ChemMedChem

Cover image for Vol. 9 Issue 5

Special Issue: AIMECS13

May 2014

Volume 9, Issue 5

Pages 861–1080

  1. Cover Pictures

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. Corrigendum
    6. News
    7. Minireviews
    8. Communications
    9. Full Papers
    1. You have free access to this content
      Cover Picture: Facile Identification of Dual FLT3–Aurora A Inhibitors: A Computer-Guided Drug Design Approach (ChemMedChem 5/2014) (page 861)

      Dr. Yung Chang Hsu, Dr. Yi-Yu Ke, Dr. Hui-Yi Shiao, Dr. Chieh-Chien Lee, Dr. Wen-Hsing Lin, Chun-Hwa Chen, Kuei-Jung Yen, Dr. John T.-A. Hsu, Dr. Chungming Chang and Dr. Hsing-Pang Hsieh

      Article first published online: 28 APR 2014 | DOI: 10.1002/cmdc.201490015

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      The front cover picture shows the in silico design of dual FMS-like receptor tyrosine kinase-3 (FLT3) and Aurora kinase A (AURKA) inhibitors—a potential new class of acute myeloid leukemia (AML) therapeutic agents. Computer-aided drug design (CADD) has various advantages over traditional approaches, such as mitigating laborious optimization work, as well as saving time and being more cost effective. In this work, two consecutive CADD approaches were employed to modify the core structure and side chain of an initial hit compound with AURKA inhibitory activity. A set of virtual compounds derived from the hit structure were designed in silico, and subsequently screened against an FLT3 homology model. The best ranked compounds were then synthesized and evaluated in vitro. Through this approach, a potent, dual FLT3–AURKA inhibitor was generated in a time-efficient manner. For further details, see the Full Paper by Hui-Yi Shiao, Hsing-Pang Hsieh et al. on p. 953 ff.

    2. You have free access to this content
      Inside Cover: Discovery of 5-(2-(Phenylamino)pyrimidin-4-yl)thiazol-2(3H)-one Derivatives as Potent Mnk2 Inhibitors: Synthesis, SAR Analysis and Biological Evaluation (ChemMedChem 5/2014) (page 862)

      Sarah Diab, Theodosia Teo, Dr. Malika Kumarasiri, Dr. Peng Li, Dr. Mingfeng Yu, Dr. Frankie Lam, Sunita K. C. Basnet, Dr. Matthew J. Sykes, Dr. Hugo Albrecht, Dr. Robert Milne and Prof. Shudong Wang

      Article first published online: 28 APR 2014 | DOI: 10.1002/cmdc.201490016

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      The inside cover picture shows the unique opportunity offered by Mnk inhibitors in simultaneously targeting the Ras/Raf/Erk, MKK/p38 and Akt/mTOR/eIF4E pathways in human cancers. The compound shown targets Mnk2 with low nanomolar potency, and is capable of abrogating anti-apoptotic protein Mcl-1 and inducing apoptosis in MV4-11 leukemia cells. For further details, see the Full Paper by Shudong Wang et al. on p. 962 ff.

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      Back Cover: 3-Phenylpropanoic Acid-Based Phosphotyrosine (pTyr) Mimetics: Hit Evolution to a Novel Orally Active Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitor (ChemMedChem 5/2014) (page 1084)

      Dr. Yan-Bo Tang, Jun-Zheng Liu, Dr. Shu-En Zhang, Xin Du, Feilin Nie, Jin-Ying Tian, Prof. Fei Ye, Dr. Kai Huang, Dr. Jin-Ping Hu, Prof. Yan Li and Prof. Zhiyan Xiao

      Article first published online: 28 APR 2014 | DOI: 10.1002/cmdc.201490019

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      The back cover picture shows the discovery of a novel orally active PTP1B inhibitor as a potential antidiabetic agent. This potent PTP1B inhibitor was evolved from a previously identified 3-phenylpropanoic acid-based hit structure. It showed significant in vivo activity and a suitable pharmacokinetic profile. The results provide a new chemotype of PTP1B inhibitors. For further details, see the Communication by Zhiyan Xiao et al. on p. 918 ff.

