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  Subjects -> CHEMISTRY (Total: 845 journals)
    - ANALYTICAL CHEMISTRY (47 journals)
    - CHEMISTRY (596 journals)
    - CRYSTALLOGRAPHY (22 journals)
    - ELECTROCHEMISTRY (26 journals)
    - INORGANIC CHEMISTRY (42 journals)
    - ORGANIC CHEMISTRY (45 journals)
    - PHYSICAL CHEMISTRY (67 journals)

CHEMISTRY (596 journals)                  1 2 3 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 5)
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: 21)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 15)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 22)
ACS Macro Letters     Full-text available via subscription   (Followers: 18)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 31)
ACS Nano     Full-text available via subscription   (Followers: 151)
ACS Photonics     Full-text available via subscription   (Followers: 6)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 16)
Acta Chemica Iasi     Open Access  
Acta Chimica Sinica     Full-text available via subscription   (Followers: 1)
Acta Chimica Slovaca     Open Access   (Followers: 2)
Acta Chromatographica     Full-text available via subscription   (Followers: 7)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 4)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 5)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 4)
Advanced Functional Materials     Hybrid Journal   (Followers: 40)
Advanced Science Focus     Free   (Followers: 2)
Advances in Chemical Engineering and Science     Open Access   (Followers: 33)
Advances in Chemical Science     Open Access   (Followers: 10)
Advances in Chemistry     Open Access   (Followers: 7)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 14)
Advances in Drug Research     Full-text available via subscription   (Followers: 21)
Advances in Environmental Chemistry     Open Access   (Followers: 1)
Advances in Enzyme Research     Open Access   (Followers: 4)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 12)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 14)
Advances in Nanoparticles     Open Access   (Followers: 11)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 12)
Advances in Polymer Science     Hybrid Journal   (Followers: 36)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 13)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 12)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Science and Technology     Full-text available via subscription   (Followers: 1)
African Journal of Chemical Education     Open Access   (Followers: 2)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 6)
Afrique Science : Revue Internationale des Sciences et Technologie     Open Access   (Followers: 2)
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 Applied Sciences     Open Access   (Followers: 26)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 68)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 12)
American Journal of Chemistry     Open Access   (Followers: 23)
American Journal of Plant Physiology     Open Access   (Followers: 13)
American Mineralogist     Full-text available via subscription   (Followers: 7)
Anadolu University Journal of Science and Technology     Open Access  
Analyst     Full-text available via subscription   (Followers: 41)
Angewandte Chemie     Hybrid Journal   (Followers: 108)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 156)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 1)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 2)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 3)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 7)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 8)
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     Full-text available via subscription  
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 5)
Applied Spectroscopy     Full-text available via subscription   (Followers: 22)
Applied Surface Science     Hybrid Journal   (Followers: 20)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 1)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 4)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 8)
Biochemistry     Full-text available via subscription   (Followers: 195)
Biochemistry Insights     Open Access   (Followers: 4)
Biochemistry Research International     Open Access   (Followers: 4)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 8)
Bioinspired Materials     Open Access   (Followers: 2)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 1)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access  
Biomacromolecules     Full-text available via subscription   (Followers: 15)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 9)
Biomedical Chromatography     Hybrid Journal   (Followers: 7)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 2)
BioNanoScience     Partially Free   (Followers: 4)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 90)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 79)
Bioorganic Chemistry     Hybrid Journal   (Followers: 9)
Biopolymers     Hybrid Journal   (Followers: 16)
Biosensors     Open Access   (Followers: 1)
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: 3)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 23)
Bulletin of the Korean Chemical Society     Hybrid Journal  
C - Journal of Carbon Research     Open Access   (Followers: 2)
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 3)
Canadian Journal of Chemistry     Full-text available via subscription   (Followers: 6)
Canadian Mineralogist     Full-text available via subscription   (Followers: 3)
Carbohydrate Research     Hybrid Journal   (Followers: 27)
Carbon     Hybrid Journal   (Followers: 64)
Catalysis for Sustainable Energy     Open Access   (Followers: 4)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 6)
Catalysis Science and Technology     Free   (Followers: 4)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 5)
Cellulose     Hybrid Journal   (Followers: 4)
Central European Journal of Chemistry     Hybrid Journal   (Followers: 6)
Cereal Chemistry     Full-text available via subscription   (Followers: 4)
ChemBioEng Reviews     Full-text available via subscription  
ChemCatChem     Hybrid Journal   (Followers: 4)
Chemical and Engineering News     Free   (Followers: 10)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 20)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 15)
Chemical Reviews     Full-text available via subscription   (Followers: 126)
Chemical Science     Open Access   (Followers: 17)
Chemical Technology     Open Access   (Followers: 5)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 4)
Chemical Week     Full-text available via subscription   (Followers: 7)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 54)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 26)
ChemInform     Hybrid Journal   (Followers: 4)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 5)
Chemistry & Biology     Full-text available via subscription   (Followers: 30)
Chemistry & Industry     Hybrid Journal   (Followers: 2)
Chemistry - A European Journal     Hybrid Journal   (Followers: 102)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 11)
Chemistry and Materials Research     Open Access   (Followers: 14)
Chemistry Central Journal     Open Access   (Followers: 5)
Chemistry Education Research and Practice     Free   (Followers: 4)
Chemistry in Education     Open Access   (Followers: 2)
Chemistry International     Hybrid Journal   (Followers: 1)
Chemistry Letters     Full-text available via subscription   (Followers: 42)
Chemistry of Materials     Full-text available via subscription   (Followers: 132)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 8)
Chemistry World     Full-text available via subscription   (Followers: 21)
Chemistry-Didactics-Ecology-Metrology     Open Access  
ChemistryOpen     Open Access   (Followers: 1)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 2)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 14)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 6)
ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 3)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 10)
Chromatographia     Hybrid Journal   (Followers: 25)
Chromatography     Open Access   (Followers: 5)
Chromatography Research International     Open Access   (Followers: 5)
Clay Minerals     Full-text available via subscription   (Followers: 9)
Cogent Chemistry     Open Access  
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 8)
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: 17)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 1)
Composite Interfaces     Hybrid Journal   (Followers: 3)
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: 10)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 10)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 9)
Coordination Chemistry Reviews     Full-text available via subscription  
Copernican Letters     Open Access  
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 4)
Crystal Structure Theory and Applications     Open Access   (Followers: 2)
CrystEngComm     Full-text available via subscription   (Followers: 6)
Current Catalysis     Hybrid Journal   (Followers: 1)
Current Metabolomics     Hybrid Journal   (Followers: 3)
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 7)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 15)
Current Research in Chemistry     Open Access   (Followers: 7)
Current Science     Open Access   (Followers: 6)
Dalton Transactions     Full-text available via subscription   (Followers: 17)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 1)
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: 3)
Eclética Química     Open Access   (Followers: 1)
Ecological Chemistry and Engineering S     Open Access   (Followers: 2)
Ecotoxicology and Environmental Contamination     Open Access  
Educación Química     Open Access   (Followers: 1)
Education for Chemical Engineers     Hybrid Journal   (Followers: 4)
Elements     Full-text available via subscription  
Environmental Chemistry     Hybrid Journal   (Followers: 5)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 2)
Environmental Science & Technology Letters     Full-text available via subscription   (Followers: 3)

        1 2 3 | Last

Journal Cover Bioorganic & Medicinal Chemistry
  [90 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0968-0896
   Published by Elsevier Homepage  [2970 journals]
  • Identification, synthesis and evaluation of SARS-CoV and MERS-CoV 3C-like
           protease inhibitors
    • Abstract: Publication date: Available online 12 May 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Vathan Kumar, Kian-Pin Tan, Ying-Ming Wang, Sheng-Wei Lin, Po-Huang Liang
      Severe acute respiratory syndrome(SARS) led to a life-threatening form of atypical pneumonia in late 2002. Following that, Middle East Respiratory Syndrome (MERS-CoV) has recently emerged, killing about 36% of patients infected globally, mainly in Saudi Arabia and South Korea. Based on a scaffold we reported for inhibiting neuraminidase (NA), we synthesized the analogues and identified compounds with low micromolar inhibitory activity against 3CLpro of SARS-CoV and MERS-CoV. Docking studies show that a carboxylate present at either R1 or R4 destabilizes the oxyanion hole in the 3CLpro. Interestingly, 3f, 3g and 3m could inhibit both NA and 3CLpro and serve as a starting point to develop broad-spectrum antiviral agents.
      Graphical abstract image

