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  Subjects -> CHEMISTRY (Total: 845 journals)
    - ANALYTICAL CHEMISTRY (51 journals)
    - CHEMISTRY (595 journals)
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CHEMISTRY (595 journals)                  1 2 3 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 8)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 26)
ACS Catalysis     Full-text available via subscription   (Followers: 34)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 18)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 23)
ACS Macro Letters     Full-text available via subscription   (Followers: 24)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 39)
ACS Nano     Full-text available via subscription   (Followers: 244)
ACS Photonics     Full-text available via subscription   (Followers: 11)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 21)
Acta Chemica Iasi     Open Access   (Followers: 2)
Acta Chimica Sinica     Full-text available via subscription   (Followers: 1)
Acta Chimica Slovaca     Open Access   (Followers: 1)
Acta Chromatographica     Full-text available via subscription   (Followers: 9)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 5)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 8)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 5)
Advanced Functional Materials     Hybrid Journal   (Followers: 51)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 56)
Advances in Chemical Science     Open Access   (Followers: 13)
Advances in Chemistry     Open Access   (Followers: 15)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Enzyme Research     Open Access   (Followers: 9)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 16)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 9)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 21)
Advances in Nanoparticles     Open Access   (Followers: 15)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15)
Advances in Polymer Science     Hybrid Journal   (Followers: 41)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 17)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Science and Technology     Full-text available via subscription   (Followers: 12)
African Journal of Bacteriology Research     Open Access  
African Journal of Chemical Education     Open Access   (Followers: 2)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 7)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 67)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 14)
American Journal of Chemistry     Open Access   (Followers: 27)
American Journal of Plant Physiology     Open Access   (Followers: 14)
American Mineralogist     Hybrid Journal   (Followers: 14)
Analyst     Full-text available via subscription   (Followers: 40)
Angewandte Chemie     Hybrid Journal   (Followers: 203)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 219)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 4)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 4)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 8)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 12)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 15)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Hybrid Journal  
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7)
Applied Spectroscopy     Full-text available via subscription   (Followers: 23)
Applied Surface Science     Hybrid Journal   (Followers: 28)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 2)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Atomization and Sprays     Full-text available via subscription   (Followers: 4)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Biochemistry     Full-text available via subscription   (Followers: 310)
Biochemistry Insights     Open Access   (Followers: 6)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 9)
Bioinspired Materials     Open Access   (Followers: 5)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access   (Followers: 1)
Biomacromolecules     Full-text available via subscription   (Followers: 19)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 6)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 5)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 118)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 91)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 1)
Bitácora Digital     Open Access  
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 2)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 24)
Bulletin of the Korean Chemical Society     Hybrid Journal   (Followers: 1)
C - Journal of Carbon Research     Open Access   (Followers: 3)
Cakra Kimia (Indonesian E-Journal of Applied Chemistry)     Open Access  
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 3)
Canadian Journal of Chemistry     Hybrid Journal   (Followers: 10)
Canadian Mineralogist     Full-text available via subscription   (Followers: 4)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 66)
Catalysis for Sustainable Energy     Open Access   (Followers: 7)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 8)
Catalysis Science and Technology     Free   (Followers: 7)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 8)
Cellulose     Hybrid Journal   (Followers: 7)
Cereal Chemistry     Full-text available via subscription   (Followers: 4)
ChemBioEng Reviews     Full-text available via subscription   (Followers: 1)
ChemCatChem     Hybrid Journal   (Followers: 8)
Chemical and Engineering News     Free   (Followers: 14)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 72)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 24)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 20)
Chemical Reviews     Full-text available via subscription   (Followers: 182)
Chemical Science     Open Access   (Followers: 22)
Chemical Technology     Open Access   (Followers: 16)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemical Week     Full-text available via subscription   (Followers: 8)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 58)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 26)
ChemInform     Hybrid Journal   (Followers: 8)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 6)
Chemistry & Biology     Full-text available via subscription   (Followers: 30)
Chemistry & Industry     Hybrid Journal   (Followers: 5)
Chemistry - A European Journal     Hybrid Journal   (Followers: 146)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 15)
Chemistry and Materials Research     Open Access   (Followers: 20)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 5)
Chemistry in Education     Open Access   (Followers: 9)
Chemistry International     Hybrid Journal   (Followers: 2)
Chemistry Letters     Full-text available via subscription   (Followers: 44)
Chemistry of Materials     Full-text available via subscription   (Followers: 258)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 22)
Chemistry-Didactics-Ecology-Metrology     Open Access   (Followers: 1)
ChemistryOpen     Open Access   (Followers: 2)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 4)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 15)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 9)
ChemPlusChem     Hybrid Journal   (Followers: 2)
ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 2)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 10)
Chromatographia     Hybrid Journal   (Followers: 24)
Clay Minerals     Full-text available via subscription   (Followers: 10)
Cogent Chemistry     Open Access  
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 10)
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 7)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
Combustion Science and Technology     Hybrid Journal   (Followers: 18)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Composite Interfaces     Hybrid Journal   (Followers: 6)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 2)
Comptes Rendus Chimie     Full-text available via subscription  
Comptes Rendus Physique     Full-text available via subscription   (Followers: 1)
Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 9)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 12)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 9)
Coordination Chemistry Reviews     Full-text available via subscription   (Followers: 3)
Copernican Letters     Open Access   (Followers: 1)
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 5)
Crystal Structure Theory and Applications     Open Access   (Followers: 4)
CrystEngComm     Full-text available via subscription   (Followers: 13)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Metabolomics     Hybrid Journal   (Followers: 5)
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 17)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 61)
Dalton Transactions     Full-text available via subscription   (Followers: 23)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)
Diamond and Related Materials     Hybrid Journal   (Followers: 12)
Dislocations in Solids     Full-text available via subscription  
Doklady Chemistry     Hybrid Journal  
Drying Technology: An International Journal     Hybrid Journal   (Followers: 4)
Eclética Química     Open Access   (Followers: 1)
Ecological Chemistry and Engineering S     Open Access   (Followers: 3)
Ecotoxicology and Environmental Contamination     Open Access  
Educación Química     Open Access   (Followers: 1)
Education for Chemical Engineers     Hybrid Journal   (Followers: 5)
EJNMMI Radiopharmacy and Chemistry     Open Access  
Elements     Full-text available via subscription   (Followers: 3)
Environmental Chemistry     Hybrid Journal   (Followers: 7)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 4)
Environmental Science & Technology Letters     Full-text available via subscription   (Followers: 5)

        1 2 3 | Last

Journal Cover Bioorganic & Medicinal Chemistry
  [SJR: 1.064]   [H-I: 119]   [118 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0968-0896
   Published by Elsevier Homepage  [3051 journals]
  • Bioactive natural products
    • Authors: Mathias Christmann
      First page: 6087
      Abstract: Publication date: 15 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22
      Author(s): Mathias Christmann


      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.10.034
       
  • Natural products and morphogenic activity of γ-Proteobacteria associated
           with the marine hydroid polyp Hydractinia echinata
    • Authors: Huijuan Guo; Maja Rischer; Martin Sperfeld; Christiane Weigel; Klaus Dieter Menzel; Jon Clardy; Christine Beemelmanns
      Pages: 6088 - 6097
      Abstract: Publication date: 15 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22
      Author(s): Huijuan Guo, Maja Rischer, Martin Sperfeld, Christiane Weigel, Klaus Dieter Menzel, Jon Clardy, Christine Beemelmanns
      Illumina 16S rRNA gene sequencing was used to profile the associated bacterial community of the marine hydroid Hydractinia echinata, a long-standing model system in developmental biology. 56 associated bacteria were isolated and evaluated for their antimicrobial activity. Three strains were selected for further in-depth chemical analysis leading to the identification of 17 natural products. Several γ-Proteobacteria were found to induce settlement of the motile larvae, but only six isolates induced the metamorphosis to the primary polyp stage within 24h. Our study paves the way to better understand how bacterial partners contribute to protection, homeostasis and propagation of the hydroid polyp.
      Graphical abstract image

      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.06.053
       
  • Synthesis of novel C-9 carbon substituted derivatives of artemisinin
    • Authors: Daniel Meyer; Toni Smeilus; Dimanthi Pliatsika; Farnoush Mousavizadeh; Athanassios Giannis
      Pages: 6098 - 6101
      Abstract: Publication date: 15 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22
      Author(s): Daniel Meyer, Toni Smeilus, Dimanthi Pliatsika, Farnoush Mousavizadeh, Athanassios Giannis
      Several artemisinin derivatives carrying several groups (alkyl, hydroxyalkyl, allyl or azide) at position 9 have been synthesized starting from artemisinin via enolate formation and subsequent reaction with appropriate electrophiles.
      Graphical abstract image

      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.03.021
       
  • Biological evaluation of pyridone alkaloids on the endocannabinoid system
    • Authors: Andrea Chicca; Regina Berg; Henning J. Jessen; Nicolas Marck; Fabian Schmid; Patrick Burch; Jürg Gertsch; Karl Gademann
      Pages: 6102 - 6114
      Abstract: Publication date: 15 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22
      Author(s): Andrea Chicca, Regina Berg, Henning J. Jessen, Nicolas Marck, Fabian Schmid, Patrick Burch, Jürg Gertsch, Karl Gademann
      Naturally occurring pyridone alkaloids as well as synthetic derivatives were previously shown to induce neurite outgrowth. However, the molecular basis for this biological effect remains poorly understood. In this work, we have prepared new pyridones, and tested the effect of thirteen 4-hydroxy-2-pyridone derivatives on the components of the endocannabinoid system. Investigation of binding affinities towards CB1 and CB2 receptors led to the identification of a compound binding selectively to CB1 (12). Compound 12 and a closely related derivative (11) also inhibited anandamide (AEA) hydrolysis by fatty acid amide hydrolase. Interestingly, none of the compounds tested showed any effect on 2-AG hydrolysis by monoacylglycerol lipase at 10μM. Assessment of AEA uptake did, however, lead to the identification of four inhibitors with IC50 values in the submicromolar range and high selectivity over the other components of the endocannabinoid system.
      Graphical abstract image