  2. Editorial

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

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. Corrigendum
    6. News
    7. Minireviews
    8. Communications
    9. Full Papers
    1. Graphical Abstract: ChemMedChem 5/2014 (pages 871–877)

      Article first published online: 28 APR 2014 | DOI: 10.1002/cmdc.201490017

  4. Corrigendum

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

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. Corrigendum
    6. News
    7. Minireviews
    8. Communications
    9. Full Papers
    1. Spotlights on our sister journals: ChemMedChem 5/2014 (pages 880–883)

      Article first published online: 28 APR 2014 | DOI: 10.1002/cmdc.201490018

  6. Minireviews

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. Corrigendum
    6. News
    7. Minireviews
    8. Communications
    9. Full Papers
    1. Getting to the Source: Selective Drug Targeting of Cancer Stem Cells (pages 885–898)

      Fatima Ismail and Prof. David A. Winkler

      Article first published online: 23 APR 2014 | DOI: 10.1002/cmdc.201400068

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      Getting to the source of cancer: The cancer stem cell hypothesis states that some tumor cells have stem-cell-like properties and consequently are typically not reached by traditional chemotherapy, causing patients to relapse after periods of remission. As such, cancer stem cells represent a novel target for the development of more efficacious drugs. Here, recent advances in the development of small molecules targeting cancer stem cells are reviewed.

    2. G-Quadruplex Structures and Their Interaction Diversity with Ligands (pages 899–911)

      Sulin Zhang, Prof. Yanling Wu and Prof. Wen Zhang

      Article first published online: 11 APR 2014 | DOI: 10.1002/cmdc.201300566

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      Polymorphism & binding modes: G-Quadruplexes display structural polymorphism based on the number of strands in the formed G-quadruplex and the interaction of the G-quadruplex with small molecules (G4-ligands). The formation and/or stabilization of these structures by G4-ligands may be crucial for the research and development of drugs that target G-quadruplexes formed from particular genes and human telomeres.

  7. Communications

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. Corrigendum
    6. News
    7. Minireviews
    8. Communications
    9. Full Papers
    1. Bis(pentafluorosulfanyl)phenyl Azide as an Expeditious Tool for Click Chemistry toward Antitumor Pharmaceuticals (pages 913–917)

      Yu-Dong Yang, Etsuko Tokunaga, Prof. Hidehiko Akiyama, Norimichi Saito and Prof. Norio Shibata

      Article first published online: 3 MAR 2014 | DOI: 10.1002/cmdc.201400059

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      Fluoro power! (5-Azido-1,3-phenylene)bis(pentafluoro-λ6-sulfane) is introduced as a powerful tool for the synthesis of pentafluorosulfanyl-containing arenes using click chemistry. A series of 13 pentafluorosulfanylarene-triazoles was synthesized and evaluated against a human leukemic monocyte lymphoma cell line. The results indicate their potential as building blocks for the further development of pentafluorosulfanyl-containing antitumor agents.

    2. 3-Phenylpropanoic Acid-Based Phosphotyrosine (pTyr) Mimetics: Hit Evolution to a Novel Orally Active Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitor (pages 918–921)

      Dr. Yan-Bo Tang, Jun-Zheng Liu, Dr. Shu-En Zhang, Xin Du, Feilin Nie, Jin-Ying Tian, Prof. Fei Ye, Dr. Kai Huang, Dr. Jin-Ping Hu, Prof. Yan Li and Prof. Zhiyan Xiao

      Article first published online: 18 MAR 2014 | DOI: 10.1002/cmdc.201400007

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      A sincere form of flattery: A novel protein tyrosine phosphatase 1B (PTP1B) inhibitor with a 3-phenylpropanoic acid moiety as a phosphotyrosine (pTyr) mimetic was optimized to provide an orally active lead compound with an IC50 value of 0.40 μM against PTP1B and more notably that displayed significant in vivo activity in a murine insulin resistance model.

