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CHEMISTRY (603 journals)                  1 2 3 4 | 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: 25)
ACS Catalysis     Full-text available via subscription   (Followers: 27)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 15)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 24)
ACS Macro Letters     Full-text available via subscription   (Followers: 20)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 35)
ACS Nano     Full-text available via subscription   (Followers: 172)
ACS Photonics     Full-text available via subscription   (Followers: 7)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 18)
Acta Chemica Iasi     Open Access  
Acta Chimica Sinica     Full-text available via subscription  
Acta Chimica Slovaca     Open Access   (Followers: 1)
Acta Chromatographica     Full-text available via subscription   (Followers: 8)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 5)
Acta Scientifica Naturalis     Open Access  
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 6)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 4)
Advanced Functional Materials     Hybrid Journal   (Followers: 43)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 50)
Advances in Chemical Science     Open Access   (Followers: 11)
Advances in Chemistry     Open Access   (Followers: 10)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 15)
Advances in Drug Research     Full-text available via subscription   (Followers: 21)
Advances in Enzyme Research     Open Access   (Followers: 5)
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: 15)
Advances in Nanoparticles     Open Access   (Followers: 12)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 14)
Advances in Polymer Science     Hybrid Journal   (Followers: 37)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 15)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 14)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Science and Technology     Full-text available via subscription   (Followers: 6)
African Journal of Bacteriology Research     Open Access  
African Journal of Chemical Education     Open Access   (Followers: 2)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 7)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Alchemy : Jurnal Penelitian Kimia     Open Access  
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 60)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 13)
American Journal of Chemistry     Open Access   (Followers: 23)
American Journal of Plant Physiology     Open Access   (Followers: 12)
American Mineralogist     Full-text available via subscription   (Followers: 8)
Anadolu University Journal of Science and Technology     Open Access  
Analyst     Full-text available via subscription   (Followers: 41)
Angewandte Chemie     Hybrid Journal   (Followers: 127)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 172)
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: 3)
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: 9)
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: 23)
Applied Surface Science     Hybrid Journal   (Followers: 22)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 2)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Atomization and Sprays     Full-text available via subscription   (Followers: 3)
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: 7)
Biochemistry     Full-text available via subscription   (Followers: 232)
Biochemistry Insights     Open Access   (Followers: 4)
Biochemistry Research International     Open Access   (Followers: 5)
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: 17)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 11)
Biomedical Chromatography     Hybrid Journal   (Followers: 7)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 2)
BioNanoScience     Partially Free   (Followers: 4)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 100)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 87)
Bioorganic Chemistry     Hybrid Journal   (Followers: 9)
Biopolymers     Hybrid Journal   (Followers: 17)
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: 25)
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: 2)
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: 66)
Catalysis for Sustainable Energy     Open Access   (Followers: 5)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 7)
Catalysis Science and Technology     Free   (Followers: 5)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 6)
Cellulose     Hybrid Journal   (Followers: 5)
Cereal Chemistry     Full-text available via subscription   (Followers: 4)
ChemBioEng Reviews     Full-text available via subscription  
ChemCatChem     Hybrid Journal   (Followers: 6)
Chemical and Engineering News     Free   (Followers: 11)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 63)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 21)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 18)
Chemical Reviews     Full-text available via subscription   (Followers: 130)
Chemical Science     Open Access   (Followers: 18)
Chemical Technology     Open Access   (Followers: 11)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 4)
Chemical Week     Full-text available via subscription   (Followers: 7)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 52)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 25)
ChemInform     Hybrid Journal   (Followers: 6)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 5)
Chemistry & Biology     Full-text available via subscription   (Followers: 29)
Chemistry & Industry     Hybrid Journal   (Followers: 3)
Chemistry - A European Journal     Hybrid Journal   (Followers: 117)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 13)
Chemistry and Materials Research     Open Access   (Followers: 15)
Chemistry Central Journal     Open Access   (Followers: 4)
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: 43)
Chemistry of Materials     Full-text available via subscription   (Followers: 152)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 8)
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: 15)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 6)
ChemPlusChem     Hybrid Journal  
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: 24)
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: 9)
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 7)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
Combustion Science and Technology     Hybrid Journal   (Followers: 19)
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: 2)
Comptes Rendus Chimie     Full-text available via subscription  
Comptes Rendus Physique     Full-text available via subscription   (Followers: 1)
Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 9)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 9)
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: 7)
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: 14)
Current Research in Chemistry     Open Access   (Followers: 7)
Current Science     Open Access   (Followers: 40)
Dalton Transactions     Full-text available via subscription   (Followers: 17)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)
Diamond and Related Materials     Hybrid Journal   (Followers: 11)
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)
EDUSAINS     Open Access  
Elements     Full-text available via subscription   (Followers: 1)
Environmental Chemistry     Hybrid Journal   (Followers: 5)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 2)

        1 2 3 4 | Last

Journal Cover Bioorganic & Medicinal Chemistry
  [SJR: 1.064]   [H-I: 119]   [100 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0968-0896
   Published by Elsevier Homepage  [3038 journals]
  • 3-Arylpropionylhydroxamic acid derivatives as Helicobacter pylori urease
           inhibitors: Synthesis, molecular docking and biological evaluation
    • Authors: Wei-Kang Shi; Rui-Cheng Deng; Peng-Fei Wang; Qin-Qin Yue; Qi Liu; Kun-Ling Ding; Mei-Hui Yang; Hong-Yu Zhang; Si-Hua Gong; Min Deng; Wen-Run Liu; Qiu-Ju Feng; Zhu-Ping Xiao; Hai-Liang Zhu
      Pages: 4519 - 4527
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Wei-Kang Shi, Rui-Cheng Deng, Peng-Fei Wang, Qin-Qin Yue, Qi Liu, Kun-Ling Ding, Mei-Hui Yang, Hong-Yu Zhang, Si-Hua Gong, Min Deng, Wen-Run Liu, Qiu-Ju Feng, Zhu-Ping Xiao, Hai-Liang Zhu
      Helicobacter pylori urease is involved in several physiologic responses such as stomach and duodenal ulcers, adenocarcinomas and stomach lymphomas. Thus, inhibition of urease is taken for a good chance to treat H. pylori-caused infections, we have therefore focused our efforts on seeking novel urease inhibitors. Here, a series of arylpropionylhydroxamic acids were synthesized and evaluated for urease inhibition. Out of these compounds, 3-(2-benzyloxy-5-chlorophenyl)-3-hydroxypropionylhydroxamic acid (d24) was the most active inhibitor with IC50 of 0.15±0.05μM, showing a mixed inhibition with both competitive and uncompetitive aspects. Non-linear fitting of kinetic data gives kinetics parameters of 0.13 and 0.12μg·mL−1 for K i and K i′, respectively. The plasma protein binding assays suggested that d24 exhibited moderate binding to human and rabbit plasma proteins.