      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.02.031
       
  • Synthesis and cytotoxic activities of goniothalamins and derivatives
    • Authors: Anja Weber; Katja Döhl; Julia Sachs; Anja C.M. Nordschild; Dennis Schröder; Andrea Kulik; Thomas Fischer; Lutz Schmitt; Nicole Teusch; Jörg Pietruszka
      Pages: 6115 - 6125
      Abstract: Publication date: 15 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22
      Author(s): Anja Weber, Katja Döhl, Julia Sachs, Anja C.M. Nordschild, Dennis Schröder, Andrea Kulik, Thomas Fischer, Lutz Schmitt, Nicole Teusch, Jörg Pietruszka
      Substituted goniothalamins containing cyclopropane-groups were efficiently prepared in high yields and good selectivity. Antiproliferative activity was measured on three human cancer cell lines (A549, MCF-7, HBL-100), to show which of the structural elements of goniothalamins is mandatory for cytotoxicity. We found that the configuration of the stereogenic centre of the δ-lactone plays an important role for cytotoxicity. In our studies only (R)-configured goniothalamins showed antiproliferative activity, whereby (R)-configuration accords to natural goniothalamin (R)-1. Additionally, the δ-lactone needs to be unsaturated whereas our results show that the vinylic double bond is not mandatory for cytotoxicity. Furthermore, with a two-fold in vitro and in vivo strategy, we determined the inhibitory effect of the compounds to the yeast protein Pdr5. Here, we clearly demonstrate that the configuration seems to be of minor influence, only, while the nature of the substituent of the phenyl ring is of prime importance.
      Graphical abstract image

      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.02.004
       
  • Simplifying nature: Towards the design of broad spectrum kinetoplastid
           inhibitors, inspired by acetogenins
    • Authors: Eoin R. Gould; Elizabeth F.B. King; Stefanie K. Menzies; Andrew L. Fraser; Lindsay B. Tulloch; Marija K. Zacharova; Terry K. Smith; Gordon J. Florence
      Pages: 6126 - 6136
      Abstract: Publication date: 15 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22
      Author(s): Eoin R. Gould, Elizabeth F.B. King, Stefanie K. Menzies, Andrew L. Fraser, Lindsay B. Tulloch, Marija K. Zacharova, Terry K. Smith, Gordon J. Florence
      The need for new treatments for the neglected tropical diseases African sleeping sickness, Chagas disease and Leishmaniasis remains urgent with the diseases widespread in tropical regions, affecting the world’s very poorest. We have previously reported bis-tetrahydropyran 1,4-triazole analogues designed as mimics of the annonaceous acetogenin natural product chamuvarinin, which maintained trypanocidal activity. Building upon these studies, we here report related triazole compounds with pendant heterocycles, mimicking the original butenolide of the natural product. Analogues were active against T. brucei, with a nitrofuran compound displaying nanomolar trypanocidal activity. Several analogues also showed strong activity against T. cruzi and L. major. Importantly, select compounds gave excellent selectivity over mammalian cells with a furan-based analogue highly selective while remaining active against all three cell lines, thus representing a potential lead for a new broad spectrum kinetoplastid inhibitor.
      Graphical abstract image

      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.01.021
       
  • Synthesis and biological evaluation of a D-ring-contracted analogue of
           lamellarin D
    • Authors: Vanessa Colligs; Steven Peter Hansen; Dennis Imbri; Ean-Jeong Seo; Onat Kadioglu; Thomas Efferth; Till Opatz
      Pages: 6137 - 6148
      Abstract: Publication date: 15 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22
      Author(s): Vanessa Colligs, Steven Peter Hansen, Dennis Imbri, Ean-Jeong Seo, Onat Kadioglu, Thomas Efferth, Till Opatz
      A D-ring contracted analogue of the strongly cytotoxic marine pyrrole alkaloid lamellarin D was synthesized and investigated for its antiproliferative action towards a wild type and a multidrug resistant (MDR) cancer cell line. The compound was found to inhibit tumor cell growth at submicromolar concentrations and showed a lower relative resistance in the MDR cell line than the antitumor drug camptothecin to which lamellarin D shows cross resistance and with which lamellarin D shares the same binding site.
      Graphical abstract image

      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.02.005
       
  • Recent developments in the isolation, biological function, biosynthesis,
           and synthesis of phenazine natural products
    • Authors: Nikolaus Guttenberger; Wulf Blankenfeldt; Rolf Breinbauer
      Pages: 6149 - 6166
      Abstract: Publication date: 15 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22
      Author(s): Nikolaus Guttenberger, Wulf Blankenfeldt, Rolf Breinbauer
      Phenazines are natural products which are produced by bacteria or by archaeal Methanosarcina species. The tricyclic ring system enables redox processes, which producing organisms use for oxidation of NADH or for the generation of reactive oxygen species (ROS), giving them advantages over other microorganisms. In this review we summarize the progress in the field since 2005 regarding the isolation of new phenazine natural products, new insights in their biological function, and particularly the now almost completely understood biosynthesis. The review is complemented by a description of new synthetic methods and total syntheses of phenazines.
      Graphical abstract image

      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.01.002
       
  • Anti-tuberculosis activity and structure–activity relationships of
           oxygenated tricyclic carbazole alkaloids and synthetic derivatives
    • Authors: Carsten Börger; Christian Brütting; Konstanze K. Julich-Gruner; Ronny Hesse; V. Pavan Kumar; Sebastian K. Kutz; Marika Rönnefahrt; Claudia Thomas; Baojie Wan; Scott G. Franzblau; Hans-Joachim Knölker
      Pages: 6167 - 6174
      Abstract: Publication date: 15 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22
      Author(s): Carsten Börger, Christian Brütting, Konstanze K. Julich-Gruner, Ronny Hesse, V. Pavan Kumar, Sebastian K. Kutz, Marika Rönnefahrt, Claudia Thomas, Baojie Wan, Scott G. Franzblau, Hans-Joachim Knölker
      A series of 49 oxygenated tricyclic carbazole derivatives has been tested for inhibition of the growth of Mycobacterium tuberculosis and a mammalian cell line (vero cells). From this series, twelve carbazoles showed a significant anti-TB activity. The four most active compounds were the naturally occurring carbazole alkaloids clauszoline-M (45), murrayaline-C (41), carbalexin-C (27), and the synthetic carbazole derivative 22 with MIC90 values ranging from 1.5 to 3.7μM. The active compounds were virtually nontoxic for the mammalian cell line in the concentration range up to 50μM.
      Graphical abstract image

      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2016.12.038
       
  • A conceptually novel construction of the 6a-hydroxypterocarpan skeleton
           – Synthesis of (±)-variabilin
    • Authors: Philipp Ciesielski; Peter Metz
      Pages: 6175 - 6177
      Abstract: Publication date: 15 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 22
      Author(s): Philipp Ciesielski, Peter Metz
      A new access to the 6a-hydroxypterocarpan variabilin was established. Key step of this concise total synthesis is a challenging cyclization of a haloketone via halogen–metal exchange and subsequent intramolecular addition to the carbonyl function.
      Graphical abstract image

      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.01.003
       
  • Recently reported biological activities of pyrazole compounds
    • Authors: Jéssica Venância Faria; Percilene Fazolin Vegi; Ana Gabriella Carvalho Miguita; Maurício Silva dos Santos; Nubia Boechat; Alice Maria Rolim Bernardino
      Pages: 5891 - 5903
      Abstract: Publication date: 1 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 21
      Author(s): Jéssica Venância Faria, Percilene Fazolin Vegi, Ana Gabriella Carvalho Miguita, Maurício Silva dos Santos, Nubia Boechat, Alice Maria Rolim Bernardino
      The pyrazole nucleus is an aromatic azole heterocycle with two adjacent nitrogen atoms. Pyrazole derivatives have exhibited a broad spectrum of biological activities, and approved pyrazole-containing drugs include celecoxib, antipyrine, phenylbutazone, rimonabant, and dipyrone. Many research groups have synthesized and evaluated pyrazoles against several biological agents. This review examines recent publications relating the structures of pyrazoles with their corresponding biological activities.
      Graphical abstract image

