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  Subjects -> CHEMISTRY (Total: 891 journals)
    - ANALYTICAL CHEMISTRY (55 journals)
    - CHEMISTRY (621 journals)
    - CRYSTALLOGRAPHY (21 journals)
    - ELECTROCHEMISTRY (28 journals)
    - INORGANIC CHEMISTRY (45 journals)
    - ORGANIC CHEMISTRY (51 journals)
    - PHYSICAL CHEMISTRY (70 journals)

CHEMISTRY (621 journals)                  1 2 3 4 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 14)
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: 43)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 21)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 23)
ACS Macro Letters     Full-text available via subscription   (Followers: 26)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 41)
ACS Nano     Full-text available via subscription   (Followers: 275)
ACS Photonics     Full-text available via subscription   (Followers: 14)
ACS Symposium Series     Full-text available via subscription  
ACS Synthetic Biology     Full-text available via subscription   (Followers: 24)
Acta Chemica Iasi     Open Access   (Followers: 5)
Acta Chimica Slovaca     Open Access   (Followers: 2)
Acta Chimica Slovenica     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: 7)
Acta Scientifica Naturalis     Open Access   (Followers: 3)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 6)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 9)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 6)
Advanced Functional Materials     Hybrid Journal   (Followers: 57)
Advanced Science Focus     Free   (Followers: 5)
Advances in Chemical Engineering and Science     Open Access   (Followers: 66)
Advances in Chemical Science     Open Access   (Followers: 18)
Advances in Chemistry     Open Access   (Followers: 21)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 19)
Advances in Drug Research     Full-text available via subscription   (Followers: 23)
Advances in Environmental Chemistry     Open Access   (Followers: 5)
Advances in Enzyme Research     Open Access   (Followers: 10)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 17)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 11)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 25)
Advances in Nanoparticles     Open Access   (Followers: 15)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 16)
Advances in Polymer Science     Hybrid Journal   (Followers: 43)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 19)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6)
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: 3)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 7)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Al-Kimia : Jurnal Penelitian Sains Kimia     Open Access  
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 64)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 17)
American Journal of Chemistry     Open Access   (Followers: 30)
American Journal of Plant Physiology     Open Access   (Followers: 11)
American Mineralogist     Hybrid Journal   (Followers: 15)
Analyst     Full-text available via subscription   (Followers: 38)
Angewandte Chemie     Hybrid Journal   (Followers: 165)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 243)
Annales UMCS, Chemia     Open Access  
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 5)
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: 9)
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: 13)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Hybrid Journal   (Followers: 2)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 9)
Applied Spectroscopy     Full-text available via subscription   (Followers: 23)
Applied Surface Science     Hybrid Journal   (Followers: 31)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 1)
Asian Journal of Biochemistry     Open Access   (Followers: 2)
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  
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Biochemistry     Full-text available via subscription   (Followers: 351)
Biochemistry Insights     Open Access   (Followers: 6)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 10)
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: 2)
Biomacromolecules     Full-text available via subscription   (Followers: 21)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 7)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 5)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 128)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 87)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 2)
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: 2)
Canadian Journal of Chemistry     Hybrid Journal   (Followers: 10)
Canadian Mineralogist     Full-text available via subscription   (Followers: 6)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 71)
Catalysis for Sustainable Energy     Open Access   (Followers: 8)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 7)
Catalysis Science and Technology     Free   (Followers: 8)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 10)
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: 18)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 73)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 26)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 22)
Chemical Reviews     Full-text available via subscription   (Followers: 192)
Chemical Science     Open Access   (Followers: 24)
Chemical Technology     Open Access   (Followers: 24)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 56)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 24)
ChemInform     Hybrid Journal   (Followers: 8)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 7)
Chemistry & Biology     Full-text available via subscription   (Followers: 32)
Chemistry & Industry     Hybrid Journal   (Followers: 7)
Chemistry - A European Journal     Hybrid Journal   (Followers: 163)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 16)
Chemistry and Materials Research     Open Access   (Followers: 21)
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: 255)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 19)
Chemistry-Didactics-Ecology-Metrology     Open Access   (Followers: 1)
ChemistryOpen     Open Access   (Followers: 1)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 4)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 14)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 11)
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: 11)
Chromatographia     Hybrid Journal   (Followers: 24)
Chromatography     Open Access   (Followers: 2)
Chromatography Research International     Open Access   (Followers: 6)
Clay Minerals     Full-text available via subscription   (Followers: 10)
Cogent Chemistry     Open Access   (Followers: 1)
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 11)
Colloids and Interfaces     Open Access  
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 6)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
Combustion Science and Technology     Hybrid Journal   (Followers: 22)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Communications Chemistry     Open Access  
Composite Interfaces     Hybrid Journal   (Followers: 7)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 1)
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: 11)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 10)
Coordination Chemistry Reviews     Full-text available via subscription   (Followers: 3)
Copernican Letters     Open Access   (Followers: 1)
Corrosion Series     Full-text available via subscription   (Followers: 6)
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 5)
Croatica Chemica Acta     Open Access  
Crystal Structure Theory and Applications     Open Access   (Followers: 4)
CrystEngComm     Full-text available via subscription   (Followers: 13)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Chromatography     Hybrid Journal  
Current Green Chemistry     Hybrid Journal  
Current Metabolomics     Hybrid Journal   (Followers: 5)
Current Microwave Chemistry     Hybrid Journal  
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 14)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 69)
Current Trends in Biotechnology and Chemical Research     Open Access   (Followers: 3)
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  

        1 2 3 4 | Last

Journal Cover
Bioorganic & Medicinal Chemistry Letters
Journal Prestige (SJR): 0.81
Citation Impact (citeScore): 3
Number of Followers: 87  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0960-894X
Published by Elsevier Homepage  [3163 journals]
  • 1,2,3,4,6-Penta-O-galloyl-β-d-glucose suppresses colon cancer through
           induction of tumor suppressor
    • Authors: Sang Hee Kawk; Ye Rim Kang; Yoon Hee Kim
      Pages: 2117 - 2123
      Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12
      Author(s): Sang Hee Kawk, Ye Rim Kang, Yoon Hee Kim
      Colon cancer is the third most common malignancy in both sexes of Korea. Here, we investigated anti-colorectal cancer effects of 1,2,3,4,6-penta-O-galloyl-β-d-glucose (PGG), a gallotannin from Galla rhois, and its possible mechanisms. PGG induced cytotoxicity and decreased proliferation of colon cancer cells without affecting normal colon fibroblasts. PGG inhibited clonogenic ability and induced apoptosis in cancer cells. One of the underlying mechanisms of the anti-cancer effect exerted by PGG, was owing to the induction p53 expression, a well-known tumor suppressor, and increased in P21, the representative target gene of p53. PGG affected cell-cycle- or apoptosis-related proteins such as cyclin E, CDK2, and Bcl-2, cleaved caspase-3. Also, PGG induced caspase-3/7 activity. These data suggest that PGG exerts anti-colorectal cancer effects.
      Graphical abstract image

      PubDate: 2018-06-05T17:11:39Z
      DOI: 10.1016/j.bmcl.2018.05.028
       
  • The discovery and preclinical evaluation of BMS-707035, a potent HIV-1
           integrase strand transfer inhibitor
    • Authors: B. Narasimhulu Naidu; Michael A. Walker; Margaret E. Sorenson; Yasutsugu Ueda; John D. Matiskella; Timothy P. Connolly; Ira B. Dicker; Zeyu Lin; Sagarika Bollini; Brian J. Terry; Helen Higley; Ming Zheng; Dawn D. Parker; Dedong Wu; Stephen Adams; Mark R. Krystal; Nicholas A. Meanwell
      Pages: 2124 - 2130
      Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12
      Author(s): B. Narasimhulu Naidu, Michael A. Walker, Margaret E. Sorenson, Yasutsugu Ueda, John D. Matiskella, Timothy P. Connolly, Ira B. Dicker, Zeyu Lin, Sagarika Bollini, Brian J. Terry, Helen Higley, Ming Zheng, Dawn D. Parker, Dedong Wu, Stephen Adams, Mark R. Krystal, Nicholas A. Meanwell
      BMS-707035 is an HIV-1 integrase strand transfer inhibitor (INSTI) discovered by systematic optimization of N-methylpyrimidinone carboxamides guided by structure-activity relationships (SARs) and the single crystal X-ray structure of compound 10. It was rationalized that the unexpectedly advantageous profiles of N-methylpyrimidinone carboxamides with a saturated C2-substitutent may be due, in part, to the geometric relationship between the C2-substituent and the pyrimidinone core. The single crystal X-ray structure of 10 provided support for this reasoning and guided the design of a spirocyclic series 12 which led to discovery of the morpholino-fused pyrimidinone series 13. Several carboxamides derived from this bicyclic scaffold displayed improved antiviral activity and pharmacokinetic profiles when compared with corresponding spirocyclic analogs. Based on the excellent antiviral activity, preclinical profiles and acceptable in vitro and in vivo toxicity profiles, 13a (BMS-707035) was selected for advancement into phase I clinical trials.
      Graphical abstract image