      Graphical abstract image

      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.07.052
  • 6-Aryl-4-amino-pyrimido[4,5-b]indole 2′-deoxyribonucleoside
           triphosphates (benzo-fused 7-deaza-dATP analogues): Synthesis, fluorescent
           properties, enzymatic incorporation into DNA and DNA-protein binding study
    • Authors: Andrea Bosáková; Pavla Perlíková; Michal Tichý; Radek Pohl; Michal Hocek
      Pages: 4528 - 4535
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Andrea Bosáková, Pavla Perlíková, Michal Tichý, Radek Pohl, Michal Hocek
      Four 6-substituted 4-amino-pyrimido[4,5-b]indole 2′-deoxyribonucleoside triphosphates (dABXTPs) were prepared by glycosylation of 4,6-dichloropyrimidoindole followed by ammonolysis, cross-coupling and triphosphorylation. They were found to be moderate to good substrates for DNA polymerases in primer extension. They also exerted fluorescence with emission maxima 335–378nm. When incorporated to oligonucleotide probes, they did not show significant mismatch discrimination but the 6-benzofuryl 4-amino-pyrimido[4,5-b]indole nucleotide displayed a useful sensitivity to protein binding in experiment with SSB protein.
      Graphical abstract image

      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.07.054
  • Ca-asp bound X-ray structure and inhibition of Bacillus anthracis
           dihydroorotase (DHOase)
    • Authors: Amy J. Rice; Hao Lei; Bernard D. Santarsiero; Hyun Lee; Michael E. Johnson
      Pages: 4536 - 4543
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Amy J. Rice, Hao Lei, Bernard D. Santarsiero, Hyun Lee, Michael E. Johnson
      Dihydroorotase (DHOase) is the third enzyme in the de novo pyrimidine synthesis pathway and is responsible for the reversible cyclization of carbamyl-aspartate (Ca-asp) to dihydroorotate (DHO). DHOase is further divided into two classes based on several structural characteristics, one of which is the length of the flexible catalytic loop that interacts with the substrate, Ca-asp, regulating the enzyme activity. Here, we present the crystal structure of Class I Bacillus anthracis DHOase with Ca-asp in the active site, which shows the peptide backbone of glycine in the shorter loop forming the necessary hydrogen bonds with the substrate, in place of the two threonines found in Class II DHOases. Despite the differences in the catalytic loop, the structure confirms that the key interactions between the substrate and active site residues are similar between Class I and Class II DHOase enzymes, which we further validated by mutagenesis studies. B. anthracis DHOase is also a potential antibacterial drug target. In order to identify prospective inhibitors, we performed high-throughput screening against several libraries using a colorimetric enzymatic assay and an orthogonal fluorescence thermal binding assay. Surface plasmon resonance was used for determining binding affinity (K D) and competition analysis with Ca-asp. Our results highlight that the primary difference between Class I and Class II DHOase is the catalytic loop. We also identify several compounds that can potentially be further optimized as potential B. anthracis inhibitors.
      Graphical abstract image

      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.07.055
  • 2-Oxoamide inhibitors of cytosolic group IVA phospholipase A2 with reduced
    • Authors: Georgia Antonopoulou; Victoria Magrioti; Maroula G. Kokotou; Aikaterini Nikolaou; Efrosini Barbayianni; Varnavas D. Mouchlis; Edward A. Dennis; George Kokotos
      Pages: 4544 - 4554
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Georgia Antonopoulou, Victoria Magrioti, Maroula G. Kokotou, Aikaterini Nikolaou, Efrosini Barbayianni, Varnavas D. Mouchlis, Edward A. Dennis, George Kokotos
      Cytosolic GIVA phospholipase A2 (GIVA cPLA2) initiates the eicosanoid pathway of inflammation and thus inhibitors of this enzyme constitute novel potential agents for the treatment of inflammatory diseases. Traditionally, GIVA cPLA2 inhibitors have suffered systemically from high lipophilicity. We have developed a variety of long chain 2-oxoamides as inhibitors of GIVA PLA2. Among them, AX048 was found to produce a potent analgesic effect. We have now reduced the lipophilicity of AX048 by replacing the long aliphatic chain with a chain containing an ether linked aromatic ring with in vitro inhibitory activities similar to AX048.
      Graphical abstract image

      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.07.057
  • The human tyrosine kinase Kit and its gatekeeper mutant T670I, show
           different kinetic properties: Implications for drug design
    • Authors: Miroslava Kissova; Giovanni Maga; Emmanuele Crespan
      Pages: 4555 - 4562
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Miroslava Kissova, Giovanni Maga, Emmanuele Crespan
      The tyrosine kinase Kit, a receptor for Stem Cell Factor, is involved, among others, in processes associated to cell survival, proliferation and migration. Upon physiological conditions, the activity of Kit is tightly regulated. However, primary mutations that lead to its constitutive activation are the causal oncogenic driver of gastrointestinal stromal tumours (GISTs). GISTs are known to be refractory to conventional therapies but the introduction of Imatinib, a selective inhibitor of tyrosine kinases Abl and Kit, significantly ameliorated the treatment options of GISTs patients. However, the acquisition of secondary mutations renders Kit resistant towards all available drugs. Mutation involving gatekeeper residues (such as V654a and T670I) influence both the structure and the catalytic activity of the enzyme. Therefore, detailed knowledge of the enzymatic properties of the mutant forms, in comparison with the wild type enzyme, is an important pre-requisite for the rational development of specific inhibitors. In this paper we report a thorough kinetic analysis of the reaction catalyzed by the Kit kinase and its gatekeeper mutated form T670I. Our results revealed the different mechanisms of action of these two enzymes and may open a new avenue for the future design of specific Kit inhibitors.
