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  • Hollow Mesoporous Silica@Metal−Organic Framework and Its Applications for pH-Responsive Doxorubicin Drug Delivery
    ChemMedChem (IF 3.225) Pub Date : 2018-01-16
    Xiaomin Jia, Zhiyuan Yang, Yujun Wang, Ya Chen, Haitao Yuan, Heyin Chen, Xiaoxiang Xu, Xueqing Gao, Zuozhong Liang, Yu Sun, Jian-Rong Li, Haoquan Zheng, Rui Cao

    Metal−organic frameworks (MOFs), a new type of porous crystalline materials, have great potential in biomedical applications, such as drug delivery. However, the efficacy of drug delivery is limited by the low loading of drugs. We have synthesized hollow mesoporous silica (HMS)@MOF capsule that can be used as pH-responsive drug delivery system for anti-cancer drug doxorubicin (DOX). DOX is loaded into the inner cavity of HMS.Then, zeolitic imidazolate framework-8 (ZIF-8) nanoparticles are coated on the outer surface of DOX loaded HMS. The obtained material is a capsule (denoted as DOX/HMS@ZIF), where DOX is encapsulated. The DOX/HMS@ZIF can be used as an efficient pH-responsive drug delivery system. The DOX is not released at physiological condition (pH 7.4) and released at low pH (4−6) from DOX/HMS@ZIF. The DOX/HMS@ZIF capsule shows a much higher cytotoxicity than free DOX and alters the delivery pathway for DOX in cancer cells, while the drug-free HMS@ZIF shows excellent biocompatibility. This opens new opportunities to construct a safe and efficient delivery system for targeted molecules using pH-responsive release for a wide range of applications.

    更新日期:2018-01-16
  • Specific Non-Covalent Interactions Determine Optimal Structure of a Buried Ligand Moiety: QM/MM and Pure QM Modeling of Complexes of the Small-Molecule CD4 Mimetics and HIV1 Gp120
    ChemMedChem (IF 3.225) Pub Date : 2018-01-16
    Francesca Moraca, David Rinaldo, Amos Brittain Smith, Cameron Abrams

    The small molecule CD4 mimetics (smCD4mc) are a class of highly potent HIV-1 entry inhibitors characterized by a unique SAR. They share a halogenated phenyl ring (region 1) that deeply inserts into an otherwise water-filled cavity at the CD4 binding site on the gp120 surface, so-called F43 cavity. Conservative modifications to region 1 away from this halogenated phenyl motif have all lead to loss of activity, despite they are predicted to bind equally well via standard empirical computational approaches making difficult to further optimize this region of the compounds to increase binding to gp120. Here, we employed quantum mechanical methods to understand the roots of the interactions between region 1 and the F43 cavity. We clearly demonstrate the presence of halogen bond/σ-hole and dispersion interactions between region 1 and the F43 cavity residues F376-N377 that are not captured by standard molecular mechanics approaches and the role played by the smCD4mc in the F43 cavity desolvation. These findings rationalize why the halogenated region 1 has proven so difficult to move beyond in smCD4mc optimization, in agreement with experimental evidence.

    更新日期:2018-01-16
  • 3D-e-Chem: Structural Cheminformatics Workflows for Computer-Aided Drug Discovery
    ChemMedChem (IF 3.225) Pub Date : 2018-01-16
    Albert J Kooistra, Marton Vass, Ross McGuire, Rob Leurs, Iwan JP de Esch, Gerrit Vriend, Stefan Verhoeven, Chris de Graaf

    eScience technologies are needed to process the information available in many heterogeneous types of protein-ligand interaction data and to capture these data into models that enable the design of efficacious and safe medicines. Here we present scientific KNIME tools and workflows that enable the integration of chemical, pharmacological, and structural information for: i) structure-based bioactivity data mapping, ii) structure-based identification of scaffold replacement strategies for ligand design, iii) ligand-based target prediction, iv) protein sequence-based binding site identification and ligand repurposing, and v) structure-based pharmacophore comparison for ligand repurposing across protein families. The modular setup of the workflows and the use of well-established standards allows the re-use of these protocols and facilitates the design of customized computer-aided drug discovery workflows.

    更新日期:2018-01-16
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  • 更新日期:2018-01-16
  • Development of potent inhibitors of the Mycobacterium tuberculosis virulence factor Zmp1 and evaluation of their effect on mycobacterial survival inside macrophages
    ChemMedChem (IF 3.225) Pub Date : 2018-01-15
    Marco Paolino, Margherita Brindisi, Alessandra Vallone, Stefania Butini, Giusepp Campiani, Chiara Nannicini, Germano Giuliani, Maurizio Anzini, Stefania Lamponi, Gianluca Giorgi, Diego Sbardella, Davide M Ferraris, Stefano Marini, Massimo Coletta, Ivana Palucci, Mariachiara Minerva, Giovanni Delogu, Ilaria Pepponi, Delia Goletti, Andrea Cappelli, Sandra Gemma, Simone Brogi

    The enzyme Zmp1 is a zinc-peptidase having a critical role in M. tuberculosis pathogenicity. Here we describe the identification of a small set of Zmp1 inhibitors based on a novel 8-hydroxyquinoline-2-hydroxamate scaffold. Among the synthesized compounds, 1c was the most potent Zmp1 inhibitor known to date, and its binding mode was analysed both through kinetic studies and molecular modelling, identifying critical interactions of 1c with the zinc-ion and residues in the active site. Effect of 1c on intracellular Mycobacterium survival was assayed in J774 murine macrophages infected with M. tuberculosis H37Rv or M. bovis BCG and human monocyte-derived macrophages infected with M. tuberculosis H37Rv. Cytotoxicity and genotoxicity were also assessed. Overall, inhibitor 1c displayed interesting in vitro antitubercular properties worth of further investigation.

    更新日期:2018-01-15
  • Design, Synthesis and Evaluation of Novel Oxazaborine Inhibitors of the NLRP3 Inflammasome
    ChemMedChem (IF 3.225) Pub Date : 2018-01-13
    Alex George Baldwin, Victor S. Tapia, Tessa Swanton, Claire S White, James A. Beswick, David Brough, Sally Freeman

    The NLRP3 inflammasome is an important regulator of the sterile inflammatory response and its activation by host-derived sterile molecules leads to the intracellular activation of caspase-1, processing of the pro-inflammatory cytokines interleukin-1β (IL 1β)/IL-18, and pyroptotic cell death. Inappropriate activation of NLRP3 drives a chronic inflammatory response and is implicated in several non-communicable diseases, including gout, atherosclerosis, type II diabetes and Alzheimer's disease. In this study, we report the design, synthesis and biological evaluation of novel boron compounds (NBCs) as NLRP3 inflammasome inhibitors. Structure-activity relationships (SAR) show that 4-F groups on the phenyl rings retain NLRP3 inhibitory activity, whereas more steric and lipophilic substituents diminish activity. Loss of inhibitory activity is also observed when the CCl3 group on the oxazaborine ring is replaced by a CF3 group. These findings provide additional understanding of the NBC series and will aid in the development of these NLRP3 inhibitors as tool compounds or therapeutic candidates for sterile inflammatory diseases.

