ChemMedChem

Cover image for Vol. 7 Issue 9

September 2012

Volume 7, Issue 9

Pages 1509–1691

  1. Cover Pictures

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      Cover Picture: Dipeptidyl Peptidase IV-Activated Prodrugs of Anti-Varicella Zoster Virus Bicyclic Nucleoside Analogues Containing Different Self-Cleavage Spacer Systems (ChemMedChem 9/2012) (page 1509)

      Dr. Alberto Diez-Torrubia, Dr. Silvia Cabrera, Dr. Ingrid De Meester, Prof. María-José Camarasa, Prof. Jan Balzarini and Dr. Sonsoles Velázquez

      Article first published online: 28 AUG 2012 | DOI: 10.1002/cmdc.201290041

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      The front cover picture shows a new type of two-step-activation prodrugs of antiviral bicyclic nucleosides based on cyclization self-cleavage spacers that efficiently release the parent nucleoside upon hydrolysis by dipeptidyl peptidase IV (DPPIV, also termed CD26). All prodrugs exhibit dramatically improved water solubility, and a 15- to 20-fold increase in oral bioavailability in mice compared with the parent compound was also observed. These results support the applicability of the DPPIV/CD26 prodrug approach for increasing the water solubility and oral bioavailability of highly lipophilic drugs. For more details, see the Full Paper by Sonsoles Velázquez et al. on p. 1612 ff.

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      Inside Cover: Modeling, Synthesis and Biological Evaluation of Potential Retinoid X Receptor-Selective Agonists: Novel Halogenated Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) (ChemMedChem 9/2012) (page 1510)

      Julie K. Furmick, Dr. Ichiro Kaneko, Angela N. Walsh, Joanna Yang, Jaskaran S. Bhogal, Geoffrey M. Gray, Juan C. Baso, Drew O. Browder, Jessica L. S. Prentice, Luis A. Montano, Chanh C. Huynh, Lisa M. Marcus, Dorian G. Tsosie, Jungeun S. Kwon, Alexis Quezada, Nicole M. Reyes, Brittney Lemming, Puneet Saini, Dr. Arjan van der Vaart, Dr. Thomas L. Groy, Dr. Pamela A. Marshall, Dr. Peter W. Jurutka and Dr. Carl E. Wagner

      Article first published online: 28 AUG 2012 | DOI: 10.1002/cmdc.201290042

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      The inside cover picture shows how selective halogenation of bexarotene-like ligands acts as a glue, helping to increase binding to and activation of retinoid X receptor (RXR), a nuclear receptor important for cancer and Alzheimer's disease. In search of better RXR agonists, a periodic trend of increased binding and homodimerization was found when introducing halogen atoms on the ortho position of the phenyl ring. For more details, see the Full Paper by Carl E. Wagner et al. on p. 1551 ff.

  2. Back Cover

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    1. Back Cover: Cinnamic Acid/Chloroquinoline Conjugates as Potent Agents against Chloroquine-Resistant Plasmodium falciparum (ChemMedChem 9/2012) (page 1692)

      Bianca Pérez, Dr. Cátia Teixeira, Jiri Gut, Prof. Philip J. Rosenthal, Dr. José R. B. Gomes and Prof. Paula Gomes

      Article first published online: 28 AUG 2012 | DOI: 10.1002/cmdc.201290046

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      The back cover picture shows a novel warhead against intraerythrocytic malaria parasites. Chloroquinoline–cinnamic acid conjugates display activities in the low nanomolar range against chloroquine-resistant Plasmodium falciparum. In the image, the general structure of such conjugates is depicted targeting a blood schizont of the 3D7 Pf strain (image from Gut and Rosenthal). For more details, see the Communication by Paula Gomes et al. on p. 1537 ff.

  3. Graphical Abstract

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      Graphical Abstract: ChemMedChem 9/2012 (pages 1511–1517)

      Article first published online: 28 AUG 2012 | DOI: 10.1002/cmdc.201290043

  4. News

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  5. Author Profile

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    1. M. Jung (page 1525)

      Article first published online: 20 JUL 2012 | DOI: 10.1002/cmdc.201200280

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      “Chemistry is fun because you can create things the world has not seen or known before. In medicinal chemistry, these would ultimately and ideally be things that benefit the patient.” This and more from Manfred Jung can be found on page 1525.