      Graphical abstract image

      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.07.059
  • Design, synthesis and biological evaluation of novel hamamelitannin
           analogues as potentiators for vancomycin in the treatment of biofilm
           related Staphylococcus aureus infections
    • Authors: Arno Vermote; Gilles Brackman; Martijn D.P. Risseeuw; Tom Coenye; Serge Van Calenbergh
      Pages: 4563 - 4575
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Arno Vermote, Gilles Brackman, Martijn D.P. Risseeuw, Tom Coenye, Serge Van Calenbergh
      Staphylococcus aureus is a frequent cause of biofilm-related infections. Bacterial cells within a biofilm are protected from attack by the immune system and conventional antibiotics often fail to penetrate the biofilm matrix. The discovery of hamamelitannin as a potentiator for antibiotics, recently led to the design of a more drug-like lead. In the present study, we want to gain further insight into the structure–activity relationship (S.A.R.) of the 5-position of the molecule, by preparing a library of 21 hamamelitannin analogues.
      Graphical abstract image

      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.07.058
  • In vitro cytotoxicity of novel 2,5,7-tricarbo-substituted indoles derived
           from 2-amino-5-bromo-3-iodoacetophenone
    • Authors: Malose J. Mphahlele; Tshepiso J. Makhafola; Mmakwena M. Mmonwa
      Pages: 4576 - 4586
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Malose J. Mphahlele, Tshepiso J. Makhafola, Mmakwena M. Mmonwa
      A series of novel 2,5,7-tricarbo-substituted indoles were prepared via sequential Sonogashira and Suzuki–Miyaura cross-coupling of 2-amino-5-bromo-3-iodoacetophenone with terminal acetylenes and aryl/styrylboronic acids followed by palladium chloride-mediated heteroannulation of the incipient 5-aryl/styryl-substituted 2-amino-3-(arylalkynyl)acetophenones. These polycarbo-substituted indole derivatives were evaluated for potential in vitro antiproliferative activity against the human breast adenocarcinoma (MCF-7) and human cervical cancer (HeLa) cell lines. Compounds 6f, 6i, 6k, 6m and 6n were found to exhibit significant cytotoxicity and selectivity against the HeLa cells. Compounds 6i and 6m were chosen as representative examples to evaluate their pro-apoptotic efficacy against the HeLa cell line. The compounds induced apoptosis through cell membrane alteration and DNA fragmentation caspase-dependent pathways.
      Graphical abstract image

      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.07.056
  • Coumarin derivatives as potential inhibitors of acetylcholinesterase:
           Synthesis, molecular docking and biological studies
    • Authors: Shaffali Singla; Poonam Piplani
      Pages: 4587 - 4599
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Shaffali Singla, Poonam Piplani
      A series of novel hybrids has been synthesized by linking coumarin moiety through an appropriate spacer to various substituted heterocyclic amines and evaluated as dual binding site acetylcholinesterase inhibitors for the treatment of cognitive dysfunction caused by increased hydrolysis of acetylcholine and scopolamine induced oxidative stress. Anti-amnesic activity of the compounds was evaluated using Morris water maze model at a dose of 1mg/kg with reference to the standard, donepezil. Biochemical estimation of oxidative stress markers (lipid peroxidation, superoxide dismutase, and plasma nitrite) was carried out to assess the antioxidant potential of the synthesized molecules. Among all the synthesized compounds (15a–i, 16a–d, 17a–b), compound 15a [4-[3-(4-phenylpiperazin-1-yl)propoxy]-2H-chromen-2-one] displayed significant antiamnesic activity, AChE inhibitory activity (IC50 =2.42μM) and antioxidant activity in comparison to donepezil (IC50 =1.82μM). Molecular docking study of 15a indicated that it interacts with all the crucial amino acids present at the CAS, mid-gorge and PAS of TcAChE resulting in increased inhibition of AChE enzyme.
      Graphical abstract image

      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.07.061
  • Toward chelerythrine optimization: Analogues designed by molecular
           simplification exhibit selective growth inhibition in non-small-cell lung
           cancer cells
    • Authors: Rosania Yang; Maurício T. Tavares; Sarah F. Teixeira; Ricardo A. Azevedo; Diego C. Pietro; Thais B. Fernandes; Adilson K. Ferreira; Gustavo H.G. Trossini; José A.M. Barbuto; Roberto Parise-Filho
      Pages: 4600 - 4610
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Rosania Yang, Maurício T. Tavares, Sarah F. Teixeira, Ricardo A. Azevedo, Diego C. Pietro, Thais B. Fernandes, Adilson K. Ferreira, Gustavo H.G. Trossini, José A.M. Barbuto, Roberto Parise-Filho
      A series of novel chelerythrine analogues was designed and synthesized. Antitumor activity was evaluated against A549, NCI-H1299, NCI-H292, and NCI-H460 non-small-cell lung cancer (NSCLC) cell lines in vitro. The selectivity of the most active analogues and chelerythrine was also evaluated, and we compared their cytotoxicity in NSCLC cells and non-tumorigenic cell lines, including human umbilical vein endothelial cells (HUVECs) and LL24 human lung fibroblasts. In silico studies were performed to establish structure–activity relationships between chelerythrine and the analogues. The results showed that analogue compound 3f induced significant dose-dependent G0/G1 cell cycle arrest in A549 and NCI-H1299 cells. Theoretical studies indicated that the molecular arrangement and electron characteristics of compound 3f were closely related to the profile of chelerythrine, supporting its activity. The present study presents a new and simplified chelerythrinoid scaffold with enhanced selectivity against NSCLC tumor cells for further optimization.