    更新日期:2018-01-13
  • Discovery and characterization of CD12681, a potent RORγ inverse agonist, preclinical candidate for the topical treatment of psoriasis
    ChemMedChem (IF 3.225) Pub Date : 2018-01-12
    Gilles Ouvry, Nicolas Atrux-Tallau, Franck Bihl, Aline Bondu, Claire Bouix-Peter, Isabelle Carlavan, Olivier Christin, Marie-Josée Cuadrado, Claire Defoin-Platel, Sophie Deret, Denis Duvert, Christophe Feret, Mathieu Forissier, Jean-François Fournier, David Froude, Fériel Hacini-Rachinel, Craig Steven Harris, Catherine Hervouet, Hélène Huguet, Guillaume Lafitte, Anne-Pascale Luzy, Branislav Musicki, Danielle Orfila, Benjamin Ozello, Coralie Pascau, Jonathan Pascau, Véronique Parnet, Guillaume Peluchon, Romain Pierre, David Piwnica, Catherine Raffin, Patricia Rossio, Delphine Spiesse, Nathalie Taquet, Etienne Thoreau, Rodolphe Vatinel, Emmanuel Vial, Laurent François Hennequin

    With possible implications in multiple autoimmune diseases, the retinoic acid receptor-related orphan receptor RORγ has become a very sought-after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated with the discovery of CD12681 (compound 14; N-(2,4-dimethylphenyl)-N-isobutyl-2-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide), a potent inverse agonist with in vivo activity in an IL-23 induced skin inflammation model in mouse.

    更新日期:2018-01-12
  • N-Benzyl substitution of polyhydroxypyrrolidines - the way to selective inhibitors of Golgi α-mannosidase II
    ChemMedChem (IF 3.225) Pub Date : 2018-01-11
    Sergej Šesták, Maroš Bella, Tomáš Klunda, Soňa Gurská, Petr Džubák, Florian Wöls, Iain BH Wilson, Vladimir Sladek, Marián Hajdúch, Monika Polakova, Juraj Kóňa

    Inhibition of biosynthesis of complex N-glycans in Golgi apparatus influence progress of tumor growth and metastasis. Golgi α-mannosidase II (GMII) has become a therapeutic target for a drug with anticancer activities. One critical task for successful application GMII drugs in medicine treatment is to reduce their unwanted co-inhibition with lysosomal α-mannosidase (LMan) by which suffer all known potent GMII inhibitors. A series of novel N-substituted polyhydroxypyrrolidines was synthesized and tested with modeled GH38 α-mannosidases from Drosophila melanogaster (GMIIb and LManII). The most potent structures inhibited GMIIb (Ki = 50-76 μM as determined by enzyme assays) with a significant selectivity index of IC50(LManII)/IC50(GMIIb) > 100. They also showed the inhibitory activity in vitro assays with MTS test towards cancer cell lines (leukemia, IC50 = 92-200 μM) and low cytotoxic activity towards normal fibroblast cell lines (IC50 > 200 μM). In addition, they did not show any significant inhibitory activity towards GH47 Aspergillus saitoi α1,2-mannosidase. An appropriate stereo configuration of -CH2OH and benzyl functional groups on the pyrrolidine ring of the inhibitor may lead to an inhibitor with the required selectivity to the active site of a target α-mannosidase.

    更新日期:2018-01-11
  • Synthesis of N-Substituted Iminosugar Derivatives and Evaluation of Their Immunosuppressive Activities
    ChemMedChem (IF 3.225) Pub Date : 2018-01-11
    Xinshan Ye, Qin Li

    It is important to find more effective and safer immunosuppressants because the clinically-used immunosuppressive agents have significant side-effects. A series of N-substituted iminosugar derivatives were designed and synthesized, and their immunosuppressive effects were evaluated by CCK-8 assay. The results revealed that iminosugars 10e and 10i exhibited the strongest inhibitory effect on mouse splenocyte proliferation (IC50 = 2.16 and 2.48 μM, respectively), whereas the iminosugars containing an amide group near the hydrophilic head (compounds 10j-n) exhibited no inhibitory effects. Further studies revealed that the inhibitory effects on splenocyte proliferation may come from the suppression of both IFN-γ and IL-4 cytokines. Our results suggested that the synthetic iminosugars, especially compounds 10e and 10i hold the potential as immunosuppressive agents.

    更新日期:2018-01-11
  • Design and Synthesis of A-Ring Simplified Pyripyropene A Analogs as Potent and Selective Synthetic SOAT2 Inhibitors
    ChemMedChem (IF 3.225) Pub Date : 2018-01-11
    Masaki Ohtawa, Shiho Arima, Naoki Ichida, Tomiaki Terayama, Hironao Ohno, Takaya Yamazaki, Taichi Ohshiro, Noriko Sato, Satoshi Omura, Hiroshi Tomoda, Tohru Nagamitsu

    Currently, pyripyropene A, which is isolated from the culture broth of Aspergillus fumigatus FO-1289, is the only compound known to strongly and selectively inhibit the isozyme sterol O-acyltransferase 2 (SOAT2). To aid in the development of new cholesterol-lowering or antiatherosclerotic agents, new A-ring simplified pyripyropene A analogs were designed and synthesized based on the total synthesis and the results of the structure-activity relationship studies of pyripyropene A achieved by our group. Among the analogs, two A-ring simplified pyripyropene A analogs exhibited equally efficient SOAT2 inhibitory activity compared with that of natural pyripyropene A. These new analogs are the most potent and selective SOAT2 inhibitors to be used as synthetic compounds and attractive seed compounds for the development of drug for dyslipidemia, including atherosclerotic disease and steatosis.

    更新日期:2018-01-11
  • Interactions Between Clinically Used Bisphosphonates and Bone Mineral. From Coordination Chemistry to Biomedical Applications and Beyond.
    ChemMedChem (IF 3.225) Pub Date : 2018-01-11
    Joanna Gałęzowska

    Bisphosphonates (BPs) are well established, widely used first-choice drugs for bone-related diseases and are one of the few classes of molecules for selective bone-targeting. Their binding to calcium cations within hydroxyapatite (HA) is a key physico-chemical event taking place on the bone surface. It is the starting point for a cascade of biochemical reactions and cellular effects that lead to the pharmacological activity of BPs. The phenomenon is known for years, yet still its physicochemical nature is not fully understood. In particular the adsorption/release processes and structure-function relationships of BPs remain to be clarified. These are elementary, yet crucial factors, which should influence design and development of new delivery tools or drugs with improved characteristics. This minireview will summarize the current understanding of the chemical interactions between clinically used BPs and bone mineral, starting from basic Ca2+ coordination chemistry through to interactions with hydroxyapatite, nanocrystalline apatites and natural bone mineral.

    更新日期:2018-01-11
  • In silico studies designed to select sesquiterpene lactones with potential antichagasic activity from an in-house Asteraceae database
    ChemMedChem (IF 3.225) Pub Date : 2018-01-11
    Chonny Herrera-Acevedo,, Luciana Scotti, Marcus Tullius Scotti

    Chagas disease is an endemic disease caused by Trypanosoma cruzi, which affects more than eight million people, mostly in the Americas. A search for new treatments is necessary to control and eliminate this disease. Sesquiterpene lactones (SLs) are an interesting group of secondary metabolites characteristic of Asteraceae that have presented a wide range of biological activities. From the ChEMBL database, we selected a diverse set of 4,452, 1,635 and 1,322 structures with tested activity against the three T. cruzi parasitic forms, amastigote, trypomastigote and epimastigote, respectively, to create random forest (RF) models with an accuracy of greater than 74% for cross-validation and test sets. Afterwards, a ligand-based virtual screen of the entire SLs of Asteraceae database stored in SistematX (1,306 structures) was performed. In addition, a structure-based virtual screen was also performed for the same set of SLs using molecular docking. Finally, using an approach combining ligand-based and structure-based virtual screening along with the equations proposed in this study to normalize the probability scores, we verified potentially active compounds and established a possible mechanism of action.