      PubDate: 2018-06-05T17:11:39Z
      DOI: 10.1016/j.bmcl.2018.05.027
       
  • Design, synthesis and biological evaluation of novel pyrimidinedione
           derivatives as DPP-4 inhibitors
    • Authors: Ning Li; Li-Jun Wang; Bo Jiang; Shu-Ju Guo; Xiang-Qian Li; Xue-Chun Chen; Jiao Luo; Chao Li; Yi Wang; Da-Yong Shi
      Pages: 2131 - 2135
      Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12
      Author(s): Ning Li, Li-Jun Wang, Bo Jiang, Shu-Ju Guo, Xiang-Qian Li, Xue-Chun Chen, Jiao Luo, Chao Li, Yi Wang, Da-Yong Shi
      A series of novel pyrimidinedione derivatives were designed and evaluated for in vitro dipeptidyl peptidase-4 (DPP-4) inhibitory activity and in vivo anti-hyperglycemic efficacy. Among them, the representative compounds 11, 15 and 16 showed excellent inhibitory activity of DPP-4 with IC50 values of 64.47 nM, 188.7 nM and 65.36 nM, respectively. Further studies revealed that compound 11 was potent in vivo hypoglycemic effect. The structure–activity relationships of these pyrimidinedione derivatives had been discussed, which would be useful for developing novel DPP-4 inhibitors as treating type 2 diabetes.
      Graphical abstract image

      PubDate: 2018-06-05T17:11:39Z
      DOI: 10.1016/j.bmcl.2018.05.022
       
  • A small diversity library of α-methyl amide analogs of sulindac for
           probing anticancer structure-activity relationships
    • Authors: Bini Mathew; Timothy S. Snowden; Michele C. Connelly; R. Kiplin Guy; Robert C. Reynolds
      Pages: 2136 - 2142
      Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12
      Author(s): Bini Mathew, Timothy S. Snowden, Michele C. Connelly, R. Kiplin Guy, Robert C. Reynolds
      Non-steroidal anti-inflammatory drugs (NSAIDs) have a variety of potential indications that include management of pain and inflammation as well as chemoprevention and/or treatment of cancer. Furthermore, a specific form of ibuprofen, dexibuprofen or the S-(+) form, shows interesting neurological activities and has been proposed for the treatment of Alzheimer’s disease. In a continuation of our work probing the anticancer activity of small sulindac libraries, we have prepared and screened a small diversity library of α-methyl substituted sulindac amides in the profen class. Several compounds of this series displayed promising activity compared with a lead sulindac analog.
      Graphical abstract image

      PubDate: 2018-06-05T17:11:39Z
      DOI: 10.1016/j.bmcl.2018.05.023
       
  • Discovery of novel N-hydroxy-2-arylisoindoline-4-carboxamides as potent
           and selective inhibitors of HDAC11
    • Authors: Matthew W. Martin; Jennifer Y. Lee; David R. Lancia; Pui Yee Ng; Bingsong Han; Jennifer R. Thomason; Maureen S. Lynes; C. Gary Marshall; Chiara Conti; Alan Collis; Monica Alvarez Morales; Kshama Doshi; Aleksandra Rudnitskaya; Lili Yao; Xiaozhang Zheng
      Pages: 2143 - 2147
      Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12
      Author(s): Matthew W. Martin, Jennifer Y. Lee, David R. Lancia, Pui Yee Ng, Bingsong Han, Jennifer R. Thomason, Maureen S. Lynes, C. Gary Marshall, Chiara Conti, Alan Collis, Monica Alvarez Morales, Kshama Doshi, Aleksandra Rudnitskaya, Lili Yao, Xiaozhang Zheng
      N-Hydroxy-2-arylisoindoline-4-carboxamides are potent and selective inhibitors of HDAC11. The discovery, synthesis, and structure activity relationships of this novel series of inhibitors are reported. An advanced analog (FT895) displays promising cellular activity and pharmacokinetic properties that make it a useful tool to study the biology of HDAC11 and its potential use as a therapeutic target for oncology and inflammation indications.
      Graphical abstract image

      PubDate: 2018-06-05T17:11:39Z
      DOI: 10.1016/j.bmcl.2018.05.021
       
  • Discovery of novel 20S proteasome inhibitors by rational topology-based
           scaffold hopping of bortezomib
    • Authors: Yulong Xu; Xicheng Yang; Yiyi Chen; Hao Chen; Huijiao Sun; Wei Li; Qiong Xie; Linqian Yu; Liming Shao
      Pages: 2148 - 2152
      Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12
      Author(s): Yulong Xu, Xicheng Yang, Yiyi Chen, Hao Chen, Huijiao Sun, Wei Li, Qiong Xie, Linqian Yu, Liming Shao
      A series of structurally novel proteasome inhibitors 1–12 have been developed based rational topology-based scaffold hopping of bortezomib. Among these novel proteasome inhibitors, compound 10 represents an important advance due to the comparable proteasome-inhibitory activity (IC50 = 9.7 nM) to bortezomib (IC50 = 8.3 nM), the remarkably higher BEI and SEI values and the effectiveness in metabolic stability. Therefore, compound 10 provides an excellent lead suitable for further optimization.
      Graphical abstract image

      PubDate: 2018-06-05T17:11:39Z
      DOI: 10.1016/j.bmcl.2018.05.018
       
  • N-aryl-piperidine-4-carboxamides as a novel class of potent inhibitors of
           MALT1 proteolytic activity
    • Authors: Achim Schlapbach; Laszlo Revesz; Carole Pissot Soldermann; Thomas Zoller; Catherine H. Régnier; Frédéric Bornancin; Thomas Radimerski; Jutta Blank; Ansgar Schuffenhauer; Martin Renatus; Paulus Erbel; Samu Melkko; Richard Heng; Oliver Simic; Ralf Endres; Markus Wartmann; Jean Quancard
      Pages: 2153 - 2158
      Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12
      Author(s): Achim Schlapbach, Laszlo Revesz, Carole Pissot Soldermann, Thomas Zoller, Catherine H. Régnier, Frédéric Bornancin, Thomas Radimerski, Jutta Blank, Ansgar Schuffenhauer, Martin Renatus, Paulus Erbel, Samu Melkko, Richard Heng, Oliver Simic, Ralf Endres, Markus Wartmann, Jean Quancard
      Starting from a weak screening hit, potent and selective inhibitors of the MALT1 protease function were elaborated. Advanced compounds displayed high potency in biochemical and cellular assays. Compounds showed activity in a mechanistic Jurkat T cell activation assay as well as in the B-cell lymphoma line OCI-Ly3, which suggests potential use of MALT1 inhibitors in the treatment of autoimmune diseases as well as B-cell lymphomas with a dysregulated NF-κB pathway. Initially, rat pharmacokinetic properties of this compound series were dominated by very high clearance which could be linked to amide cleavage. Using a rat hepatocyte assay a good in vitro-in vivo correlation could be established which led to the identification of compounds with improved PK properties.
      Graphical abstract image