      PubDate: 2016-05-14T22:55:23Z
       
  • Computer-Aided Drug Design Guided by Hydrogen/Deuterium Exchange Mass
           Spectrometry: A Powerful Combination for the Development of Potent and
           Selective Inhibitors of Group VIA Calcium-Independent Phospholipase A2
    • Abstract: Publication date: Available online 10 May 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Varnavas D. Mouchlis, Christophe Morisseau, Bruce D. Hammock, Sheng Li, J. Andrew McCammon, Edward A. Dennis
      Potent and selective inhibitors for phospholipases A2 (PLA2) are useful for studying their intracellular functions. PLA2 enzymes liberate arachidonic acid from phospholipids activating eicosanoid pathways that involve cyclooxygenases (COX) and lipoxygenases (LOX) leading to inflammation. Anti-inflammatory drugs target COX and LOX; thus, PLA2 can also be targeted to diminish inflammation. This paper describes the employment of enzymatic assays, hydrogen/deuterium exchange mass spectrometry (DXMS) and computational chemistry to develop PLA2 inhibitors. Beta-thioether trifluoromethylketones (TFKs) were screened against human GVIA calcium-independent, GIVA cytosolic and GV secreted PLA2s. These compounds exhibited inhibition towards Group VIA calcium-independent PLA2 (GVIA iPLA2), with the most potent and selective inhibitor 3 (OTFP) obtaining an XI(50) of 0.0002 mole fraction (IC50 of 110 nM). DXMS binding experiments in the presence of OTFP revealed the peptide regions of GVIA iPLA2 that interact with the inhibitor. Molecular docking and dynamics simulations in the presence of a membrane were guided by the DXMS data in order to identify the binding mode of OTFP. Clustering analysis showed the binding mode of OTFP that occurred 70% during the simulation. The resulted 3D complex was used for docking studies and a structure-activity relationship (SAR) was established. This paper describes a novel multidisciplinary approach in which a 3D complex of GVIA iPLA2 with an inhibitor is reported and validated by experimental data. The SAR showed that the sulfur atom is vital for the potency of beta-thioether analogues, while the hydrophobic chain is important for selectivity. This work constitutes the foundation for further design, synthesis and inhibition studies in order to develop new beta-thioether analogues that are potent and selective for GVIA iPLA2 exclusively.
      Graphical abstract image

      PubDate: 2016-05-14T22:55:23Z
       
  • Pterostilbene-mediated Nrf2 activation: Mechanistic Insights on Keap1:Nrf2
           Interface
    • Abstract: Publication date: Available online 11 May 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Bhakkiyalakshmi Elango, Dineshkumar Kesavan, Karthik Suresh, Sireesh Dornadulla, Waheetha Hooper, Ramasamy Paulmurugan, Kunka Mohanram Ramkumar
      The discovery of Keap1-Nrf2 protein-protein interaction (PPI) inhibitors has become a promising strategy to develop novel lead molecules against variety of stress. Hence, Keap1-Nrf2 system plays an important role in oxidative/electrophilic stress associated disorders. Our earlier studies identified pterostilbene (PTS), a natural analogue of resveratrol, as a potent Nrf2 activator and Keap1-Nrf2 PPI inhibitor as assessed by luciferase complementation assay. In this study, we further identified the potential of PTS in Nrf2 activation and ARE-driven downstream target genes expression by nuclear translocation experiments and ARE-luciferase reporter gene assay, respectively. Further, the luciferase complementation assay identified that PTS inhibits Keap1-Nrf2 PPI in both dose and time-dependent manner. Computational studies using molecular docking and dynamic simulation revealed that PTS directly interacts with the basic amino acids of kelch domain of Keap1 and perturb Keap1-Nrf2 interaction pattern. This manuscript not only shows the binding determinants of Keap1-Nrf2 proteins but also provides mechanistic insights on Nrf2 activation potential of PTS.
      Graphical abstract image

      PubDate: 2016-05-14T22:55:23Z
       
  • Synthesis of 4-(thiazol-2-ylamino)-benzenesulfonamides with carbonic
           anhydrase I, II and IX inhibitory activity and cytotoxic effects against
           breast cancer cell lines
    • Abstract: Publication date: Available online 12 May 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Nagwa M. Abdel Gawad, Noha H. Amin, Mohammed T. Elsaadi, Fatma M.M. Mohamed, Andrea Angeli, Viviana De Luca, Clemente Capasso, Claudiu T. Supuran
      A series of 4-(thiazol-2-ylamino)-benzenesulfonamides was synthesized and screened for their carbonic anhydrase (CA, EC 4.2.1.1) inhibitory and cytotoxic activity on human breast cancer cell line MCF-7. Human (h) CA isoforms I, II and IX were included in the study. The new sulfonamides showed excellent inhibition of all three isoforms, with KIs in the range of 0.84-702 nM against hCA I, of 0.41 – 288 nM against hCA II and of 5.6 – 29.2 against the tumor-associated hCA IX, a validated anti-tumor target, with a sulfonamide (SLC-0111) in Phase I clinical trials for the treatment of hypoxic, metastatic solid tumors overexpressing CA IX. The new compounds showed micromolar inhibitory of growth efficacy against breast cancer MCF-7 cell lines.
      Graphical abstract image

      PubDate: 2016-05-14T22:55:23Z
       
  • Comparing the Efficacy of Photodynamic and Sonodynamic Therapy in
           Non-Melanoma and Melanoma Skin Cancer
    • Abstract: Publication date: Available online 12 May 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Conor McEwan, Heather Nesbitt, Dean Nicholas, Oisin N. Kavanagh, Kevin McKenna, Philip Loan, Iain G. Jack, Anthony P. McHale, John F. Callan
      Sonodynamic therapy (SDT) involves the activation of a non-toxic sensitiser drug using low-intensity ultrasound to produce cytotoxic reactive oxygen species (ROS). Given the low tissue attenuation of ultrasound, SDT provides a significant benefit over the more established photodynamic therapy (PDT) as it enables activation of sensitisers at a greater depth within human tissue. In this manuscript, we compare the efficacy of aminolevulinic acid (ALA) mediated PDT and SDT in a squamous cell carcinoma (A431) cell line as well as the ability of these treatments to reduce the size of A431 ectopic tumours in mice. Similarly, the relative cytotoxic ability of Rose Bengal mediated PDT and SDT was investigated in a B16-melanoma cell line and also in a B16 ectopic tumour model. The results reveal no statistically significant difference in efficacy between ALA mediated PDT or SDT in the non-melanoma model while Rose Bengal mediated SDT was significantly more efficacious than PDT in the melanoma model. This difference in efficacy was, at least in part, attributed to the dark pigmentation of the melanoma cells that effectively filtered the excitation light preventing it from activating the sensitiser while the use of ultrasound circumvented this problem. These results suggest SDT may provide a better outcome than PDT when treating highly pigmented cancerous skin lesions.
      Graphical abstract image

      PubDate: 2016-05-14T22:55:23Z
       
  • Synthesis and In vitro α-Chymotrypsin Inhibitory Activity of
           6-Chlorobenzimidazole Derivatives
    • Abstract: Publication date: Available online 12 May 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Hina Siddiqui, Rabia Farooq, Bishnu P. Marasini, Rizwana Malik, Naima Syed, Syed Tarique Moin, Atta-ur-Rahman, M. Iqbal Choudhary
      A library of benzimidazole derivatives 1-20 were synthesized, and studied for their α-chymotrypsin (α-CT) inhibitory activity in vitro. Kinetics studies and molecular docking studies were performed to identify the type of inhibition. Compound 1 was found to be a good inhibitor of α-chymotrypsin enzyme (IC50 = 14.8 μM, Ki = 16.4 μM), when compared with standard chymostatin (IC50 = 5.7±0.13 μM). Compounds 2-8, 15, 17, and 18 showed significant inhibitory activities. All the inhibitors were found to be competitive inhibitors, except compound 17, which was a mixed type inhibitor. The substituents (R) in para and ortho positions of phenyl ring B, apparently played a key role in the inhibitory potential of the series. Compounds 1-20 were also studied for their cytotoxicity profile by using 3T3 mouse fibroblast cells and compounds 3, 5, 6, 8, 12-14, 16, 17, 19, and 20 were found to be cytotoxic. Molecular docking was performed on the most active member of the series in comparison to the standard compound, chymostatin, to show the most likely binding modes. The compounds reported here can serve as templates for further studies of new inhibitors of α- chymotrypsin and other chymotrypsin-like serine proteases enzymes.
      Graphical abstract image

      PubDate: 2016-05-14T22:55:23Z
       
  • Inhibitors of secreted phospholipase A2 suppress the release of PGE2 in
           renal mesangial cells
    • Abstract: Publication date: Available online 13 May 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Sofia Vasilakaki, Efrosini Barbayianni, Victoria Magrioti, Oleksandr Pastukhov, Violetta Constantinou-Kokotou, Andrea Huwiler, George Kokotos
      The upregulation of PGE2 by mesangial cells has been observed under chronic inflammation condition. In the present work, renal mesangial cells were stimulated to trigger a huge increase of PGE2 synthesis and were treated in the absence or presence of known PLA2 inhibitors. A variety of synthetic inhibitors, mainly developed in our labs, which are known to selectively inhibit each of GIVA cPLA2, GVIA iPLA2, and GIIA/GV sPLA2, were used as tools in this study. Synthetic sPLA2 inhibitors, such as GK115 (an amide derivative based on the non-natural amino acid (R)-γ-norleucine) as well as GK126 and GK241 (2-oxoamides based on the natural (S)-α-amino acid leucine and valine, respectively) presented an interesting effect on the suppression of PGE2 formation.
      Graphical abstract image

      PubDate: 2016-05-14T22:55:23Z
       
  • Novel Approaches to Map Small Molecule-Target Interactions
    • Abstract: Publication date: Available online 13 May 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Shobhna Kapoor, Herbert Waldmann, Slava Ziegler
      The quest for small molecule perturbators of protein function or a given cellular process lies at the heart of chemical biology and pharmaceutical research. Bioactive compounds need to be extensively characterized in the context of the modulated protein(s) or process(es) in living systems to unravel and confirm their mode of action. A crucial step in this workflow is the identification of the molecular targets for these small molecules, for which a generic methodology is lacking. Herein we summarize recently developed approaches for target identification spurred by advances in omics techniques and chemo- and bioinformatics analysis.
      Graphical abstract image