    更新日期:2018-01-11
  • Discovery of Novel Muscarinic Receptor Modulators by Integrating Natural Product Framework with Bioactive Molecule
    ChemMedChem (IF 3.225) Pub Date : 2018-01-10
    Rajesh Varkhedkar, Shalini Dogra, Divya Tiwari, Yusuf Hussain, Prem Narayan Yadav, Ganesh Pandey

    Muscarinic acetylcholine receptors (mAChRs) are important therapeutic targets for several diseases of central nervous system and periphery. However, lack of subtype selective ligands of these receptors is a major challenge. A novel approach of integrating natural product framework with bioactive molecule (iNPBM) by utilizing the Gephyrotoxin and isoindoline framework, is demonstrated for discovery of new and selective mAChR modulators. We established a scalable and versatile synthetic scheme to enable synthesis of various analogues that provided the first SAR study of this class of compounds. Pharmacological profiling of these compounds demonstrated several high affinity and selective ligands of mAChRs. Specifically, RG-06 and RG-09 as antagonist of M3-mAChR, while RG-02 as agonist at M2-mAChR. Furthermore, RG-02 exhibits salutary effects in an established pharmacological model of cognitive deficit in mice.

    更新日期:2018-01-10
  • A Novel Prodrug of a γ-Glutamylcyclotransferase Inhibitor Suppresses Cancer Cell Proliferation in vitro and Inhibits Tumor Growth in a Xenograft Mouse Model of Prostate Cancer
    ChemMedChem (IF 3.225) Pub Date : 2018-01-09
    Hiromi Ii, Taku Yoshiya, Susumu Nakata, Keiko Taniguchi, Koushi Hidaka, Shugo Tsuda, Masayoshi Mochizuki, Yuji Nishiuchi, Yuko Tsuda, Kosei Ito, Susumu Kageyama, Tatsuhiro Yoshiki
    更新日期:2018-01-09
  • Front Cover: Mitochondria-Targeting Polyamine–Protoporphyrin Conjugates for Photodynamic Therapy (ChemMedChem 1/2018)
    ChemMedChem (IF 3.225) Pub Date : 2018-01-08
    Fargol Taba, Akira Onoda, Urara Hasegawa, Toshiaki Enoki, Yousuke Ooyama, Joji Ohshita, Takashi Hayashi
    更新日期:2018-01-08
  • Cover Feature: LEGO-Inspired Drug Design: Unveiling a Class of Benzo[d]thiazoles Containing a 3,4-Dihydroxyphenyl Moiety as Plasma Membrane H+-ATPase Inhibitors (ChemMedChem 1/2018)
    ChemMedChem (IF 3.225) Pub Date : 2018-01-08
    Truong-Thanh Tung, Trong T. Dao, Marta G. Junyent, Michael Palmgren, Thomas Günther-Pomorski, Anja T. Fuglsang, Søren B. Christensen, John Nielsen
    更新日期:2018-01-08
  • Diversity in Medicinal Chemistry
    ChemMedChem (IF 3.225) Pub Date : 2018-01-08
    David Peralta
    更新日期:2018-01-08
  • Evidence for novel action at the cell binding site of human Angiogenin revealed by heteronuclear NMR spectroscopy, in silico and in vivo studies
    ChemMedChem (IF 3.225) Pub Date : 2018-01-04
    Demetra SM Chatzileontiadou, Aikaterini C Tsika, Zoi Diamantopoulou, Jean Delbé, Josette Badet, José Courty, Vassiliki T Skamnaki, Vanessa Parmenopoulou, Dimitri Komiotis, Joseph M Hayes, Georgios A Spyroulias, Demetres D. Leonidas

    A member of Ribonuclease A superfamily, human Angiogenin (hAng) is a potent angiogenic factor. Heteronuclear NMR spectroscopy combined with induced-fit docking revealed a dual binding mode for the most antiangiogenic compound of a series of ribofuranosyl pyrimidine nucleosides that strongly inhibit hAng's angiogenic activity in vivo. While modelling suggests the potential of a simultaneous binding of the inhibitors at the active and cell binding sites, NMR indicates greater affinity for the cell binding site than for the active site. Additionally, a 100 nanoseconds molecular dynamics simulation have confirmed the stability of the binding at the cell-binding site with the predicted protein-ligand interactions in excellent agreement with the NMR data. This is the first time that a nucleoside inhibitor is reported to inhibit completely the angiogenic activity of hAng in vivo by exerting dual inhibitory activity on hAng, blocking both the entrance of hAng into the cell and the ribonucleolytic activity.

    更新日期:2018-01-04
  • Superior HIV-1 TAR-Binders with Conformationally Constrained R52 Arginine Mimics in Tat (48-57) Peptide
    ChemMedChem (IF 3.225) Pub Date : 2018-01-04
    Govind S. Bhosle, Shalmali Kharche, Santosh Kumar, Durba Sengupta, Souvik Maiti, Moneesha Fernandes

    We report a hundred-fold increase in binding affinity of the Tat(48-57) peptide to HIV-1 TAR RNA by replacing R52, an essential and critical residue for Tat's specific binding, by (2S,4S)-4-guanidinoproline. The resulting αTat1M peptide is a far superior binder than γTat1M, a peptide containing another conformationally constrained arginine mimic, (2S,4S)-4-amino-N-(3-guanidinopropyl)-proline, or even the control Tat (CtrlTat) itself. Our observations are supported by CD, ITC, gel electrophoresis and UV spectroscopy studies. Molecular dynamics simulations suggest increased interactions between the more compact αTat1M and TAR RNA, in comparison to CtrlTat. The CD signature of the RNA itself remains largely unchanged upon binding of the peptides. The Tat mimetics further have better cell uptake properties in comparison to the control Tat peptide, thus increasing their application potential as specific TAR-binding molecules.

    更新日期:2018-01-04
  • Bioisosteric Replacements Extracted from High Quality Structures in the Protein Databank
    ChemMedChem (IF 3.225) Pub Date : 2018-01-03
    Val Gillet, Matthew P. Seddon, David A. Cosgrove

    Bioisosterism is an important concept in the lead optimization phase of drug discovery where the aim is to make modifications to parts of a molecule with the aim of improving some properties while maintaining others. We present an analysis of bioisosteric fragments extracted from the ligands in an established data set consisting of 121 protein targets. A pairwise analysis is carried out of all ligands for a given target. The ligands are fragmented using the BRICS fragmentation scheme and a pair of fragments is deemed to be bioisosteric if they occupy a similar volume of the protein binding site. We consider two levels of generality, one which does not consider the number of attachment points in the fragments and a more restricted case in which both fragments are required to have the same number of attachments. We investigate the extent to which the bioisosteric pairs that are found are common across different target.