      Graphical abstract image

      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.07.065
  • Oleanolic acid-NO donor-platinum(II) trihybrid molecules: Targeting
           cytotoxicity on hepatoma cells with combined action mode and good safety
    • Authors: Lei Fang; Minchang Feng; Feihong Chen; Xia Liu; Hong Shen; Jian Zhao; Shaohua Gou
      Pages: 4611 - 4619
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Lei Fang, Minchang Feng, Feihong Chen, Xia Liu, Hong Shen, Jian Zhao, Shaohua Gou
      By taking advantage of good affinity of oleanolic acid (OA) to the bile acid transporter, a series of hybrid compounds from oleanolic acid (OA) or OA-nitric oxide (NO) donor derivative coordinating to platinum(II) complexes were designed and synthesized. As expected, complexes 1c and 1d showed selective cytotoxicity to hepatoma carcinoma cells (e.g. HepG2, SMMC-7721, BEL-7402 cells) rather than other tumor cells. Interestingly, they had only a weak toxicity to normal hepatic cells (e.g. LO2 cells). Mechanism studies revealed that 1c could effectively bind to the ligand domain of the farnesoid X receptor and maintain the normal function of liver cells. Furthermore, the NO donor moiety could moderately release cytotoxic NO and finally enhance the cytotoxic effect, while the cytotoxicity of the corresponding complexes was decreased when the cells were pretreated with NO scavenger. Additionally, the agarose gel electrophoresis revealed that the Pt(II) part could also offer DNA binding activity, suggesting the complexes possess a combined action mode which may help to overcome the resistance of cisplatin. The flow cytometry studies found that 1c caused tumor apoptosis and blocked cell-cycle progression in the G2 phase.
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      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.07.066
  • 2-(4-Fluorophenyl)-quinazolin-4(3H)-one as a novel tyrosinase inhibitor:
           Synthesis, inhibitory activity, and mechanism
    • Authors: Rui Wang; Wei-Ming Chai; Qin Yang; Man-Kun Wei; Yiyuan Peng
      Pages: 4620 - 4625
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Rui Wang, Wei-Ming Chai, Qin Yang, Man-Kun Wei, Yiyuan Peng
      2-(4-Fluorophenyl)-quinazolin-4(3H)-one (FQ) was synthesized, and its structure was identified with 1H nuclear magnetic resonance (1H NMR), 13C nuclear magnetic resonance (13C NMR), fourier transform infrared spectroscopy (FTIR), and high resolution mass spectrometry (HRMS). From the enzyme analysis, the results showed that it could inhibit the diphenolase activity of tyrosinase (IC50 =120±2μM). Furthermore, the results of kinetic studies showed that the compound was a reversible mixed-type inhibitor, and that the inhibition constants were determined to be 703.2 (K I) and 222.1μM (K IS). The results of fluorescence quenching experiment showed that the compound could interact with tyrosinase and the substrates (tyrosine and l-DOPA). Molecular docking analysis revealed that the mass transfer rate was affected by FQ blocking the enzyme catalytic center. In brief, current study identified a novel tyrosinase inhibitor which deserved further study for hyperpigmentation drugs.
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      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.07.068
  • Structure–activity relationship of Garcinia xanthones analogues: Potent
           Hsp90 inhibitors with cytotoxicity and antiangiogenesis activity
    • Authors: Xiaoli Xu; Yue Wu; Mingyang Hu; Xiang Li; Congying Gu; Qidong You; Xiaojin Zhang
      Pages: 4626 - 4635
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Xiaoli Xu, Yue Wu, Mingyang Hu, Xiang Li, Congying Gu, Qidong You, Xiaojin Zhang
      Hsp90 has long been recognized as an attractive and crucial molecular target for cancer therapy. Gambogic acid (GA), the main active compound of Gamboge hanburyi, has been reported as a natural inhibitor of Hsp90. Here, we present the structure–activity relationship of Garcinia xanthones analogues as Hsp90 inhibitors and identify that compound 25, with a simplified skeleton, had an improved inhibitory effect toward Hsp90. Compound 25 inhibited the ATPase activity of Hsp90 with an IC50 value of 3.68±0.18μM. It also exhibited potent antiproliferative activities in some solid tumor cells. In SK-BR-3 cells with high Hsp90 expression, compound 25 induced the degradation of Hsp90 client proteins including Akt and Erk1/2 without causing the heat shock response. Additionally, compound 25 inhibited angiogenesis in HUVEC cells through Hsp90 regulation of the HIF-1α pathway. These results demonstrate that compound 25 as an Hsp90 inhibitor with a new structure could be further studied for the development of tumor therapy.
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      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.07.067
  • New antiproliferative 7-(4-(N-substituted carbamoylmethyl)piperazin-1-yl)
           derivatives of ciprofloxacin induce cell cycle arrest at G2/M phase
    • Authors: Hamada H.H. Mohammed; Amer Ali Abd El-Hafeez; Samar H. Abbas; El-Shimaa M.N. Abdelhafez; Gamal El-Din A. Abuo-Rahma
      Pages: 4636 - 4646
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Hamada H.H. Mohammed, Amer Ali Abd El-Hafeez, Samar H. Abbas, El-Shimaa M.N. Abdelhafez, Gamal El-Din A. Abuo-Rahma
      New N-4-piperazinyl derivatives of ciprofloxacin 2a–g were prepared and tested for their cytotoxic activity. The primary in vitro one dose anticancer assay experienced promising cytotoxic activity against different cancer cell lines especially non-small cell lung cancer. Independently, compounds 2b, 2d, 2f and 2g showed anticancer activity against human non-small cell lung cancer A549 cells (IC50 =14.8, 24.8, 23.6 and 20.7μM, respectively) compared to the parent ciprofloxacin (IC50 >100μM) and doxorubicin as a positive control (IC50 =1μM). The flow cytometric analysis for 2b showed dose dependent G2/M arrest in A549 cells. Also, 2b increased the expression of p53 and p21 and decreased the expression of cyclin B1 and Cdc2 proteins in A549 cells without any effect on the same proteins expression in WI-38 cells. Specific inhibition of p53 by pifithrin-α reversed the G2/M phase arrest induced by the 2b compound, suggesting contribution of p53 to increase. Taken together, 2b induced G2/M phase arrest via p53/p21 dependent pathway. The results indicate that 2b can be used as a lead compound for further development of new derivatives against non-small cell lung cancer.