      PubDate: 2018-06-05T17:11:39Z
      DOI: 10.1016/j.bmcl.2018.05.017
       
  • Design and synthesis of a series of bioavailable fatty acid synthase
           (FASN) KR domain inhibitors for cancer therapy
    • Authors: Tianbao Lu; Carsten Schubert; Maxwell D. Cummings; Gilles Bignan; Peter J. Connolly; Karine Smans; Donald Ludovici; Michael H. Parker; Christophe Meyer; Christian Rocaboy; Richard Alexander; Bruce Grasberger; Sabine De Breucker; Norbert Esser; Erwin Fraiponts; Ron Gilissen; Boudewijn Janssens; Danielle Peeters; Luc Van Nuffel; Peter Vermeulen; James Bischoff; Lieven Meerpoel
      Pages: 2159 - 2164
      Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12
      Author(s): Tianbao Lu, Carsten Schubert, Maxwell D. Cummings, Gilles Bignan, Peter J. Connolly, Karine Smans, Donald Ludovici, Michael H. Parker, Christophe Meyer, Christian Rocaboy, Richard Alexander, Bruce Grasberger, Sabine De Breucker, Norbert Esser, Erwin Fraiponts, Ron Gilissen, Boudewijn Janssens, Danielle Peeters, Luc Van Nuffel, Peter Vermeulen, James Bischoff, Lieven Meerpoel
      We designed and synthesized a new series of fatty acid synthase (FASN) inhibitors with potential utility for the treatment of cancer. Extensive SAR studies led to highly active FASN inhibitors with good cellular activity and oral bioavailability, exemplified by compound 34. Compound 34 is a potent inhibitor of human FASN (IC50 = 28 nM) that effectively inhibits proliferation of A2780 ovarian cells (IC50 = 13 nM) in lipid-reduced serum (LRS). This cellular activity can be rescued by addition of palmitate, consistent with an on-target effect. Compound 34 is also active in many other cell types, including PC3M (IC50 = 25 nM) and LnCaP-Vancouver prostate cells (IC50 = 66 nM), and is highly bioavailable (F 61%) with good exposure after oral administration. In a pharmacodynamics study in H460 lung xenograft-bearing mice, oral treatment with compound 34 results in elevated tumor levels of malonyl-CoA and decreased tumor levels of palmitate, fully consistent with the desired target engagement.
      Graphical abstract image

      PubDate: 2018-06-05T17:11:39Z
      DOI: 10.1016/j.bmcl.2018.05.014
       
  • Synthesis and antiviral evaluation of novel peptidomimetics as norovirus
           protease inhibitors
    • Authors: Franck Amblard; Shaoman Zhou; Peng Liu; Jack Yoon; Bryan Cox; Kendall Muzzarelli; Benjamin D. Kuiper; Ladislau C. Kovari; Raymond F. Schinazi
      Pages: 2165 - 2170
      Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12
      Author(s): Franck Amblard, Shaoman Zhou, Peng Liu, Jack Yoon, Bryan Cox, Kendall Muzzarelli, Benjamin D. Kuiper, Ladislau C. Kovari, Raymond F. Schinazi
      A series of tripeptidyl transition state inhibitors with new P1 and warhead moieties were synthesized and evaluated in a GI-1 norovirus replicon system and against GII-4 and GI-1 norovirus proteases. Compound 19, containing a 6-membered ring at the P1 position and a reactive aldehyde warhead exhibited sub-micromolar replicon inhibition. Retaining the same peptidyl scaffold, several reactive warheads were tested for protease inhibition and norovirus replicon inhibition. Of the six that were synthesized and tested, compounds 42, 43, and 45 potently inhibited the protease in biochemical assay and GI-1 norovirus replicon in the nanomolar range.
      Graphical abstract image

      PubDate: 2018-06-05T17:11:39Z
      DOI: 10.1016/j.bmcl.2018.05.012
       
  • Effective gene silencing activity of prodrug-type
           2′-O-methyldithiomethyl siRNA compared with non-prodrug-type
           2′-O-methyl siRNA
    • Authors: Junsuke Hayashi; Misa Nishigaki; Yosuke Ochi; Shun-ichi Wada; Fumito Wada; Osamu Nakagawa; Satoshi Obika; Mariko Harada-Shiba; Hidehito Urata
      Pages: 2171 - 2174
      Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12
      Author(s): Junsuke Hayashi, Misa Nishigaki, Yosuke Ochi, Shun-ichi Wada, Fumito Wada, Osamu Nakagawa, Satoshi Obika, Mariko Harada-Shiba, Hidehito Urata
      Small interfering RNAs (siRNAs) are an active agent to induce gene silencing and they have been studied for becoming a biological and therapeutic tool. Various 2′-O-modified RNAs have been extensively studied to improve the nuclease resistance. However, the 2′-O-modified siRNA activities were often decreased by modification, since the bulky 2′-O-modifications inhibit to form a RNA-induced silencing complex (RISC). We developed novel prodrug-type 2′-O-methyldithiomethyl (MDTM) siRNA, which is converted into natural siRNA in an intracellular reducing environment. Prodrug-type 2′-O-MDTM siRNAs modified at the 5′-end side including 5′-end nucleotide and the seed region of the antisense strand exhibited much stronger gene silencing effect than non-prodrug-type 2′-O-methyl (2′-O-Me) siRNAs. Furthermore, the resistances for nuclease digestion of siRNAs were actually enhanced by 2′-O-MDTM modifications. Our results indicate that 2′-O-MDTM modifications improve the stability of siRNA in serum and they are able to be introduced at any positions of siRNA.
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      PubDate: 2018-06-05T17:11:39Z
      DOI: 10.1016/j.bmcl.2018.05.016
       
  • The discovery of VU0486846: steep SAR from a series of M1 PAMs based on a
           novel benzomorpholine core
    • Authors: Jeanette L. Bertron; Hyekyung P. Cho; Pedro M. Garcia-Barrantes; Joseph D. Panarese; James M. Salovich; Kellie D. Nance; Darren W. Engers; Jerri M. Rook; Anna L. Blobaum; Colleen M. Niswender; Shaun R. Stauffer; P. Jeffrey Conn; Craig W. Lindsley
      Pages: 2175 - 2179
      Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12
      Author(s): Jeanette L. Bertron, Hyekyung P. Cho, Pedro M. Garcia-Barrantes, Joseph D. Panarese, James M. Salovich, Kellie D. Nance, Darren W. Engers, Jerri M. Rook, Anna L. Blobaum, Colleen M. Niswender, Shaun R. Stauffer, P. Jeffrey Conn, Craig W. Lindsley
      This letter describes the chemical optimization of a new series of M1 positive allosteric modulators (PAMs) based on a novel benzomorpholine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0486846 (7), devoid of adverse effect liability. This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0486846 and details all of the challenges faced in allosteric modulator programs (both steep and flat SAR, as well as subtle structural changes affecting CNS penetration and overall physiochemical and DMPK properties).
      Graphical abstract image

      PubDate: 2018-06-05T17:11:39Z
      DOI: 10.1016/j.bmcl.2018.05.009
       
  • Design, synthesis and evaluation of photoactivatable derivatives of
           microtubule (MT)-active [1,2,4]triazolo[1,5-a]pyrimidines
    • Authors: Killian Oukoloff; Jane Kovalevich; Anne-Sophie Cornec; Yuemang Yao; Zachary A. Owyang; Michael James; John Q. Trojanowski; Virginia M.-Y. Lee; Amos B. Smith; Kurt R. Brunden; Carlo Ballatore
      Pages: 2180 - 2183
      Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12
      Author(s): Killian Oukoloff, Jane Kovalevich, Anne-Sophie Cornec, Yuemang Yao, Zachary A. Owyang, Michael James, John Q. Trojanowski, Virginia M.-Y. Lee, Amos B. Smith, Kurt R. Brunden, Carlo Ballatore
      The [1,2,4]triazolo[1,5-a]pyrimidines comprise a promising class of non-naturally occurring microtubule (MT)-active compounds. Prior studies revealed that different triazolopyrimidine substitutions can yield molecules that either promote MT stabilization or disrupt MT integrity. These differences can have important ramifications in the therapeutic applications of triazolopyrimidines and suggest that different analogues may exhibit different binding modes within the same site or possibly interact with tubulin/MTs at alternative binding sites. To help discern these possibilities, a series of photoactivatable triazolopyrimidine congeners was designed, synthesized and evaluated in cellular assays with the goal of identifying candidate probes for photoaffinity labeling experiments. These studies led to the identification of different derivatives that incorporate a diazirine ring in the amine substituent at position 7 of the triazolopyrimidine heterocycle, resulting in molecules that either promote stabilization of MTs or disrupt MT integrity. These photoactivatable candidate probes hold promise to investigate the mode of action of MT-active triazolopyrimidines.
      Graphical abstract image