    更新日期:2018-01-04
  • Designing Novel Dual Transglutaminase 2 / Histone Deacetylase Inhibitors Effective in Halting Neuronal Death
    ChemMedChem (IF 3.225) Pub Date : 2017-12-29
    Manuela Basso, Huan Huan Chen, Debasmita Tripathy, Mariarosaria Conte, Kim Y.P. Apperley, Angela De Simone, Jeffrey w Keillor, Rajiv Ratan, Angela Nebbioso, Federica Sarno, Lucia Altucci, Andrea Milelli

    In recent years there has been a clear consensus that neurodegenerative conditions can be better treated through concurrent modulation of different targets. Herein, we report that combined inhibition of Transglutaminase 2 (TG2) and Histone Deacetylases (HDACs) protects synergistically against toxic stimuli mediated by glutamate. Based on these findings, we designed and synthesized a series of novel dual TG2-HDAC binding agents. Compound 3 emerges as the most interesting of the series being able to inhibit TG2 and HDACs both in vitro (TG2, IC50 = 13.3 ± 1.5 μM; HDAC1, IC50 = 3.38 ± 0.14 μM; HDAC6, IC50 = 4.10 ± 0.13 μM) and in cell-based assay. Furthermore, compound 3 does not exert any toxic effects in cortical neurons up to 50 μM and protects neurons against toxic insults induced by glutamate (5 mM) with an EC50 of 3.7 ± 0.5 µM.

    更新日期:2017-12-31
  • Hit Dexter: A Machine-learning Model for the Prediction of Frequent Hitters
    ChemMedChem (IF 3.225) Pub Date : 2017-12-29
    Conrad Stork, Johannes Wagner, Nils-Ole Friedrich, Christina de Bruyn Kops, Martin Šícho, Johannes Kirchmair

    False-positive assay readouts caused by badly behaving compounds (frequent hitters, pan-assay interference compounds - PAINS, aggregators and others) continue to pose a major challenge to experimental screening. Few in silico methods exist that allow the prediction of such problematic compounds. We report on the development of Hit Dexter, two extremely randomized trees classifiers for the prediction of compounds likely to trigger positive assay readouts either by true promiscuity or by assay interference. The models were trained on a well-prepared dataset extracted from the PubChem Bioassay database, consisting of approximately 311k compounds tested for activity on at least 50 proteins. Hit Dexter reached MCC and AUC values of up to 0.67 and 0.96 on an independent test set, respectively. The models are expected to be of high value, in particular to medicinal chemists and biochemists who can use Hit Dexter to identify compounds for which extra caution should be exercised with positive assay readouts. Hit Dexter is available as a free web service at http://hitdexter.zbh.uni-hamburg.de.

    更新日期:2017-12-31
  • The anticancer potential of Peroxisome Proliferator-Activated Receptor antagonists
    ChemMedChem (IF 3.225) Pub Date : 2017-12-24
    Laura De Lellis, Annamaria Cimini, Serena Veschi, Elisabetta benedetti, Rosa Amoroso, Alessandro Cama, Alessandra Ammazzalorso

    The effects on cancer cell proliferation and differentiation mediated by Peroxisome Proliferator-Activated Receptors (PPARs) were widely studied, with pleiotropic outcomes in different cancer models and experimental conditions. Interestingly, relatively few studies and preclinical evidences report the potential antitumor activity of PPAR antagonists. This review focuses on recent findings about the antitumor in vitro and in vivo effects observed for compounds able to inhibit the three PPAR subtypes in different tumor models, providing a rationale for the use of PPAR antagonists in the treatment of tumors expressing the corresponding receptors.

    更新日期:2017-12-27
  • Structure Based Design of Selective Non-covalent CDK12 Inhibitors
    ChemMedChem (IF 3.225) Pub Date : 2017-12-20
    Jeffrey Johannes, Christopher R. Denz, Nancy Su, Allan Wu, Anna C. Impastato, Scott Mlynarski, Jeffrey G. Varnes, D. Bryan Prince, Justin Cidado, Ning Gao, Malcolm Haddrick, Natalie H. Jones, Shaobin Li, Xiuwei Li, Yang Liu, Toan B. Nguyen, Nichole O'Connell, Emma Rivers, Daniel W. Robbins, Ronald Tomlinson, Tieguang Yao, Andrew D. Ferguson, Michelle L. Lamb, John I. Manchester, Sylvie Guichard

    CDK12 knockdown via siRNA reduces transcription of DNA damage response genes and sensitizes BRCA wild type cells to PARP inhibition. To recapitulate this effect with a small molecule, we sought a potent, selective CDK12 inhibitor. Crystal structures and modeling informed hybridization between dinaciclib and SR-3029, resulting in lead compound 5. Further structure guided optimization delivered a series of selective CDK12 inhibitors, including compound 7. Profiling of this compound across CDK9, 7, 2 and 1 at high ATP concentration, single point kinase panel screening against 352 targets at 0.1 µM, and proteomics via kinase affinity matrix technology demonstrated selectivity. This series of compounds inhibit phosphorylation of Ser2 on the C-terminal repeat domain of RNA pol II, consistent with CDK12 inhibition. These selective compounds were also acutely toxic to OV90 as well as THP1 cells

    更新日期:2017-12-21
  • Binding Mode and Structure-Activity Relationships of ITE as Aryl Hydrocarbon Receptor (AhR) Agonist.
    ChemMedChem (IF 3.225) Pub Date : 2017-12-20
    Daniela Dolciami, Marco Gargaro, Bruno Cerra, Giulia Scalisi, Luana Bagnoli, Giuseppe Servillo, Maria Agnese Della Fazia, Paolo Puccetti, Francisco J Quintana, Francesca Fallarino, Antonio Macchiarulo

    Discovered as modulator of the toxic response to environmental pollutants, aryl hydrocarbon receptor (AhR) has recently gained attention for its involvement in various physiological and pathological pathways. AhR is a ligand-dependent transcription factor activated by a large array of chemical compounds, which include metabolites of L-Tryptophan (L-Trp) catabolism as endogenous ligands of the receptor. Among these, 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is attracting interest in the scientific community, being endowed with non-toxic, immunomodulatory and anticancer AhR-mediated functions. So far, no information about the binding mode and interactions of ITE to AhR is available. In this study, we used docking and molecular dynamics to propose a putative binding mode of ITE into the ligand binding pocket of AhR. Mutagenesis studies were then instrumental to validate the proposed binding mode, identifying His285 and Tyr316 as important key residues for ligand-dependent receptor activation. Finally, a set of ITE analogues was synthesized and tested to further probe molecular interactions of ITE to AhR, and characterize the relevance of specific functional groups in the chemical structure for receptor activity.