    3. Design, Synthesis, and Activity Evaluation of GK/PPARγ Dual-Target-Directed Ligands as Hypoglycemic Agents (pages 922–927)

      Dr. Jianxun Lu, Lei Lei, Yi Huan, Yongqiang Li, Dr. Lijing Zhang, Zhufang Shen, Dr. Wenxiang Hu and Zhiqiang Feng

      Article first published online: 15 APR 2014 | DOI: 10.1002/cmdc.201400009

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      Two birds, one stone: GK/PPARγ dual-target ligands were constructed by rational combination of pharmacophores from known GK activators and PPARγ agonists. Their ability to induce GK and PPARγ transcriptional activity were evaluated, and the putative binding modes of one of the most promising compounds were also explored by molecular docking simulations with GK and PPARγ.

    4. Fluorescence Polarization for the Evaluation of Small-Molecule Inhibitors of PCAF BRD/Tat-AcK50 Association (pages 928–931)

      Ping Hu, Xinghui Wang, Baiqun Zhang, Shuai Zhang, Qiang Wang and Prof. Zhiyong Wang

      Article first published online: 28 JAN 2014 | DOI: 10.1002/cmdc.201300499

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      Efficient with polarization! A fluorescence polarization (FP) competition assay was developed to screen and evaluate inhibitors for the PCAF bromodomain (PCAF BRD)/Tat-AcK50 protein–peptide interaction. A series of pyridine 1-oxide derivatives were synthesized and evaluated. Some of these compounds, 2-(3-aminopropylamino) pyridine 1-oxide derivatives, could be effective inhibitors of PCAF BRD/Tat-AcK50 association.

  8. Full Papers

    1. Top of page
    2. Cover Pictures
    3. Editorial
    4. Graphical Abstract
    5. Corrigendum
    6. News
    7. Minireviews
    8. Communications
    9. Full Papers
    1. Delivery of Suramin as an Antiviral Agent through Liposomal Systems (pages 933–939)

      Dr. Eloise Mastrangelo, Dr. Stefania Mazzitelli, Jacopo Fabbri, Dr. Jacques Rohayem, Prof. Janne Ruokolainen, Dr. Antti Nykänen, Dr. Mario Milani, Dr. Margherita Pezzullo, Prof. Claudio Nastruzzi and Prof. Martino Bolognesi

      Article first published online: 11 MAR 2014 | DOI: 10.1002/cmdc.201300563

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      Suramin, an established drug, suffers from low membrane permeability and limited cell internalization. Lipophilic carriers, such as liposomes, can enhance cellular uptake and delivery to the target cell. As such, suramin-cationic liposome complexes, prepared through an ethanol injection method, were investigated for their ability to overcome the limitations of suramin.

    2. In silico Design, Synthesis, and Screening of Novel Deoxyhypusine Synthase Inhibitors Targeting HIV-1 Replication (pages 940–952)

      Dr. Marcus Schroeder, Adrian Kolodzik, Katharina Pfaff, Dr. Poornima Priyadarshini, Dr. Marcel Krepstakies, Prof. Dr. Joachim Hauber, Prof. Dr. Matthias Rarey and Prof. Dr. Chris Meier

      Article first published online: 11 MAR 2014 | DOI: 10.1002/cmdc.201300481

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      Combating drug resistance: The in silico design, synthesis, and biological evaluation of deoxyhypusine synthase (DHS) inhibitors are described. DHS is involved in post-translational modification of the protein eIF-5A, which is needed for the translocation of HIV RNA from the nucleus into the cytosol. A newly designed inhibitor showed dose-dependent inhibition of DHS in vitro and suppression of HIV replication in cell cultures without cytotoxic effects.

