ChemMedChem

Cover image for Vol. 8 Issue 7

July 2013

Volume 8, Issue 7

Pages 1021–1223

  1. Cover Pictures

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Communication
    6. Full Papers
    1. You have free access to this content
      Cover Picture: The Lab Oddity Prevails: Discovery of Pan-CDK Inhibitor (R)-S-Cyclopropyl-S-(4-{[4-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)sulfoximide (BAY 1000394) for the Treatment of Cancer (ChemMedChem 7/2013) (page 1021)

      Dr. Ulrich Lücking, Dr. Rolf Jautelat, Dr. Martin Krüger, Dr. Thomas Brumby, Dr. Philip Lienau, Dr. Martina Schäfer, Dr. Hans Briem, Dr. Julia Schulze, Prof. Dr. Alexander Hillisch, Dr. Andreas Reichel, Dr. Antje Margret Wengner and Dr. Gerhard Siemeister

      Version of Record online: 26 JUN 2013 | DOI: 10.1002/cmdc.201390025

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      The front cover picture shows the pan-cyclin-dependent kinase (CDK) inhibitor BAY 1000394 embedded in a schematic depiction of the cell cycle and a colored paraffin section of an untreated A2780Cis ovarian cancer tumor grown on a nude mouse. Aminopyrimdine BAY 1000394 is a balanced, orally available pan-CDK inhibitor with potent, broad-spectrum antiproliferative activity against human cancer cell lines, and is currently being investigated in a phase I clinical trial in patients with advanced solid tumors. For more details, see the Full Paper by Ulrich Lücking et al. on p. 1067 ff.

    2. You have free access to this content
      Inside Cover: Alzheimer’s Disease: Identification and Development of β-Secretase (BACE-1) Binding Fragments and Inhibitors by Dynamic Ligation Screening (DLS) (ChemMedChem 7/2013) (page 1022)

      Dr. María Isabel Fernández-Bachiller, Dr. André Horatscheck, Dr. Michael Lisurek and Prof. Dr. Jörg Rademann

      Version of Record online: 26 JUN 2013 | DOI: 10.1002/cmdc.201390026

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      The inside cover picture shows the discovery of fragments binding to β-secretase (BACE-1) by dynamic ligation screening (DLS). A peptidic aldehyde serves as a chemically reactive inhibitor, which enables the site-directed identification of protein-binding fragments in the presence of the target enzyme and a protease substrate for detection. The fragment hit was then used as a starting point for the development of entirely nonpeptidic BACE-1 inhibitors. For more details, see the Full Paper by Jörg Rademann et al. on p. 1041 ff.

    3. You have free access to this content
      Back Cover: From On-Target to Off-Target Activity: Identification and Optimisation of Trypanosoma brucei GSK3 Inhibitors and Their Characterisation as Anti-Trypanosoma brucei Drug Discovery Lead Molecules (ChemMedChem 7/2013) (page 1228)

      Dr. Andrew Woodland, Raffaella Grimaldi, Dr. Torsten Luksch, Dr. Laura A. T. Cleghorn, Dr. Kayode K. Ojo, Prof. Wesley C. Van Voorhis, Dr. Ruth Brenk, Prof. Julie A. Frearson, Prof. Ian H. Gilbert and Prof. Paul G. Wyatt

      Version of Record online: 26 JUN 2013 | DOI: 10.1002/cmdc.201390029

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      The back cover picture shows the discovery of Trypanosoma brucei protein kinase GSK3 short (TbGSK3) inhibitors and their characterization as leads in the development of novel therapeutics against Human African trypanosomiasis (HAT). Hit validation and optimization gave rise to a series of diaminothiazoles with low nanomolar activities against TbGSK3 that are potent in vitro inhibitors of T. brucei proliferation. For more details, see the Full Paper by Ian H. Gilbert, Paul G. Wyatt et al. on p. 1127 ff.

  2. Graphical Abstract

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Communication
    6. Full Papers
    1. You have free access to this content
  3. News

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Communication
    6. Full Papers
  4. Communication

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Communication
    6. Full Papers
    1. Synthesis of an 11C-Labeled Antiprion GN8 Derivative and Evaluation of Its Brain Uptake by Positron Emission Tomography (pages 1035–1039)

      Dr. Tsutomu Kimura, Dr. Takeo Sako, Dr. Siqin, Dr. Junji Hosokawa-Muto, Dr. Yi Long Cui, Dr. Yasuhiro Wada, Dr. Yosky Kataoka, Dr. Hisashi Doi, Prof. Suehiro Sakaguchi, Prof. Masaaki Suzuki, Prof. Yasuyoshi Watanabe and Prof. Kazuo Kuwata

      Version of Record online: 24 MAY 2013 | DOI: 10.1002/cmdc.201300167

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      A radiolabeled PET! A 11C-labeled derivative of N,N′-(methylenedi-4,1-phenylene)bis[2-(1-pyrrolidinyl) acetamide] (GN8), an antiprion agent currently under development, was synthesized by palladium-catalyzed rapid methylation of aryltributylstannane and assessed for brain penetration and organ distribution in rats by positron emission tomography (PET).