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      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.07.070
  • Discovery and antiparasitic activity of AZ960 as a Trypanosoma brucei ERK8
    • Authors: Ana L. Valenciano; Aaron C. Ramsey; Webster L. Santos; Zachary B. Mackey
      Pages: 4647 - 4651
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Ana L. Valenciano, Aaron C. Ramsey, Webster L. Santos, Zachary B. Mackey
      Human African trypanosomiasis (HAT) is a lethal, vector-borne disease caused by the parasite Trypanosoma brucei. Therapeutic strategies for this neglected tropical disease suffer from disadvantages such as toxicity, high cost, and emerging resistance. Therefore, new drugs with novel modes of action are needed. We screened cultured T. brucei against a focused kinase inhibitor library to identify promising bioactive compounds. Among the ten hits identified from the phenotypic screen, AZ960 emerged as the most promising compound with potent antiparasitic activity (IC50 =120nM) and was shown to be a selective inhibitor of an essential gene product, T. brucei extracellular signal-regulated kinase 8 (TbERK8). We report that AZ960 has a K i of 1.25μM for TbERK8 and demonstrate its utility in establishing TbERK8 as a potentially druggable target in T. brucei.
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      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.07.069
  • Discovery of N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide
           derivatives as potential antiproliferative agents by inhibiting MEK
    • Authors: Xian-Hai Lv; Zi-Li Ren; Ben-Guo Zhou; Qing-Shan Li; Ming-Jie Chu; Dao-Hong Liu; Kai Mo; Li-Song Zhang; Xiao-Kang Yao; Hai-Qun Cao
      Pages: 4652 - 4659
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Xian-Hai Lv, Zi-Li Ren, Ben-Guo Zhou, Qing-Shan Li, Ming-Jie Chu, Dao-Hong Liu, Kai Mo, Li-Song Zhang, Xiao-Kang Yao, Hai-Qun Cao
      Mitogen activated protein kinase (MAPK) signal transduction pathway has been proved to play an important role in tumorigenesis and cancer development. MEK inhibitor has been demonstrated significant clinical benefit for blocking MAPK pathway activation and possibly could block reactivation of the MAPK pathway at the time of BRAF inhibitor resistance. Twenty N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives have been designed and synthesized as MEK inhibitors, and their biological activities were evaluated. Among these compounds, compound 7b showed the most potent inhibitory activity with IC50 of 91nM for MEK1 and GI50 value of 0.26μM for A549 cells. The SAR analysis and docking simulation were performed to provide crucial pharmacophore clues that could be used in further structure optimization.
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      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.08.002
  • Discovery and synthetic optimization of a novel scaffold for hydrophobic
           tunnel-targeted autotaxin inhibition
    • Authors: Lauren E. Ragle; Dilip J. Palanisamy; Margaux J. Joe; Rachel S. Stein; Derek D. Norman; Gabor Tigyi; Daniel L. Baker; Abby L. Parrill
      Pages: 4660 - 4674
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Lauren E. Ragle, Dilip J. Palanisamy, Margaux J. Joe, Rachel S. Stein, Derek D. Norman, Gabor Tigyi, Daniel L. Baker, Abby L. Parrill
      Autotaxin (ATX) is a ubiquitous ectoenzyme that hydrolyzes lysophosphatidylcholine (LPC) to form the bioactive lipid mediator lysophosphatidic acid (LPA). LPA activates specific G-protein coupled receptors to elicit downstream effects leading to cellular motility, survival, and invasion. Through these pathways, upregulation of ATX is linked to diseases such as cancer and cardiovascular disease. Recent crystal structures confirm that the catalytic domain of ATX contains multiple binding regions including a polar active site, hydrophobic tunnel, and a hydrophobic pocket. This finding is consistent with the promiscuous nature of ATX hydrolysis of multiple and diverse substrates and prior investigations of inhibitor impacts on ATX enzyme kinetics. The current study used virtual screening methods to guide experimental identification and characterization of inhibitors targeting the hydrophobic region of ATX. An initially discovered inhibitor, GRI392104 (IC50 4μM) was used as a lead for synthetic optimization. In total twelve newly synthesized inhibitors of ATX were more potent than GRI392104 and were selective for ATX as they had no effect on other LPC-specific NPP family members or on LPA1–5 GPCR.