    3. Facile Identification of Dual FLT3–Aurora A Inhibitors: A Computer-Guided Drug Design Approach (pages 953–961)

      Dr. Yung Chang Hsu, Dr. Yi-Yu Ke, Dr. Hui-Yi Shiao, Dr. Chieh-Chien Lee, Dr. Wen-Hsing Lin, Chun-Hwa Chen, Kuei-Jung Yen, Dr. John T.-A. Hsu, Dr. Chungming Chang and Dr. Hsing-Pang Hsieh

      Article first published online: 24 MAR 2014 | DOI: 10.1002/cmdc.201300571

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      In silico selection: We selected an Aurora hit compound as a starting point, followed by two consecutive computer-guided strategies to rapidly and efficiently modify the side chain and core. These efforts resulted in the identification of a potential FLT3–Aurora A inhibitor for further development to treat acute myeloid leukemia (AML).

    4. Discovery of 5-(2-(Phenylamino)pyrimidin-4-yl)thiazol-2(3H)-one Derivatives as Potent Mnk2 Inhibitors: Synthesis, SAR Analysis and Biological Evaluation (pages 962–972)

      Sarah Diab, Theodosia Teo, Dr. Malika Kumarasiri, Dr. Peng Li, Dr. Mingfeng Yu, Dr. Frankie Lam, Sunita K. C. Basnet, Dr. Matthew J. Sykes, Dr. Hugo Albrecht, Dr. Robert Milne and Prof. Shudong Wang

      Article first published online: 12 FEB 2014 | DOI: 10.1002/cmdc.201300552

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      Highly active Mnk2 inhibitors: Mnk-related cancer biology is an area of intensive research, but its inhibitor discovery has lagged behind due to a lack of understanding of the protein structure. Herein we report the discovery of Mnk2 inhibitors (e.g. 8 e). These potent and selective inhibitors are extremely valuable for target validation and drug discovery.

    5. Discovery of 14-3-3 Protein–Protein Interaction Inhibitors that Sensitize Multidrug-Resistant Cancer Cells to Doxorubicin and the Akt Inhibitor GSK690693 (pages 973–983)

      Dr. Mattia Mori, Dr. Giulia Vignaroli, Ylenia Cau, Dr. Jelena Dinić, Dr. Richard Hill, Matteo Rossi, Dr. David Colecchia, Dr. Milica Pešić, Prof. Wolfgang Link, Dr. Mario Chiariello, Prof. Christian Ottmann and Prof. Maurizio Botta

      Article first published online: 8 APR 2014 | DOI: 10.1002/cmdc.201400044

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      Pièce de résistance! Multidrug resistance (MDR) is the main obstacle toward effective anticancer therapy. Herein we report the discovery of two small-molecule 14-3-3 protein–protein interaction inhibitors that promote the translocation of c-Abl and FOXO pro-apoptotic factors into the nucleus and sensitize MDR cancer cells to doxorubicin and the pan-Akt inhibitor GSK690693.

    6. Synthesis and Biological Evaluation of 2-Substituted-5-(4-nitrophenylsulfonamido)benzoxazoles as Human GST P1-1 Inhibitors, and Description of the Binding Site Features (pages 984–992)

      Dr. Tuğba Ertan-Bolelli, Dr. Yaman Musdal, Kayhan Bolelli, Serap Yilmaz, Prof. Yasemin Aksoy, Prof. Ilkay Yildiz, Prof. Esin Aki-Yalcin and Prof. Ismail Yalcin

      Article first published online: 26 MAR 2014 | DOI: 10.1002/cmdc.201400010

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      Irresistible conjugates: We report the synthesis of some novel sulfonamido-containing benzoxazoles. Among the tested compounds, 5 f was found to be the most active hGST P1-1 inhibitor, showing similar potency to that of the reference agent, ethacrynic acid. Molecular docking studies revealed that the synthesized sulfonamido-containing benzoxazoles act as inhibitors of hGST P1-1 by binding to the H-site and forming conjugates with GSH via nucleophilic aromatic substitution.