  5. Full Papers

    1. Top of page
    2. Cover Pictures
    3. Graphical Abstract
    4. News
    5. Communication
    6. Full Papers
    1. Alzheimer’s Disease: Identification and Development of β-Secretase (BACE-1) Binding Fragments and Inhibitors by Dynamic Ligation Screening (DLS) (pages 1041–1056)

      Dr. María Isabel Fernández-Bachiller, Dr. André Horatscheck, Dr. Michael Lisurek and Prof. Dr. Jörg Rademann

      Version of Record online: 11 JUN 2013 | DOI: 10.1002/cmdc.201300078

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      Fragment's guide to chemical space! Dynamic ligation screening (DLS) was applied successfully to an aspartic protease. A peptide aldehyde was used as a directing probe to pick inhibitory fragments for the S1′ pocket of the aspartic protease BACE-1. The hit fragments can be extended into compounds containing the N-acylated ethane-1,2-diamine motif. The identified 3-(aminophenyl)coumarin fragment was set as a starting point for developing entirely nonpeptidic drug-like BACE-1 inhibitors with low-micromolar activity and the potential for further optimization.

    2. Rational Design of Angiotensin-I-Converting Enzyme Inhibitory Peptides by Integrating in silico Modeling and an in vitro Assay (pages 1057–1066)

      Dr. Tao Jing, Dr. Jian Feng, Dr. De Li, Dr. Jianping Liu and Prof. Dr. Guoxiang He

      Version of Record online: 5 JUN 2013 | DOI: 10.1002/cmdc.201300132

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      Rational peptide design that flows: We describe a synthetic pipeline that combines in silico modeling and an in vitro assay to directly optimize the atomic interactions between angiotensin-I-converting enzyme (ACE) and its peptide ligands. Several new peptides with high ACE-inhibitory activities were successfully designed with the pipeline.

    3. The Lab Oddity Prevails: Discovery of Pan-CDK Inhibitor (R)-S-Cyclopropyl-S-(4-{[4-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)sulfoximide (BAY 1000394) for the Treatment of Cancer (pages 1067–1085)

      Dr. Ulrich Lücking, Dr. Rolf Jautelat, Dr. Martin Krüger, Dr. Thomas Brumby, Dr. Philip Lienau, Dr. Martina Schäfer, Dr. Hans Briem, Dr. Julia Schulze, Prof. Dr. Alexander Hillisch, Dr. Andreas Reichel, Dr. Antje Margret Wengner and Dr. Gerhard Siemeister

      Version of Record online: 13 MAY 2013 | DOI: 10.1002/cmdc.201300096

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      The unconventional proposal to introduce a sulfoximine group into a lead series of aminopyrimidine pan-CDK inhibitors was initially met with much skepticism. However, it was the introduction of the sulfoximine group that finally allowed the project problems to be overcome, culminating in the identification of BAY 1000394, a nanomolar pan-CDK inhibitor that is currently being investigated in phase I clinical trials.

    4. Aquaporin Inhibition by Gold(III) Compounds: New Insights (pages 1086–1092)

      Ana Paula Martins, Dr. Antonella Ciancetta, Andreia de Almeida, Dr. Alessandro Marrone, Prof. Nazzareno Re, Prof. Graça Soveral and Dr. Angela Casini

      Version of Record online: 7 MAY 2013 | DOI: 10.1002/cmdc.201300107

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      Clogging up the plumbing: Aquaglyceroporin-3 (AQP3) inhibition by gold(III) compounds with nitrogen donor ligands was demonstrated in human red blood cells. Computational studies provided insight into the possible molecular mechanism and binding mode to their putative target (AQP3).

    5. Probing the Structural Properties of DNA/RNA Grooves with Sterically Restricted Phosphonium Dyes: Screening of Dye Cytotoxicity and Uptake (pages 1093–1103)

      Dr. Ivo Crnolatac, Dr. Lidija-Marija Tumir, Nedyalko Y. Lesev, Dr. Aleksey A. Vasilev, Prof. Todor G. Deligeorgiev, Dr. Katarina Mišković, Prof. Ljubica Glavaš-Obrovac, Dr. Oliver Vugrek and Dr. Ivo Piantanida

      Version of Record online: 31 MAY 2013 | DOI: 10.1002/cmdc.201300085

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      DNA/RNA markers with groove: Structure–activity relationship studies revealed that fine tuning steric properties and hydrogen bonding factors within a series of six phosphonium dyes results in significantly varied spectroscopic responses to various ds DNA/RNAs, and very different and selective antiproliferative activities toward cell lines. The nontoxic dyes underwent efficient cellular uptake and specific accumulation in mitochondria.