      PubDate: 2018-06-05T17:11:39Z
      DOI: 10.1016/j.bmcl.2018.05.010
       
  • In vitro activity of salicylamide derivatives against vancomycin-resistant
           enterococci
    • Authors: Sarka Pospisilova; Hana Michnova; Tereza Kauerova; Karel Pauk; Peter Kollar; Jarmila Vinsova; Ales Imramovsky; Alois Cizek; Josef Jampilek
      Pages: 2184 - 2188
      Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12
      Author(s): Sarka Pospisilova, Hana Michnova, Tereza Kauerova, Karel Pauk, Peter Kollar, Jarmila Vinsova, Ales Imramovsky, Alois Cizek, Josef Jampilek
      A series of 13 salicylamide derivatives was assessed for antibacterial activity against three isolates of vancomycin-resistant Enterococcus faecalis (VRE) and Enterococcus faecalis ATCC 29212 as a quality standard. The minimum inhibitory concentration was determined by the broth microdilution method with subsequent subcultivation of aliquots to assess minimum bactericidal concentration. The growth kinetics was established by the time-kill assay. Ampicillin, ciprofloxacin, tetracycline and vancomycin were used as the reference antibacterial drugs. Three of the investigated compounds showed strong bacteriostatic activity against VRE (0.199–25 µM) comparable to or more potent than ampicillin and ciprofloxacin. In addition, these compounds were tested for synergistic effect with vancomycin, ciprofloxacin and tetracycline, while 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)phenyl]benzamide showed the highest potency as well as synergistic activity with vancomycin against VRE 368. Screening of the cytotoxicity of the most effective compounds was performed using human monocytic leukemia THP-1 cells, and based on LD50 values, it can be stated that the compounds have insignificant toxicity against human cells.
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      PubDate: 2018-06-05T17:11:39Z
      DOI: 10.1016/j.bmcl.2018.05.011
       
  • Insight into the recognition mechanism of DNA cytosine-5
           methyltransferases (DNMTs) by incorporation of acyclic 5-fluorocytosine
           (FC) nucleosides into DNA
    • Authors: Shohei Utsumi; Kousuke Sato; Satoshi Ichikawa
      Pages: 2189 - 2194
      Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12
      Author(s): Shohei Utsumi, Kousuke Sato, Satoshi Ichikawa
      DNA cytosine-5 methyltransferase (DNMT) catalyzes methylation at the C5 position of cytosine in the CpG sequence in double stranded DNA to give 5-methylCpG (mCpG) in the epigenetic regulation step in human cells. The entire reaction mechanism of DNMT is divided into six steps, which are scanning, recognition, flipping, loop locking, methylation, and releasing. The methylation and releasing mechanism are well-investigated; however, few reports are known about other reaction steps. To obtain insight into the reaction mechanism, we planned the incorporation of acyclic nucleosides, which make it easy to flip out the target nucleobase, into oligodeoxynucleotides (ODNs) and investigated the interaction between the ODN and DNMT. Here, we describe the design and synthesis of ODNs containing new acyclic 5-fluorocytosine nucleosides and their physiological and biological properties, including their interactions with DNMT. We found that the ODNs containing the acyclic 5-fluorocytosine nucleoside showed higher flexibility than those that contain 5-fluoro-2′-deoxycytidine. The observed flexibility of ODNs is expected to influence the scanning and recognition steps due to the decrease in helicity of the B-form.
      Graphical abstract image

      PubDate: 2018-06-05T17:11:39Z
      DOI: 10.1016/j.bmcl.2018.05.008
       
  • Discovery of amino-1,4-oxazines as potent BACE-1 inhibitors
    • Authors: Siem Jakob Veenstra; Heinrich Rueeger; Markus Voegtle; Rainer Lueoend; Philipp Holzer; Konstanze Hurth; Marina Tintelnot-Blomley; Mathias Frederiksen; Jean-Michel Rondeau; Laura Jacobson; Matthias Staufenbiel; Ulf Neumann; Rainer Machauer
      Pages: 2195 - 2200
      Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12
      Author(s): Siem Jakob Veenstra, Heinrich Rueeger, Markus Voegtle, Rainer Lueoend, Philipp Holzer, Konstanze Hurth, Marina Tintelnot-Blomley, Mathias Frederiksen, Jean-Michel Rondeau, Laura Jacobson, Matthias Staufenbiel, Ulf Neumann, Rainer Machauer
      New amino-1,4-oxazine derived BACE-1 inhibitors were explored and various synthetic routes developed. The binding mode of the inhibitors was elucidated by co-crystallization of 4 with BACE-1 and X-ray analysis. Subsequent optimization led to inhibitors with low double digit nanomolar activity in a biochemical and single digit nanomolar potency in a cellular assays. To assess the inhibitors for their permeation properties and potential to cross the blood-brain-barrier a MDR1-MDCK cell model was successfully applied. Compound 8a confirmed the in vitro results by dose-dependently reducing Aβ levels in mice in an acute treatment regimen.
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      PubDate: 2018-06-05T17:11:39Z
      DOI: 10.1016/j.bmcl.2018.05.003
       
  • Synthesis and biological evaluation of 6-hydroxyl C-aryl glucoside
           derivatives as novel sodium glucose co-transporter 2 (SGLT2) inhibitors
    • Authors: Xiaoyu Zhao; Bin Sun; Hongbo Zheng; Jun Liu; Lilin Qian; Xiaoning Wang; Hongxiang Lou
      Pages: 2201 - 2205
      Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12
      Author(s): Xiaoyu Zhao, Bin Sun, Hongbo Zheng, Jun Liu, Lilin Qian, Xiaoning Wang, Hongxiang Lou
      The sodium glucose co-transporter 2 (SGLT2) was considered as an important target for the treatment of type 2 diabetes mellitus in recent years. This report describes the design and synthesis of a series of novel SGLT2 inhibitors (11a–17a) as well as their dehydrate dihydrofuran derivatives (11b–17b), which were prepared by Mitsunobu reaction. Their SGLT2 inhibitory activity was also evaluated, and 16a and 17a were found to be the most potent compounds with IC50 values of 0.63 and 0.81 nM, respectively. However, all the dehydrate derivatives lose the SGLT2 inhibitory activity, with inhibition percentage no more than 66.5% at the concentration of 0.5 μM, which might because of the configuration inversion at C-2 of glucose. In conclusion, the present study improves understanding of the SAR of SGLT2 inhibitors, and provided more information that could be applied to design new molecules.
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      PubDate: 2018-06-05T17:11:39Z
      DOI: 10.1016/j.bmcl.2018.04.070
       
  • Kakeromamide A, a new cyclic pentapeptide inducing astrocyte
           
    • Authors: Fumiaki Nakamura; Hiroshi Maejima; Midori Kawamura; Daisuke Arai; Tatsufumi Okino; Meng Zhao; Tao Ye; Jungyeol Lee; Young-Tae Chang; Nobuhiro Fusetani; Yoichi Nakao
      Pages: 2206 - 2209
      Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12
      Author(s): Fumiaki Nakamura, Hiroshi Maejima, Midori Kawamura, Daisuke Arai, Tatsufumi Okino, Meng Zhao, Tao Ye, Jungyeol Lee, Young-Tae Chang, Nobuhiro Fusetani, Yoichi Nakao
      Kakeromamide A (1), a new cyclic pentapeptide encompassing a thiazole ring moiety and a β-amino acid, was isolated from the marine cyanobacterium Moorea bouillonii. Its structure was elucidated by the spectral analysis and the modified Marfey’s method. Compound 1 induced differentiation of neural stem cells into astrocytes at the concentration of 10 µM.
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      PubDate: 2018-06-05T17:11:39Z
      DOI: 10.1016/j.bmcl.2018.04.067
       