      PubDate: 2016-05-14T22:55:23Z
       
  • Design, biological evaluation and 3D QSAR studies of novel
           dioxin-containing triaryl pyrazoline derivatives as potential B-Raf
           inhibitors
    • Abstract: Publication date: Available online 12 May 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Yu-Shun Yang, Bing Yang, Yan Zou, Gui-Gen Li, Hai-Liang Zhu
      A series of novel dioxin-containing triaryl pyrazoline derivatives C1-C20 have been synthesized. Their B-Raf inhibitory and anti-proliferation activities were evaluated. Compound C6 displayed the most potent biological activity against B-RafV600E and WM266.4 human melanoma cell line with corresponding IC50 value of 0.04 μM and GI50 value of 0.87 μM, being comparable with the positive controls and more potent than our previous best compounds. Moreover, C6 was selective for B-RafV600E from B-RafWT, C-Raf and EGFR and low toxic. The docking simulation suggested the potent bioactivity might be caused by breaking the limit of previous binding pattern. A new 3D QSAR model was built with the activity data and binding conformations to conduct visualized SAR discussion as well as to introduce new directions. Stretching the backbone to outer space or totally reversing the backbone are both potential orientations for future researches.
      Graphical abstract image

      PubDate: 2016-05-14T22:55:23Z
       
  • Substituted quinolines as noncovalent proteasome inhibitors
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
      Author(s): Tanner J. McDaniel, Theresa A. Lansdell, Amila A. Dissanayake, Lauren M. Azevedo, Jacob Claes, Aaron L. Odom, Jetze J. Tepe
      Screening of a library of diverse heterocyclic scaffolds identified substituted quinolines as inhibitors of the human proteasome. The heterocyclic library was prepared via a novel titanium-catalyzed multicomponent coupling reaction, which rendered a diverse set of isoxazoles, pyrimidines, pyrroles, pyrazoles and quinolines. SAR of the parent lead compound indicated that hydrophobic residues on the benzo-moiety significantly improved potency. Lead compound 25 inhibits the chymotryptic-like proteolytic activity of the proteasome (IC50 5.4μM), representing a new class of nonpeptidic, noncovalent proteasome inhibitors.
      Graphical abstract image

      PubDate: 2016-05-03T07:49:17Z
       
  • Cytoprotective small molecule modulators of endoplasmic reticulum stress
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
      Author(s): Soumyabrata Munshi, Russell Dahl
      Cellular health depends on the normal function of the endoplasmic reticulum (ER) to fold, assemble, and modify critical proteins to maintain viability. When the ER cannot process proteins effectively, a condition known as ER stress ensues. When this stress is excessive or prolonged, cell death via apoptotic pathways is triggered. Interestingly, most major diseases have been shown to be intimately linked to ER stress, including diabetes, stroke, neurodegeneration, and many cancers. Thus, controlling ER stress presents a significant strategy for drug development for these diseases. The goal of this review is to present various small molecules that alleviate ER stress with the intention that they may serve as useful starting points for therapeutic agent development.
      Graphical abstract image

      PubDate: 2016-05-03T07:49:17Z
       
  • New imidazoquinoxaline derivatives: Synthesis, biological evaluation on
           melanoma, effect on tubulin polymerization and structure–activity
           relationships
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
      Author(s): Zahraa Zghaib, Jean-François Guichou, Johanna Vappiani, Nicole Bec, Kamel Hadj-Kaddour, Laure-Anaïs Vincent, Stéphanie Paniagua-Gayraud, Christian Larroque, Georges Moarbess, Pierre Cuq, Issam Kassab, Carine Deleuze-Masquéfa, Mona Diab-Assaf, Pierre-Antoine Bonnet
      Microtubules are considered as important targets of anticancer therapy. EAPB0503 and its structural imidazo[1,2-a]quinoxaline derivatives are major microtubule-interfering agents with potent anticancer activity. In this study, the synthesis of several new derivatives of EAPB0503 is described, and the anticancer efficacy of 13 novel derivatives on A375 human melanoma cell line is reported. All new compounds show significant antiproliferative activity with IC50 in the range of 0.077–122μM against human melanoma cell line (A375). Direct inhibition of tubulin polymerization assay in vitro is also assessed. Results show that compounds 6b, 6e, 6g, and EAPB0503 highly inhibit tubulin polymerization with percentages of inhibition of 99%, 98%, 90%, and 84% respectively. Structure–activity relationship studies within the series are also discussed in line with molecular docking studies into the colchicine-binding site of tubulin.
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      PubDate: 2016-05-03T07:49:17Z
       
  • Synthesis and evaluation of 4-(2-hydroxypropyl)piperazin-1-yl) derivatives
           as Hsp90 inhibitors
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
      Author(s): Bahidja Cherfaoui, Tian-kun Guo, Hao-Peng Sun, Wei-Lin Cheng, Fang Liu, Fen Jiang, Xiao-Li Xu, Qi-Dong You
      We previously reported 4-(3-((6-bromonaphthalen-2-yl)oxy)-2-hydroxypropyl)-N,N-dimethylpiperazine-1-sulfonamide (1) as a novel heat shock protein 90 inhibitor with moderate activity. In our ongoing efforts for the discovery of Hsp90 modulators we undertake structural investigations on 1. Series of the titled compound were designed, synthesized and evaluated. We have found that compounds with a hydroxyl group at C-4 of the aryl ring on the piperazine moiety possess Hsp90 inhibition properties. Compound 6f with improved activity could be further developed and optimized as Hsp90 inhibitor.
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      PubDate: 2016-05-03T07:49:17Z
       
  • Synergistic reduction of HIV-1 infectivity by 5-azacytidine and inhibitors
           of ribonucleotide reductase
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
      Author(s): Jonathan M.O. Rawson, Megan E. Roth, Jiashu Xie, Michele B. Daly, Christine L. Clouser, Sean R. Landman, Cavan S. Reilly, Laurent Bonnac, Baek Kim, Steven E. Patterson, Louis M. Mansky
      Although many compounds have been approved for the treatment of human immunodeficiency type-1 (HIV-1) infection, additional anti-HIV-1 drugs (particularly those belonging to new drug classes) are still needed due to issues such as long-term drug-associated toxicities, transmission of drug-resistant variants, and development of multi-class resistance. Lethal mutagenesis represents an antiviral strategy that has not yet been clinically translated for HIV-1 and is based on the use of small molecules to induce excessive levels of deleterious mutations within the viral genome. Here, we show that 5-azacytidine (5-aza-C), a ribonucleoside analog that induces the lethal mutagenesis of HIV-1, and multiple inhibitors of the enzyme ribonucleotide reductase (RNR) interact in a synergistic fashion to more effectively reduce the infectivity of HIV-1. In these drug combinations, RNR inhibitors failed to significantly inhibit the conversion of 5-aza-C to 5-aza-2′-deoxycytidine, suggesting that 5-aza-C acts primarily as a deoxyribonucleoside even in the presence of RNR inhibitors. The mechanism of antiviral synergy was further investigated for the combination of 5-aza-C and one specific RNR inhibitor, resveratrol, as this combination improved the selectivity index of 5-aza-C to the greatest extent. Antiviral synergy was found to be primarily due to the reduced accumulation of reverse transcription products rather than the enhancement of viral mutagenesis. To our knowledge, these observations represent the first demonstration of antiretroviral synergy between a ribonucleoside analog and RNR inhibitors, and encourage the development of additional ribonucleoside analogs and RNR inhibitors with improved antiretroviral activity.
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      PubDate: 2016-05-03T07:49:17Z
       
  • Synthesis and biological evaluation of sialyl-oligonucleotide conjugates
           targeting leukocyte B trans-membranal receptor CD22 as delivery agents for
           nucleic acid drugs
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
      Author(s): Gabrielle St-Pierre, Sudip Pal, Michael E. Østergaard, Tianyuan Zhou, Jinghua Yu, Michael Tanowitz, Punit P. Seth, Stephen Hanessian
      Antisense oligonucleotides (ASOs) modified with ligands which target cell surface receptors have the potential to significantly improve potency in the target tissue. This has recently been demonstrated using triantennary N-acetyl d-galactosamine conjugated ASOs. CD22 is a cell surface receptor expressed exclusively on B cells thus presenting an attractive target for B cell specific delivery of drugs. Herein, we reported the synthesis of monovalent and trivalent ASO conjugates with biphenylcarbonyl (BPC) modified sialic acids and their study as ASO delivery agents into B cells. CD22 positive cells exhibited reduced potency when treated with ligand modified ASOs and mechanistic examination suggested reduced uptake into cells potentially as a result of sequestration of ASO by other cell-surface proteins.
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      PubDate: 2016-05-03T07:49:17Z
       