      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.09.035
       
  • In silico analysis and in vitro evaluation of immunogenic and
           immunomodulatory properties of promiscuous peptides derived from
           Leishmania infantum eukaryotic initiation factor
    • Authors: Olga S. Koutsoni; John G. Routsias; Ioannis D. Kyriazis; Mourad Barhoumi; Ikram Guizani; Athanassios Tsakris; Eleni Dotsika
      Pages: 5904 - 5916
      Abstract: Publication date: 1 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 21
      Author(s): Olga S. Koutsoni, John G. Routsias, Ioannis D. Kyriazis, Mourad Barhoumi, Ikram Guizani, Athanassios Tsakris, Eleni Dotsika
      It is generally considered as imperative the ability to control leishmaniasis through the development of a protective vaccine capable of inducing long-lasting and protective cell-mediated immune responses. In this current study, we demonstrated potential epitopes that bind to H2 MHC class I and II molecules by conducting the in silico analysis of Leishmania infantum eukaryotic Initiation Factor (LieIF) protein, using online available algorithms. Moreover, we synthesized five peptides (16–18 amino acids long) which are part of the N-terminal portion of LieIF and contain promising MHC class I and II-restricted epitopes and afterwards, their predicted immunogenicity was evaluated in vitro by monitoring peptide-specific T-cell responses. Additionally, the immunomodulatory properties of these peptides were investigated in vitro by exploring their potential of inducing phenotypic maturation and functional differentiation of murine Bone-Marrow derived Dendritic Cells (BM-DCs). It was revealed by our data that all the synthetic peptides predicted for H2 alleles; present the property of immunogenicity. Among the synthetic peptides which contained T-cell epitopes, the peptide 52–68 aa (LieIF_2) exhibited immunomodulatory properties with the larger potential. LieIF_2-pulsed BM-DCs up-regulated the expression of the co-stimulatory surface molecules CD80 and CD86, as well as the production of the proinflammatory cytokine TNF-α and of the Th1-polarizing cytokines IL-12 and IFN-γ. The aforementioned data suggest that selected parts of LieIF could be used to develop innovative subunit protective vaccines able to induce effective immunity mediated by MHC class I-restricted as well as class II-restricted T-cell responses.
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      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.07.013
       
  • Design, synthesis, and evaluation of salicyladimine derivatives as
           multitarget-directed ligands against Alzheimer’s disease
    • Authors: Hua-Li Yang; Pei Cai; Qiao-Hong Liu; Xue-Lian Yang; Si-Qiang Fang; Yan-Wei Tang; Cheng Wang; Xiao-Bing Wang; Ling-Yi Kong
      Pages: 5917 - 5928
      Abstract: Publication date: 1 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 21
      Author(s): Hua-Li Yang, Pei Cai, Qiao-Hong Liu, Xue-Lian Yang, Si-Qiang Fang, Yan-Wei Tang, Cheng Wang, Xiao-Bing Wang, Ling-Yi Kong
      A series of salicyladimine derivatives were designed, synthesized and evaluated as multi-target-directed ligands for the treatment of Alzheimer’s disease (AD). Biological activity results demonstrated that some derivatives possessed significant inhibitory activities against amyloid-β (Aβ) aggregation and human monoamine oxidase B (hMAO-B) as well as remarkable antioxidant effects and low cell toxicity. The optimal compound, 5, exhibited excellent potency for inhibition of self-induced Aβ 1–42 aggregation (91.3±2.1%, 25μM), inhibition of hMAO-B (IC50, 1.73±0.39μM), antioxidant effects (43.4±2.6μM of IC50 by DPPH method, 0.67±0.06 trolox equivalent by ABTS method), metal chelation and BBB penetration. Furthermore, compound 5 had neuroprotective effects against ROS generation, H2O2-induced apoptosis, 6-OHDA-induced cell injury, and a significant in vitro anti-inflammatory activity. Collectively, these findings highlighted that compound 5 was a potential balanced multifunctional neuroprotective agent for the development of anti-AD drugs.
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      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.08.048
       
  • Synthesis, computational studies and enzyme inhibitory kinetics of
           substituted
           methyl[2-(4-dimethylamino-benzylidene)-hydrazono)-4-oxo-thiazolidin-5-ylidene]acetates
           as mushroom tyrosinase inhibitors
    • Authors: Pervaiz Ali Channar; Aamer Saeed; Fayaz Ali Larik; Muhammad Rafiq; Zaman Ashraf; Farukh Jabeen; Tanzeela Abdul Fattah
      Pages: 5929 - 5938
      Abstract: Publication date: 1 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 21
      Author(s): Pervaiz Ali Channar, Aamer Saeed, Fayaz Ali Larik, Muhammad Rafiq, Zaman Ashraf, Farukh Jabeen, Tanzeela Abdul Fattah
      The present article describes the synthesis and enzyme inhibitory kinetics of methyl[2-(arylmethylene-hydrazono)-4-oxo-thiazolidin-5-ylidene]acetates 5a–j as mushroom tyrosinase inhibitors. The title compounds were synthesized via cyclocondensation of thiosemicarbazones 3a–j with dimethyl but-2-ynedioate (DMAD) 4 in good yields under solvent-free conditions. The synthesized compounds were evaluated for their potential to inhibit the activity of mushroom tyrosinase. It was unveiled that compounds 5i showed excellent enzyme inhibitory activity with IC50 3.17µM while IC50 of standard kojic acid is 15.91µM. The presence of heterocyclic pyridine ring in compound 5i play important role in enzyme inhibitory activity as rest of the functional groups are common in all synthesized compounds. The enzyme inhibitory kinetics of the most potent derivative 5i determined by Lineweaver-Burk plots and Dixon plots showed that it is non-competitive inhibitor with Ki value 1.5µM. It was further investigated that the wet lab results are in good agreement with the computational results. The molecular docking of the synthesized compounds was performed against tyrosinase protein (PDBID 2Y9X) to delineate ligand-protein interactions at molecular level. The docking results showed that the major interacting residues are His244, His85, His263, Val 283, His 296, Asn260, Val248, His260, His261 and Phe264 which are located in active binding site of the protein. The molecular modeling demonstrates that the oxygen atom of the compound 5i coordinated with the key residues in the active site of mushroom tyrosinase contribute significantly against inhibitory ability and diminishing the human melanin synthesis. These results evident that compound 5i is a lead structure in developing most potent mushroom tyrosinase inhibitors.
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      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.09.009
       
  • Design, synthesis and biological evaluation of
           2-phenylquinoline-4-carboxamide derivatives as a new class of tubulin
           polymerization inhibitors
    • Authors: Li Zhu; Kaixiu Luo; Ke Li; Yi Jin; Jun Lin
      Pages: 5939 - 5951
      Abstract: Publication date: 1 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 21
      Author(s): Li Zhu, Kaixiu Luo, Ke Li, Yi Jin, Jun Lin
      A novel series of 2-phenylquinoline-4-carboxamide derivatives was synthesized, characterized and evaluated for its antiproliferative activity against five cancer cell lines, Hela, SK-OV-3, HCT116, A549 and MDA-MB-468, and a normal human fetal lung fibroblastic cell line, MRC-5. Among them, compound 7b displayed potent cytotoxic activity in vitro against SK-OV-3 and HCT116 cell lines with IC50 values of 0.5 and 0.2μM, respectively. In general, the antiproliferative activity was correlated with the binding property of the colchicine binding site and inhibitory effect on tubulin polymerization. In addition, immunofluorescence and flow cytometry analysis revealed that selected compounds caused disruption of the mitotic spindle assembly and G2/M phase arrest of the cell cycle, which correlated with proliferation inhibitory activity. Molecular docking analysis demonstrated the interaction of 7b at the colchicine binding site of tubulin. These results indicate these compounds are promising inhibitors of tubulin polymerization for the potent treatment of cancer.
      Graphical abstract image

      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.09.004
       
  • In vivo programming of endogenous antibodies via oral administration of
           adaptor ligands
    • Authors: Masanobu Nagano; Nancy Carrillo; Nobumasa Otsubo; Wataru Hakamata; Hitoshi Ban; Roberta P. Fuller; Nasir K. Bashiruddin; Carlos F. Barbas
      Pages: 5952 - 5961
      Abstract: Publication date: 1 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 21
      Author(s): Masanobu Nagano, Nancy Carrillo, Nobumasa Otsubo, Wataru Hakamata, Hitoshi Ban, Roberta P. Fuller, Nasir K. Bashiruddin, Carlos F. Barbas
      Vaccination is a reliable method of prophylaxis and a crucial measure for public health. However, the majority of vaccines cannot be administered orally due to their degradation in the harsh gut environment or inability to cross the GI tract. In this study, we report the first proof-of-concept study of orally producible chemically programmed antibodies via specific conjugation of adaptor ligands to endogenous antibodies, in vivo. Pre-immuniztion with 2,4-dinitrophenyl (DNP), or the reactive hapten, 1,3-diketone (DK), or a novel reactive hapten, vinyl sulfone (VS) in mice, followed by oral administration of adaptor ligands composed of the hapten and biotin to the pre-immunized mice resulted in successful in vivo formation of the biotin-hapten-antibody complexes within 2h. Pharmacokinetic evaluations revealed that apparent serum concentrations of programmed antibodies were up to 144nM and that the serum half-lives reached up to 34.4h. These findings show promise for the future development of orally bioavailable drug-hapten-antibody complexes asa strategy to quickly and easily modulate immune targets for aggressive pathogens as well as cancer.
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      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.09.010
       
  • A ‘catch and release’ strategy towards HPLC-free purification of
           synthetic oligonucleotides by a combination of the strain-promoted
           alkyne-azide cycloaddition and the photocleavage
    • Authors: Yosuke Igata; Noriko Saito-Tarashima; Daiki Matsumoto; Kazuyuki Sagara; Noriaki Minakawa
      Pages: 5962 - 5967
      Abstract: Publication date: 1 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 21
      Author(s): Yosuke Igata, Noriko Saito-Tarashima, Daiki Matsumoto, Kazuyuki Sagara, Noriaki Minakawa
      A convenient strategy to purify oligonucleotides (ONs) synthesized by solid phase synthesis on an automatic DNA/RNA synthesizer was described. By attaching a photocleavable azide linker as the last phosphoramidite unit in the ON synthesis, only the desired full-length sequence was ‘caught’ on a controlled pore glass (CPG) resin possessing an aza-dimethoxycyclooctyne (DIBAC) derivative. Washing the resulting CPG resin to remove all unbounded species, the subsequent photoirradiation allowed the pure ONs to be ‘released’ without leaving any chemical modifications on native ON structure or chemical reagents from the solid phase ON synthesis.
      Graphical abstract image