    更新日期:2017-12-20
  • Co-administration of Antimicrobial Peptides (AMPs) EnhancesToll-like Receptor 4 (TLR4) Antagonist Activity of a Synthetic Glycolipid
    ChemMedChem (IF 3.225) Pub Date : 2017-12-19
    Francesco Peri, Fabio Alessandro Facchini, Helena Coelho, Stefania Enza Sestito, Sandra Delgado, Alberto Minotti, David Andreu, Jesús Jiménez-Barbero

    This study describes the effect of co-administration of antimicrobial peptides (AMPs) and synthetic glycolipid FP7, active in inhibiting inflammatory cytokine production caused by TLR4 activation and signaling. The co-administration of two LPS-neutralizing peptides (a cecropin A-melittin hybrid peptide and a human cathelicidin) enhances by an order of magnitude the potency of FP7 in blocking the TLR4 signal. Interestingly, this is not an additional effect of LPS neutralization by peptides, since it also occurs when cells are stimulated by the plant lectin phytohemagglutinin (PHA), a non-LPS TLR4 agonist. Our data suggest a dual mechanism of action for the peptides, not exclusively based on LPS binding and neutralization, but also on a direct effect on LPS-binding proteins of the TLR4 receptor complex. NMR experiments in solution show that peptide addition changes the aggregation state of FP7, promoting the formation of larger micelles. These results suggest a relationship between the aggregation state of lipid A-like ligands and the type and intensity of TLR4 response.

    更新日期:2017-12-19
  • Front Cover: DNA Microcapsule for Photo-Triggered Drug Release Systems (ChemMedChem 24/2017)
    ChemMedChem (IF 3.225) Pub Date : 2017-12-19
    Yukiko Kamiya, Yoshinobu Yamada, Takahiro Muro, Kazunori Matsuura, Hiroyuki Asanuma
    更新日期:2017-12-19
  • 更新日期:2017-12-19
  • The 10th Joint Meeting on Medicinal Chemistry (JMMC 2017) Held in Dubrovnik, Croatia
    ChemMedChem (IF 3.225) Pub Date : 2017-12-18
    Ivana Perković, Višnja Stepanić, Vesna Gabelica Marković
    更新日期:2017-12-18
  • 更新日期:2017-12-15
  • Nitrate esters of heteroaromatic compounds as novel Candida albicans CYP51 enzyme inhibitors
    ChemMedChem (IF 3.225) Pub Date : 2017-12-13
    Marija Smiljkovic, Minos-Timotheos Matsoukas, Eftichia Kritsi, Urska Zelenko, Simona Golic Grdodolnik, Ricardo Calhelha, Isabel Ferreira, Snezana Sankovic-Babic, Jasmina Glamoclija, Theano Fotopoulou, Maria Koufaki, Panagiotis Zoumpoulakis, Marina Sokovic

    Four heteroaromatic compounds bearing nitrate esters were selected using a virtual screening procedure as putative sterol 14α-demethylase (CYP51) Candida albicans inhibitors. Compounds were examined for their inhibition on C. albicans growth and biofilm formation as well as for their toxicity. NMR studies, in silico docking and molecular dynamics simulations were used to further investigate selectivity of compounds to fungal CYP51. All compounds exhibited good antimicrobial properties, indicated with low minimal inhibitory concentrations and ability to inhibit formation of fungal biofilm. Moreover, all the compounds had the ability to inhibit growth of C. albicans cells. N-(2-nitooxyethyl)-1Η-indol-2-carboxamide was the only compound with selectivity on C. albicans CYP51 which did not exhibit cytotoxic effect on cells isolated from liver and should be further investigated for selective application in new leads for the treatment of candidiasis.

    更新日期:2017-12-13
  • Synthesis of α-branched acyclic nucleoside phosphonates as potential inhibitors of bacterial adenylate cyclases
    ChemMedChem (IF 3.225) Pub Date : 2017-12-13
    Jan Frydrych, Jan Skácel, Markéta Šmídková, Helena Mertlíková-Kaiserová, Martin Dračínský, Ramachandran Gnanasekaran, Martin Lepšík, Monica Soto-Velasquez, Val J. Watts, Zlatko Janeba

    Inhibition of Bordetella pertussis adenylate cyclase toxin (ACT) and Bacillus anthracis edema factor (EF), the key virulence factors with adenylate cyclase (AC) activity, represents a potential method how to treat or prevent toxemia related to whooping cough and anthrax, respectively. A novel series of α-branched acyclic nucleoside phosphonates (ANPs) having a hemiaminal ether moiety was synthesized as potential inhibitors of bacterial adenylate cyclases. ANPs prepared as bisamidates were not cytotoxic but did not exhibited any profound activity (IC50 > 10 µM) towards ACT in J774A.1 macrophage cells. The apparent lack of activity of the bisamidates was speculated to be due to the inefficient formation of the biologically active species (ANPpp) in the cells. On the other hand, two 5-haloanthraniloyl-substituted ANPs in the form of diphosphates (ANPpp) were shown to be potent ACT and EF inhibitors with IC50 values ranging from 55 to 360 nM.

    更新日期:2017-12-13
  • Discovery and Mechanistic Elucidation of a Class of PDI Inhibitors for the Treatment of Glioblastoma
    ChemMedChem (IF 3.225) Pub Date : 2017-12-12
    Anahita Kyani, Shuzo Tamura, Suhui Yang, Andrea Shergalis, Soma Somanta, Yuting Kuang, Mats Ljungman, Nouri Neamati

    Protein disulfide isomerase (PDI) is overexpressed in glioblastoma, the most aggressive form of brain cancer, and folds nascent proteins responsible for the progression and spread of the disease. Herein, we describe a novel, nanomolar PDI inhibitor, pyrimidotriazinedione 35G8, that is toxic in a panel of human glioblastoma cell lines. We performed a medium throughput 20,000-compound screen of a diverse subset of 1,000,000 compounds to identify cytotoxic small molecules. Cytotoxic compounds were screened for PDI inhibition, and, from the screen, 35G8 emerged as the most cytotoxic inhibitor of PDI. Bromouridine-labeling and sequencing (Bru-seq) of nascent RNA revealed that 35G8 induced Nrf2 (nuclear factor-like 2) antioxidant response, endoplasmic reticulum stress response, and autophagy. Specifically, 35G8 upregulated heme oxygenase 1 and SLC7A11 (solute carrier family 7 member 11) transcription and protein expression and repressed PDI target genes such as TXNIP (thioredoxin-interacting protein 1) and EGR1 (early growth response 1). Interestingly, 35G8-induced cell death did not proceed via apoptosis or necrosis, but by a mixture of autophagy and ferroptosis. Cumulatively, our data demonstrate a mechanism for a novel PDI inhibitor as a chemical probe to validate PDI as a target for brain cancer.

    更新日期:2017-12-13
  • Achieving biocompatible SABRE: An in vitro cytotoxicity study
    ChemMedChem (IF 3.225) Pub Date : 2017-12-12
    Simon Duckett, Anand Manoharan, Peter J Rayner, Michael J Burns, Wissam Iali, V. Hugh Perry

    Production of a biocompatible hyperpolarized bolus by Signal Amplification By Reversible Exchange (SABRE) could open the door to simple clinical diagnosis via magnetic resonance imaging. Essential to successful progression to pre-clinical/clinical applications is the determination of the toxicology profile of the SABRE reaction mixture. Here we exemplify the cytotoxicity of the SABRE approach using in vitro cell assay. We conclude that the main cause of observed toxicity is due to the SABRE catalyst. Thus we develop two catalyst removal methods, one involving deactivation and ion-exchange chromatography and the second biphasic catalysis. These routes produce a bolus suitable for future in vivo study.