  • Exploration of 3-methylisoquinoline-4-carbonitriles as protein kinase A
           inhibitors of Plasmodium falciparum
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
      Author(s): Melissa J. Buskes, Katherine L. Harvey, Boris Prinz, Brendan S. Crabb, Paul R. Gilson, David J.D. Wilson, Belinda M. Abbott
      A series of isoquinolines have been evaluated in a homology model of Plasmodium falciparum Protein Kinase A (PfPKA) using molecular dynamics. Synthesis of these compounds was then undertaken to investigate their structure–activity relationships. One compound was found to inhibit parasite growth in an in vitro assay and provides a lead to further develop 3-methylisoquinoline-4-carbonitriles as antimalarial compounds. Development of a potent and selective PfPKA inhibitor would provide a useful tool to shed further insight into the mechanisms enabling malaria parasites to establish infection.
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      PubDate: 2016-05-03T07:49:17Z
       
  • Editorial board
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11




      PubDate: 2016-05-03T07:49:17Z
       
  • Quinazolines and quinazolinones as ubiquitous structural fragments in
           medicinal chemistry: An update on the development of synthetic methods and
           pharmacological diversification
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
      Author(s): Imtiaz Khan, Sumera Zaib, Sadaf Batool, Naeem Abbas, Zaman Ashraf, Jamshed Iqbal, Aamer Saeed
      Nitrogen-rich heterocycles, particularly quinazolines and quinazolinones, represent a unique class of diversified frameworks displaying a broad spectrum of biological functions. Over the past several years, intensive medicinal chemistry efforts have generated numerous structurally functionalized quinazoline and quinazolinone derivatives. Interest in expanding the biological effects, demonstrated by these motifs, is growing exponentially, as indicated by the large number of publications reporting the easy accessibility of these skeletons in addition to the diverse nature of synthetic as well as biological applications. Therefore, the main focus of the present review is to provide an ample but condensed overview on various synthetic approaches providing access to quinazoline and quinazolinone compounds with multifaceted biological activities. Furthermore, mechanistic insights, synthetic utilization, structure–activity relationships and molecular modeling inputs for the potent derivatives have also been discussed.
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      PubDate: 2016-05-03T07:49:17Z
       
  • Synthesis of novel amide and urea derivatives of thiazol-2-ethylamines and
           their activity against Trypanosoma brucei rhodesiense
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
      Author(s): Donald A. Patrick, Tanja Wenzler, Sihyung Yang, Patrick T. Weiser, Michael Zhuo Wang, Reto Brun, Richard R. Tidwell
      2-(2-Benzamido)ethyl-4-phenylthiazole (1) was one of 1035 molecules (grouped into 115 distinct scaffolds) found to be inhibitory to Trypanosoma brucei, the pathogen causing human African trypanosomiasis, at concentrations below 3.6μM and non-toxic to mammalian (Huh7) cells in a phenotypic high-throughput screen of a 700,000 compound library performed by the Genomics Institute of the Novartis Research Foundation (GNF). Compound 1 and 72 analogues were synthesized in this lab by one of two general pathways. These plus 10 commercially available analogues were tested against T. brucei rhodesiense STIB900 and L6 rat myoblast cells (for cytotoxicity) in vitro. Forty-four derivatives were more potent than 1, including eight with IC50 values below 100nM. The most potent and most selective for the parasite was the urea analogue 2-(2-piperidin-1-ylamido)ethyl-4-(3-fluorophenyl)thiazole (70, IC50 =9nM, SI>18,000). None of 33 compounds tested were able to cure mice infected with the parasite; however, seven compounds caused temporary reductions of parasitemia (⩾97%) but with subsequent relapses. The lack of in vivo efficacy was at least partially due to their poor metabolic stability, as demonstrated by the short half-lives of 15 analogues against mouse and human liver microsomes.
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      PubDate: 2016-05-03T07:49:17Z
       
  • Discovery and optimization of
           1,7-disubstituted-2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-ones as potent
           and selective PKCθ inhibitors
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
      Author(s): Taisuke Katoh, Takafumi Takai, Takafumi Yukawa, Tetsuya Tsukamoto, Etsurou Watanabe, Hideyuki Mototani, Takeo Arita, Hiroki Hayashi, Hideyuki Nakagawa, Michael G. Klein, Hua Zou, Bi-Ching Sang, Gyorgy Snell, Yoshihisa Nakada
      A high-throughput screening campaign helped us to identify an initial lead compound (1) as a protein kinase C-θ (PKCθ) inhibitor. Using the docking model of compound 1 bound to PKCθ as a model, structure-based drug design was employed and two regions were identified that could be explored for further optimization, i.e., (a) a hydrophilic region around Thr442, unique to PKC family, in the inner part of the hinge region, and (b) a lipophilic region at the forefront of the ethyl moiety. Optimization of the hinge binder led us to find 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one as a potent and selective hinge binder, which resulted in the discovery of compound 5. Filling the lipophilic region with a suitable lipophilic substituent boosted PKCθ inhibitory activity and led to the identification of compound 10. The co-crystal structure of compound 10 bound to PKCθ confirmed that both the hydrophilic and lipophilic regions were fully utilized. Further optimization of compound 10 led us to compound 14, which demonstrated an improved pharmacokinetic profile and inhibition of IL-2 production in a mouse.
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      PubDate: 2016-05-03T07:49:17Z
       
  • 1,6-Bis[(benzyloxy)methyl]uracil derivatives—Novel antivirals with
           activity against HIV-1 and influenza H1N1 virus
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
      Author(s): Alexander N. Geisman, Vladimir T. Valuev-Elliston, Alexander A. Ozerov, Anastasia L. Khandazhinskaya, Alexander O. Chizhov, Sergey N. Kochetkov, Christophe Pannecouque, Lieve Naesens, Katherine L. Seley-Radtke, Mikhail S. Novikov
      A series of 1,6-bis[(benzyloxy)methyl]uracil derivatives combining structural features of both diphenyl ether and pyridone types of NNRTIs were synthesized. Target compounds were found to inhibit HIV-1 reverse transcriptase at micro- and submicromolar levels of concentrations and exhibited anti-HIV-1 activity in MT-4 cell culture, demonstrating resistance profile similar to first generation NNRTIs. The synthesized compounds also showed profound activity against influenza virus (H1N1) in MDCK cell culture without detectable cytotoxicity. The lead compound of this assay appeared to exceed rimantadine, amantadine, ribavirin and oseltamivir carboxylate in activity. The mechanism of action of 1,6-bis[(benzyloxy)methyl]uracils against influenza virus is currently under investigation.
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      PubDate: 2016-05-03T07:49:17Z
       
  • Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel
           1-(1H-benzimidazol-6-yl)pyridin-2(1H)-one derivatives and design to avoid
           CYP3A4 time-dependent inhibition
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
      Author(s): Hideyuki Igawa, Masashi Takahashi, Mikio Shirasaki, Keiko Kakegawa, Asato Kina, Minoru Ikoma, Jumpei Aida, Tsuneo Yasuma, Shoki Okuda, Yayoi Kawata, Toshihiro Noguchi, Syunsuke Yamamoto, Yasushi Fujioka, Mrinalkanti Kundu, Uttam Khamrai, Masaharu Nakayama, Yasutaka Nagisa, Shizuo Kasai, Tsuyoshi Maekawa
      Melanin-concentrating hormone (MCH) is an attractive target for antiobesity agents, and numerous drug discovery programs are dedicated to finding small-molecule MCH receptor 1 (MCHR1) antagonists. We recently reported novel pyridine-2(1H)-ones as aliphatic amine-free MCHR1 antagonists that structurally featured an imidazo[1,2-a]pyridine-based bicyclic motif. To investigate imidazopyridine variants with lower basicity and less potential to inhibit cytochrome P450 3A4 (CYP3A4), we designed pyridine-2(1H)-ones bearing various less basic bicyclic motifs. Among these, a lead compound 6a bearing a 1H-benzimidazole motif showed comparable binding affinity to MCHR1 to the corresponding imidazopyridine derivative 1. Optimization of 6a afforded a series of potent thiophene derivatives (6q–u); however, most of these were found to cause time-dependent inhibition (TDI) of CYP3A4. As bioactivation of thiophenes to form sulfoxide or epoxide species was considered to be a major cause of CYP3A4 TDI, we introduced electron withdrawing groups on the thiophene and found that a CF3 group on the ring or a Cl adjacent to the sulfur atom helped prevent CYP3A4 TDI. Consequently, 4-[(5-chlorothiophen-2-yl)methoxy]-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (6s) was identified as a potent MCHR1 antagonist without the risk of CYP3A4 TDI, which exhibited a promising safety profile including low CYP3A4 inhibition and exerted significant antiobesity effects in diet-induced obese F344 rats.
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      PubDate: 2016-05-03T07:49:17Z
       
  • Amine-free melanin-concentrating hormone receptor 1 antagonists: Novel
           non-basic 1-(2H-indazole-5-yl)pyridin-2(1H)-one derivatives and mitigation
           of mutagenicity in Ames test
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
      Author(s): Hideyuki Igawa, Masashi Takahashi, Minoru Ikoma, Hiromi Kaku, Keiko Kakegawa, Asato Kina, Jumpei Aida, Shoki Okuda, Yayoi Kawata, Toshihiro Noguchi, Natsu Hotta, Syunsuke Yamamoto, Masaharu Nakayama, Yasutaka Nagisa, Shizuo Kasai, Tsuyoshi Maekawa
      To develop non-basic melanin-concentrating hormone receptor 1 (MCHR1) antagonists with a high probability of target selectivity and therapeutic window, we explored neutral bicyclic motifs that could replace the previously reported imidazo[1,2-a]pyridine or 1H-benzimidazole motif. The results indicated that the binding affinity of a chemically neutral 2H-indazole derivative 8a with MCHR1 (hMCHR1: IC50 =35nM) was comparable to that of the imidazopyridine and benzimidazole derivatives (1 and 2, respectively) reported so far. However, 8a was positive in the Ames test using TA1537 in S9− condition. Based on a putative intercalation of 8a with DNA, we introduced a sterically-hindering cyclopropyl group on the indazole ring to decrease planarity, which led to the discovery of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-{[5-(trifluoromethyl)thiophen-3-yl]methoxy}pyridin-2(1H)-one 8l without mutagenicity in TA1537. Compound 8l exerted significant antiobesity effects in diet-induced obese F344 rats and exhibited promising safety profile.
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      PubDate: 2016-05-03T07:49:17Z
       