      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.09.014
       
  • Conjugation of the CRM197-inulin conjugate significantly increases the
           immunogenicity of Mycobacterium tuberculosis CFP10-TB10.4 fusion protein
    • Authors: Shun Hu; Weili Yu; Chunyang Hu; Dong Wei; Lijuan Shen; Tao Hu; Youjin Yi
      Pages: 5968 - 5974
      Abstract: Publication date: 1 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 21
      Author(s): Shun Hu, Weili Yu, Chunyang Hu, Dong Wei, Lijuan Shen, Tao Hu, Youjin Yi
      Mycobacterium tuberculosis (Mtb) is a serious fatal pathogen that causes tuberculosis (TB). Effective vaccination is urgently needed to deal with the serious threat from TB. Mtb-secreted protein antigens are important virulence determinants of Mtb with poor immunogenicity. Adjuvants and antigen delivery systems are thus highly desired to improve the immunogenicity of protein antigens. Inulin is a biocompatible polysaccharide (PS) adjuvant that can stimulate a strong cellular and humoral immunity. Bacterial capsular PS and haptens have been conjugated with cross-reacting material 197 (CRM197) to improve their immunogenicity. CFP10 and TB10.4 were two Mtb-secreted immunodominant protein antigens. A CFP10-TB10.4 fusion protein (CT) was used as the antigen for covalent conjugation with the CRM197-inulin conjugate (CRM-inu). The resultant conjugate (CT-CRM-inu) elicited high CT-specific IgG titers, stimulated splenocyte proliferation and provoked the secretion of Th1-type and Th2-type cytokines. Conjugation with CRM-inu significantly prolonged the systemic circulation of CT and exposure to the immune system. Moreover, CT-CRM-inu showed no apparent toxicity to cardiac, hepatic and renal functions. Thus, conjugation of CT with CRM-inu provided an effective strategy for development of protein-based vaccines against Mtb infection.
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      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.09.027
       
  • Bifunctional aryliodonium salts for highly efficient radioiodination and
           astatination of antibodies
    • Authors: F. Guérard; L. Navarro; Y.-S. Lee; A. Roumesy; C. Alliot; M. Chérel; M.W. Brechbiel; J.-F. Gestin
      Pages: 5975 - 5980
      Abstract: Publication date: 1 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 21
      Author(s): F. Guérard, L. Navarro, Y.-S. Lee, A. Roumesy, C. Alliot, M. Chérel, M.W. Brechbiel, J.-F. Gestin
      In this report we describe the development of an alternative approach to arylstannane chemistry for radiolabeling antibodies with radioiodine or astatine based on aryliodonium salts precursors. Bifunctional aryliodonium salts were designed and tested for the synthesis of 125I and 211At labeled prosthetic groups for bioconjugation. The nature of the electron rich aryl group was varied and its impact on the regioselectivity of radiohalogenation was evaluated. Unexpectedly, whereas the 2-thienyl group provided the best regioselectivity towards the radioiodination of the aryl moiety of interest (98:2), it was less selective for astatination (87:13); the anisyl group providing the best regioselectivity of astatination (94:6). Under optimized conditions, both radioiodination and astatination could be performed very efficiently in mild conditions (radiochemical yields>85%). The ionic nature of the precursors was exploited to develop an efficient purification approach: the HPLC step that is usually necessary in conventionnal approaches to optimize removal of organotin toxic precursors and side products was replaced by a filtration through a silica cartridge with a significantly reduced loss of radiolabeled product. The purified radioiodinated and astatinated prosthetic groups were then conjugated efficiently to an anti-CD138 monoclonal antibody (75–80% conjugation yield). By using this novel and simple radiohalogenation procedure, higher overall radiochemical yields of astatination were obtained in comparison with the use of an arylstannane precursor and procedures of the litterature for labeling the same antibody. Overall, due to their simplicity of use and high robustness, these new precursors should simplify the labeling of proteins of interest with iodine and astatine radioisotopes for imaging and therapeutic applications.
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      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.09.022
       
  • 9-Substituted acridine derivatives as acetylcholinesterase and
           butyrylcholinesterase inhibitors possessing antioxidant activity for
           Alzheimer's disease treatment
    • Authors: Galina F. Makhaeva; Sofya V. Lushchekina; Natalia P. Boltneva; Olga G. Serebryakova; Elena V. Rudakova; Alexey A. Ustyugov; Sergey O. Bachurin; Alexander V. Shchepochkin; Oleg N. Chupakhin; Valery N. Charushin; Rudy J. Richardson
      Pages: 5981 - 5994
      Abstract: Publication date: 1 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 21
      Author(s): Galina F. Makhaeva, Sofya V. Lushchekina, Natalia P. Boltneva, Olga G. Serebryakova, Elena V. Rudakova, Alexey A. Ustyugov, Sergey O. Bachurin, Alexander V. Shchepochkin, Oleg N. Chupakhin, Valery N. Charushin, Rudy J. Richardson
      We investigated the inhibitory activity of 4 groups of novel acridine derivatives against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carboxylesterase (CaE) using the methods of enzyme kinetics and molecular docking. Antioxidant activity of the compounds was determined using the 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS + ) radical decolorization assay as their ability to scavenge free radicals. Analysis of the esterase profiles and antiradical activities of the acridine derivatives showed that 9-aryl(heteroaryl)-N-methyl-9,10-dihydroacridines have a high radical-scavenging activity but low potency as AChE and BChE inhibitors, whereas 9-aryl(heteroaryl)-N-methyl-acridinium tetrafluoroborates effectively inhibit cholinesterases but do not exhibit antiradical activity. In contrast, a group of derivatives of 9-heterocyclic amino-N-methyl-9,10-dihydroacridine has been found that combine effective inhibition of AChE and BChE with rather high radical-scavenging activity. The results of molecular docking well explain the observed features in the efficacy, selectivity, and mechanism of cholinesterase inhibition by the acridine derivatives. Thus, in a series of acridine derivatives we have found compounds possessing dual properties of effective and selective cholinesterase inhibition together with free radical scavenging, which makes promising the use of the acridine scaffold to create multifunctional drugs for the therapy of neurodegenerative diseases.
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      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.09.028
       
  • Design and synthesis of a novel series of orally active, selective
           somatostatin receptor 2 agonists for the treatment of type 2 diabetes
    • Authors: Yoshihiro Banno; Shigekazu Sasaki; Makoto Kamata; Jun Kunitomo; Yasufumi Miyamoto; Hidenori Abe; Naohiro Taya; Satoru Oi; Masanori Watanabe; Tomoko Urushibara; Masatoshi Hazama; Shin-ichi Niwa; Saku Miyamoto; Akira Horinouchi; Ken-ichi Kuroshima; Nobuyuki Amano; Shin-ichi Matsumoto; Shinichiro Matsunaga
      Pages: 5995 - 6006
      Abstract: Publication date: 1 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 21
      Author(s): Yoshihiro Banno, Shigekazu Sasaki, Makoto Kamata, Jun Kunitomo, Yasufumi Miyamoto, Hidenori Abe, Naohiro Taya, Satoru Oi, Masanori Watanabe, Tomoko Urushibara, Masatoshi Hazama, Shin-ichi Niwa, Saku Miyamoto, Akira Horinouchi, Ken-ichi Kuroshima, Nobuyuki Amano, Shin-ichi Matsumoto, Shinichiro Matsunaga
      The discovery of a novel series of β-methyltryptophan (β MeTrp) derivatives as selective and orally active non-peptide somatostatin receptor 2 (SSTR2) agonists for the treatment of Type 2 diabetes is described. In our previous research, Compound A, β-MeTrp derivative with highly potent and selective SSTR2 agonistic activity IC50 (SSTR2/SSTR5)=0.3/>100 (nM), was identified asa drug candidate for treatment of Type 2 diabetes which lowers significantly plasma glucose level in Wistar fatty rats in its oral administrations. However, as serious increase in AUC and phospholipidosis (PLsis) were observed in its toxicological studies in rats, follow-up compounds were searched to avoid risk of PLsis with reference to their in vitro PLsis potentials evaluated on the basis of accumulation of phospholipids in HepG2 cells exposed to the compounds. It has been found that introduction of a carbonyl group onto the piperidine and piperazine or aniline moiety of compounds A and B reduced markedly the in vitro PLsis potentials. And further modification of the compounds and their evaluation led to a discovery of compounds 3k with lower in vitro PLsis potentials exhibiting lowering effect of hypoglycemia-induced glucagon secretion in SD rats (ED50 =1.1mg/kg) and glucose excursion in meal tolerance test in Wistar fatty diabetic rats (MED=3.0mg/kg) in oral administrations. Compound 3k was selected asa new drug candidate of selective and orally active non-peptide SSTR2 agonists for treatment of Type 2 diabetes with low in vivo PLsis potential.
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      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.09.031
       