  6. Minireview

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    1. Recent Advances in Neuraminidase Inhibitor Development as Anti-influenza Drugs (pages 1527–1536)

      Dr. Enguang Feng, Dr. Deju Ye, Dr. Jian Li, Dr. Dengyou Zhang, Dr. Jinfang Wang, Dr. Fei Zhao, Prof. Rolf Hilgenfeld, Prof. Mingyue Zheng, Prof. Hualiang Jiang and Prof. Hong Liu

      Article first published online: 16 JUL 2012 | DOI: 10.1002/cmdc.201200155

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      Attacking back: The emergence of new and highly pathogenic influenza virus strains have emphasized the need for effective anti-influenza drugs. Inhibition of neuraminidase (NA), which plays a key role in the life cycle of influenza, has become an attractive antiviral strategy, benefiting from structure-based design approaches. Resistance to current NA inhibitors suggests that ongoing development of new molecules will afford better protection against possible future influenza outbreaks.

  7. Communications

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    1. Cinnamic Acid/Chloroquinoline Conjugates as Potent Agents against Chloroquine-Resistant Plasmodium falciparum (pages 1537–1540)

      Bianca Pérez, Dr. Cátia Teixeira, Jiri Gut, Prof. Philip J. Rosenthal, Dr. José R. B. Gomes and Prof. Paula Gomes

      Article first published online: 29 JUN 2012 | DOI: 10.1002/cmdc.201200257

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      Cinnamic acid derivatives containing a 4-amino-7-chloroquinoline scaffold (blue) and substituted cinnamoyl building blocks (green) linked through an alkylamine chain (red) were found to have potent (11–59 nM) in vitro activities against erythrocytic chloroquine- resistant Plasmodium falciparum.

      Corrected by:

      Corrigendum: Corrigendum: Cinnamic Acid/Chloroquinoline Conjugates as Potent Agents against Chloroquine-Resistant Plasmodium falciparum

      Vol. 8, Issue 8, 1238, Article first published online: 29 JUL 2013

    2. Evaluation of Flavonoid and Resveratrol Chemical Libraries Reveals Abyssinone II as a Promising Antibacterial Lead (pages 1541–1545)

      Prof. Dianqing Sun, Prof. Julian G. Hurdle, Robin Lee, Prof. Richard Lee, Prof. Mark Cushman and Prof. John M. Pezzuto

      Article first published online: 30 JUL 2012 | DOI: 10.1002/cmdc.201200253

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      Lead on! In the course of screening flavonoid and resveratrol libraries, abyssinone II, a naturally occurring prenylated flavonoid, was found to exhibit relatively good antitubercular and antibacterial activity. Preliminary mechanistic studies revealed that abyssinone II hyperpolarizes the bacterial membrane potential and inhibits the biosynthesis of key cellular macromolecules (DNA, RNA, and protein).

    3. Anti-influenza Drug Discovery: Identification of an Orally Bioavailable Quinoline Derivative through Activity- and Property-Guided Lead Optimization (pages 1546–1550)

      Dr. Jiann-Yih Yeh, Dr. Mohane Selvaraj Coumar, Dr. Hui-Yi Shiao, Ta-Jen Lin, Yen-Chun Lee, Dr. Hui-Chen Hung, Dr. Shengkai Ko, Fu-Ming Kuo, Ming-Yu Fang, Yu-Lin Huang, Dr. John T. A. Hsu, Dr. Teng-Kuang Yeh, Dr. Shin-Ru Shih, Dr. Yu-Sheng Chao, Dr. Jim-Tong Horng and Dr. Hsing-Pang Hsieh

      Article first published online: 23 JUL 2012 | DOI: 10.1002/cmdc.201200259

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      From a high-throughput screening (HTS) hit with inhibitory activity against virus-induced cytophathic in the low micromolar range, we have developed a potent anti-influenza lead through careful optimization without compromising the drug-like properties of the compound. An orally bioavailable compound was identified as a lead agent with nanomolar activity against influenza, representing a 140-fold improvement over the initial hit.