  • Design, discovery, modelling, synthesis, and biological evaluation of
           novel and small, low toxicity s-triazine derivatives as HIV-1
           non-nucleoside reverse transcriptase inhibitors
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
      Author(s): Birgit Viira, Anastasia Selyutina, Alfonso T. García-Sosa, Maarit Karonen, Jari Sinkkonen, Andres Merits, Uko Maran
      A set of top-ranked compounds from a multi-objective in silico screen was experimentally tested for toxicity and the ability to inhibit the activity of HIV-1 reverse transcriptase (RT) in cell-free assay and in cell-based assay using HIV-1 based virus-like particles. Detailed analysis of a commercial sample that indicated specific inhibition of HIV-1 reverse transcription revealed that a minor component that was structurally similar to that of the main compound was responsible for the strongest inhibition. As a result, novel s-triazine derivatives were proposed, modelled, discovered, and synthesised, and their antiviral activity and cellular toxicity were tested. Compounds 18a and 18b were found to be efficient HIV-1 RT inhibitors, with an IC50 of 5.6±1.1μM and 0.16±0.05μM in a cell-based assay using infectious HIV-1, respectively. Compound 18b also had no detectable toxicity for different human cell lines. Their binding mode and interactions with the RT suggest that there was strong and adaptable binding in a tight (NNRTI) hydrophobic pocket. In summary, this iterative study produced structural clues and led to a group of non-toxic, novel compounds to inhibit HIV-RT with up to nanomolar potency.
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      PubDate: 2016-05-03T07:49:17Z
       
  • 2-Arylacetamido-4-phenylamino-5-substituted pyridazinones as formyl
           peptide receptors agonists
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
      Author(s): Claudia Vergelli, Igor A. Schepetkin, Giovanna Ciciani, Agostino Cilibrizzi, Letizia Crocetti, Maria Paola Giovannoni, Gabriella Guerrini, Antonella Iacovone, Liliya N. Kirpotina, Andrei I. Khlebnikov, Richard D. Ye, Mark T. Quinn
      N-Formyl peptide receptors (FPRs: FPR1, FPR2, and FPR3) are G protein-coupled receptors that play key roles in modulating immune cells. FPRs represent potentially important therapeutic targets for the development of drugs that could enhance endogenous anti-inflammation systems associated with various pathologies, thereby reducing the progression of inflammatory conditions. Previously, we identified 2-arylacetamide pyridazin-3(2H)-ones as FPR1- or FPR2-selective agonists, as well as a large number of FPR1/FPR2-dual agonists and several mixed-agonists for the three FPR isoforms. Here, we report a new series of 2-arylacetamido-4-aniline pyridazin-3(2H)-ones substituted in position 5 as a further development of these FPR agonists. Chemical manipulation presented in this work resulted in mixed FPR agonists 8a, 13a and 27b, which had EC50 values in nanomolar range. In particular, compound 8a showed a preference for FPR1 (EC50 =45nM), while 13a and 27b showed a moderate preference for FPR2 (EC50 =35 and 61nM, respectively). Thus, these compounds may represent valuable tools for studying FPR activation and signaling.
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      PubDate: 2016-05-03T07:49:17Z
       
  • Antiplasmodial phloroglucinol derivatives from Syncarpia glomulifera
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
      Author(s): Qingxi Su, Seema Dalal, Michael Goetz, Maria B. Cassera, David G.I. Kingston
      Bioassay guided fractionation of a MeOH extract of the stem bark of Syncarpia glomulifera (Myrtaceae) led to the isolation of the two new phloroglucinol derivatives (±)-rhodomyrtosone F (1) and (±)-calliviminone C (2), the three known triterpenes, betulinic acid (3), ursolic acid-3-acetate (4), and ursolic acid (5), and 1-(2,4,6-trihydroxyphenyl)-1-hexanone (6). Compound 1 exhibited strong antiplasmodial activity, while compounds 2–4 were moderately active and 5 and 6 were inactive in this assay. The structures of 1 and 2 were elucidated based on analyses of their mass spectrometric data, 1D and 2D NMR spectra, and comparison with related compounds.
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      PubDate: 2016-05-03T07:49:17Z
       
  • Design, synthesis and biological evaluation of
           benzyloxyphenyl-methylaminophenol derivatives as STAT3 signaling pathway
           inhibitors
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
      Author(s): Dingding Gao, Qiang Xiao, Mingming Zhang, Yingxia Li
      STAT3 signaling pathway has been validated as a vital therapeutic target for cancer therapy. Based on the novel STAT3 inhibitor of a benzyloxyphenyl-methylaminophenol scaffold hit (1) discovered through virtual screening, a series of analogues had been designed and synthesized for more potent inhibitors. The preliminary SAR had been discussed and the unique binding site in SH2 domain was predicted by molecular docking. Among them, compounds 4a and 4b exhibited superior activities than hit compound (1) against IL-6/STAT3 signaling pathway with IC50 values as low as 7.71μM and 1.38μM, respectively. Compound 4a also displayed potent antiproliferative activity against MDA-MB-468 cell line with an IC50 value of 9.61μM. We believe that these benzyloxyphenyl-methylaminophenol derivatives represent a unique mechanism for interrogating STAT3 as well as a potential structure type for further exploration.
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      PubDate: 2016-05-03T07:49:17Z
       
  • Synthesis of 24(S)-hydroxycholesterol esters responsible for the induction
           of neuronal cell death
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
      Author(s): Kimiyuki Shibuya, Toshiaki Watanabe, Yasuomi Urano, Wakako Takabe, Noriko Noguchi, Hiroaki Kitagishi
      We synthesized several candidates of 24(S)-hydroxycholesterol (24S-OHC) esters, which are involved in neuronal cell death, through catalysis with acyl-CoA:cholesterol acyltransferase-1 (ACAT-1). We studied the regioselectivity of the acylation of the secondary alcohol at the 3- or 24-position of 24S-OHC. The appropriate saturated and unsaturated long-chain fatty acids were esterified with the protected 24S-OHC and then de-protected to afford the desired esters at a satisfactory yield. We then confirmed by HPLC monitoring that the retention times of four esters of 24S-OHC, namely 3-oleate, 3-linoleate, 3-arachidonoate and 3-docosahexaenoate, were consistent with those of 24S-OHC esters observed in 24S-OHC-treated SH-SY5Y cells.
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      PubDate: 2016-05-03T07:49:17Z
       
  • Design, synthesis and in vitro evaluation studies of
           sulfonyl-amino-acetamides as small molecule BACE-1 inhibitors
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
      Author(s): Priti Jain, Pankaj K. Wadhwa, Sinduri Gunapati, Hemant R. Jadhav
      The identification of a series of sulfonyl-amino-acetamides as BACE-1 (β-secretase) inhibitors for the treatment of Alzheimer’s disease is reported. The derivatives were designed based on the docking simulation study, synthesized and assessed for BACE-1 inhibition in vitro. The designed ligands revealed desired binding interactions with the catalytic aspartate dyad and occupance of S1 and S2′ active site regions. These in silico results correlated well with in vitro activity. Out of 33 compounds synthesized, 12 compounds showed significant inhibition at 10μM concentration. The most active compound 2.17S had IC50 of 7.90μM against BACE-1, which was concomitant with results of in silico docking study.
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      PubDate: 2016-05-03T07:49:17Z
       
  • 3D-QSAR-aided design, synthesis, in vitro and in vivo evaluation of
           dipeptidyl boronic acid proteasome inhibitors and mechanism studies
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
      Author(s): Meng Lei, Huayun Feng, Cheng Wang, Hailing Li, Jingmiao Shi, Jia Wang, Zhaogang Liu, Shanshan Chen, Shihe Hu, Yongqiang Zhu
      Proteasome had been clinically validated as an effective target for the treatment of cancers. Up to now, many structurally diverse proteasome inhibitors were discovered. And two of them were launched to treat multiple myeloma (MM) and mantle cell lymphoma (MCL). Based on our previous biological results of dipeptidyl boronic acid proteasome inhibitors, robust 3D-QSAR models were developed and structure–activity relationship (SAR) was summarized. Several structurally novel compounds were designed based on the theoretical models and finally synthesized. Biological results showed that compound 12e was as active as the standard bortezomib in enzymatic and cellular activities. In vivo pharmacokinetic profiles suggested compound 12e showed a long half-life, which indicated that it could be administered intravenously. Cell cycle analysis indicated that compound 12e inhibited cell cycle progression at the G2M stage.
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      PubDate: 2016-05-03T07:49:17Z
       