  • Anti-allergic inflammatory components from Sanguisorba officinalis L.
    • Authors: Xiang Dong Su; Rui Hong Guo; Hong Xu Li; Jin Yeul Ma; Young Ran Kim; Young Ho Kim; Seo Young Yang
      Pages: 2210 - 2216
      Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12
      Author(s): Xiang Dong Su, Rui Hong Guo, Hong Xu Li, Jin Yeul Ma, Young Ran Kim, Young Ho Kim, Seo Young Yang
      Sanguisorba officinalis L. was well known as a traditional herbal medicine to treat inflammation and allergic skin diseases. The aim of this research was to indentify compounds with anti-allergic inflammatory property. Twenty-five compounds (1–25) were isolated from S. officinalis including two new compounds (1 and 8), and their chemical structures were identified by NMR and ESIMS analysis. Consequently, the anti-allergic inflammatory activities of these isolates were investigated by inhibiting β-hexosaminidase and IL-4 production in PMA/A23187-stimulated RBL-2H3 cells. Compounds 6, 8, 13, 17–18 and 25 significantly inhibited β-hexosaminidase release and IL-4 production. Additionally, compounds 8, 17 and 25 effectively suppressed the activation of NF-κB and NF-κB p65 translocation into the nucleus. Anti-inflammatory effects of isolated compounds were evaluated in LPS-stimulated RAW264.7 macrophages, and they showed dramatic inhibition on LPS-induced overproduction of nitric oxide (NO) and TNF-α. Consistently, the protein levels of iNOS and COX-2 were remarkably decreased by the single compounds 8, 13 and 25. These results showed that compounds 8, 13 and 25 from S. officinalis may have a therapeutic potential for allergic inflammatory diseases.
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      PubDate: 2018-06-05T17:11:39Z
      DOI: 10.1016/j.bmcl.2018.04.033
       
  • Valproic acid induces three novel cytotoxic secondary metabolites in
           Diaporthe sp., an endophytic fungus from Datura inoxia Mill.
    • Authors: Vishal Sharma; Venugopal Singamaneni; Nisha Sharma; Amit Kumar; Divya Arora; Manoj Kushwaha; Shashi Bhushan; Sundeep Jaglan; Prasoon Gupta
      Pages: 2217 - 2221
      Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12
      Author(s): Vishal Sharma, Venugopal Singamaneni, Nisha Sharma, Amit Kumar, Divya Arora, Manoj Kushwaha, Shashi Bhushan, Sundeep Jaglan, Prasoon Gupta
      Addition of the valproic acid (histone deacetylases inhibitor) to a culture of an endophytic fungus Diaporthe sp. harbored from Datura inoxia significantly altered its secondary metabolic profile and resulted in the isolation of three novel compounds, identified as xylarolide A (1), diportharine A (2) and xylarolide B (3) along with one known compound xylarolide (4). The structures of all the compounds (1–4) were determined by detailed analysis of 1D and 2D NMR spectroscopic data. The relative configurations of compounds 1–3 were determined with the help of NOESY data and comparison of optical rotations with similar compounds with established stereochemistry. All the isolated compounds were screened for antibacterial, antioxidant and cytotoxic activities. Xylarolide A (1) and xylarolide (4) displayed significant growth inhibition of MIAPaCa-2 with an IC50 of 20 and 32 µM respectively and against PC-3 with an IC50 of 14 and 18 µM respectively. Moreover, compound 1 displayed significant DPPH scavenging activity with EC50 of 10.3 µM using ascorbic acid as a positive control.
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      PubDate: 2018-06-05T17:11:39Z
      DOI: 10.1016/j.bmcl.2018.04.018
       
  • Discovery of a bicyclo[4.3.0]nonane derivative DS88790512 as a potent,
           selective, and orally bioavailable blocker of transient receptor potential
           canonical 6 (TRPC6)
    • Authors: Keisuke Motoyama; Tsutomu Nagata; Jun Kobayashi; Akifumi Nakamura; Naoki Miyoshi; Miho Kazui; Ken Sakurai; Tomoko Sakakura
      Pages: 2222 - 2227
      Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12
      Author(s): Keisuke Motoyama, Tsutomu Nagata, Jun Kobayashi, Akifumi Nakamura, Naoki Miyoshi, Miho Kazui, Ken Sakurai, Tomoko Sakakura
      In this study, we aimed to synthesize a novel blocker of transient receptor potential canonical 6 (TRPC6). The sp2 carbon atoms of the aminoindane skeleton of the known inhibitor were replaced with sp3 carbon atoms to increase the molecular complexity, measured by fraction sp3 (Fsp3). The representative compound, a bicyclo[4.3.0]nonane derivative DS88790512, inhibited TRPC6 with an IC50 value of 11 nM. Notably, DS88790512 exhibited excellent selectivity against hERG and hNaV1.5 channels, and was identified as an orally bioavailable compound.
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      PubDate: 2018-06-05T17:11:39Z
      DOI: 10.1016/j.bmcl.2018.03.056
       
  • Corrigendum to “Design, solvent free synthesis, and antimicrobial
           evaluation of 1,4 dihydropyridines” [Bioorg. Med. Chem. Lett. 22 (2012)
           6016–6023]
    • Authors: Rajack Abdul; Taraka Ramji Moturu; J. Jeson babu; K. Aruna Lakshmi
      First page: 2228
      Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12
      Author(s): Rajack Abdul, Taraka Ramji Moturu, J. Jeson babu, K. Aruna Lakshmi


      PubDate: 2018-06-05T17:11:39Z
      DOI: 10.1016/j.bmcl.2018.03.054
       
  • ROCK inhibitors 2. Improving potency, selectivity and solubility through
           the application of rationally designed solubilizing groups
    • Abstract: Publication date: Available online 21 June 2018
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): Huai Gao, Craig Marhefka, Marc D. Jacobs, Jingrong Cao, Upul K. Bandarage, Jeremy Green
      Solubilizing groups have been frequently appended to kinase inhibitor drug molecules when solubility is insufficient for pharmaceutical development. Such groups are usually located at substitution sites that have minimal impact on target activity. In this report we describe the incorporation of solubilizing groups in a class of Rho kinase (ROCK) inhibitors that not only confer improved solubility, but also enhance target potency and selectivity against a closely related kinase, PKA.
      Graphical abstract image

      PubDate: 2018-06-23T14:21:16Z
       
  • Computer-aided discovery and biological characterization of human lactate
           dehydrogenase 5 inhibitors with anti-osteosarcoma activity
    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13
      Author(s): Wei Cao, Le Fang, Siyong Teng, Hongwei Chen, Zhan Wang
      Human lactate dehydrogenase 5 (hLDH5) is overexpressed in various tissues of human tumors, which could be a potential therapeutic target for cancer treatment. Herein, we describe the computer-aided discovery and biological characterizations of hLDH5 inhibitors with anti-osteosarcoma activity. Biochemical assay indicated that the identified compounds 3 and 9 strongly inhibited hLDH5 function with EC50 values of 0.67 and 0.39 µM, respectively. The MTT assay revealed that most of the identified inhibitors had little effect on MG-63 cell proliferation at 4 µM, only 9 reduced the cancer cell proliferation at the same concentration, with an IC50 value of 3.18 µM. Our data suggested that 9 could be a starting lead of developing potent hLDH5 inhibitor for the anti-osteosarcoma agents in cancer treatment.
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      PubDate: 2018-06-18T00:51:47Z
       