  8. Full Papers

    1. Top of page
    2. Cover Pictures
    3. Back Cover
    4. Graphical Abstract
    5. News
    6. Author Profile
    7. Minireview
    8. Communications
    9. Full Papers
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    1. Modeling, Synthesis and Biological Evaluation of Potential Retinoid X Receptor-Selective Agonists: Novel Halogenated Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) (pages 1551–1566)

      Julie K. Furmick, Dr. Ichiro Kaneko, Angela N. Walsh, Joanna Yang, Jaskaran S. Bhogal, Geoffrey M. Gray, Juan C. Baso, Drew O. Browder, Jessica L. S. Prentice, Luis A. Montano, Chanh C. Huynh, Lisa M. Marcus, Dorian G. Tsosie, Jungeun S. Kwon, Alexis Quezada, Nicole M. Reyes, Brittney Lemming, Puneet Saini, Dr. Arjan van der Vaart, Dr. Thomas L. Groy, Dr. Pamela A. Marshall, Dr. Peter W. Jurutka and Dr. Carl E. Wagner

      Article first published online: 23 AUG 2012 | DOI: 10.1002/cmdc.201200319

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      Transcriptional signaling: An analogue of bexarotene with two fluorine atoms ortho to the carboxylic acid group has a lower EC50 value (34 nM) than bexarotene (55 nM) for the retinoid X receptor in HCT-116 cells. A low-energy docked conformation of the difluorobexarotene analogue in the ligand binding pocket of RXR as modeled in AutoDock 4.2 is shown.

    2. Curcumin Analogues with Potent and Selective Anti-proliferative Activity on Acute Promyelocytic Leukemia: Involvement of Accumulated Misfolded Nuclear Receptor Co-repressor (N-CoR) Protein as a Basis for Selective Activity (pages 1567–1579)

      Kheng-Lin Tan, Siang-Boon Koh, Rachel Pui-Lai Ee, Dr. Matiullah Khan and Prof. Mei-Lin Go

      Article first published online: 6 AUG 2012 | DOI: 10.1002/cmdc.201200293

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      Keep calm and curry on: Curcumin, an active compound found in turmeric, was structurally modified to give analogues that promote growth arrest of acute promyelocytic leukemia (APL) cells at sub-micromolar concentrations. APL-selective analogues 11 and 22 induced accumulation of cytosolic misfolded nuclear receptor co-repressor (N-CoR) by inhibiting the human 20S proteasome, thus sensitizing APL cells to apoptosis.

    3. Differentiating between Models of Epothilone Binding to Microtubules Using Tubulin Mutagenesis, Cytotoxicity, and Molecular Modeling (pages 1580–1586)

      Dr. Ruth A. Entwistle, Dr. Rania S. Rizk, Daniel M. Cheng, Dr. Gerald H. Lushington, Prof. Richard H. Himes and Prof. Mohan L. Gupta Jr.

      Article first published online: 16 JUL 2012 | DOI: 10.1002/cmdc.201200286

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      Stabilizing microtubules with small molecules is a proven strategy for cancer treatment. Site-directed mutagenesis of five sites in the epothilone binding pocket of tubulin created a panel of yeast strains with graded sensitivity to epothilone B. In vivo cytotoxicity data were combined with molecular mechanics simulations to discriminate between proposed models of epothilone binding to microtubules.

    4. Synthesis and Antimicrobial Activities of Oximes Derived from O-Benzylhydroxylamine as FabH Inhibitors (pages 1587–1593)

      Dr. Yin Luo, Dr. Li-Rong Zhang, Dr. Yang Hu, Dr. Shuai Zhang, Dr. Jie Fu, Prof. Xiao-Ming Wang and Prof. Hai-Liang Zhu

      Article first published online: 18 JUL 2012 | DOI: 10.1002/cmdc.201200225

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      The FabH 44! We demonstrated the antimicrobial activities of a series of oxime derivatives. Compounds with the highest activities were tested for their capacity to inhibit E. coli FabH. Docking simulations were then performed, positioning the most active compound into the E. coli FabH active site in order to determine the most probable binding conformation.