  • Synthesis of photocaged 6-O-(2-nitrobenzyl)guanosine and
           4-O-(2-nitrobenzyl) uridine triphosphates for photocontrol of the RNA
           transcription reaction
    • Authors: Kentaro Ohno; Daiki Sugiyama; Leo Takeshita; Takashi Kanamori; Yoshiaki Masaki; Mitsuo Sekine; Kohji Seio
      Pages: 6007 - 6015
      Abstract: Publication date: 1 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 21
      Author(s): Kentaro Ohno, Daiki Sugiyama, Leo Takeshita, Takashi Kanamori, Yoshiaki Masaki, Mitsuo Sekine, Kohji Seio
      6-O-(2-Nitrobenzyl)guanosine and 4-O-(2-nitrobenzyl)uridine triphosphates (NBGTP, NBUTP) were synthesized, and their biochemical and photophysical properties were evaluated. We synthesized NBUTP using the canonical triphosphate synthesis method and NBGTP from 2′,3′-O-TBDMS guanosine via a triphosphate synthesis method by utilizing mild acidic desilylation conditions. Deprotection of the nitrobenzyl group in NBGTP and NBUTP proceeded within 60s by UV irradiation at 365nm. Experiments using NBGTP or NBUTP in T7-RNA transcription reactions showed that NBGTP could be useful for the photocontrol of transcription by UV irradiation.
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      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.09.032
       
  • Synthesis and photophysical properties of a fluorescent cyanoquinoline
           probe for profiling ERBB2 kinase inhibitor response
    • Authors: Heajin Lee; Ralf Landgraf; James N. Wilson
      Pages: 6016 - 6023
      Abstract: Publication date: 1 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 21
      Author(s): Heajin Lee, Ralf Landgraf, James N. Wilson
      A fluorescent probe targeting the ERBB2 receptor tyrosine was designed, synthesized and evaluated as reporter of ERBB2 dynamics in overexpressing BT474, i.e. Her2(+), cells. Two cyanoquinazoline (CQ) probes modeled after type-I (CQ1) or active state and type-II (CQ2) or inactive state inhibitors were designed and synthesized with extended π systems that impart binding-induced, turn-on fluorescence. Solution spectroscopy revealed that CQ1 exhibited attractive photophysical properties and displayed turn-on emission in the presence of purified, soluble ERBB2 kinase domain, while CQ2 was found to be non-emissive, likely due to quenching via a photoinduced electron transfer mechanism. Live cell imaging with CQ1 revealed that this probe targeted an intracellular population of ERBB2, which increased following treatment with type-I inhibitors, gefinitib and canertinib, but showed no response to type-II inhibitors. CQ1 thus provides a novel means of imaging the dynamic response of ERBB2(+) cells to kinase inhibitors.
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      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.09.034
       
  • Synthesis and structure activity relationships of carbamimidoylcarbamate
           derivatives as novel vascular adhesion protein-1 inhibitors
    • Authors: Susumu Yamaki; Hiroyoshi Yamada; Akira Nagashima; Mitsuhiro Kondo; Yoshiaki Shimada; Keitaro Kadono; Kosei Yoshihara
      Pages: 6024 - 6038
      Abstract: Publication date: 1 November 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 21
      Author(s): Susumu Yamaki, Hiroyoshi Yamada, Akira Nagashima, Mitsuhiro Kondo, Yoshiaki Shimada, Keitaro Kadono, Kosei Yoshihara
      Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted structural optimization of the glycine amide derivative 1, which we previously reported as a novel VAP-1 inhibitor, to improve stability in dog and monkey plasma, and aqueous solubility. By chemical modification of the right part in the glycine amide derivative, we identified the carbamimidoylcarbamate derivative 20c, which showed stability in dog and monkey plasma while maintaining VAP-1 inhibitory activity. We also found that conversion of the pyrimidine ring in 20c into saturated rings was effective for improving aqueous solubility. This led to the identification of 28a and 35 as moderate VAP-1 inhibitors with excellent aqueous solubility. Further optimization led to the identification of 2-fluoro-3-{3-[(6-methylpyridin-3-yl)oxy]azetidin-1-yl}benzyl carbamimidoylcarbamate (40b), which showed similar human VAP-1 inhibitory activity to 1 with improved aqueous solubility. 40b showed more potent ex vivo efficacy than 1, with rat plasma VAP-1 inhibitory activity of 92% at 1h after oral administration at 0.3mg/kg. In our pharmacokinetic study, 40b showed good oral bioavailability in rats, dogs, and monkeys, which may be due to its improved stability in dog and monkey plasma.
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      PubDate: 2017-11-01T15:31:06Z
      DOI: 10.1016/j.bmc.2017.09.036
       
  • Discovery of novel purine nucleoside derivatives as phosphodiesterase 2
           (PDE2) inhibitors: structure-based virtual screening, optimization and
           biological evaluation
    • Abstract: Publication date: Available online 14 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Xiaoxia Qiu, Yiyou Huang, Deyan Wu, Fei Mao, Jin Zhu, Wenzhong Yan, Hai-Bin Luo, Jian Li
      Phosphodiesterase 2 (PDE2) has received much attention for the potential treatment of the central nervous system (CNS) disorders and pulmonary hypertension. Herein, we identified that clofarabine (4), an FDA-approved drug, displayed potential PDE2 inhibitory activity (IC50 = 3.12 ± 0.67 μM) by structure-based virtual screening and bioassay. Considering the potential therapeutic benefit of PDE2, a series of purine nucleoside derivatives based on the structure and binding mode of 4 were designed, synthesized and evaluated, which led to the discovery of the best compound 14e with a significant improvement of inhibitory potency (IC50 = 0.32 ± 0.04 μM). Further molecular docking and molecular dynamic (MD) simulations studies revealed that 5’-benzyl group of 14e could interact with the unique hydrophobic pocket of PDE2 by forming extra van der Waals interactions with hydrophobic residues such as Leu770, Thr768, Thr805 and Leu809, which might contribute to its enhancement of PDE2 inhibition. These potential compounds reported in this article and the valuable structure-activity relationships (SARs) might bring significant instruction for further development of potent PDE2 inhibitors.
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      PubDate: 2017-11-16T15:00:10Z
       
  • Bioluminescence Probe for γ-Glutamyl Transpeptidase Detection in vivo
    • Abstract: Publication date: Available online 14 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Yuxing Lin, Yuqi Gao, Zhao Ma, Tianyu Jiang, Xin Zhou, Zhenzhen Li, Xiaojun Qin, Yun Huang, Lupei Du, Minyong Li
      To detect γ-Glutamyl Transpeptidase (GGT) activity in vitro and in vivo, a bioluminescence probe with high sensitivity and specificity was well designed and synthesized. This probe can be recognized by GGT and release strong bioluminescence with its further reaction with luciferase. The performance of this probe was demonstrated in vitro and in cells. Finally, we applied the probe for detection of GGT activity in xenograft model.
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      PubDate: 2017-11-16T15:00:10Z
       
  • Design and synthesis of highly selective pyruvate dehydrogenase complex E1
           inhibitors as bactericides
    • Abstract: Publication date: Available online 13 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Yuan Zhou, Shasha Zhang, Hongwu He, Wen Jiang, Leifeng Hou, Dan Xie, Meng Cai, Hao Peng, Lingling Feng
      In order to obtain PDHc-E1 inhibitors with high selectivity and efficacy, four series (7, 12, 15, and 19) of 35 novel 4-aminopyrimidine derivatives were rationally designed and synthesized based on the binding site of ThDP in E. coli PDHc-E1. 12, 15, and 19 were confirmed to be potent inhibitors against E. coli PDHc-E1. Selected compounds 12g, 12i, 15f, and 19a showed negligible inhibition against porcine PDHc-E1. To understand their selectivity, the interaction of inhibitor and E. coli PDHc-E1 or porcine PDHc-E1 was studied by molecular docking. The newly introduced acylhydrazone and N-phenylbenzamide moieties could form stronger interaction by hydrogen bond at the active site of E. coli PDHc-E1 compared with that of porcine PDHc-E1. A part of title compounds as potent PDHc-E1 inhibitors also exhibited notable antibacterial activity. In particular, 12e, 12f, 12g, 12o, and 19a exhibited 72-92% inhibition against Xanthomonas oryzae pv. Oryzae and Ralstonia solanacearum at 100 μg/mL, which was better than thiodiazole-copper (34 and 29%, respectively) and bismerthiazol (56 and 55%, respectively). The results proved that we could obtain effective bactericidal compounds as highly selective PDHc inhibitors by rational molecular design utilizing the binding model of active site of E. coli PDHc-E1.
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      PubDate: 2017-11-16T15:00:10Z
       
  • N-Arylsulfonylsubstituted-1H indole derivatives as small molecule dual
           inhibitors of signal transducer and activator of transcription 3 (STAT3)
           and tubulin
    • Abstract: Publication date: Available online 13 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Qiang Zhou, Jinjin Zhu, Jinglei Chen, Peng Ji, Chunhua Qiao
      Signal transducer and activator of transcription (STAT3) is a proposed therapeutictarget for the development of anti-cancer agents. In this report, a series of N-arylsulfonylsubstituted-1H indole derivatives were designed and synthesized as STAT3 inhibitors, their anti-proliferative activities were evaluated against a number of tumor cells, some potent compounds exhibited IC50 values less than 10 μM. The most potent compound 4a was further confirmed to inhibit STAT3 phosphorylation at Tyr705. It was further revealed that 4a arrested the cell cycle at the G2/M phase and inhibited tubulin polymerization. This study describes a series of N-arylsulfonylsubstituted-1H indole derivatives as potent anti-cancer agents targeting both STAT3 and tubulin.
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      PubDate: 2017-11-16T15:00:10Z
       