    更新日期:2017-12-12
  • [Carboxyl-11C]-Labeling of four high-affinity cPLA2a inhibitors and their evaluation as radioligands in mice with positron emission tomography
    ChemMedChem (IF 3.225) Pub Date : 2017-12-12
    Martin J Fisher, Lindsay McMurray, Shuiyu Lu, Cheryl L Morse, Jeih-San Liow, Sami S Zoghbi, Aneta Kowalski, Geroge L Tye, Robert B Innis, Franklin I Aigbirhio, Victor W Pike

    Cytosolic phospholipase A2α (cPLA2α) may play a critical role in neuropsychiatric and neurodegenerative disorders associated with oxidative stress and neuroinflammation. An effective PET radioligand for imaging cPLA2α in living brain might prove useful for biomedical research, especially on neuroinflammation. We selected four high-affinity (IC50 2.1 to 12 nM) indole-5-carboxylic acid-based inhibitors of cPLA2α (1-4), for labelling in carboxyl position with carbon-11 (t1/2 = 20.4 min) to provide candidate PET radioligands for imaging brain cPLA2α. [11C]1-4 were obtained for intravenous injection in adequate overall yields (1.1−5.5%) from cyclotron-produced [11C]carbon dioxide and with moderate molar activities (70−141 GBq/μmol) through the use of Pd(0)-mediated [11C]carbon monoxide insertion on iodo precursors. Measured logD7.4 values were within a narrow moderate range (1.9−2.4). After intravenous injection of [11C]1-4 in mice, radioactivity uptakes in brain peaked at low values (≤ 0.8 SUV) and decreased by about 90% over 15 min. Pre-treatments of the mice with high doses of the corresponding non-radioactive ligands did not alter brain time-activity curves. Brain uptakes of radioactivity after administration of [11C]1 to wild type and P-gp/BCRP dual knock-out mice were similar (peak 0.4 vs. 0.5 SUV), indicating that [11C]1 and others in this structural class, are not efflux transporters substrates.

    更新日期:2017-12-12
  • New Potent Inhibitors against Newcastle Disease Virus Haemagglutinin−Neuraminidase
    ChemMedChem (IF 3.225) Pub Date : 2017-12-12
    Paola Rota, Paolo La Rocca, Marco Piccoli, Marco Montefiori, Federica Cirillo, Lars Olsen, Marica Orioli, Pietro Allevi, Luigi Anastasia

    Neuraminidase activity is essential for the infection and propagation of Paramyxoviruses, including human parainfluenza viruses (hPIVs) and the Newcastle Disease Virus (NDV). Thus, many inhibitors have been developed based on the 2-deoxy-2,3-didehydro-D-N-acetylneuraminic acid inhibitor (DANA) backbone. Along this line, we report here a series of neuraminidase inhibitors, having C-4 (ptoluensulfonamide and azido substituents) and C-5 (N-perfluorinated chains) modifications to the DANA backbone, that resulted 5- to 15-folds more potent than the current most active compound, the Ntrifluoroacetyl derivative of DANA (FANA), on the NDV haemagglutinin-neuraminidase (NDV-HN). Remarkably, these inhibitors resulted essentially inactive toward the human sialidase NEU3, which is present on the outer layer of the cell membrane and is highly affected by current NDV inhibitor FANA.

    更新日期:2017-12-12
  • Activities of 11-Azaartemisinin and N-Sulfonyl Derivatives against Asexual and Transmissible Malaria Parasites
    ChemMedChem (IF 3.225) Pub Date : 2017-12-08
    Rozanne Harmse, Dina Coertzen, Ho Ning Wong, Frans J. Smit, Mariette E. van der Watt, Janette Reader, Sindiswe H. Nondaba, Lyn-Marie Birkholtz, Richard K. Haynes, David D. N'Da

    Dihydroartemisinin (DHA), either used in its own right or as the active drug generated in vivo from the other artemisinins in current clinical use—artemether and artesunate—induces quiescence in ring-stage parasites of Plasmodium falciparum (Pf). This induction of quiescence is linked to artemisinin resistance. Thus, we have turned to structurally disparate artemisinins that are incapable of providing DHA on metabolism. Accordingly, 11-azaartemisinin 5 and selected N-sulfonyl derivatives were screened against intraerythrocytic asexual stages of drug-sensitive Pf NF54 and drug-resistant K1 and W2 parasites. Most displayed appreciable activities against all three strains, with IC50 values <10.5 nm. The p-trifluoromethylbenzenesulfonyl-11-azaartemisinin derivative 11 [(4′-trifluoromethyl)benzenesulfonylazaartemisinin] was the most active, with IC50 values between 2 and 3 nm. The compounds were screened against Pf NF54 early and transmissible late intraerythrocytic-stage gametocytes using luciferase and parasite lactate dehydrogenase (pLDH) assays. The 2′-thienylsulfonyl derivative 16 (2′-thiophenesulfonylazaartemisinin) was notably active against late-stage (IV–V) gametocytes with an IC50 value of 8.7 nm. All compounds were relatively nontoxic to human fetal lung WI-38 fibroblasts, showing selectivity indices of >2000 toward asexual parasites. Overall, the readily accessible 11-azaartemisinin 5 and the sulfonyl derivatives 11 and 16 represent potential candidates for further development, in particular for transmission blocking of artemisinin-resistant parasites. Resistance fighters: New artemisinin antimalarial drugs that do not provide dihydroartemisinin upon hydrolysis or metabolism and that are active against transmissible blood stages of the malaria parasite are urgently required. We examined 11-azaartemisinin and sulfonyl derivatives, some of which possess low-nanomolar activities against the transmissible late-stage gametocytes of Plasmodium falciparum.

    更新日期:2017-12-11
  • LEGO-Inspired Drug Design: Unveiling a Class of Benzo[d]thiazoles Containing a 3,4-Dihydroxyphenyl Moiety as Plasma Membrane H+-ATPase Inhibitors
    ChemMedChem (IF 3.225) Pub Date : 2017-12-07
    Truong-Thanh Tung, Trong T. Dao, Marta G. Junyent, Michael Palmgren, Thomas Günther-Pomorski, Anja T. Fuglsang, Søren B. Christensen, John Nielsen
    更新日期:2017-12-07
  • Front Cover: A Dithiol Compound Binds to the Zinc Finger Protein TRAF6 and Suppresses Its Ubiquitination (ChemMedChem 23/2017)
    ChemMedChem (IF 3.225) Pub Date : 2017-12-07
    Ryoko Koga, Mohamed O. Radwan, Tomohiko Ejima, Yosuke Kanemaru, Hiroshi Tateishi, Taha F. S. Ali, Halil Ibrahim Ciftci, Yuri Shibata, Yuu Taguchi, Jun-ichiro Inoue, Masami Otsuka, Mikako Fujita
    更新日期:2017-12-07
  • Cover Feature: Methyl Fumarate-Derived Iron Carbonyl Complexes (FumET-CORMs) as Powerful Anti-inflammatory Agents (ChemMedChem 23/2017)
    ChemMedChem (IF 3.225) Pub Date : 2017-12-07
    Britta Bauer, Anna-Lena Göderz, Heidi Braumüller, Jörg Martin Neudörfl, Martin Röcken, Thomas Wieder, Hans-Günther Schmalz
    更新日期:2017-12-07
  • Exploring structure-activity relationships with three-dimensional matched molecular pairs - A review
    ChemMedChem (IF 3.225) Pub Date : 2017-12-06
    Emanuel S. R. Ehmki, Matthias Rarey

    A Matched Molecular Pair consists of two small molecules which differ by a few atoms only. The minor structural difference between the molecules allows a detailed analysis of changes in property. Three dimensional matched molecular pairs extend the concept of chemical similarity by spatial similarity. Conformations have to be generated and superpositions have to be calculated. The additional complexity and uncertainty as well as the smaller amount of available experimental data substantially complicates derivation of models. Nonetheless, there are some benefits making the transition worthwhile. Detailed insights into mechanisms behind disrupted series of structure activity relations, extending the MMP concept with scaffold hopping or high confidence structure activity relationship transfer between series of analogs are just some examples the 3D concept provides access to. Several groups approached the problem from different directions. The models vary especially in three-dimensional similarity measure used and complexity of the applied descriptor selected or designed. Nonetheless, all approaches have increased the gain in information with incorporating three-dimensional structural information.