  • Synthesis of carbon-11-labeled CK1 inhibitors as new potential PET
           radiotracers for imaging of Alzheimer’s disease
    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13
      Author(s): Mingzhang Gao, Min Wang, Qi-Huang Zheng
      The reference standards methyl 3-((2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoate (5a) and N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-methoxybenzamide (5c), and their corresponding desmethylated precursors 3-((2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoic acid (6a) and N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-hydroxybenzamide (6b), were synthesized from 5-amino-2,2-difluoro-1,3-benzodioxole and 3-substituted benzoic acids in 5 and 6 steps with 33% and 11%, 30% and 7% overall chemical yield, respectively. Carbon-11-labeled casein kinase 1 (CK1) inhibitors, [11C]methyl 3-((2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoate ([11C]5a) and N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-[11C]methoxybenzamide ([11C]5c), were prepared from their O-desmethylated precursor 6a or 6b with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 40–45% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (MA) at EOB was 370–740 GBq/μmol with a total synthesis time of ∼40-min from EOB.
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      PubDate: 2018-06-18T00:51:47Z
       
  • ‘Tethering’ fragment-based drug discovery to identify inhibitors of
           the essential respiratory membrane protein type II NADH dehydrogenase
    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13
      Author(s): Adam Heikal, Yoshio Nakatani, Wanting Jiao, Chris Wilson, David Rennison, Marion R. Weimar, Emily J. Parker, Margaret A. Brimble, Gregory M. Cook
      Energy generation is a promising area of drug discovery for both bacterial pathogens and parasites. Type II NADH dehydrogenase (NDH-2), a vital respiratory membrane protein, has attracted attention as a target for the development of new antitubercular and antimalarial agents. To date, however, no potent, specific inhibitors have been identified. Here, we performed a site-directed screening technique, tethering-fragment based drug discovery, against wild-type and mutant forms of NDH-2 containing engineered active-site cysteines. Inhibitory fragments displayed IC50 values between 3 and 110 μM against NDH-2 mutants. Possible binding poses were investigated by in silico modelling, providing a basis for optimisation of fragment binding and improved potency against NDH-2.
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      PubDate: 2018-06-18T00:51:47Z
       
  • lH-Pyrazolo[3,4-b]quinolin-3-amine derivatives inhibit growth of colon
           cancer cells via apoptosis and sub G1 cell cycle arrest
    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13
      Author(s): Chandrabose Karthikeyan, Haneen Amawi, Arabela Guedes Viana, Leticia Sanglard, Noor Hussein, Maria Saddler, Charles R. Ashby, N.S. Hari Narayana Moorthy, Piyush Trivedi, Amit K. Tiwari
      A series of lH-pyrazolo[3,4-b]quinolin-3-amine derivatives were synthesized and evaluated for anticancer efficacy in a panel of ten cancer cell lines, including breast (MDAMB-231 and MCF-7), colon (HCT-116, HCT-15, HT-29 and LOVO), prostate (DU-145 and PC3), brain (LN-229), ovarian (A2780), and human embryonic kidney (HEK293) cells, a non-cancerous cell line. Among the eight derivatives screened, compound QTZ05 had the most potent and selective antitumor efficacy in the four colon cancer cell lines, with IC50 values ranging from 2.3 to 10.2 µM. Furthermore, QTZ05 inhibited colony formation in HCT-116 cells in a concentration-dependent manner. Cell cycle analysis data indicated that QTZ05 caused an arrest in the sub G1 cell cycle in HCT-116 cells. QTZ05 induced apoptosis in HCT-116 cells in a concentration-dependent manner that was characterized by chromatin condensation and increase in the fluorescence of fluorochrome-conjugated Annexin V. The findings from our study suggest that QTZ05 may be a valuable prototype for the development of chemotherapeutics targeting apoptotic pathways in colorectal cancer cells.
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      PubDate: 2018-06-18T00:51:47Z
       
  • Benzofuro[3,2-d]pyrimidines inspired from cercosporamide CaPkc1 inhibitor:
           Synthesis and evaluation of fluconazole susceptibility restoration
    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13
      Author(s): Viet Hung Dao, Isabelle Ourliac-Garnier, Marc-Antoine Bazin, Catherine Jacquot, Blandine Baratte, Sandrine Ruchaud, Stéphane Bach, Olivier Grovel, Patrice Le Pape, Pascal Marchand
      In a context of growing resistance to classical antifungal therapy, the design of new drugs targeting alternative pathways is highly expected. Benzofuro[3,2-d]pyrimidine derivatives, derived from (−)-cercosporamide, were synthesized and evaluated as potential Candida albicans PKC inhibitors in the aim of restoring susceptibility to azole treatment. Co-administration assay of benzofuropyrimidinedione 23 and fluconazole highlighted a synergistic effect on inhibition of cell growth of a Candida albicans resistant strain.
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      PubDate: 2018-06-18T00:51:47Z
       
  • Structural basis for the selective inhibition of activated
           thrombin-activatable fibrinolysis inhibitor (TAFIa) by a
           selenium-containing inhibitor with chloro-aminopyridine as a basic group
    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13
      Author(s): Toshimasa Itoh, Nobuko Yoshimoto, Yoshinari Hirano, Keiko Yamamoto
      Activated thrombin-activatable fibrinolysis inhibitor (TAFIa) is a target molecule for treating thromboembolic disorders. We previously reported that design and synthesis of compound 1 containing a selenol group and chloloaminopyridine. Compound 1 showed high inhibitory activity towards TAFIa, with a high degree of selectivity for TAFIa over carboxypeptidase N (CPN). Here we report investigation of this selectivity. To obtain co-crystal of 1/pp-CPB (a surrogate of TAFIa), we synthesized protected compound 5 as a stabilized precursor of 1. The X-ray crystal structure and docking study indicated that the Cl substituent is accommodated in the pp-CPB specific pocket whereas CPN has no identical pocket. This is important information for the design of drugs targeting TAFIa with high selectivity.
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      PubDate: 2018-06-18T00:51:47Z
       
  • Synthesis of C-ring-modified blebbistatin derivatives and evaluation of
           their myosin II ATPase inhibitory potency
    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13
      Author(s): Bart I. Roman, Sigrid Verhasselt, Christophe W. Mangodt, Olivier De Wever, Christian V. Stevens
      (S)-Blebbistatin is a micromolar myosin II ATPase inhibitor that is extensively used in research. In search of analogs with improved potency, we have synthesized for the first time C-ring modified analogs. We introduced hydroxymethyl or allyloxymethyl functionalities in search of additional favorable interactions and a more optimal filling of the binding pocket. Unfortunately, the resulting compounds did not significantly inhibit the ATPase activity of rabbit skeletal-muscle myosin II. This and earlier reports suggest that rational design of potent myosin II inhibitors based on the architecture of the blebbistatin binding pocket is an ineffective strategy.
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      PubDate: 2018-06-18T00:51:47Z
       
  • Hexahydrobenzophenanthridine alkaloids from Corydalis bungeana Turcz. and
           their anti-inflammatory activity
    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13
      Author(s): Chang Gao, Yue Du, Xin Wang, Huikun Cao, Bin Lin, Youping Liu, Xin Di
      As part of a bioprospecting program aimed at the discovery of anti-inflammatory agents from the Corydalis bungeana Turcz. (C. bungeana), five new hexahydrobenzophenanthridine alkaloids, corycaline A-E (1–5), along with four known alkaloids, were isolated from the whole plant of C. bungeana. Their structures including absolute configurations were elucidated on the basis of extensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. The inhibitory activities of the nine compounds on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 mouse macrophage cells were determined; all tested compounds except 2 and 7 exhibited significant inhibitory effects with IC50 values in the range of 1.00–2.79 μM.
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      PubDate: 2018-06-18T00:51:47Z
       