  • TLR8 activation and inhibition by guanosine analogs in RNA: importance of
           functional groups and chain length
    • Abstract: Publication date: Available online 11 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Tiannan Hu, Scott R. Suter, Madeline M. Mumbleau, Peter A. Beal
      Toll-like receptor 8 (TLR8) is an important component of the human innate immune system that recognizes single stranded RNA (ssRNA). Recent x-ray crystal structures of TLR8 bound to ssRNA revealed a previously unrecognized binding site for a 5’-UpG-3’ dinucleotide. Here we use an atomic mutagenesis strategy coupled with a cellular TLR8 activation assay to probe the importance of specific functional groups present on the guanine base in RNA-mediated receptor agonism and antagonism. Results from RNA analogs containing 7-deazaguanosine, 2-aminopurine and inosine confirm the importance of guanine N7, O6 and N2, respectively, in TLR8 activation. Nevertheless, these RNAs each retained TLR8 antagonism activity. RNA containing 7-deaza-8-azainosine (7d8aI) was prepared from a novel phosphoramidite and found to be a weaker TLR8 activator than guanosine-containing RNA. However, 7d8aI-containing RNA also retained TLR8 antagonism activity indicating that removal of multiple TLR8 H-bonding sites on guanine is insufficient for blocking TLR8 antagonism by guanine-containing RNA. We also identified an oligoribonucleotide length dependence on both TLR8 activation and antagonism. These studies extend our understanding of the effects of nucleobase modification on immune stimulation and will inform the design of novel RNA-based therapeutics.
      Graphical abstract image

      PubDate: 2017-11-16T15:00:10Z
       
  • A Novel Series of Enoyl Reductase Inhibitors Targeting the ESKAPE
           Pathogens, Staphylococcus aureus and Acinetobacter baumannii
    • Abstract: Publication date: Available online 11 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Jieun Kwon, Tina Mistry, Jinhong Ren, Michael E. Johnson, Shahila Mehboob
      S. aureus and A. baumannii are among the ESKAPE pathogens that are increasingly difficult to treat due to the rise in the number of drug resistant strains. Novel therapeutics targeting these pathogens are much needed. The bacterial enoyl reductase (FabI) is as potentially significant drug target for developing pathogen-specific antibiotics due to the presence of alternate FabI isoforms in many other bacterial species. We report the identification and development of a novel N-carboxy pyrrolidine scaffold targeting FabI in S. aureus and A. baumannii, two pathogens for which FabI essentiality has been established. This scaffold is unrelated to other known antibiotic families, and FabI is not targeted by any currently approved antibiotic. Our data shows that this scaffold displays promising enzyme inhibitory activity against FabI from both S. aureus and A. baumannii, as well as encouraging antibacterial activity in S. aureus. Compounds also display excellent synergy when combined with colistin and tested against A. baumannii. In this combination the MIC of colistin is reduced by 10 fold. Our first generation compound displays promising enzyme inhibition, targets FabI in S. aureus with a favorable selectivity index (ratio of cytotoxicity to MIC), and has excellent synergy with colistin against A. baumannii, including a multidrug resistant strain.
      Graphical abstract image

      PubDate: 2017-11-16T15:00:10Z
       
  • Organoselenium compounds from Purines: Synthesis of 6-arylselanylpurines
           with antioxidant and anticholinesterase activities and memory improvement
           effect
    • Abstract: Publication date: Available online 10 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Luis Fernando B. Duarte, Renata L. Oliveira, Karline C. Rodrigues, Guilherme T. Voss, Benhur Godoi, Ricardo F. Schumacher, Gelson Perin, Ethel A. Wilhelm, Cristiane Luchese, Diego Alves
      We describe here a simple method for the synthesis of 6-arylselanylpurines with antioxidant and anticholinesterase activities, and memory improvement effect. This class of compounds was synthesized in good yields by a reaction of 6-chloropurine with diaryl diselenides using NaBH4 as reducing agent and PEG-400 as solvent. Furthermore, the synthesized compounds were evaluated for their in vitro antioxidant and acetylcholinesterase (AChE) inhibitor activities. The best AChE inhibitor was assessed on the in vivo memory improvement. Our results demonstrated that the 6-((4-chlorophenyl)selanyl)-9H-purine and 6-(p-tolylselanyl)-9H-purine presented in vitro antioxidant effect. In addition, 6-((4-fluorophenyl)selanyl)-9H-purine inhibited the AChE activity and improved memory, being a promising therapeutic agent for the treatment of Alzheimer’s disease.
      Graphical abstract image

      PubDate: 2017-11-16T15:00:10Z
       
  • Design and synthesis of aminoester heterodimers containing flavone or
           chromone moieties as modulators of P-glycoprotein-based multidrug
           resistance (MDR)
    • Abstract: Publication date: Available online 10 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Silvia Dei, Maria Novella Romanelli, Dina Manetti, Niccolò Chiaramonte, Marcella Coronnello, Milena Salerno, Elisabetta Teodori
      In this study, a new series of heterodimers was synthesized. These derivatives are N,N -bis(alkanol)amine aryl esters or N,N -bis(ethoxyethanol)amine aryl esters carrying a methoxylated aryl residue combined with a flavone or chromone moiety. The new compounds were studied to evaluate their P-gp modulating activity on a multidrug-resistant leukemia cell line. Some of the new compounds show a good MDR reversing activity; interestingly this new series of compounds does not comply with the structure-activity relationships (SAR) outlined by previously synthesized analogs carrying different aromatic moieties. In the case of the compounds described in this paper, activity is linked to different features, in particular the characteristics of the spacer, which seem to be critical for the interaction with the pump. This fact indicates that the presence of a flavone or chromone residue influences the SAR of these series of products, and that flexible molecules can find different productive binding modes with the P-gp recognition site. These results support the synthesis of new compounds that might be useful leads for the development of drugs to control P-gp-dependent MDR.
      Graphical abstract image

      PubDate: 2017-11-16T15:00:10Z
       
  • Anticancer activities of emetine prodrugs that are proteolytically
           activated by the prostate specific antigen (PSA) and evaluation of in vivo
           toxicity of emetine derivatives
    • Abstract: Publication date: Available online 10 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Emmanuel S. Akinboye, Marc D. Rosen, Oladapo Bakare, Samuel R. Denmeade
      Emetine is a small molecule protein synthesis inhibitor that is toxic to all cell types and therefore suitable for complete killing of all types of heterogeneous cancer cells within a tumor. It becomes significantly inactive (non-toxic) when derivatized at its N-2′ secondary amine. This provides a strategy for targeting emetine to cancerous tumor without killing normal cells. In this report, PSA activatable peptide prodrugs of emetine were synthesized. To overcome steric hindrances and enhance protease specific cleavage, a 2-stage prodrug activation process was needed to release emetine in cancer cells. In this 2-stage process, emetine prodrug intermediates are coupled to PSA peptide substrate (Ac-His-Ser-Ser-Lys-Leu-Gln) to obtain the full prodrug. Both prodrug intermediates 10 (Ala-Pro-PABC-Emetine) and 14 (Ser-Leu-PABC-Emetine) were evaluated for kinetics of hydrolysis to emetine and potency [Where PABC = p-aminobenzyloxycarbonyl]. While both intermediates quantitatively liberate emetine when incubated under appropriate conditions, upon coupling of PSA substrate to give the full prodrugs, only prodrug 16, the prodrug obtained from 14 was hydrolyzable by PSA. Cytotoxicity studies in PSA producing LNCaP and CWR22Rv1 confirm the activation of the prodrug by PSA with an IC50 of 75 nM and 59 nM respectively. The cytotoxicity of 16 is significantly reduced in cell lines that do not produce PSA. Further, in vivo toxicity studies are done on these prodrugs and other derivatives of emetine. The results show the significance of conformational modulation in obtaining safe emetine prodrugs.
      Graphical abstract image

      PubDate: 2017-11-16T15:00:10Z
       
  • Unique arginine array improves cytosolic localization of
           hydrocarbon-stapled peptides
    • Authors: Kim Quach; Jonathan LaRochelle; Xiao-Han Li; Elizabeth Rhoades; Alanna Schepartz
      Abstract: Publication date: Available online 7 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Kim Quach, Jonathan LaRochelle, Xiao-Han Li, Elizabeth Rhoades, Alanna Schepartz
      We have previously reported that miniature proteins containing a distinct array of 5 arginine residues on a folded α-helix–a penta-arg motif–traffic with high efficiency from endosomes into the cytosol and nucleus of mammalian cells. Here we evaluate whether a penta-arg motif can improve the intracellular trafficking of an otherwise impermeant hydrocarbon-stapled peptide, SAH-p53-4Rho. We prepared a panel of SAH-p53-4Rho variants containing penta-arg sequences with different spacings and axial arrangement and evaluated their overall uptake (as judged by flow cytometry) and their intracellular access (as determined by fluorescence correlation spectroscopy, FCS). One member of this panel reached the cytosol extremely well, matching the level achieved by SAH-p53-8Rho, a previously reported and highly permeant hydrocarbon-stapled peptide. Notably, we found no relationship between cellular uptake as judged by flow cytometry and cytosolic access as determined by FCS. This result emphasizes the importance of accessing intracellular access directly via FCS or an analogous method and reiterates that overall uptake and endosomal release represent fundamentally different biological processes. To determine cytosolic and/or nuclear access, one must measure concentration directly using a quantitative tool such as FCS. Our results also suggest that optimal penetration of hydrocarbon-stapled peptides into the cell cytosol results when the penta-arg motif is located within more (as opposed to less) structured regions.
      Graphical abstract image