  • Highly efficient method for 125I-radiolabeling of biomolecules using
           inverse-electron-demand Diels–Alder reaction
    • Abstract: Publication date: 1 June 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 11
      Author(s): Mi Hee Choi, Ha Eun Shim, Seong-Jae Yun, Hye Rim Kim, Sajid Mushtaq, Chang Heon Lee, Sang Hyun Park, Dae Seong Choi, Dong-Eun Lee, Eui-Baek Byun, Beom-Su Jang, Jongho Jeon
      In this report, we present a rapid and highly efficient method for radioactive iodine labeling of trans-cyclooctene group conjugated biomolecules using inverse-electron-demand Diels–Alder reaction. Radioiodination reaction of the tetrazine structure was carried out using the stannylated precursor 2 to give 125I-labeled product ([125I]1) with high radiochemical yield (65±8%) and radiochemical purity (>99%). For radiolabeling application of [125I]1, trans-cyclooctene derived cRGD peptide and human serum albumin were prepared. These substrates were reacted with [125I]1 under mild condition to provide the radiolabeled products [125I]6 and [125I]8, respectively, with excellent radiochemical yields. The biodistribution study of [125I]8 in normal ICR mice showed significantly lower thyroid uptake values than that of 125I-labeled human serum albumin prepared by a traditional radiolabeling method. Therefore [125I]8 will be a useful radiolabeled tracer in various molecular imaging and biological studies. Those results clearly demonstrate that [125I]1 will be used as a valuable prosthetic group for radiolabeling of biomolecules.
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      PubDate: 2016-05-03T07:49:17Z
       
  • Studies on phenothiazines: New microtubule-interacting compounds with
           phenothiazine A-ring as potent antineoplastic agents
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Alina Ghinet, Iuliana-Monica Moise, Benoît Rigo, Germain Homerin, Amaury Farce, Joëlle Dubois, Elena Bîcu
      New phenothiazine derivatives 6–20 have been designed, synthesized and evaluated in vitro for their ability to inhibit tubulin polymerization and antiproliferative activity against 60 cancer cell lines, including several multi-drug resistant (MDR) tumor cell lines. The phenothiazine unit may successfully replace the classical 3,4,5-trimethoxyphenyle A ring of parent combretastatin A-4 or phenstatin, confirming previous studies. The most promising structural modulations have been realized on the B ring, the 2′-fluoro-4′-methoxy substitution in compound 6 and the 2′-trifluoromethyl-4′-methoxy substitution in compound 7 providing the best antitubulin and antitumor activity in the current study. Compounds 6–8 and 16 exhibited more important cell growth inhibition than parent phenstatin 2 on human colon Duke’s type D, colorectal adenocarcinoma COLO 205 and on human kidney adenocarcinoma A498 cell lines. 10-Methylphenothiazine derivatives 19 and 20 did not show biological activity but exerted bright fluorescence and solvatochromism effects. These molecules deserve further chemical efforts in order to provide valuable tools for biophysical studies.
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      PubDate: 2016-04-20T13:51:13Z
       
  • Synthesis and molecular docking of
           N′-arylidene-5-(4-chlorophenyl)-1-(3,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbohydrazides
           as novel hypoglycemic and antioxidant dual agents
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Eduardo Hernández-Vázquez, Sandybel Salgado-Barrera, Juan José Ramírez-Espinosa, Samuel Estrada-Soto, Francisco Hernández-Luis
      Herein, the design and synthesis of 10 novel N′-arylidene pyrazole-3-carbohydrazides are described. Compounds were pretended to act as dual agents against diabetes and oxidative stress, two correlated pathologies involved in metabolic syndrome development and progression. The antioxidant capacity was evaluated by means of DPPH and FRAP in vitro assays. It was found that compounds bearing a hydroxyl group at 4-position of the hydrazone moiety are potent antioxidant entities, being compound 3g (a syringaldehyde derivative) the most active compound. In addition, the in vivo hypoglycemic effect of the analogues was determined. With regard to the above, the cinnamaldehyde derivatives showed a scarce biological activity, while the 4-hydroxy analogues showed the higher glycemia reduction at 7h after administration. Interestingly, the most potent antioxidants 3b and 3g also were of the most active compounds in reducing the plasma glucose, reaching 80% of reduction in the case of 3g. Molecular docking binding poses conducted to a plausible interpretation of the biological outcomes and a possible interaction between a hydroxy group and Asn287 of CB1R was proposed as an important feature for enhancing the observed activity.
      Graphical abstract image

      PubDate: 2016-04-20T13:51:13Z
       
  • Design, synthesis and biological evaluation of LBM-A5 derivatives as
           potent P-glycoprotein-mediated multidrug resistance inhibitors
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Yuxiang Wu, Miaobo Pan, Yuxuan Dai, Baomin Liu, Jian Cui, Wei Shi, Qianqian Qiu, Wenlong Huang, Hai Qian
      A novel series of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) inhibitors with triazol-N-phenethyl-tetrahydroisoquinoline or triazol-N-ethyl-tetrahydroisoquinoline scaffold were designed and synthesized via click chemistry. Most of the synthesized compounds showed higher reversal activity than verapamil (VRP). Among them, the most potent compound 4 showed a comparable activity with the known potent P-gp inhibitor WK-X-34 with lower cytotoxicity toward K562 cells (IC50 >100μM). Compared with VRP, compound 4 exhibited more potency in increasing drug accumulation in K562/A02 MDR cells. Moreover, compound 4 could significantly reverse MDR in a dose-dependent manner and also persist longer chemo-sensitizing effect than VRP with reversibility. Further mechanism studies revealed that compound 4 could remarkably increase the intracellular accumulation of Adriamycin (ADM) in K562/A02 cells as well as inhibit rhodamine-123 (Rh123) efflux from the cells. These results suggested that compound 4 may represent a promising candidate for developing P-gp-mediated MDR inhibitors.
      Graphical abstract image

      PubDate: 2016-04-20T13:51:13Z
       
  • Inhibitory effect of flavonoids on human glutaminyl cyclase
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Manman Li, Yao Dong, Xi Yu, Yongdong Zou, Yizhi Zheng, Xianzhang Bu, Junmin Quan, Zhendan He, Haiqiang Wu
      Glutaminyl cyclase (QC) plays an important role in the pathogenesis of Alzheimer’s disease (AD) and can be a potential target for the development of novel anti-AD agents. However, the study of QC inhibitors are still less. Here, phenol-4′ (R1-), C5-OH (R2-) and C7-OH (R3-) modified apigenin derivatives were synthesized as a new class of human QC (hQC) inhibitors. The efficacy investigation of these compounds was performed by spectrophotometric assessment and the structure–activity relationship (SAR) was evaluated. Molecular docking was also carried out to analyze the binding mode of the synthesized flavonoid to the active site of hQC.
      Graphical abstract image

      PubDate: 2016-04-20T13:51:13Z
       
  • Synthesis, identification, and biological activity of metabolites of two
           novel selective S1P1 agonists
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Qiong Xiao, Jing Jin, Xiaojian Wang, Jinping Hu, Meiyang Xi, Yulin Tian, Dali Yin
      SYL927 and SYL930 are selective S1P1 agonists under preclinical development. However, during their pharmacokinetic studies we detected two metabolites in rat blood that were tentatively identified as monohydroxylated metabolites of SYL927 and SYL930 based on LC–MS/MS data. In this study, we designed and synthesized possible monohydroxylated products 6a–e and used them as references to confirm the structures of the two metabolites detected by LC–MS/MS. We also evaluated the in vitro and in vivo biological activities of these two metabolites.
      Graphical abstract image

      PubDate: 2016-04-20T13:51:13Z
       
  • Orally bioavailable pyridine and pyrimidine-based Factor XIa inhibitors:
           Discovery of the methyl N-phenyl carbamate P2 prime group
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): James R. Corte, Tianan Fang, Donald J.P. Pinto, Michael J. Orwat, Alan R. Rendina, Joseph M. Luettgen, Karen A. Rossi, Anzhi Wei, Vidhyashankar Ramamurthy, Joseph E. Myers, Steven Sheriff, Rangaraj Narayanan, Timothy W. Harper, Joanna J. Zheng, Yi-Xin Li, Dietmar A. Seiffert, Ruth R. Wexler, Mimi L. Quan
      Pyridine-based Factor XIa (FXIa) inhibitor (S)-2 was optimized by modifying the P2 prime, P1, and scaffold regions. This work resulted in the discovery of the methyl N-phenyl carbamate P2 prime group which maintained FXIa activity, reduced the number of H-bond donors, and improved the physicochemical properties compared to the amino indazole P2 prime moiety. Compound (S)-17 was identified as a potent and selective FXIa inhibitor that was orally bioavailable. Replacement of the basic cyclohexyl methyl amine P1 in (S)-17 with the neutral p-chlorophenyltetrazole P1 resulted in the discovery of (S)-24 which showed a significant improvement in oral bioavailability compared to the previously reported imidazole (S)-23. Additional improvements in FXIa binding affinity, while maintaining oral bioavailability, was achieved by replacing the pyridine scaffold with either a regioisomeric pyridine or pyrimidine ring system.
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      PubDate: 2016-04-20T13:51:13Z
       