  • Design and synthesis of functionalized piperazin-1yl-(E)-stilbenes as
           inhibitors of 17α-hydroxylase-C17,20-lyase (Cyp17)
    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13
      Author(s): Benjamin E. Blass, Pravin Iyer, Magid Abou-Gharbia, Wayne E. Childers, John C. Gordon, Mercy Ramanjulu, George Morton, Premkumar Arumugam, Joshodeep Boruwa, John Ellingboe, Sayan Mitra, Rajashekar Reddy Nimmareddy, Shalini Paliwal, Jamallamudi Rajasekhar, Savithiri Shivakumar, Pratima Srivastava, Raghuram S. Tangirala, Konda Venkataramanaiah, Ramreddy Bobbala, Mahesh Yanamandra, L. Krishnakanth Reddy
      The synthesis of steroid hormones is critical to human physiology and improper regulation of either the synthesis of these key molecules or activation of the associated receptors can lead to disease states. This has led to intense interest in developing compounds capable of modulating the synthesis of steroid hormones. Compounds capable of inhibiting Cyp19 (Aromatase), a key enzyme in the synthesis of estrogens, have been successfully employed as breast cancer therapies, while inhibitors of Cyp17 (17α-hydroxylase-17,20-lyase), a key enzyme in the synthesis of glucocorticoids, mineralocorticoids and steroidal sex hormones, are a key component of prostate cancer therapy. Inhibition of CYP17 has also been suggested as a possible target for the treatment of Cushing Syndrome and Metabolic Syndrome. We have identified two novel series of stilbene based CYP17 inhibitors and demonstrated that exemplary compounds in these series have pharmacokinetic properties consistent with orally delivered drugs. These findings suggest that compounds in these classes may be useful for the treatment of diseases and conditions associated with improper regulation of glucocorticoids synthesis and glucocorticoids receptor activation.
      Graphical abstract image

      PubDate: 2018-06-18T00:51:47Z
       
  • Design, synthesis and biological evaluation of artemisinin derivatives
           containing fluorine atoms as anticancer agents
    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13
      Author(s): Shu Li, Gongming Li, Xiaohong Yang, Qian Meng, Shuo Yuan, Yun He, Dequn Sun
      Ten novel artemisinin derivatives containing fluorine atoms were synthesized and their structures were confirmed by 1H NMR, 13C NMR and HRMS technologies in this study. The in vitro cytotoxicity against U87MG, SH-SY5Y, MCF-7, MDA-MB-231, A549 and A375 cancer cell lines was evaluated by MTT assay. Compound 9j was the most potent anti-proliferative agent against the human breast cancer MCF-7 cells (IC50 = 2.1 μM). The mechanism of action of compound 9j was further investigated by analysis of cell apoptosis and cell cycle. Compound 9j induced cell apoptosis and arrested cell cycle at G1 phase in MCF-7 cells. Our promising findings indicated that the compound 9j could stand as potential lead compound for further investigation.
      Graphical abstract image

      PubDate: 2018-06-18T00:51:47Z
       
  • Development of autotaxin inhibitors: A series of zinc binding triazoles
    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13
      Author(s): Christopher G. Thomson, Darren Le Grand, Mark Dowling, Cara E. Brocklehurst, Colin Chinn, Lucy Elphick, Michael Faller, Mark Freeman, Vikki Furminger, Cornelia Gasser, Ahmed Hamadi, Elizabeth Hardaker, Victoria Head, Johan C. Hill, Diana I. Janus, David Pearce, Anne-Sophie Poulaud, Emily Stanley, Lilya Sviridenko
      A series of inhibitors of Autotaxin (ATX) has been developed using the binding mode of known inhibitor, PF-8380, as a template. Replacement of the benzoxazolone with a triazole zinc-binding motif reduced crystallinity and improved solubility relative to PF-8380. Modification of the linker region removed hERG activity and led to compound 12 – a selective, high affinity, orally-bioavailable inhibitor of ATX. Compound 12 concentration-dependently inhibits autotaxin and formation of LPA in vivo, as shown in pharmacokinetic-pharmacodynamic experiments.
      Graphical abstract image

      PubDate: 2018-06-18T00:51:47Z
       
  • Isoxazole-tethered diarylheptanoid analogs: Discovery of a new drug-like
           PAR2 antagonist
    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13
      Author(s): Debnath Bhuniya, Sandeep Bhosale, Satyanarayana B. Reddy, Sudharshan N. Reddy
      A new class of isoxazole-tethered diarylheptanoids having characteristic 1,3-syn-diol and 1,3-anti-diol chemophoric moieties, e.g. 4a–d and 5a–c respectively, have been designed and synthesized starting from d-glucose following a stereo-conserved general synthetic strategy. The isoxazole heterocycle was installed using our recently elaborated methodology deploying Magtrieve™ as a selective oxidizing agent. Two of these new analogs 4a and 5a exhibited significantly improved in vitro drug-like properties including solubility, metabolic stability, cell permeability and lack of nonspecific cytotoxicity when compared with curcumin-I. In a HEK293 cell-based intracellular calcium [Ca2+]i release assay, 4a and 5a, when tested at 30 μM, inhibited the trypsin agonist induced protease-activated receptor-2 (PAR2) activity by 80% and 70% respectively. IC50 of 4a (SB70) has been determined as 6 μM which is in the same range of current benchmarks for PAR2 antagonists.
      Graphical abstract image

      PubDate: 2018-06-18T00:51:47Z
       
  • New TRAP1 and Hsp90 chaperone inhibitors with cationic components:
           Preliminary studies on mitochondrial targeting
    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13
      Author(s): R. Rondanin, G. Lettini, P. Oliva, R. Baruchello, C. Costantini, C. Trapella, D. Simoni, T. Bernardi, L. Sisinni, M. Pietrafesa, G. Ponterini, M.P. Costi, T. Vignudelli, R. Luciani, D.S. Matassa, F. Esposito, M. Landriscina
      TRAP1 (Hsp75) is the mitochondrial paralog of the Hsp90 molecular chaperone family. Due to structural similarity among Hsp90 chaperones, a potential strategy to induce apoptosis through mitochondrial TRAP1 ATPase inhibition has been envisaged and a series of compounds has been developed by binding the simple pharmacophoric core of known Hsp90 inhibitors with various appendages bearing a permanent cationic head, or a basic group highly ionizable at physiologic pH. Cationic appendages were selected as vehicles to deliver drugs to mitochondria. Indeed, masses of new derivatives were evidenced to accumulate in the mitochondrial fraction from colon carcinoma cells and a compound in the series, with a guanidine appendage, demonstrated good activity in inhibiting recombinant TRAP1 ATPase and cell growth and in inducing apoptotic cell death in colon carcinoma cells.
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      PubDate: 2018-06-18T00:51:47Z
       
  • Structure activity relationships of anthranilic acid-based compounds on
           cellular and in vivo mitogen activated protein kinase-5 signaling pathways
           
    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13
      Author(s): Suravi Chakrabarty, Darlene A. Monlish, Mohit Gupta, Thomas D. Wright, Van T. Hoang, Mitchel Fedak, Ishveen Chopra, Patrick T. Flaherty, Jeffry Madura, Shankar Mannepelli, Matthew E. Burow, Jane E. Cavanaugh
      Graphical abstract image

      PubDate: 2018-06-18T00:51:47Z
       
  • Adamantyl thioureas as soluble epoxide hydrolase inhibitors
    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13
      Author(s): Vladimir Burmistrov, Christophe Morisseau, Dmitry Pitushkin, Dmitry Karlov, Robert R. Fayzullin, Gennady M. Butov, Bruce D. Hammock
      A series of inhibitors of the soluble epoxide hydrolase (sEH) containing one or two thiourea groups has been developed. Inhibition potency of the described compounds ranges from 50 μM to 7.2 nM. 1,7-(Heptamethylene)bis[(adamant-1-yl)thiourea] (6f) was found to be the most potent sEH inhibitor, among the thioureas tested. The inhibitory activity of the thioureas against the human sEH is closer to the value of activity against rat sEH rather than murine sEH. While being less active, thioureas are up to 7-fold more soluble than ureas, which makes them more bioavailable and thus promising as sEH inhibitors.
      Graphical abstract image