      PubDate: 2017-11-09T00:16:43Z
      DOI: 10.1016/j.bmc.2017.11.008
       
  • Bimodal Fluorescence/129Xe NMR Probe for Molecular Imaging and Biological
           Inhibition of EGFR in Non-Small Cell Lung Cancer
    • Authors: Gaëlle Milanole; Bo Gao; Audrey Paoletti; Grégory Pieters; Christophe Dugave; Eric Deutsch; Sofia Rivera; Frédéric Law; Jean-Luc Perfettini; Emilie Mari; Estelle Léonce; Céline Boutin; Patrick Berthault; Hervé Volland; François Fenaille; Thierry Brotin; Bernard Rousseau
      Abstract: Publication date: Available online 6 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Gaëlle Milanole, Bo Gao, Audrey Paoletti, Grégory Pieters, Christophe Dugave, Eric Deutsch, Sofia Rivera, Frédéric Law, Jean-Luc Perfettini, Emilie Mari, Estelle Léonce, Céline Boutin, Patrick Berthault, Hervé Volland, François Fenaille, Thierry Brotin, Bernard Rousseau
      Although Non-Small Cell Lung Cancer (NSCLC) is one of the main causes of cancer death, very little improvement has been made in the last decades regarding diagnosis and outcomes. In this study, a bimodal fluorescence/129Xe NMR probe containing a xenon host, a fluorescent moiety and a therapeutic antibody has been designed to target the Epidermal Growth Factor Receptors (EGFR) overexpressed in cancer cells. This biosensor shows high selectivity for the EGFR, and a biological activity similar to that of the antibody. It is detected with high specificity and high sensitivity (sub-nanomolar range) through hyperpolarized 129Xe NMR. This promising system should find important applications for theranostic use.
      Graphical abstract image

      PubDate: 2017-11-09T00:16:43Z
      DOI: 10.1016/j.bmc.2017.11.002
       
  • Discovery and in vivo effects of novel human Natriuretic Peptide Receptor
           A (NPR-A) agonists with improved activity for rat NPR-A
    • Authors: Takehiko Iwaki; Taisaku Tanaka; Kazuo Miyazaki; Yamato Suzuki; Yoshihiko Okamura; Akira Yamaki; Makoto Iwanami; Naomi Morizumi; Mayumi Furuya; Yoshiaki Oyama
      Abstract: Publication date: Available online 6 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Takehiko Iwaki, Taisaku Tanaka, Kazuo Miyazaki, Yamato Suzuki, Yoshihiko Okamura, Akira Yamaki, Makoto Iwanami, Naomi Morizumi, Mayumi Furuya, Yoshiaki Oyama
      Natriuretic peptide receptor A (NPR-A) agonists were evaluated in vivo by optimizing the structure of quinazoline derivatives to improve agonistic activity for rat NPR-A. A 1,4-cis-aminocyclohexylurea moiety at 4-position and hydroxy group of D-alaninol at 2-position on the quinazoline ring were found to be important factors in improving rat NPR-A activity. We identified potent quinazoline and pyrido[2,3-d]pyrimidine derivatives against rat NPR-A, with double-digit nanomolar EC50 values. The in vivo results showed that compound 56b administered at 1.0 mg/kg/min significantly increased plasma cGMP concentration and urine volume in rats. We discovered novel potent NPR-A agonists that showed agonistic effects similar to those of atrial natriuretic peptide.
      Graphical abstract image

      PubDate: 2017-11-09T00:16:43Z
      DOI: 10.1016/j.bmc.2017.11.006
       
  • UVA irradiation of BrU-substituted DNA in the presence of Hoechst 33258
    • Authors: Abhijit Saha; Seiichiro Kizaki; Ji Hoon Han; Zutao Yu; Hiroshi Sugiyama
      Abstract: Publication date: Available online 6 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Abhijit Saha, Seiichiro Kizaki, Ji Hoon Han, Zutao Yu, Hiroshi Sugiyama
      Given that our knowledge of DNA repair is limited because of the complexity of the DNA system, a technique called UVA micro-irradiation has been developed that can be used to visualize the recruitment of DNA repair proteins at double-strand break (DSB) sites. Interestingly, Hoechst 33258 was used under micro-irradiation to sensitize 5-bromouracil (BrU)-labelled DNA, causing efficient DSBs. However, the molecular basis of DSB formation under UVA micro-irradiation remains unknown. Herein, we investigated the mechanism of DSB formation under UVA micro-irradiation conditions. Our results suggest that the generation of a uracil-5-yl radical through electron transfer from Hoechst 33258 to BrU caused DNA cleavage preferentially at self-complementary 5’-AABrUBrU-3’ sequences to induce DSB. We also investigated the DNA cleavage in the context of the nucleosome to gain a better understanding of UVA micro-irradiation in a cell-like model. We found that DNA cleavage occurred in both core and linker DNA regions although its efficiency reduced in core DNA.
      Graphical abstract image

      PubDate: 2017-11-09T00:16:43Z
      DOI: 10.1016/j.bmc.2017.11.011
       
  • Discovery of imidazo[1,2-a]pyridine-based anthelmintic targeting
           cholinergic receptors of Haemonchus Contortus
    • Authors: Jean-Paul Déto Ursul N'Guessan; Pierre-Olivier Delaye; Mélanie Pénichon; Claude L. Charvet; Cédric Neveu; Mahama Ouattara; Cécile Enguehard-Gueiffier; Alain Gueiffier; Hassan Allouchi
      Abstract: Publication date: Available online 6 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Jean-Paul Déto Ursul N'Guessan, Pierre-Olivier Delaye, Mélanie Pénichon, Claude L. Charvet, Cédric Neveu, Mahama Ouattara, Cécile Enguehard-Gueiffier, Alain Gueiffier, Hassan Allouchi
      We report the synthesis of a series of imidazo[1,2-a]pyridine-based molecules as anthelmintic against the livestock parasite Haemonchus contortus. The molecules were tested by using Larval Paralysis Test (LPT), in order to target ionic channels, as most of the prominent marketed anthelminthics present such mechanism of action. The most active compound (5e) displayed paralysis on H. contortus stage 3 larvae until 31.25µM. Effect of 5e on H. contortus cholinergic receptors (L-AChR1 and 2) was characterized via electrophysiological measurement and a rare antagonist mode of action was unveiled.
      Graphical abstract image

      PubDate: 2017-11-09T00:16:43Z
      DOI: 10.1016/j.bmc.2017.11.012
       
  • An opportunistic route to success: towards a change of paradigm to fully
           exploit the potential of Cell-Penetrating Peptides
    • Authors: Estel Collado Camps; Roland Brock
      Abstract: Publication date: Available online 4 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Estel Collado Camps, Roland Brock
      About 25 years ago it was demonstrated that certain peptides possess the ability to cross the plasma membrane. This led to the development of cell-penetrating peptides (CPPs) as vectors to mediate the cellular entry of (macro-)molecules that do not show cell entry by themselves. Nonetheless, in spite of an early bloom of promising pre-clinical studies, not a single CPP-based drug has been approved, yet. It is a paradigm in CPP research that the peptides are taken up by virtually all cells. In exploratory research and early preclinical development, this assumption guides the choice of the therapeutic target. However, while this indiscriminatory uptake may be the case for tissue culture experiments, in an organism this is clearly not the case. Biodistribution analyses demonstrate that CPPs only target a very limited number of cells and many tissues are hardly reached at all. Here, we review biodistribution analyses of CPPs and CPP-based drug delivery systems. Based on this analysis we propose a paradigm change towards a more opportunistic approach in CPP research. The application of CPPs should focus on those pathophysiologies for which the relevant target cells have been shown to be targeted in vivo.
      Graphical abstract image

      PubDate: 2017-11-09T00:16:43Z
      DOI: 10.1016/j.bmc.2017.11.004
       
  • Design, synthesis and evaluation of 3-arylidene azetidin-2-ones as
           potential antifungal agents against Alternaria solani Sorauer
    • Authors: Wang Delong; Wu Yongling; Wang Lanying; Feng Juntao; Zhang Xing
      Abstract: Publication date: Available online 4 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Wang Delong, Wu Yongling, Wang Lanying, Feng Juntao, Zhang Xing
      A new concise and facile method was explored to synthesize a collection of new 3-arylidene azetidin-2-ones, which could be regarded as the derivatives of the hybrid scaffold of bioactive natural cinnamamide and heterocycle azetidi-2-one. The structures of the synthesized compounds were characterized by 1H-, 13C NMR, and MS; and their antifungal activity were evaluated against Alternaria solani Sorauer. These antifungal data were subjected to a quantitative structure–activity relationship (QSAR) analysis using Codessa software on the basis of the results from B3LYP/6-31G(d,p) quantum calculations. The best regressive model revealed that potentially more active compounds should have low dipole moments and QC-min (minimal net atomic charge for a C atom), and high QO-max (maximal net atomic charge for an O atom) and QN-min (minimal net atomic charge for an N atom). The most potent compound 7k could lead to intracellular accumulation of reactive oxygen species, dissipation of mitochondrial transmembrane potential, and an autophagy-like cell death process in A. solani Sorauer. Taken together, these results laid the foundation for further design of improved crop-protection agents based on this hybrid scaffold.
      Graphical abstract image