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      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.08.004
  • Discovery of a 7-arylaminobenzimidazole series as novel CRF1 receptor
    • Authors: Michiyo Mochizuki; Masakuni Kori; Mitsunori Kono; Takahiko Yano; Yuu Sako; Maiko Tanaka; Naoyuki Kanzaki; Albert C. Gyorkos; Christopher P. Corrette; Kazuyoshi Aso
      Pages: 4675 - 4691
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Michiyo Mochizuki, Masakuni Kori, Mitsunori Kono, Takahiko Yano, Yuu Sako, Maiko Tanaka, Naoyuki Kanzaki, Albert C. Gyorkos, Christopher P. Corrette, Kazuyoshi Aso
      A promising lead compound 1 of a benzimidazole series has been identified as a corticotropin-releasing factor 1 (CRF1) receptor antagonist. In this study, we focused on replacement of a 7-alkylamino group of 1, predicted to occupy a large lipophilic pocket of a CRF1 receptor, with an aryl group. During the course of this examination, we established new synthetic approaches to 2,7-diarylaminobenzimidazoles. The novel synthesis of 7-arylaminobenzimidazoles culminated in the identification of compounds exhibiting inhibitory activities comparable to the alkyl analog 1. A representative compound, p-methoxyanilino analog 16g, showed potent CRF binding inhibitory activity against a human CRF1 receptor and human CRF1 receptor antagonistic activity (IC50 =27nM, 56nM, respectively). This compound exhibited ex vivo 125I-Tyr0 (125I-CRF) binding inhibitory activity in mouse frontal cortex, olfactory bulb, and pituitary gland at 20mg/kg after oral administration. In this report, we discuss the structure–activity-relationship of these 7-arylamino-1H-benzimidazoles and their synthetic method.
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      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.08.005
  • Design, synthesis, and biological evaluation of
           1,9-diheteroarylnona-1,3,6,8-tetraen-5-ones as a new class of
           anti-prostate cancer agents
    • Authors: Xiaojie Zhang; Rubing Wang; German Ruiz Perez; Guanglin Chen; Qiang Zhang; Shilong Zheng; Guangdi Wang; Qiao-Hong Chen
      Pages: 4692 - 4700
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Xiaojie Zhang, Rubing Wang, German Ruiz Perez, Guanglin Chen, Qiang Zhang, Shilong Zheng, Guangdi Wang, Qiao-Hong Chen
      In search of more effective chemotherapeutics for the treatment of castration-resistant prostate cancer and inspired by curcumin analogues, twenty five (1E,3E,6E,8E)-1,9-diarylnona-1,3,6,8-tetraen-5-ones bearing two identical terminal heteroaromatic rings have been successfully synthesized through Wittig reaction followed by Horner–Wadsworth–Emmons reaction. Twenty-three of them are new compounds. The WST-1 cell proliferation assay was employed to assess their anti-proliferative effects toward both androgen-sensitive and androgen-insensitive human prostate cancer cell lines. Eighteen out of twenty-five synthesized compounds possess significantly improved potency as compared with curcumin. The optimal compound, 78, is 14- to 23-fold more potent than curcumin in inhibiting prostate cancer cell proliferation. It can be concluded from our data that 1,9-diarylnona-1,3,6,8-tetraen-5-one can serve as a new potential scaffold for the development of anti-prostate cancer agents and that pyridine-4-yls and quinolin-4-yl act as optimal heteroaromatic rings for the enhanced potency of this scaffold. Two of the most potent compounds, 68 and 75, effectively suppress PC-3 cell proliferation by activating cell apoptosis and by arresting cell cycle in the G0/G1 phase.
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      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.08.006
  • CpG methylation increases the DNA binding of 9-aminoacridine carboxamide
           Pt analogues
    • Authors: Hieronimus W. Kava; Vincent Murray
      Pages: 4701 - 4710
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Hieronimus W. Kava, Vincent Murray
      This study investigated the effect of CpG methylation on the DNA binding of cisplatin analogues with an attached aminoacridine intercalator. DNA-targeted 9-aminoacridine carboxamide Pt complexes are known to bind at 5′-CpG sequences. Their binding to methylated and non-methylated 5′-CpG sequences was determined and compared with cisplatin. The damage profiles of each platinum compound were quantified via a polymerase stop assay with fluorescently labelled primers and capillary electrophoresis. Methylation at 5′-CpG was shown to significantly increase the binding intensity for the 9-aminoacridine carboxamide compounds, whereas no significant increase was found for cisplatin. 5′-CpG methylation had the largest effect on the 9-ethanolamine-acridine carboxamide Pt complex, followed by the 9-aminoacridine carboxamide Pt complex and the 7-fluoro complex. The methylation state of a cell’s genome is important in maintaining normal gene expression, and is often aberrantly altered in cancer cells. An analogue of cisplatin which differentially targets methylated DNA may be able to improve its therapeutic activity, or alter its range of targets and evade the chemoresistance which hampers cisplatin efficacy in clinical use.
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      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.08.011
  • Design, synthesis, and evaluation of 4,6-diaminonicotinamide derivatives
           as novel and potent immunomodulators targeting JAK3
    • Authors: Yutaka Nakajima; Naohiro Aoyama; Fumie Takahashi; Hiroshi Sasaki; Keiko Hatanaka; Ayako Moritomo; Masamichi Inami; Misato Ito; Koji Nakamura; Fumihiro Nakamori; Takayuki Inoue; Shohei Shirakami
      Pages: 4711 - 4722
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Yutaka Nakajima, Naohiro Aoyama, Fumie Takahashi, Hiroshi Sasaki, Keiko Hatanaka, Ayako Moritomo, Masamichi Inami, Misato Ito, Koji Nakamura, Fumihiro Nakamori, Takayuki Inoue, Shohei Shirakami
      In organ transplantation, T cell-mediated immune responses play a key role in the rejection of allografts. Janus kinase 3 (JAK3) is specifically expressed in hematopoietic cells and associated with regulation of T cell development via interleukin-2 signaling pathway. Here, we designed novel 4,6-diaminonicotinamide derivatives as immunomodulators targeting JAK3 for prevention of transplant rejection. Our optimization of C4- and C6-substituents and docking calculations to JAK3 protein confirmed that the 4,6-diaminonicotinamide scaffold resulted in potent inhibition of JAK3. We also investigated avoidance of human ether-a-go-go related gene (hERG) inhibitory activity. Selected compound 28 in combination with tacrolimus prevented allograft rejection in a rat heterotopic cardiac transplantation model.
