highlighting the role of shielded fluorine atoms in protein recognition, selectivity and chemical properties. Based on these findings, novel chemical scaffolds for recognizing distinct structural motifs in proteins are proposed.

    4. Discovery and Characterization of Atropisomer PH-797804, a p38 MAP Kinase Inhibitor, as a Clinical Drug Candidate (pages 273–280)

      Dr. Li Xing, Dr. Balekudru Devadas, Dr. Rajesh V. Devraj, Dr. Shaun R. Selness, Dr. Huey Shieh, Dr. John K. Walker, Dr. Michael Mao, Dean Messing, Brian Samas, Dr. Jerry Z. Yang, Gary D. Anderson, Elizabeth G. Webb and Dr. Joseph B. Monahan

      Version of Record online: 15 DEC 2011 | DOI: 10.1002/cmdc.201100439

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      Restricted twist: The excellent selectivity and oral efficacy of PH-797804 (green, at top) in preclinical disease models make it a suitable candidate for interrogating the role of p38 kinase as a therapeutic target, in contrast to its inactive atropisomer (in blue). PH-797804 is currently under phase II clinical investigation for the treatment of several inflammation-mediated diseases.

    5. RAFT-Derived Polymer–Drug Conjugates: Poly(hydroxypropyl methacrylamide) (HPMA)–7-Ethyl-10-hydroxycamptothecin (SN-38) Conjugates (pages 281–291)

      Dr. Charlotte C. Williams, Dr. San H. Thang, Tina Hantke, Uwe Vogel, Prof. Dr. Peter H. Seeberger, Dr. John Tsanaktsidis and Dr. Bernd Lepenies

      Version of Record online: 5 DEC 2011 | DOI: 10.1002/cmdc.201100456

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      A life RAFT! A series of well-defined polymer–drug conjugates have been prepared to increase the bioavailability of the known cytotoxic drug 7-ethyl-10-hydroxycamptothecin (SN-38). Reversible addition–fragmentation chain transfer (RAFT) polymerisation was used to covalently and site-specifically append an N-(2-hydroxypropyl)methacrylamide (HPMA) polymer to SN-38. The poly-HPMA–SN-38 conjugates displayed excellent aqueous solubility, cytotoxic activity, and specificity for cancer cells.

    6. 3-Substituted 2-Phenylimidazo[2,1-b]benzothiazoles: Synthesis, Anticancer Activity, and Inhibition of Tubulin Polymerization (pages 292–300)

      Dr. Ahmed Kamal, Farheen Sultana, Dr. M. Janaki Ramaiah, Dr. Y. V. V. Srikanth, A. Viswanath, Chandan Kishor, Pranjal Sharma, Dr. S. N. C. V. L. Pushpavalli, Dr. Anthony Addlagatta and Dr. Manika Pal-Bhadra

      Version of Record online: 12 JAN 2012 | DOI: 10.1002/cmdc.201100511

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      Benefits of benzothiazoles: A series of substituted benzothiazoles were designed, synthesized, and evaluated for their anticancer activity and their capacity to block tubulin polymerization. Three have promising anticancer activity, while one compound effects cell-cycle arrest and inhibition of tubulin polymerization on par with combretastatin A-4. Modeling studies with the colchicine binding site gave insight into the SARs of these and other benzothiazole derivatives.

    7. Study of the Anticancer Properties of Tin(IV) Carboxylate Complexes on a Panel of Human Tumor Cell Lines (pages 301–310)

      Lourdes Rocamora-Reverte, Dr. Estefanía Carrasco-García, Jesús Ceballos-Torres, Dr. Sanjiv Prashar, Dr. Goran N. Kaluđerović, Prof. José A. Ferragut and Dr. Santiago Gómez-Ruiz

      Version of Record online: 13 DEC 2011 | DOI: 10.1002/cmdc.201100432

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      Tin can do it! A variety of tin(IV) carboxylate complexes were synthesized and characterized. Studies with a daunomycin-resistant K562/R cell line expressing P-glycoprotein (Pgp) showed that these complexes are not substrates of this protein pump, indicating that these compounds do not induce multidrug resistance associated with the overexpression of Pgp.

    8. Galloflavin (CAS 568-80-9): A Novel Inhibitor of Lactate Dehydrogenase (pages 311–317)

      Dr. Marcella Manerba, Dr. Marina Vettraino, Prof. Luigi Fiume, Prof. Giuseppina Di Stefano, Dr. Andrea Sartini, Dr. Elisa Giacomini, Dr. Rosa Buonfiglio, Prof. Marinella Roberti and Prof. Maurizio Recanatini

      Version of Record online: 4 NOV 2011 | DOI: 10.1002/cmdc.201100471

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      An Achilles' heel for tumors: The strict dependence of cancer cells on the glycolytic pathway for ATP generation led to the evaluation of lactate dehydrogenase (LDH) inhibitors as potential anticancer agents. We identified a compound, galloflavin, which combines inhibitory efficacy toward LDH-A and -B (in both purified enzyme and whole-cell assays) with a lack of toxicity toward cell respiration.

    9. Elucidation of the Structure–Activity Relationships of Apelin: Influence of Unnatural Amino Acids on Binding, Signaling, and Plasma Stability (pages 318–325)

      Alexandre Murza, Alexandre Parent, Elie Besserer-Offroy, Hugo Tremblay, Félix Karadereye, Nicolas Beaudet, Prof. Richard Leduc, Prof. Philippe Sarret and Prof. Éric Marsault

      Version of Record online: 13 DEC 2011 | DOI: 10.1002/cmdc.201100492

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      Unnatural influences: The SAR of apelin-13 with the APJ receptor was evaluated by D-Ala scan, replacement of Phe 13 and Pro 12, and the central portion with selected unnatural amino acids. The activity of the resulting analogues was tested in binding and functional assays on the Gi and β-arrestin2 pathways, and their stability in plasma assessed.

    10. Synthesis and Functional Characterization of Tridegin and Its Analogues: Inhibitors and Substrates of Factor XIIIa (pages 326–333)

      Miriam Böhm, Toni Kühl, Kornelia Hardes, Richard Coch, Dr. Christoph Arkona, Dr. Bernhard Schlott, Prof. Dr. Torsten Steinmetzer and Prof. Dr. Diana Imhof

      Version of Record online: 7 DEC 2011 | DOI: 10.1002/cmdc.201100405

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      Leeching potent compounds: Tridegin is a potent factor XIIIa inhibitor, and is the only characterized peptidic compound that inhibits this target. Herein we describe the full synthesis of the 66-mer peptide and its analogues and show that some derivatives are cleaved as substrates. The region that interacts with the active site of the enzyme is located around a glutamine residue (Q52) in the C-terminal part of tridegin.

  10. Book Review

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Review
    9. Communications
    10. Full Papers
    11. Book Review
    12. Preview
    1. Antiviral Drug Strategies. Edited by Erik De Clercq. (page 334)

      Dr. Gilles Gosselin

      Version of Record online: 13 DEC 2011 | DOI: 10.1002/cmdc.201100548

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      Wiley-VCH, Weinheim 2011. 406 pp., hardcover € 138.00.—ISBN 978-3-527-32696-9

  11. Preview

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Back Cover
    5. Graphical Abstract
    6. News
    7. Author Profile
    8. Review
    9. Communications
    10. Full Papers
    11. Book Review
    12. Preview
    1. You have free access to this content
      Preview: ChemMedChem 3/2012 (page 335)

      Version of Record online: 27 JAN 2012 | DOI: 10.1002/cmdc.201290004

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