  • Development of 99mTc-labeled asymmetric urea derivatives that target
           prostate-specific membrane antigen for single-photon emission computed
           tomography imaging
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Hiroyuki Kimura, Sotaro Sampei, Daiko Matsuoka, Naoya Harada, Hiroyuki Watanabe, Kenji Arimitsu, Masahiro Ono, Hideo Saji
      Prostate-specific membrane antigen (PSMA) is expressed strongly in prostate cancers and is, therefore, an attractive diagnostic and radioimmunotherapeutic target. In contrast to previous reports of PMSA-targeting 99mTc-tricarbonyl complexes that are cationic or lack a charge, no anionic 99mTc-tricarbonyl complexes have been reported. Notably, the hydrophilicity conferred by both cationic and anionic charges leads to rapid hepatobiliary clearance, whereas an anionic charge might better enhance renal clearance relative to a cationic charge. Therefore, an improvement in rapid clearance would be expected with either cationic or anionic charges, particularly anionic charges. In this study, we designed and synthesized a novel anionic 99mTc-tricarbonyl complex ([99mTc]TMCE) and evaluated its use as a single-photon emission computed tomography (SPECT) imaging probe for PSMA detection. Direct synthesis of [99mTc]TMCE from dimethyl iminodiacetate, which contains both the asymmetric urea and succinimidyl moiety important for PSMA binding, was performed using our microwave-assisted one-pot procedure. The chelate formation was successfully achieved even though the precursor included a complicated bioactive moiety. The radiochemical yield of [99mTc]TMCE was 12–17%, with a radiochemical purity greater than 98% after HPLC purification. [99mTc]TMCE showed high affinity in vitro, with high accumulation in LNCaP tumors and low hepatic retention in biodistribution and SPECT/CT studies. These findings warrant further evaluation of [99mTc]TMCE as an imaging agent and support the benefit of this strategy for the design of other PSMA imaging probes.
      Graphical abstract image

      PubDate: 2016-04-20T13:51:13Z
       
  • N-Indolylglycosides bearing modifications at the glucose C6-position as
           sodium-dependent glucose co-transporter 2 inhibitors
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Kuang-Feng Chu, Chun-Hsu Yao, Jen-Shin Song, Chiung-Tong Chen, Teng-Kuang Yeh, Tsung-Chih Hsieh, Chung-Yu Huang, Min-Hsien Wang, Szu-Huei Wu, Wei-En Chang, Yu-Sheng Chao, Jinq-Chyi Lee
      Suppression of glucose reabsorption through the inhibition of sodium-dependent glucose co-transporter 2 (SGLT2) is a promising therapeutic approach for the treatment of type 2 diabetes. To investigate the effect of C6-substitution on inhibition of SGLT2 by N-indolylglucosides, a small library of 6-triazole, 6-amide, 6-urea, and 6-thiourea N-indolylglycosides were synthesized and tested. A detailed structure–activity relationship (SAR) study culminated in the identification of 6-amide derivatives 6a and 6o as potent SGLT2 inhibitors, which were further tested for inhibitory activity against SGLT1. The data obtained indicated that 6a and 6o are mildly to moderately selective for SGLT2 over SGLT1. Both compounds were also evaluated in a urinary glucose excretion test and pharmacokinetic study; 6a was found capable of inducing urinary glucose excretion in normal SD rats.
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      PubDate: 2016-04-20T13:51:13Z
       
  • Short cationic lipopeptides as effective antibacterial agents: Design,
           physicochemical properties and biological evaluation
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Fazren Azmi, Alysha G. Elliott, Nirmal Marasini, Soumya Ramu, Zyta Ziora, Angela M. Kavanagh, Mark A.T. Blaskovich, Matthew A. Cooper, Mariusz Skwarczynski, Istvan Toth
      The spread of drug-resistant bacteria has imparted a sense of urgency in the search for new antibiotics. In an effort to develop a new generation of antibacterial agents, we have designed de novo charged lipopeptides inspired by natural antimicrobial peptides. These short lipopeptides are composed of cationic lysine and hydrophobic lipoamino acids that replicate the amphiphilic properties of natural antimicrobial peptides. The resultant lipopeptides were found to self-assemble into nanoparticles. Some were effective against a variety of Gram-positive bacteria, including strains resistant to methicillin, daptomycin and/or vancomycin. The lipopeptides were not toxic to human kidney and liver cell lines and were highly resistant to tryptic degradation. Transmission electron microscopy analysis of bacteria cells treated with lipopeptide showed membrane-damage and lysis with extrusion of cytosolic contents. With such properties in mind, these lipopeptides have the potential to be developed as new antibacterial agents against drug-resistant Gram-positive bacteria.
      Graphical abstract image

      PubDate: 2016-04-20T13:51:13Z
       
  • Purinylpyridinylamino-based DFG-in/αC-helix-out B-Raf inhibitors:
           Applying mutant versus wild-type B-Raf selectivity indices for compound
           profiling
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Longbin Liu, Matthew R. Lee, Joseph L. Kim, Douglas A. Whittington, Howard Bregman, Zihao Hua, Richard T. Lewis, Matthew W. Martin, Nobuko Nishimura, Michele Potashman, Kevin Yang, Shuyan Yi, Karina R. Vaida, Linda F. Epstein, Carol Babij, Manory Fernando, Josette Carnahan, Mark H. Norman
      One of the challenges for targeting B-RafV600E with small molecule inhibitors had been achieving adequate selectivity over the wild-type protein B-RafWT, as inhibition of the latter has been associated with hyperplasia in normal tissues. Recent studies suggest that B-Raf inhibitors inducing the ‘DFG-in/αC-helix-out’ conformation (Type IIB) likely will exhibit improved selectivity for B-RafV600E. To explore this hypothesis, we transformed Type IIA inhibitor (1) into a series of Type IIB inhibitors (sulfonamides and sulfamides 4–6) and examined the SAR. Three selectivity indices were introduced to facilitate the analyses: the B-RafV600E/B-RafWT biochemical (bS), cellular (cS) selectivity, and the phospho-ERK activation (pA). Our data indicates that α-branched sulfonamides and sulfamides show higher selectivities than the linear derivatives. We rationalized this finding based on analysis of structural information from the literature and provided evidence for a monomeric B-Raf-inhibitor complex previously hypothesized to be responsible for the desired B-RafV600E selectivity.
      Graphical abstract image

      PubDate: 2016-04-20T13:51:13Z
       
  • Editorial board
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10




      PubDate: 2016-04-20T13:51:13Z
       
  • Towards understanding the unbound state of drug compounds: Implications
           for the intramolecular reorganization energy upon binding
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Nicolas Foloppe, I-Jen Chen
      There has been an explosion of structural information for pharmaceutical compounds bound to biological targets, but the conformations and dynamics of compounds free in solution are poorly characterized, if at all. Yet, knowledge of the unbound state is essential to understand the fundamentals of molecular recognition, including the much debated conformational intramolecular reorganization energy of a compound upon binding (ΔE Reorg). Also, dependable observation of the unbound compounds is important for ligand-based drug discovery, e.g. with pharmacophore modelling. Here, these questions are addressed with long (⩾0.5μs) state-of-the-art molecular dynamics (MD) simulations of 26 compounds (including 7 approved drugs) unbound in explicit solvent. These compounds were selected to be chemically diverse, with a range of flexibility, and good quality bioactive X-ray structures. The MD-simulated free compounds are compared to their bioactive structure and conformers generated with ad hoc sampling in vacuo or with implicit generalized Born (GB) aqueous solvation models. The GB conformational models clearly depart from those obtained in explicit solvent, and suffer from conformational collapse almost as severe as in vacuo. Thus, the global energy minima in vacuo or with GB are not suitable representations of the unbound state, which can instead be extensively sampled by MD simulations. Many, but not all, MD-simulated compounds displayed some structural similarity to their bioactive structure, supporting the notion of conformational pre-organization for binding. The ligand–protein complexes were also simulated in explicit solvent, to estimate ΔE Reorg as an enthalpic difference ΔH Reorg between the intramolecular energies in the bound and unbound states. This fresh approach yielded ΔH Reorg values⩽6kcal/mol for 18 out of 26 compounds. For three particularly polar compounds 15⩽ΔH Reorg ⩽20kcal/mol, supporting the notion that ΔH Reorg can be substantial. Those large ΔH Reorg values correspond to a redistribution of electrostatic interactions upon binding. Overall, the study illustrates how MD simulations offer a promising avenue to characterize the unbound state of medicinal compounds.
      Graphical abstract image

      PubDate: 2016-04-20T13:51:13Z
       
  • Tumour-specific cytotoxicity and structure–activity relationships of
           novel
           1-[3-(2-methoxyethylthio)propionyl]-3,5-bis(benzylidene)-4-piperidones
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Mohammad Hossain, Umashankar Das, Naoki Umemura, Hiroshi Sakagami, Jan Balzarini, Erik De Clercq, Masami Kawase, Jonathan R. Dimmock
      A series of 1-acyl-3,5-bis(benzylidene)-4-piperidones 3–7 were designed and synthesized as novel cytotoxic agents. These compounds displayed potent cytotoxic properties towards human Molt4/C8, CEM, HSC-2, HSC-3 and HSC-4 neoplasms and also to murine L1210 cells. The majority of the compounds have sub-micromolar or very low micromolar IC50 and CC50 values and are significantly more potent than the reference alkylating drug melphalan. Evaluation of these compounds against non-malignant HGF and HPLF cells revealed the tumour-specific toxicity. In particular, 3e emerged as a promising lead cytotoxic agent which caused apoptosis and PARP1 cleavage in HSC-2 cells.
      Graphical abstract image