      PubDate: 2017-11-09T00:16:43Z
      DOI: 10.1016/j.bmc.2017.11.003
       
  • Synthesis and biological evaluation of isobutyrophenone analogs as
           potential inhibitors of class-II fructose-1,6-bisphosphate aldolase
    • Authors: Ding Li; Tuong Thi Mai Luong; Wen-Jia Dan; Yanliang Ren; Hoang Xuan Nien; An-Ling Zhang; Jin-Ming Gao
      Abstract: Publication date: Available online 4 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Ding Li, Tuong Thi Mai Luong, Wen-Jia Dan, Yanliang Ren, Hoang Xuan Nien, An-Ling Zhang, Jin-Ming Gao
      Several recently identified antifungal compounds share the backbone structure of acetophenones. The aim of the present study was to develop new isobutyrophenone analogs as new antifungal agents. A series of new 2,4-dihydroxy-5-methyl isobutyrophenone derivatives were prepared and characterized by 1H, 13C NMR and MS spectroscopic data. These products were evaluated for in vitro antifungal activities against seven plant fungal pathogens by the mycelial growth inhibitory rate assay. Compounds 3, 4a, 5a, 5b, 5e, 5f and 5g showed a broad-spectrum high antifungal activity. On the other hand, for the first time, these compounds were also assayed as potential inhibitors against Class II fructose-1,6-bisphosphate aldolase (Fba) from the rice blast fungus, Magnaporthe grisea. Compounds 5e and 5g were found to exhibit the inhibition constants (Ki) for 15.12 and 14.27 μM, respectively, as the strongest competitive inhibitors against Fba activity. The possible binding-modes of compounds 5e and 5g were further analyzed by molecular docking algorithms. The results strongly suggested that compound 5g could be a promising lead for the discovery of new fungicides via targeting Class II Fba.
      Graphical abstract image

      PubDate: 2017-11-09T00:16:43Z
      DOI: 10.1016/j.bmc.2017.10.046
       
  • Peptide Therapeutics for the Treatment of Gastrointestinal Disorders
    • Authors: Angelika Fretzen
      Abstract: Publication date: Available online 4 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Angelika Fretzen
      Graphical abstract image

      PubDate: 2017-11-09T00:16:43Z
      DOI: 10.1016/j.bmc.2017.11.007
       
  • Exploiting a water network to achieve enthalpy-driven,
           bromodomain-selective BET inhibitors
    • Authors: William R. Shadrick; Peter J. Slavish; Sergio C. Chai; Brett Waddell; Michele Connelly; Jonathan A. Low; Cynthia Tallant; Brandon M. Young; Nagakumar Bharatham; Stefan Knapp; Vincent A. Boyd; Marie Morfouace; Martine F. Roussel; Taosheng Chen; Richard E. Lee; R. Kiplin Guy; Anang A. Shelat; Philip M. Potter
      Abstract: Publication date: Available online 4 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): William R. Shadrick, Peter J. Slavish, Sergio C. Chai, Brett Waddell, Michele Connelly, Jonathan A. Low, Cynthia Tallant, Brandon M. Young, Nagakumar Bharatham, Stefan Knapp, Vincent A. Boyd, Marie Morfouace, Martine F. Roussel, Taosheng Chen, Richard E. Lee, R. Kiplin Guy, Anang A. Shelat, Philip M. Potter
      Within the last decade, the Bromodomain and Extra-Terminal domain family (BET) of proteins have emerged as promising drug targets in diverse clinical indications including oncology, auto-immune disease, heart failure, and male contraception. The BET family consists of four isoforms (BRD2, BRD3, BRD4, and BRDT/BRDT6) which are distinguished by the presence of two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine (KAc) residues and appear to have distinct biological roles. BET BD1 and BD2 bromodomains differ at five positions near the substrate binding pocket: the variation in the ZA channel induces different water networks nearby. We designed a set of congeneric 2- and 3-heteroaryl substituted tetrahydroquinolines (THQ) to differentially engage bound waters in the ZA channel with the goal of achieving bromodomain selectivity. SJ830599 (9) showed modest, but consistent, selectivity for BRD2-BD2. Using isothermal titration calorimetry, we showed that the binding of all THQ analogs in our study to either of the two bromodomains was enthalpy driven. Remarkably, the binding of 9 to BRD2-BD2 was marked by negative entropy and was entirely driven by enthalpy, consistent with significant restriction of conformational flexibility and/or engagement with bound waters. Co-crystallography studies confirmed that 9 did indeed stabilize a water-mediated hydrogen bond network. Finally, we report that 9 retained cytotoxicity against several pediatric cancer cell lines with EC50 values comparable to BET inhibitor (BETi) clinical candidates.
      Graphical abstract image

      PubDate: 2017-11-09T00:16:43Z
      DOI: 10.1016/j.bmc.2017.10.042
       
  • Design, synthesis and biological mechanisms research on 1,2,3-triazole
           derivatives of Jiyuan Oridonin A
    • Authors: Yu Ke; Wang Wang; Long-Fei Zhao; Jian-Jia Liang; Ying Liu; Xiao Zhang; Kai Feng; Hong-Min Liu
      Abstract: Publication date: Available online 4 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Yu Ke, Wang Wang, Long-Fei Zhao, Jian-Jia Liang, Ying Liu, Xiao Zhang, Kai Feng, Hong-Min Liu
      Two series of derivatives with 1,2,3-triazole as heterocyclic moiety of Jiyuan Oridonin A, a new ent-kaurene diterpenoid which was isolated from genus Isodon rubescens, were synthesized and biologically evaluated. All the derivatives possessed good anti-proliferative activities. Among them, compound 8g was found to significantly induce cell apoptosis and cell cycle arrest in MGC-803 via a series of signals activated by the increased intracellular ROS levels.
      Graphical abstract image

      PubDate: 2017-11-09T00:16:43Z
      DOI: 10.1016/j.bmc.2017.11.005
       
  • Design, synthesis, and biological evaluation of thieno[2,3-d]pyrimidine
           derivatives as novel dual c-Met and VEGFR-2 kinase inhibitors
    • Authors: Jieming Li; Weijie Gu; Xinzhou Bi; Huilan Li; Chen Liao; Chunxia Liu; Wenlong Huang; Hai Qian
      Abstract: Publication date: Available online 4 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Jieming Li, Weijie Gu, Xinzhou Bi, Huilan Li, Chen Liao, Chunxia Liu, Wenlong Huang, Hai Qian
      Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing thieno[2,3-d]pyrimidine scaffold. The cell proliferation assay in vitro demonstrated that most target compounds had inhibition potency both on c-Met and VEGFR-2 with IC50 values in nanomolar range, especially compound 12j and 12m. Based on the further enzyme assay in vitro, compound 12j was considered as the most potent one, the IC50 values of which were 25 nM and 48 nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 12j with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogues. All the results indicate that 12j is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential.
      Graphical abstract image

      PubDate: 2017-11-09T00:16:43Z
      DOI: 10.1016/j.bmc.2017.11.010
       
  • Nose-to-brain peptide delivery – the potential of nanotechnology
    • Authors: Eleni Samaridou; María José Alonso
      Abstract: Publication date: Available online 4 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Eleni Samaridou, María José Alonso
      Nose-to-Brain (N-to-B) delivery offers to protein and peptide drugs the possibility to reach the brain in a non-invasive way. This article is a comprehensive review of the state-of-the-art of this emerging peptide delivery route, as well as of the challenges associated to it. Emphasis is given on the potential of nanosized drug delivery carriers to enhance the direct N-to-B transport of protein or peptide drugs. In particular, polymer- and lipid- based nanocarriers are comparatively analyzed in terms of the influence of their physicochemical characteristics and composition on their in vivo fate and efficacy. The use of biorecognitive ligands and permeation enhancers in order to enhance their brain targeting efficiency is also discussed. The article concludes highlighting the early stage of this research field and its still unveiled potential. The final message is that more explicatory PK/PD studies are required in order to achieve the translation from preclinical to the clinical development phase.
      Graphical abstract image

      PubDate: 2017-11-09T00:16:43Z
      DOI: 10.1016/j.bmc.2017.11.001
       
  • Identification of cytotoxic, glutathione-reactive moieties inducing
           accumulation of reactive oxygen species via glutathione depletion
    • Authors: Julian Wilke; Tatsuro Kawamura; Nobumoto Watanabe; Hiroyuki Osada; Slava Ziegler; Herbert Waldmann
      Abstract: Publication date: Available online 4 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Julian Wilke, Tatsuro Kawamura, Nobumoto Watanabe, Hiroyuki Osada, Slava Ziegler, Herbert Waldmann
      Reactive oxygen species (ROS) play an essential role in the survival and progression of cancer. Moderate oxidative stress drives proliferation, whereas high levels of ROS induce cytotoxicity. Compared to cancer cells, healthy cells often exhibit lower levels of oxidative stress. Elevation of cellular ROS levels by small molecules could therefore induce cancer-specific cytotoxicity. We have employed high-throughput phenotypic screening to identify inducers of ROS accumulation. We found 4,5-dihalo-2-methylpyridazin-3-one (DHMP) and 2,3,4,5(6)-tetrachloro-6(5)-methylpyridine (TCMP) moieties to strongly deplete GSH, to cause ROS accumulation and to induce cell death.. Small molecules containing these fragments will most likely share the same properties and should therefore be carefully considered in the development of bioactive molecules.
      Graphical abstract image

      PubDate: 2017-11-09T00:16:43Z
      DOI: 10.1016/j.bmc.2017.11.009
       
  • Optimization of Peptide-based Polyagonists for Treatment of Diabetes and
           Obesity
    • Authors: Patrick Knerr; Brian Finan; Vasily Gelfanov; Diego Perez-Tilve; Matthias H. Tschöp; Richard D. DiMarchi
      Abstract: Publication date: Available online 2 November 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Patrick Knerr, Brian Finan, Vasily Gelfanov, Diego Perez-Tilve, Matthias H. Tschöp, Richard D. DiMarchi
      Graphical abstract image

      PubDate: 2017-11-09T00:16:43Z
      DOI: 10.1016/j.bmc.2017.10.047
       
 
 
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