    5. Synthesis and Molecular Modeling Studies of Derivatives of a Highly Potent Peptidomimetic Vinyl Ester as Falcipain-2 Inhibitors (pages 1594–1600)

      Dr. Roberta Ettari, Dr. Nicola Micale, Dr. Giovanni Grazioso, Dr. Floriana Bova, Prof. Dr. Tanja Schirmeister, Prof. Silvana Grasso and Prof. Maria Zappalà

      Article first published online: 29 JUN 2012 | DOI: 10.1002/cmdc.201200274

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      Constrained peptidomimetics 616 are equipped with an electrophilic vinyl ester warhead and are structurally related to a previously identified potent and irreversible inhibitor of falcipain-2 (FP-2), the main hemoglobinase of P. falciparum. The new compounds were evaluated as inhibitors of FP-2, and docking experiments were performed to rationalize the results.

    6. An Efficient Synthesis of a Hydroxyethylamine (HEA) Isostere and Its α-Aminophosphonate and Phosphoramidate Derivatives as Potential Anti-HIV Agents (pages 1601–1611)

      Dr. Asish K. Bhattacharya, Dr. Kalpeshkumar C. Rana, Prof. Dr. Christophe Pannecouque and Prof. Dr. Eric De Clercq

      Article first published online: 11 JUL 2012 | DOI: 10.1002/cmdc.201200271

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      Getting there faster: Efficient synthesis of a hydroxyethylamine (HEA) isostere was carried out with a one-pot reduction–transimination–reduction reaction sequence. α-Aminophosphonate and phosphoramidate derivatives of the HEA isostere were designed and synthesized. All of the synthesized α-aminophosphonate and phosphoramidate derivatives were assayed for their anti-HIV activities.

    7. Dipeptidyl Peptidase IV-Activated Prodrugs of Anti-Varicella Zoster Virus Bicyclic Nucleoside Analogues Containing Different Self-Cleavage Spacer Systems (pages 1612–1622)

      Dr. Alberto Diez-Torrubia, Dr. Silvia Cabrera, Dr. Ingrid De Meester, Prof. María-José Camarasa, Prof. Jan Balzarini and Dr. Sonsoles Velázquez

      Article first published online: 6 AUG 2012 | DOI: 10.1002/cmdc.201200295

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      Better solubility and oral bioavailability! We describe a new type of water-soluble prodrug of anti-varicella zoster virus bicyclic nucleosides based on the cyclization self-cleavage spacers that efficiently release the parent nucleoside upon hydrolysis by DPPIV/CD26. A marked increase in transport through Caco-2 monolayers and in vivo oral bioavailability is reported.

    8. Synthesis and Biological Evaluation of CTP Synthetase Inhibitors as Potential Agents for the Treatment of African Trypanosomiasis (pages 1623–1634)

      Dr. Lucia Tamborini, Dr. Andrea Pinto, Dr. Terry K. Smith, Dr. Louise L. Major, Dr. Maria C. Iannuzzi, Dr. Sandro Cosconati, Dr. Luciana Marinelli, Prof. Ettore Novellino, Dr. Leonardo Lo Presti, Dr. Pui E. Wong, Prof. Michael P. Barrett, Prof. Carlo De Micheli and Prof. Paola Conti

      Article first published online: 2 AUG 2012 | DOI: 10.1002/cmdc.201200304

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      Increasing molecular complexity is a tool to improve the activity of CTPS inhibitors: New potent inhibitors of CTPS were designed based on the Acivicin scaffold as potential anti-trypanosomal agents. Compounds that can establish additional interactions with CTPS have greater inhibitory efficacy.

    9. Semisynthetic Ursolic Acid Fluorolactone Derivatives Inhibit Growth with Induction of p21waf1 and Induce Apoptosis with Upregulation of NOXA and Downregulation of c-FLIP in Cancer Cells (pages 1635–1646)

      Ana S. Leal, Dr. Rui Wang, Prof. Jorge A. R. Salvador and Prof. Yongkui Jing

      Article first published online: 16 JUL 2012 | DOI: 10.1002/cmdc.201200282

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      Semisynthetic derivatives of ursolic acid were synthesized and evaluated for their antiproliferative activity in AsPC-1 pancreatic cancer cells. Introduction of a fluorolactone moiety improved the antiproliferative activity, and preliminary evaluation revealed a novel mode of action.