      PubDate: 2016-04-20T13:51:13Z
       
  • Synthesis and evaluation of novel opioid ligands with a C-homomorphinan
           skeleton
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Kyoko Ishikawa, Yusuke Mochizuki, Shigeto Hirayama, Toru Nemoto, Kenichiro Nagai, Kennosuke Itoh, Hideaki Fujii
      As the reports about C-homomorphinans with the seven-membered C-ring are much fewer than those of morphinan derivatives with a six-membered C-ring, we attempted to synthesize C-homomorphinan derivatives and to evaluate their opioid activities. C-Homomorphinan 5 showed sufficient binding affinities to the opioid receptors. C-Homomorphinan derivatives possessing the δ address moiety such as indole (NTI-type), quinoline, or benzylidene (BNTX-type) functionalities showed the strongest binding affinities for the δ receptor among the three types of opioid receptors, which indicated that the C-homomorphinan skeleton sufficiently functions as a message-part in the ligand. Although NTI-type compound 8 and quinoline compound 9 with C-homomorphinan scaffold exhibited lower affinities and selectivities for the δ receptor than the corresponding morphinan derivatives did, both the binding affinity and selectivity for the δ receptor of BNTX-type compound 12 with a seven-membered C-ring were improved compared with the corresponding compounds with a six-membered C-ring including BNTX itself. BNTX-Type compound 12 was the most selective δ receptor antagonist among the tested compounds.
      Graphical abstract image

      PubDate: 2016-04-20T13:51:13Z
       
  • The Cu/ligand stoichiometry effect on the coordination behavior of aroyl
           hydrazone with copper(II): Structure, anticancer activity and anticancer
           mechanism
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): JunGang Deng, Yi Gou, Wei Chen, Xiang Fu, Hang Deng
      In an effort to better understand the biological efficacy of the tridentate aroyl hydrazone Cu(II) complexes, three Cu(II) complexes of acetylpyridine benzoyl hydrazone (HL), [Cu(L)(NO3) (H2O)]·H2O (C1), [Cu(L)2] (C2) and [Cu(L)(HL)]·(NO3)(Sas) (C3) (Sas=salicylic acid) were synthesized and characterized. X-ray crystal structures and infrared (IR) spectra of the complexes reveal that the L− ligand of C1 and C2 are predominantly in the enolate resonance form, while one L− ligand in C3 is represented enolate resonance form and the other HL ligand exhibits keto resonance form. All Cu(II) complexes showed significantly more anticancer activity than the ligand alone. Interestingly, the Cu complexes where the ligand/metal ratio was 1:1 (C1) rather than 2:1 (C2 and C3) had higher antitumor efficacy. Moreover, the 1:1 Cu/ligand complex, C1, promotes A549 cell apoptosis possibly through the intrinsic reactive oxygen species (ROS) mediated mitochondrial pathway, accompanied by the regulation of Bcl-2 family proteins.
      Graphical abstract image

      PubDate: 2016-04-20T13:51:13Z
       
  • Acetylcholinesterase and carbonic anhydrase inhibitory properties of novel
           urea and sulfamide derivatives incorporating dopaminergic 2-aminotetralin
           scaffolds
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Bünyamin Özgeriş, Süleyman Göksu, Leyla Polat Köse, İlhami Gülçin, Ramin Ekhteiari Salmas, Serdar Durdagi, Ferhan Tümer, Claudiu T. Supuran
      In the present study a series of urea and sulfamide compounds incorporating the tetralin scaffolds were synthesized and evaluated for their acetylcholinesterase (AChE), human carbonic anhydrase (CA, EC 4.2.1.1) isoenzyme I, and II (hCA I and hCA II) inhibitory properties. The urea and their sulfamide analogs were synthesized from the reactions of 2-aminotetralins with N,N-dimethylcarbamoyl chloride and N,N-dimethylsulfamoyl chloride, followed by conversion to the corresponding phenols via O-demethylation with BBr3. The novel urea and sulfamide derivatives were tested for inhibition of hCA I, II and AChE enzymes. These derivatives exhibited excellent inhibitory effects, in the low nanomolar range, with K i values of 2.61–3.69nM against hCA I, 1.64–2.80nM against hCA II, and in the range of 0.45–1.74nM against AChE. In silico techniques such as, atomistic molecular dynamics (MD) and molecular docking simulations, were used to understand the scenario of the inhibition mechanism upon approaching of the ligands into the active site of the target enzymes. In light of the experimental and computational results, crucial amino acids playing a role in the stabilization of the enzyme–inhibitor adducts were identified.
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      PubDate: 2016-04-20T13:51:13Z
       
  • Synthesis and anticancer activity of some 5-fluoro-2′-deoxyuridine
           phosphoramidates
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Marta Lewandowska, Piotr Ruszkowski, Kinga Chojnacka, Natalia Kleczewska, Marcin Hoffmann, Karol Kacprzak, Lech Celewicz
      Two series of novel 4-chlorophenyl N-alkyl phosphoramidates of 3′-O-(t-butoxycarbonyl)-5-fluoro-2′-deoxyuridine (3′-BOC-FdU) (9a–9j) and 5-fluoro-2′-deoxyuridine (FdU) (10a–10j) were synthesized by means of phosphorylation of 3′-BOC-FdU (4) with 4-chlorophenyl phosphoroditriazolide (7), followed by a reaction with the appropriate amine. Phosphoramidates 9a–9j were converted to the corresponding 10a–10j by removal of the 3′-t-butoxycarbonyl protecting group (BOC) under acidic conditions. The synthesized phosphoramidates 9a–9j and 10a–10j were evaluated for their cytotoxic activity in five human cancer cell lines: cervical (HeLa), nasopharyngeal (KB), breast (MCF-7), liver (HepG2), osteosarcoma (143B) and normal human dermal fibroblast cell line (HDF) using the sulforhodamine B (SRB) assay. Two phosphoramidates 9b and 9j with the N-ethyl and N-(methoxy-(S)-alaninyl) substituents, respectively, displayed remarkable activity in all the investigated cancer cells, and the activity was considerably higher than that of the parent nucleoside 4 and FdU. Among phosphoramidates 10a–10j compound 10c with the N-(2,2,2-trifluoroethyl) substituent showed the highest activity. Phosphoramidate 10c was more active than the FdU in all the cancer cell lines tested.
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      PubDate: 2016-04-20T13:51:13Z
       
  • Synthesis and evaluation of 4-hydroxyl aurone derivatives as
           multifunctional agents for the treatment of Alzheimer’s disease
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Yan Li, Xiaoming Qiang, Li Luo, Yuxing Li, Ganyuan Xiao, Zhenghuai Tan, Yong Deng
      A series of 4-hydroxyl aurone derivatives were designed synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer’s disease. The results demonstrated that most of the derivatives exhibited good multifunctional properties. Among them, compound 14e displayed good inhibitory activities of self- and Cu2+-induced Aβ 1–42 aggregation with 99.2% and 84.0% at 25μM, respectively, and high antioxidant activity with a value 1.90-fold of Trolox. In addition, 14e also showed remarkable inhibitory activities of both monoamine oxidase A and B with IC50 values of 0.271μM and 0.393μM, respectively. However the 6-methoxyl aurones 15a–c revealed excellent selectivity toward MAO-B. Furthermore, the representative compounds 14e and 15b displayed good metal-chelating abilities and blood–brain barrier (BBB) permeabilities in vitro.
      Graphical abstract image

      PubDate: 2016-04-20T13:51:13Z
       
  • Biological evaluation of synthetic α,β-unsaturated carbonyl
           based cyclohexanone derivatives as neuroprotective novel inhibitors of
           acetylcholinesterase, butyrylcholinesterase and amyloid-β aggregation
           
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Gao-Feng Zha, Cheng-Pan Zhang, Hua-Li Qin, Ibrahim Jantan, Muhammad Sher, Muhammad Wahab Amjad, Muhammad Ajaz Hussain, Zahid Hussain, Syed Nasir Abbas Bukhari
      A series of new α,β-unsaturated carbonyl-based cyclohexanone derivatives was synthesized by simple condensation method and all compounds were characterized by using various spectroscopic techniques. New compounds were evaluated for their effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These compounds were also screened for in vitro cytotoxicity and for inhibitory activity for self-induced Aβ1–42 aggregation. The effect of these compounds against amyloid β-induced cytotoxicity was also investigated. The findings of in vitro experiment revealed that most of these compounds exhibited potent inhibitory activity against AChE and self-induced Aβ1–42 aggregation. The compound 3o exhibited best AChE (IC50 =0.037μM) inhibitory potential. Furthermore, compound 3o disassembled the Aβ fibrils produced by self-induced Aβ aggregation by 76.6%. Compounds containing N-methyl-4-piperidone linker, showed high acetylcholinesterase and self-induced Aβ aggregation inhibitory activities as compared to reference drug donepezil. The pre-treatment of cells with synthetic compounds protected them against Aβ-induced cell death by up to 92%. Collectively, these findings suggest that some compounds from this series have potential to be promising multifunctional agents for AD treatment and our study suggest the cyclohexanone derivatives as promising new inhibitors for AChE and BuChE, potentially useful to treat neurodegenerative diseases.
      Graphical abstract image

      PubDate: 2016-04-20T13:51:13Z
       
 
 
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