      PubDate: 2018-06-18T00:51:47Z
       
  • Synthesis, characterization and cytotoxicity studies of 1,2,3-triazoles
           and 1,2,4-triazolo [1,5-a] pyrimidines in human breast cancer cells
    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13
      Author(s): Maryam Gilandoust, Kachigere B. Harsha, Chakrabhavi Dhananjaya Mohan, Ainiah Rushdiana Raquib, Shobith Rangappa, Vijay Pandey, Peter E. Lobie, Basappa, Kanchugarakoppal S. Rangappa
      Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) is essential for physiological functions of tissues and neovasculature. VEGFR signaling is associated with the progression of pathological angiogenesis in various types of malignancies, making it an attractive therapeutic target in cancer treatment. In the present work, we report the synthesis of 1,4-disubstituted 1,2,3-triazoles and 1,2,4-triazolo[1, 5-a]pyrimidine derivatives via copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and screened for their anticancer activity against MCF7 cells. We identified 1-(2′-ethoxy-4′-fluoro-[1,1′-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole (EFT) as lead cytotoxic agent against MCF7 cell lines with an IC50 value of 1.69 µM. Further evaluation revealed that EFT induces cytotoxicity on Ishikawa, MDA-MB-231 and BT474 cells with IC50 values of 1.97, 4.81 and 4.08 µM respectively. However, EFT did not induce cytotoxicity in normal lung epithelial (BEAS-2B) cells. Previous reports suggested that 1,2,3-triazoles are the inhibitors of VEGFR1 and therefore, we evaluated the effect of EFT on the expression of VEGFR1. The results demonstrated that EFT downregulates the expression of VEGFR1 in MCF7 cells. In summary, we identified a potent cytotoxic agent that imparts its antiproliferative activity by targeting VEGFR1 in breast cancer cells. The novel compound could serve as a lead structure in developing VEGFR1 inhibitors.
      Graphical abstract image

      PubDate: 2018-06-18T00:51:47Z
       
  • Chemical space screening around Phe3 in opioid peptides: Modulating µ
           versus δ agonism by Suzuki-Miyaura cross-couplings
    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13
      Author(s): Tom Willemse, Emilie Eiselt, Karlijn Hollanders, Wim Schepens, Herman W.T. van Vlijmen, Nga N. Chung, Véronique Blais, Brain Holleran, Jean-Michel Longpré, Peter W. Schiller, Bert U.W. Maes, Philippe Sarret, Louis Gendron, Steven Ballet
      In this study, affinities and activities of derivatized analogues of Dmt-dermorphin[1–4] (i.e. Dmt-d-Ala-Phe-GlyNH2, Dmt = 2′,6′-dimethyl-(S)-tyrosine) for the µ opioid receptor (MOP) and δ opioid receptor (DOP) were evaluated using radioligand binding studies, functional cell-based assays and isolated organ bath experiments. By means of solid-phase or solution-phase Suzuki-Miyaura cross-couplings, various substituted regioisomers of the phenylalanine moiety in position 3 of the sequence were prepared. An 18-membered library of opioid tetrapeptides was generated via screening of the chemical space around the Phe3 side chain. These substitutions modulated bioactivity, receptor subtype selectivity and highly effective ligands with subnanomolar binding affinities, contributed to higher functional activities and potent analgesic actions. In search of selective peptidic ligands, we show here that the Suzuki-Miyaura reaction is a versatile and robust tool which could also be deployed elsewhere.
      Graphical abstract image

      PubDate: 2018-06-18T00:51:47Z
       
  • Structure-activity relationship of uridine-based nucleoside
           phosphoramidate prodrugs for inhibition of dengue virus RNA-dependent RNA
           polymerase
    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13
      Author(s): Gang Wang, Siew Pheng Lim, Yen-Liang Chen, Jürg Hunziker, Ranga Rao, Feng Gu, Cheah Chen Seh, Nahdiyah Abdul Ghafar, Haoying Xu, Katherine Chan, Xiaodong Lin, Oliver L. Saunders, Martijn Fenaux, Weidong Zhong, Pei-Yong Shi, Fumiaki Yokokawa
      To identify a potent and selective nucleoside inhibitor of dengue virus RNA-dependent RNA polymerase, a series of 2′- and/or 4′-ribose sugar modified uridine nucleoside phosphoramidate prodrugs and their corresponding triphosphates were synthesized and evaluated. Replacement of 2′-OH with 2′-F led to be a poor substrate for both dengue virus and human mitochondrial RNA polymerases. Instead of 2′-fluorination, the introduction of fluorine at the ribose 4′-position was found not to affect the inhibition of the dengue virus polymerase with a reduction in uptake by mitochondrial RNA polymerase. 2′-C-ethynyl-4′-F-uridine phosphoramidate prodrug displayed potent anti-dengue virus activity in the primary human peripheral blood mononuclear cell-based assay with no significant cytotoxicity in human hepatocellular liver carcinoma cell lines and no mitochondrial toxicity in the cell-based assay using human prostate cancer cell lines.
      Graphical abstract image

      PubDate: 2018-06-18T00:51:47Z
       
  • Synthesis of novel hetero ring fused pyridine derivatives; Their
           anticancer activity, CoMFA and CoMSIA studies
    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13
      Author(s): G. Santhosh Kumar, Y. Poornachandra, Shravan Kumar Gunda, K. Ratnakar Reddy, Jaheer Mohmed, Kamal Shaik, C. Ganesh Kumar, B. Narsaiah
      A series of novel furo[2,3-b]pyridine-2-carboxamide 4a–h/pyrido[3′,2′:4,5]furo[3,2-d] pyrimidin-4(3H)-one derivatives 5a–p were prepared from pyridin 2(1H) one 1 via selective O-alkylation with α-bromoethylester followed by cyclization, then reaction with different aliphatic primary amines to obtain 4 and further reaction with triethyl orthoacetate/triethyl orthoformate. Also prepared novel furo[2,3-b]pyridine-2-carbohydrazide Schiff’s bases 7a–h and pyrido [3′,2′:4,5]furo[3,2-d]pyrimidin-4(3H)-one derivatives 8a–h starting from furo[2,3-b]pyridine carboxylate derivatives 3 by reaction with hydrazine hydrate to form 6 and reaction with diverse substituted aldehydes and cyclization. Products 4a–h, 5a–p, 7a–h and 8a–h were screened against four human cancer cell lines (HeLa, COLO205, Hep G2 and MCF 7) and one normal cell line (HEK 293). Compounds 4e, 4f, 4g, 5h, 7c, 7d, 7e and 7f showed significant anticancer activity against all the cell lines at micro molar concentration and found to be non-toxic to normal cell line. Studies for HeLa, COLO205 and MCF-7 using CoMFA and CoMSIA. Models from 3D-QSAR provided a strong basis for future rational design of more active and selective HeLa, COLO205 and MCF-7 cell line inhibitors.
      Graphical abstract image

      PubDate: 2018-06-18T00:51:47Z
       
  • Pyrrolinone derivatives as a new class of P2X3 receptor antagonists. Part
           1: Initial structure-activity relationship studies of a hit from a high
           throughput screening
    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13
      Author(s): Hiroyuki Tobinaga, Takayuki Kameyama, Miho Oohara, Naotake Kobayashi, Masahide Ohdan, Natsuki Ishizuka, Masaharu Kume, Maki Tomari, Yoshikazu Tanaka, Fumiyo Takahashi, Haruki Kinoshita, Shinji Shimada, Shunji Shinohara, Hiroyuki Kai
      The P2X3 receptor is primarily expressed in the peripheral sensory nerves, and therefore, antagonists of this receptor may be useful for the treatment of chronic pain. Pyrrolinone derivatives have been identified as a novel class of P2X3 receptor antagonists. A lead structure with moderate activity was discovered through a high-throughput screening assay. A structure-activity study led to the discovery of several P2X3 receptor antagonists. Compound 34 showed potent and specific antagonistic activity and analgesic efficacy.
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      PubDate: 2018-06-18T00:51:47Z
       
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    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13


      PubDate: 2018-06-18T00:51:47Z
       
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    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13


      PubDate: 2018-06-18T00:51:47Z
       
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    • Abstract: Publication date: 15 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13


      PubDate: 2018-06-18T00:51:47Z
       
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    • Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12


      PubDate: 2018-06-05T17:11:39Z
       
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    • Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12


      PubDate: 2018-06-05T17:11:39Z
       
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    • Abstract: Publication date: 1 July 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12


      PubDate: 2018-06-05T17:11:39Z
       
 
 
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