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      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.08.007
  • Synthesis and aromatase inhibitory evaluation of 4-N-nitrophenyl
           substituted amino-4H-1,2,4-triazole derivatives
    • Authors: Zhidan Song; Yanchun Liu; Zhoutong Dai; Wei Liu; Kai Zhao; Tongcun Zhang; Yanying Hu; Xiuli Zhang; Yujie Dai
      Pages: 4723 - 4730
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Zhidan Song, Yanchun Liu, Zhoutong Dai, Wei Liu, Kai Zhao, Tongcun Zhang, Yanying Hu, Xiuli Zhang, Yujie Dai
      In this paper, 13 4-N-nitrophenyl substituted amino-4H-1,2,4-triazole derivatives were synthesized and their aromatase inhibitory activities were measured. The results show that the substitution of the groups on benzyl group can further improve their bioactivity and the compound with Cl on the para position of benzyl has the highest bioactivity (IC50 =9.02nM). A QSAR model was constructed from the 13 compounds with genetic function approximation using DS 2.1 package. This model can explain 90.09% of the variance (R 2 Adj), while it can predict 84.95% of the variance (R 2 cv) with the confidence interval of 95%.
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      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.08.014
  • Novel tricyclic poly (ADP-ribose) polymerase-1/2 inhibitors with potent
           anticancer chemopotentiating activity: Design, synthesis and biological
    • Authors: Hui Li; Yan Hu; Xueyan Wang; Guangwei He; Yungen Xu; Qihua Zhu
      Pages: 4731 - 4740
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Hui Li, Yan Hu, Xueyan Wang, Guangwei He, Yungen Xu, Qihua Zhu
      8,9-Dihydro-2,4,7,9a-tetraazabenzo[cd]azulen-6(7H)-ones were designed and synthesized as a new class of PARP-1/2 inhibitors. The compounds displayed a variable pattern of PARP-1/2 enzymes inhibition profile that, in part, paralleled the antiproliferative activity in cell lines. Among them, compound 9e exhibited not only the significant IC50 value of 28nM in the PARP-1 and 7.7nM in PARP-2 enzyme assay, but also a profound synergic efficacy combined with temozolomide with PF50 values of 2.6, 2.5, and 6.5 against MDA-MB-468, SW-620 and A549 and cell line, respectively.
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      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.08.016
  • Synthesis and evaluation of 8-hydroxyquinolin derivatives substituted with
           (benzo[d][1,2]selenazol-3(2H)-one) as effective inhibitor of metal-induced
           Aβ aggregation and antioxidant
    • Authors: Bo Wang; Zhiren Wang; Hong Chen; Chuan-Jun Lu; Xingshu Li
      Pages: 4741 - 4749
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Bo Wang, Zhiren Wang, Hong Chen, Chuan-Jun Lu, Xingshu Li
      A series of 8-hydroxyquinolin derivatives substituted with (benzo[d][1,2]selenazol-3(2H)-one) at the 2-position were synthesized and evaluated for treatment of Alzheimer’s disease. In vitro assays demonstrated that most of the target compounds exhibit significant inhibition of Cu(II)-induced Aβ1–42 aggregation, rapid H2O2 scavenging and glutathione peroxidise (GPx)-like catalytic activity. Among these molecules, compound 9a is the most potent peroxide scavenger that possesses the ability to scavenge most H2O2 within 200–220min and possesses GPx-like activity (v 0 =106.0μM·min−1), enabling modulation of metal-induced Aβ aggregation.
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      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.08.017
  • Novel small molecule binders of human N-glycanase 1, a key player in the
           endoplasmic reticulum associated degradation pathway
    • Authors: Bharath Srinivasan; Hongyi Zhou; Sreyoshi Mitra; Jeffrey Skolnick
      Pages: 4750 - 4758
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Bharath Srinivasan, Hongyi Zhou, Sreyoshi Mitra, Jeffrey Skolnick
      Peptide:N-glycanase (NGLY1) is an enzyme responsible for cleaving oligosaccharide moieties from misfolded glycoproteins to enable their proper degradation. Deletion and truncation mutations in this gene are responsible for an inherited disorder of the endoplasmic reticulum-associated degradation pathway. However, the literature is unclear whether the disorder is a result of mutations leading to loss-of-function, loss of substrate specificity, loss of protein stability or a combination of these factors. In this communication, without burdening ourselves with the mechanistic underpinning of disease causation because of mutations on the NGLY1 protein, we demonstrate the successful application of virtual ligand screening (VLS) combined with experimental high-throughput validation to the discovery of novel small-molecules that show binding to the transglutaminase domain of NGLY1. Attempts at recombinant expression and purification of six different constructs led to successful expression of five, with three constructs purified to homogeneity. Most mutant variants failed to purify possibly because of misfolding and the resultant exposure of surface hydrophobicity that led to protein aggregation. For the purified constructs, our threading/structure-based VLS algorithm, FINDSITEcomb, was employed to predict ligands that may bind to the protein. Then, the predictions were assessed by high-throughput differential scanning fluorimetry. This led to the identification of nine different ligands that bind to the protein of interest and provide clues to the nature of pharmacophore that facilitates binding. This is the first study that has identified novel ligands that bind to the NGLY1 protein as a possible starting point in the discovery of ligands with potential therapeutic applications in the treatment of the disorder caused by NGLY1 mutants.