    6. Design and Synthesis of 4-(2,4,5-Trifluorophenyl)butane-1,3-diamines as Dipeptidyl Peptidase IV Inhibitors (pages 1104–1116)

      Linrong Zhu, Dr. Yuanyuan Li, Dr. Ling Qiu, Dr. Mingbo Su, Prof. Xin Wang, Chunmei Xia, Dr. Yi Qu, Prof. Jingya Li, Prof. Jia Li, Prof. Bing Xiong and Prof. Jingkang Shen

      Version of Record online: 13 MAY 2013 | DOI: 10.1002/cmdc.201300104

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      Blocking IV for type II: A series of triazole compounds were designed and synthesized based on analysis of DPP4 complex structures in the PDB. Enzyme assays and in vitro DMPK tests showed that these compounds are moderately active against DPP4, yet they also have undesirable metabolic properties related to CYP2D6. We therefore substituted the triazole group with an amide moiety to obtain a new series of DPP4 inhibitors with excellent selectivity and in vivo PK and PD efficacies similar to those of sitagliptin.

    7. Discovery of Piperidine-Linked Pyridine Analogues as Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors (pages 1117–1126)

      Dr. Xuwang Chen, Yuanyuan Li, Shufang Ding, Prof. Jan Balzarini, Prof. Christophe Pannecouque, Prof. Erik De Clercq, Dr. Huiqing Liu and Prof. Xinyong Liu

      Version of Record online: 3 MAY 2013 | DOI: 10.1002/cmdc.201300130

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      Selective and effective! Compound BD-c1 shows impressively low cytotoxicity (CC50>146 μM), high selectivity (SI>14,126), and good inhibitory activity toward HIV-1 reverse transcriptase. With qualities similar to those of the new FDA-approved drug etravirine (CC50=28 μM, SI=12 884), BD-c1 is a promising lead compound for the development of even more efficacious anti-HIV drugs.

    8. You have full text access to this OnlineOpen article
      From On-Target to Off-Target Activity: Identification and Optimisation of Trypanosoma brucei GSK3 Inhibitors and Their Characterisation as Anti-Trypanosoma brucei Drug Discovery Lead Molecules (pages 1127–1137)

      Dr. Andrew Woodland, Raffaella Grimaldi, Dr. Torsten Luksch, Dr. Laura A. T. Cleghorn, Dr. Kayode K. Ojo, Prof. Wesley C. Van Voorhis, Dr. Ruth Brenk, Prof. Julie A. Frearson, Prof. Ian H. Gilbert and Prof. Paul G. Wyatt

      Version of Record online: 14 JUN 2013 | DOI: 10.1002/cmdc.201300072

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      Powerful parasite fighters: From a screen of a focused kinase library against Trypanosoma brucei GSK3, we optimised a series of diaminothiazoles, identifying low-nanomolar inhibitors of TbGSK3, which are potent in vitro inhibitors of T. brucei proliferation. These compounds have other molecular targets in addition to GSK3.

    9. Modification of Triclosan Scaffold in Search of Improved Inhibitors for Enoyl-Acyl Carrier Protein (ACP) Reductase in Toxoplasma gondii (pages 1138–1160)

      Dr. Jozef Stec, Alina Fomovska, Gustavo A. Afanador, Prof. Dr. Stephen P. Muench, Dr. Ying Zhou, Bo-Shiun Lai, Prof. Dr. Kamal El Bissati, Dr. Mark R. Hickman, Patty J. Lee, Susan E. Leed, Jennifer M. Auschwitz, Dr. Caroline Sommervile, Dr. Stuart Woods, Prof. Dr. Craig W. Roberts, Prof. Dr. David Rice, Dr. Sean T. Prigge, Dr. Rima McLeod and Prof. Dr. Alan P. Kozikowski

      Version of Record online: 14 JUN 2013 | DOI: 10.1002/cmdc.201300050

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      Crystal structures of the TgENR–NAD+–triclosan complex (A) with docked compounds 16 c (B) and 37 c (C): The latter two compounds have high potency, improved physicochemical properties, and lower toxicity than triclosan. Two new hydrogen bonding interactions with the surrounding TgENR residues are likely to be decisive for the high inhibitory activity of 16 c. Compound 37 c is bulkier, but binds in the same manner as triclosan.