    7. Unfolding and Conformational Variations of Thrombin-Binding DNA Aptamers: Synthesis, Circular Dichroism and Molecular Dynamics Simulations (pages 993–1001)

      Dr. Lidan Sun, Dr. Hongwei Jin, Xiaoyang Zhao, Dr. Zhenming Liu, Prof. Yifu Guan, Prof. Zhenjun Yang, Prof. Liangren Zhang and Prof. Lihe Zhang

      Article first published online: 8 APR 2014 | DOI: 10.1002/cmdc.201300564

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      Unraveling the mystery! The unfolding process of thrombin-binding DNA aptamer (TBA) G-quadruplexes and conformational variations of TBA oligonucleotides modified with locked nucleoside or 2'-O-methyl-nucleoside were studied by molecular dynamics and circular dichroism spectroscopy. The computational protocol described offers a novel tool for the investigation of other G-quadruplex systems.

    8. Location and Conformation of Amyloid β(25–35) Peptide and its Sequence-Shuffled Peptides within Membranes: Implications for Aggregation and Toxicity in PC12 Cells (pages 1002–1011)

      Prof. Hui-Hsu Gavin Tsai, Jian-Bin Lee, Yuan-Ci Shih, Prof. Lei Wan, Prof. Fa-Kuen Shieh and Prof. Chin-Yu Chen

      Article first published online: 11 APR 2014 | DOI: 10.1002/cmdc.201400062

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      Rates of aggregation: Multiple lines of evidence implicate amyloid β peptide as a causative agent in the etiology of Alzheimer's disease. The location and conformation of the peptide within the membrane affects its neurotoxicity. If a peptide is deeply inserted into the membrane, it diffuses slowly because of the membrane matrix. Such slowly diffusing peptides have a lower aggregation rate in the membrane and thus lower toxicity; rapid aggregation yields higher toxicity.

    9. Computational Insight into p21-Activated Kinase 4 Inhibition: A Combined Ligand- and Structure-Based Approach (pages 1012–1022)

      Rui-Juan Li, Jian Wang, Zhen Xu, Wan-Xu Huang, Jia Li, Sheng-Fei Jin, Prof. Dong-Mei Zhao and Prof. Mao-Sheng Cheng

      Article first published online: 18 MAR 2014 | DOI: 10.1002/cmdc.201400016

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      PAKed with information! p21-Activated kinase 4 (PAK4) is a serine/threonine protein kinase that plays important roles in a wide variety of human diseases, including cancer. Its interaction with ATP-competitive inhibitors was investigated by a combination of ligand- and structure-based approaches. The results led us to propose an interaction model inside the PAK4 active site, providing guidance for the design of more potent PAK4 inhibitors.

    10. Development of a Growth-Hormone-Conjugated Nanodiamond Complex for Cancer Therapy (pages 1023–1029)

      Dr. Hsueh-Liang Chu, Hung-Wei Chen, Dr. Shin-Hua Tseng, Prof. Ming-Hua Hsu, Dr. Li-Ping Ho, Fu-Hsuan Chou, MD. PhD. Hsing-Yuan Li, Yu-Chuan Chang, Pei-Hsin Chen, Dr. Li-Yun Tsai, Ching-Chung Chou, Prof. Jyh Shin Chen, Prof. Tsai-Mu Cheng and Prof. Chia-Ching Chang

      Article first published online: 23 FEB 2014 | DOI: 10.1002/cmdc.201300541

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      Small but significant: A new nanosurgery platform was formed using a laser-mediated, cancer-targeting nanodiamond (ND) complex. Laser irradiation at 532 nm created a nanoblast of the ND complex and induced cell death within a growth-hormone-receptor-containing lung cancer cell line.