    更新日期:2017-12-06
  • Chemogenomic active learning's domain of applicability on small, sparse qHTS matrices: a study using CYP450 and nuclear hormone receptor families
    ChemMedChem (IF 3.225) Pub Date : 2017-12-06
    Christin Rakers, Rifat Ara Najnin, Ahsan Habib Polash, Shunichi Takeda, J.B. Brown

    Computational models for predicting the activity of small molecules against targets are now routinely developed and used in academia and industry, partially due to public bioactivity databases. While models based on bigger datasets are the trend, recent studies such as chemogenomic active learning have shown that only a fraction of data is needed for effective models in many cases. In this article, the chemogenomic active learning method is discussed and used to newly analyze public databases containing nuclear hormone receptor and cytochrome P450 receptor family bioactivity. In addition to existing results on kinases and G-protein coupled receptors, results here demonstrate the active learning methodology's effectiveness on extracting informative ligand-target pairs in sparse data scenarios. Experiments to assess the domain of the applicability demonstrate the influence of ligand profiles of similar targets within the family.

    更新日期:2017-12-06
  • A comprehensive structural overview of p38α MAPK in complex with ATP-site and non-ATP-site binders
    ChemMedChem (IF 3.225) Pub Date : 2017-12-06
    Andrea Astolfi, Giuseppe Manfroni, Violetta Cecchetti, Maria Letizia Barreca

    We herein review all the currently available PDB ATP-site and non-ATP-site ligands bound to p38α MAPK. The co-crystallized inhibitors have been classified into different families according to their experimental binding mode and chemical structure, and the ligand-protein interactions discussed using the most representative compounds. This systematic structural analysis could provide take-home lessons for drug discovery programs aimed at the rational identification and optimization of new p38α MAPK inhibitors.

    更新日期:2017-12-06
  • Novel Gold and Silver Carbene Complexes Exert Antitumor Effects Triggering the Reactive Oxygen Species Dependent Intrinsic Apoptotic Pathway
    ChemMedChem (IF 3.225) Pub Date : 2017-12-06
    Domenico Iacopetta, Annaluisa Mariconda, Carmela Saturnino, Anna Caruso, Giuseppe Palma, Jessica Ceramella, Noemi Muià, Mariarita Perri, Maria Stefania Sinicropi, Maria Cristina Caroleo, Pasquale Longo
    更新日期:2017-12-06
  • Activities of 11-Azaartemisinin and N-Sulfonyl Derivatives against Neospora caninum and Comparative Cytotoxicities
    ChemMedChem (IF 3.225) Pub Date : 2017-12-06
    Rozanne Harmse, Ho Ning Wong, Frans J. Smit, Joachim Müller, Andrew Hemphill, David D. N'Da, Richard K. Haynes
    更新日期:2017-12-06
  • 更新日期:2017-12-06
  • Design, Synthesis, and Evaluation of ω-(Isothiocyanato)alkylphosphinates and Phosphine Oxides as Antiproliferative Agents
    ChemMedChem (IF 3.225) Pub Date : 2017-12-06
    Łukasz Janczewski, Mateusz Psurski, Marta Świtalska, Anna Gajda, Tomasz M. Goszczyński, Józef Oleksyszyn, Joanna Wietrzyk, Tadeusz Gajda
    更新日期:2017-12-06
  • Synthesis and Evaluation of N-Phenylpyrrolamides as DNA Gyrase B Inhibitors
    ChemMedChem (IF 3.225) Pub Date : 2017-12-05
    Martina Durcik, Päivi Tammela, Michaela Barančoková, Tihomir Tomašič, Janez Ilaš, Danijel Kikelj, Nace Zidar

    ATP-competitive inhibitors of DNA gyrase and topoisomerase IV (topo IV) are among the most interesting classes of antibacterial drugs that do not have any representative in the antibacterial pipeline. We have developed thirty-two new N-phenylpyrrolamides and evaluated them against DNA gyrase and topoisomerase IV from Escherichia coli and Staphylococcus aureus. Antibacterial activities were studied against Gram-positive and Gram-negative bacterial strains. The most potent compound displayed an IC50 of 47 nM against E. coli DNA gyrase, and a minimum inhibitory concentration (MIC) of 12.5 µM against Gram-positive Enterococcus faecalis. Some compounds displayed good antibacterial activities against the efflux pump deficient E. coli strain (MICs = 6.25 µM) and against wild type E. coli in the presence of efflux pump inhibitor PAβN (MIC = 3.13 µM). We describe here new findings regarding structure-activity relationship of N-phenylpyrrolamide DNA gyrase B inhibitors and explore factors that are important for antibacterial activity of this class of compounds.

    更新日期:2017-12-05
  • Improving the Potency of Cancer Immunotherapy by Dual Targeting IDO1 and DNA
    ChemMedChem (IF 3.225) Pub Date : 2017-12-04
    kun Fang, Guoqiang Dong, Hongyu Wang, Shipeng He, Shanchao Wu, Wei Wang, Chunquan Sheng

    Here we report the first effort on exploration of the dual-targeting drug design strategy to improve the efficacy of small molecule cancer immunotherapy. New hybrids of IDO1 (indoleamine 2, 3-dioxygenase 1) inhibitors and DNA alkylating nitrogen mustards targeting respective IDO1 and DNA are rationally designed. As the first-in-class example of such molecules, they exhibited significantly enhanced anticancer activity in vitro and in vivo with low toxicity. The proof-of-concept by the studies has established a critical step toward developing novel and effective immunotherapy for the treatment of cancers.