    10. Designing Multitarget Anti-inflammatory Agents: Chemical Modulation of the Lumiracoxib Structure toward Dual Thromboxane Antagonists–COX-2 Inhibitors (pages 1647–1660)

      Prof. Dr. Massimo Bertinaria, Dr. Mohammed Abrar Abdul Gaffar Shaikh, Dr. Carola Buccellati, Prof. Dr. Clara Cena, Dr. Barbara Rolando, Dr. Loretta Lazzarato, Prof. Roberta Fruttero, Prof. Alberto Gasco, Dr. Malvina Hoxha, Dr. Valérie Capra, Prof. Dr. Angelo Sala and Prof. Dr. G. Enrico Rovati

      Article first published online: 2 AUG 2012 | DOI: 10.1002/cmdc.201200272

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      Striking a balance: A series of lumiracoxib derivatives were designed to explore the influence of isosteric substitution on balancing COX-2 inhibition and thromboxane A2 prostanoid (TP) receptor antagonism.

    11. Synthesis of Stable Genipin Derivatives and Studies of Their Neuroprotective Activity in PC12 Cells (pages 1661–1668)

      Jun Luo, Rikang Wang, Zhao Huang, Jian Yang, Xinsheng Yao, Prof. Dr. Heru Chen and Prof. Dr. Wenhua Zheng

      Article first published online: 30 JUL 2012 | DOI: 10.1002/cmdc.201200258

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      Greater stability, higher potency: Stable derivatives of genipin were synthesized, and all the prepared compounds displayed better neurotrophic activity than genipin. In particular, compound 4 proved to be a promising candidate for further research.

    12. β-D-Glucosyl Conjugates of Highly Potent Inhibitors of Blood Coagulation Factor Xa Bearing 2-Chorothiophene as a P1 Motif (pages 1669–1677)

      Dr. Gianfranco Lopopolo, Dr. Modesto de Candia, Prof. Luigi Panza, Dr. Maria Rosaria Romano, Prof. Marcello Diego Lograno, Prof. Francesco Campagna and Prof. Cosimo Altomare

      Article first published online: 31 JUL 2012 | DOI: 10.1002/cmdc.201200224

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      O-Glucosides of fXa inhibitors: β-D-Glucose was conjugated through an ether-linked C3-alkyl spacer to the central phenyl ring of compound 1, providing 16, which showed picomolar inhibitory potency (Ki=60 pM) against factor Xa (fXa), good selectivity over thrombin, sub-micromolar in vitro activity in the prothrombin time (PT) clotting assay, and a significant (1.6-fold) prolongation of the basal PT in an ex vivo assay in mice.

    13. Library Screening by Means of Mass Spectrometry (MS) Binding Assays—Exemplarily Demonstrated for a Pseudostatic Library Addressing γ-Aminobutyric Acid (GABA) Transporter 1 (GAT1) (pages 1678–1690)

      Miriam Sindelar and Prof. Dr. Klaus T. Wanner

      Article first published online: 11 JUN 2012 | DOI: 10.1002/cmdc.201200201

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      Mix and measure: The generation of compound libraries by dynamic combinatorial chemistry in the presence of a target and subsequent library screening by competitive mass spectrometry (MS) binding assays represents a new and highly efficient approach to drug discovery. This method, which requires the compound libraries to be rendered pseudostatic, has been successfully applied to mGAT1, the most abundant GABA transporter in the brain, leading to potent hits for this target.

  9. Preview

    1. Top of page
    2. Cover Pictures
    3. Back Cover
    4. Graphical Abstract
    5. News
    6. Author Profile
    7. Minireview
    8. Communications
    9. Full Papers
    10. Preview
    1. You have free access to this content
      Preview: ChemMedChem 10/2012 (page 1691)

      Article first published online: 28 AUG 2012 | DOI: 10.1002/cmdc.201290045

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