    11. Hepatocellular Carcinoma Targeting Agents: Conjugates of Nitroimidazoles with Trimethyl Nordihydroguaiaretic Acid (pages 1030–1037)

      Dr. Ming-Hua Hsu, Szu-Chun Wu, Kuan-Chuan Pao, Irem Unlu, Dr. John N. Gnabre, Dr. David E. Mold, Prof. Ru Chih C. Huang and Prof. Jih Ru Hwu

      Article first published online: 19 MAR 2014 | DOI: 10.1002/cmdc.201300521

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      High performance at low O2: Nordihydroguaiaretic acid (NDGA) is a natural product that has been used in many medical research fields. A series of novel nitroimidazole-conjugated NDGA compounds were synthesized and shown to possess good activity against hepatocellular carcinoma (HCC) Hep3B cells. The 4′-trimethyl NDGA derivatives are more potent than their unconjugated counterparts in hypoxic cells. These compounds can therefore be regarded as good HCC-targeting agents.

    12. High-Throughput Synthesis of Peptide α-Thioesters: A Safety Catch Linker Approach Enabling Parallel Hydrogen Fluoride Cleavage (pages 1038–1046)

      Dr. Andreas Brust, Dr. Christina I. Schroeder and Prof. Paul F. Alewood

      Article first published online: 3 MAR 2014 | DOI: 10.1002/cmdc.201300524

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      A boost for NCL: A synthetic route to cysteine-rich peptide α-thioesters employing a safety catch linker is described. The linker strategy allows parallel Boc chemistry including parallel HF cleavage, and removes the bottleneck of peptide thioester accessibility.

    13. Nonlinear Dimensionality Reduction for Visualizing Toxicity Data: Distance-Based Versus Topology-Based Approaches (pages 1047–1059)

      Dr. Natalia V. Kireeva, Svetlana I. Ovchinnikova, Dr. Igor V. Tetko, Dr. Abdullah M. Asiri, Dr. Konstantin V. Balakin  and Prof. Aslan Yu. Tsivadze

      Article first published online: 11 APR 2014 | DOI: 10.1002/cmdc.201400027

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      On the map: Dimensionality reduction techniques are of great benefit during the early stages of drug discovery. A comparison between different types of chemography methods has been performed. Methods of intrinsic dimensionality were used for data analysis. Three measures have been applied for quantitative assessment of the quality of the obtained maps, and the efficiency of the different methods has been compared.

    14. Synthesis and Anti-HCV Entry Activity Studies of β-Cyclodextrin–Pentacyclic Triterpene Conjugates (pages 1060–1070)

      Dr. Sulong Xiao, Dr. Qi Wang, Longlong Si, Yongying Shi, Han Wang, Fei Yu, Prof. Yongmin Zhang, Yingbo Li, Yongxiang Zheng, Chuanling Zhang, Prof. Chunguang Wang, Lihe Zhang and Demin Zhou

      Article first published online: 12 MAR 2014 | DOI: 10.1002/cmdc.201300545

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      An awesome CD collection: A series of water-soluble triazole-bridged β-cyclodextrin (CD)–pentacyclic triterpene conjugates were synthesized, and their hydrophobicity, anti-HCV entry activities, and toxicity were studied. Easy access to such conjugates may provide a way to obtain a new class of anti-HCV entry inhibitors.

    15. Total Synthesis of Anticoagulant Pentasaccharide Fondaparinux (pages 1071–1080)

      Dr. Tiehai Li, Hui Ye, Xuefeng Cao, Jiajia Wang, Yonghui Liu, Lifei Zhou, Qiang Liu, Wenjun Wang, Dr. Jie Shen, Dr. Wei Zhao and Prof. Peng Wang

      Article first published online: 11 APR 2014 | DOI: 10.1002/cmdc.201400019

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      A matter of protection! The anticoagulant pentasaccharide fondaparinux was synthesized using an improved and optimized synthetic strategy. The process of total synthesis was monitored by HPLC and NMR. This work will contribute to continued improvement of the multistep production of fondaparinux and provide abundant information for the synthesis of heparin-like oligosaccharides.

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