    10. 5′-Trityl-Substituted Thymidine Derivatives as a Novel Class of Antileishmanial Agents: Leishmania infantum EndoG as a Potential Target (pages 1161–1174)

      Dr. Elena Casanova, Dr. David Moreno, Alba Gigante, Dr. Eva Rico, Carlos Mario Genes, Cristina Oliva, Prof. María-José Camarasa, Prof. Federico Gago, Prof. Antonio Jiménez-Ruiz and Prof. María-Jesús Pérez-Pérez

      Version of Record online: 26 APR 2013 | DOI: 10.1002/cmdc.201300129

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      LiEndoG as drug target? Thymidine derivatives with a triphenylmethyl substituent at the 5′-position exhibit significant activity against Leishmania infantum parasites. Characterization of cell death points toward the mitochondrial endonuclease G (LiEndoG) as a target.

    11. Inhibition of Leishmania infantum Trypanothione Reductase by Azole-Based Compounds: a Comparative Analysis with Its Physiological Substrate by X-ray Crystallography (pages 1175–1183)

      Dr. Paola Baiocco, Dr. Giovanna Poce, Dr. Salvatore Alfonso, Dr. Martina Cocozza, Dr. Giulio Cesare Porretta, Dr. Gianni Colotti, Dr. Mariangela Biava, Dr. Francesca Moraca, Dr. Maurizio Botta, Dr. Vanessa Yardley, Dr. Annarita Fiorillo, Dr. Antonella Lantella, Dr. Francesco Malatesta and Dr. Andrea Ilari

      Version of Record online: 3 JUN 2013 | DOI: 10.1002/cmdc.201300176

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      LiTR in pictures: We identified a new class of azole-based compounds that are active against the amastigote stage of Leishmania parasites. Steady-state inhibition studies indicate that compound 1, the most active, competes with trypanothione for the binding site of trypanothione reductase (TR). These results were confirmed by our determination of the X-ray crystal structure of the complex between compound 1 and TR, which shows that compound 1 impedes substrate binding to TR.

    12. Adamantyl Arotinoids That Inhibit IκB Kinase α and IκB Kinase β (pages 1184–1198)

      Dr. Paula Lorenzo, Dr. María A. Ortiz, Prof. Dr. Rosana Álvarez, Dr.  F. Javier Piedrafita and Prof. Dr. Ángel R. de Lera

      Version of Record online: 7 MAY 2013 | DOI: 10.1002/cmdc.201300100

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      An important MEMO: Adamantyl arotinoids related to MX781 are dual IKKα/IKKβ inhibitors. Their effects correlate with growth inhibitory activities and induction of apoptosis in cancer cell lines, effects that are independent of RAR/RXR modulation. The reactive Michael acceptor present in MX781 and other natural chalcones is absent in some of these analogues, indicating that alternative mechanisms must operate in the inhibition of IKK by these compounds.

    13. Water-Soluble Nitric-Oxide-Releasing Acetylsalicylic Acid (ASA) Prodrugs (pages 1199–1209)

      Dr. Barbara Rolando, Dr. Loretta Lazzarato, Dr. Monica Donnola, Dr. Elisabetta Marini, Dr. Sony Joseph, Prof. Dr. Giuseppina Morini, Dr. Cristina Pozzoli, Prof. Roberta Fruttero and Prof. Alberto Gasco

      Version of Record online: 10 JUN 2013 | DOI: 10.1002/cmdc.201300105

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      A new look for aspirin: Acetylsalicylic acid (ASA) derivatives bearing NO-releasing nitrooxy group and a solubilizing moiety at the benzoyl ring were designed as ASA prodrugs. When evaluated, all the products displayed good antiaggregatory properties, and two derivatives (shown) also exhibited improved in vivo anti-inflammatory properties and decreased gastrotoxicity when compared with ASA.

    14. Design, Synthesis, and Structure–Activity Relationships of 3,4,5-Trisubstituted 4,5-Dihydro-1,2,4-oxadiazoles as TGR5 Agonists (pages 1210–1223)

      Junjie Zhu, Yangliang Ye, Mengmeng Ning, Attila Mándi, Ying Feng, Qingan Zou, Dr. Tibor Kurtán, Prof. Dr. Ying Leng and Prof. Dr. Jianhua Shen

      Version of Record online: 11 JUN 2013 | DOI: 10.1002/cmdc.201300144

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      Binding pocket elaboration: A plausible pharmacophore model was used to design a novel class of TGR5 agonists based on a 3,4,5-trisubstituted 4,5-dihydro-1,2,4-oxadiazole core. New methods for constructing 4,5-dihydro-1,2,4-oxadiazoles were developed. An extensive structure–activity relationship study resulted in the identification of compound 54 n, which has excellent potency toward hTGR5. The configuration of the enantiomers was determined by solid-state TDDFT-ECD calculations.

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