    更新日期:2017-12-05
  • Phthalocyanine-Conjugated Upconversion NaYF4:Yb3+/Er3+@SiO2 Nanospheres for NIR-Triggered Photodynamic Therapy in a Tumor Mouse Model
    ChemMedChem (IF 3.225) Pub Date : 2017-12-05
    Uliana Kostiv, Vitalii Patsula, Agnieszka Noculak, Artur Podhorodecki, David Větvička, Pavla Poučková, Zdenka Sedláková, Daniel Horák
    更新日期:2017-12-05
  • Live Cell Labeling with Terpyridine Derivative Proligands to Measure Cytotoxicity Mediated by Immune Cells
    ChemMedChem (IF 3.225) Pub Date : 2017-12-04
    Yuki Sakai, Satoshi Mizuta, Asuka Kumagai, Mohammed S. O. Tagod, Hiroaki Senju, Tatsufumi Nakamura, Craig T. Morita, Yoshimasa Tanaka
    更新日期:2017-12-05
  • Synthetic Indolactam V Analogs as Inhibitors of PAR2 Induced Calcium Mobilization in Triple Negative Breast Cancer Cells
    ChemMedChem (IF 3.225) Pub Date : 2017-12-01
    Jan Stein, Sonja Stahn, Jörg-Martin Neudörfl, Julia Sperlich, Hans-Günther Schmalz, Nicole Teusch

    Human proteinase-activated receptor 2 (PAR2), a transmembrane G-Protein-coupled receptor (GPCR), represents an attractive target for a novel anti-cancer therapy as it plays a critical role in cell migration and invasion. Thus, selective PAR2 inhibitors possess a potential as anti-metastatic drugs. Knowing that the natural product teleocidin A2 is able to inhibit PAR2 in tumor cells, the goal of the present study was to elaborate structure-activity relationships and to identify potent PAR2 inhibitors with lower activity against the adverse target protein kinase C (PKC). For this purpose, an efficient gram scale total synthesis of indolactam V (i.e. the parent structure of all teleocidins) was developed and a library of derivatives was prepared. Some compounds indeed exhibited high potency as PAR2 inhibitors at low nanomolar concentrations with improved selectivity (as compared to teleocidin A2). The pseudopeptidic fragment bridging the C-3 and the C-4 positions of the indole core proved to be essential for target binding, while activity and target selectivity depends on the substituents at N-1 or C-7. The study revealed novel derivatives depicting high efficacy in PAR2 antagonism combined with increased selectivity.

    更新日期:2017-12-01
  • Consensus Predictive Model for the prediction of Human K562 Cell Growth Inhibition through Enalos Cloud Platform
    ChemMedChem (IF 3.225) Pub Date : 2017-12-01
    Antreas Afantitis, Georgios Leonis, Roberto Gambari, Georgia Melagraki

    Beta thalassemia is an inherited hematologic disorder caused by various mutations of the β-globin gene, thus resulting in a significant decrease of adult hemoglobin (HbA) production. Since no other specific treatment exists to date, apart from blood transfusion and chelation therapy, the increase of fetal hemoglobin (HbF) levels by drug molecules is considered of great potential in β-thalassemia treatment, being expected to counterbalance the impaired production of HbA. Within this context, we have worked towards the development of a predictive model that will allow the identification of new possible HbF inducers. To this end, we have selected the human erythroleukemia K562 cell line as a suitable target, since K562 cells are a well established system for validation of novel HbF inducers. Based on an available set of 129 experimentally tested biological inhibitors, we have developed and validated a computational QSAR model for the prediction of K562 functional inhibition, possibly associated with HbF induction. In an effort to facilitate future advancements in the field, we have incorporated our model into Enalos Cloud Platform that enabled online access to our computational scheme (http://enalos.insilicotox.com/K562) through a user-friendly interface. This online web service, dedicated to K562 biological inhibition assessment, is offered to the wider community in order to promote the in silico drug discovery through fast and reliable predictions.

    更新日期:2017-12-01
  • Monosaccharide derivatives with low nM lectin affinity and high selectivity based on combined fluorine-amide, phenyl-arginine, sulfur-π, and halogen bond interactions
    ChemMedChem (IF 3.225) Pub Date : 2017-12-01
    Fredrik Richard Zetterberg, Kristoffer Peterson, Richard Johnsson, Thomas Brimert, Maria Håkansson, Derek T. Logan, Hakon Leffler, Ulf J Nilsson

    The design of small and high affinity lectin inhibitors remains a major challenge because lectin natural ligand binding sites often are shallow and have polar character. We report that derivatizing galactose with un-natural structural elements that form multiple non-natural lectin-ligand interactions (orthogonal multipolar fluorine-amide, phenyl-arginine, sulfur-π, and halogen bond) can provide inhibitors with extraordinary affinity (low nM) for the model lectin, galectin-3, which is over 5 orders of magnitude higher than the parent galactose, and, moreover, is selective compared to other galectins.

    更新日期:2017-12-01
  • Harnessing the Maltodextrin Transport Mechanism for Targeted Bacterial Imaging: Structural Requirements for improved in vivo Stability in Tracer Design
    ChemMedChem (IF 3.225) Pub Date : 2017-11-30
    Alexander Axer, Sven Hermann, Gerald Kehr, David Clases, Uwe Karst, Lena Fischer-Riepe, Johannes Roth, Manfred Fobker, Michael Schäfers, Ryan Gilmour, Andreas Faust

    Diagnosis and localization of bacterial infections remains a significant clinical challenge. Harnessing bacteria-specific metabolic pathways such as the maltodextrin transport mechanism may allow to specifically localize and image even small or hidden colonies. This requires that the intra-bacterial tracer accumulation provided by the transporter is matched by high serum stability of the tracer molecule. Herein we report radiolabeled maltodextrins of varying chain lengths and with free non-reducing/reducing ends and evaluate their behavior against the starch degrading enzymes in the blood that compromise their serum stability. We show successful SPECT/CT imaging in a footpad infection model in vivo using the newly developed model tracer [99mTc]MB1143, and compare the signal with [18F]FDG-PET as a non-bacterial specific marker for inflammation. Although the [99mTc]MB1143 imaging signal is highly specific it is low, most probably due to insufficient serum stability of the tracer. A series of stability tests with different 18F-labelled maltodextrins finally yielded clear structural guidelines regarding substitution patterns and chain lengths of maltodextrin-based tracers for nuclear imaging of bacterial infections.

    更新日期:2017-11-30
  • Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Amine-based Histone Deacetylase Inhibitors
    ChemMedChem (IF 3.225) Pub Date : 2017-11-30
    Hazem Abdelkarim, Raghupathi Neelarapu, Antonett Madriaga, Aditya S. Vaidya, Irida Kastrati, Bhargava Karumudi, Yue-ting Wang, Taha Y. Taha, Gregory R. J. Thatcher, Jonna Frasor, Pavel A. Petukhov
    更新日期:2017-11-30
  • A Molecular Hybrid for Mitochondria-Targeted NO Photodelivery
    ChemMedChem (IF 3.225) Pub Date : 2017-11-30
    Federica Sodano, Elena Gazzano, Aurore Fraix, Barbara Rolando, Loretta Lazzarato, Marina Russo, Marco Blangetti, Chiara Riganti, Roberta Fruttero, Alberto Gasco, Salvatore Sortino
    更新日期:2017-11-30
  • Structure–Activity Relationship of Propargylamine-Based HDAC Inhibitors
    ChemMedChem (IF 3.225) Pub Date : 2017-11-30
    Matthias Wünsch, Johanna Senger, Philipp Schultheisz, Sabrina Schwarzbich, Karin Schmidtkunz, Carmela Michalek, Michaela Klaß, Stefanie Goskowitz, Philipp Borchert, Lucas Praetorius, Wolfgang Sippl, Manfred Jung, Norbert Sewald
    更新日期:2017-11-30
  • Synthesis and Biological Evaluation of Stilbene Analogues as Hsp90 C-Terminal Inhibitors
    ChemMedChem (IF 3.225) Pub Date : 2017-11-30
    Katherine M. Byrd, Caitlin N. Kent, Brian S. J. Blagg
    更新日期:2017-11-30
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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