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      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.08.019
  • Towards the PET radiotracer for p75 neurotrophin receptor: [11C]LM11A-24
           shows biological activity in vitro, but unfavorable ex vivo and in vivo
    • Authors: Julien Gibon; Min Su Kang; Arturo Aliaga; Behrang Sharif; Pedro Rosa-Neto; Philippe Séguéla; Philip A. Barker; Alexey Kostikov
      Pages: 4759 - 4765
      Abstract: Publication date: 1 October 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 19
      Author(s): Julien Gibon, Min Su Kang, Arturo Aliaga, Behrang Sharif, Pedro Rosa-Neto, Philippe Séguéla, Philip A. Barker, Alexey Kostikov
      Mature neurotrophins as well as their pro forms are critically involved in the regulation of neuronal functions. They are signaling through three distinct types of receptors: tropomyosin receptor kinase family (TrkA/B/C), p75 neurotrophin receptor (p75NTR) and sortilin. Aberrant expression of p75NTR in the CNS is implicated in a variety of neurodegenerative diseases, including Alzheimer’s disease. The goal of this work was to evaluate one of the very few reported p75NTR small molecule ligands as a lead compound for development of novel PET radiotracers for in vivo p75NTR imaging. Here we report that previously described ligand LM11A-24 shows significant inhibition of carbachol-induced persistent firing (PF) of entorhinal cortex (EC) pyramidal neurons in wild-type mice via selective interaction with p75NTR. Based on this electrophysiological assay, the compound has very high potency with an EC50 <10nM. We optimized the radiosynthesis of [11C]LM11A-24 as the first attempt to develop PET radioligand for in vivo imaging of p75NTR. Despite some weak interaction with CNS tissues, the radiolabeled compound showed unfavorable in vivo profile presumably due to high hydrophilicity.
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      PubDate: 2016-09-04T08:23:01Z
      DOI: 10.1016/j.bmc.2016.08.020
  • Dual and antagonic therapeutic effects of sulfated glycans
    • Authors: Vitor H. Pomin
      Pages: 3965 - 3971
      Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Vitor H. Pomin
      Sulfated glycans currently explored in medicine like glycosaminoglycans (GAGs) or those of potential medical application like algal sulfated galactans (SGs) and fucoidans exhibit significant effects in numerous pathophysiological systems. According to the structure of these sulfated glycans, sample concentration and the method utilized in the approach opposite effects can be achieved. The effects aimed at down-regulating the events usually dominate. These effects are expected in most clinical endeavors. However, the effects capable of accelerating the events can be also beneficial in certain circumstances. Besides discoursing about the paradoxical effects of sulfated glycans in coagulation/thrombosis, angiogenesis, inflammation and microbial infections; this report aims primarily at highlighting the possible contribution of the neglected activities of some well-known sulfated glycans in up-regulating the events of these pathophysiological systems. The representative sulfated glycans taken here are the mammalian-derived GAGs, the unique holothurian GAG, the red algal SGs and the brown algal fucoidans. The current discussion is highly relevant in light of the future strategies for developing novel sulfated glycan-based therapies.
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      PubDate: 2016-08-18T08:58:06Z
      DOI: 10.1016/j.bmc.2016.07.037
  • Antileishmanial activity of new thiophene–indole hybrids: Design,
           synthesis, biological and cytotoxic evaluation, and chemometric studies
    • Authors: Mayara B. Félix; Edson R. de Souza; Maria do C.A. de Lima; Daiana Karla G. Frade; Vanessa de L. Serafim; Klinger Antonio da F. Rodrigues; Patrícia Lima do N. Néris; Frederico F. Ribeiro; Luciana Scotti; Marcus T. Scotti; Thiago M. de Aquino; Francisco Jaime B. Mendonça Junior; Márcia R. de Oliveira
      Pages: 3972 - 3977
      Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Mayara B. Félix, Edson R. de Souza, Maria do C.A. de Lima, Daiana Karla G. Frade, Vanessa de L. Serafim, Klinger Antonio da F. Rodrigues, Patrícia Lima do N. Néris, Frederico F. Ribeiro, Luciana Scotti, Marcus T. Scotti, Thiago M. de Aquino, Francisco Jaime B. Mendonça Junior, Márcia R. de Oliveira
      In the present work, thirty-two hybrid compounds containing cycloalka[b]thiophene and indole moieties (TN5, TN5 1–7, TN6, TN6 1–7, TN7, TN7 1–7, TN8, TN8 1–7) were designed, synthesized and evaluated for their cytotoxic and antileishmanial activity against Leishmania amazonensis promastigotes. More than half of the compounds (18 compounds) exhibited significant antileishmanial activity (IC50 lower than 10.0μg/L), showing better performance than the reference drugs (tri- and penta-valent antimonials). The most active compounds were TN8-7, TN6-1 and TN7 with respective IC50 values of 2.1, 2.3 and 3.2μg/mL. Demonstrating that all of the compounds were less toxic than the reference drugs, even at the highest evaluated concentration (400μg/mL), no compound tested presented human erythrocyte cytotoxicity. Compound TN8-7’s effectiveness against a trivalent antimony-resistant culture was demonstrated. It was observed that TN8-7’s antileishmanial activity is associated with DNA fragmentation of L. amazonensis promastigotes. Chemometric studies (CPCA, PCA, and PLS) highlight intrinsic solubility/lipophilicity, and compound size and shape as closely related to activity. Our results suggest that hybrid cycloalka[b]thiophene–indole derivatives may be considered as lead compounds for further development of new drugs for the treatment of leishmaniasis.
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      PubDate: 2016-08-18T08:58:06Z
      DOI: 10.1016/j.bmc.2016.04.057
  • Small molecule non-peptide inhibitors of botulinum neurotoxin serotype E:
           Structure–activity relationship and a pharmacophore model
    • Authors: Gyanendra Kumar; Rakhi Agarwal; Subramanyam Swaminathan
      Pages: 3978 - 3985
      Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Gyanendra Kumar, Rakhi Agarwal, Subramanyam Swaminathan
      Botulinum neurotoxins (BoNTs) are the most poisonous biological substance known to humans. They cause flaccid paralysis by blocking the release of acetylcholine at the neuromuscular junction. Here, we report a number of small molecule non-peptide inhibitors of BoNT serotype E. The structure–activity relationship and a pharmacophore model are presented. Although non-peptidic in nature, these inhibitors mimic key features of the uncleavable substrate peptide Arg-Ile-Met-Glu (RIME) of the SNAP-25 protein. Among the compounds tested, most of the potent inhibitors bear a zinc-chelating moiety connected to a hydrophobic and aromatic moiety through a carboxyl or amide linker. All of them show low micromolar IC50 values.
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      PubDate: 2016-08-18T08:58:06Z
      DOI: 10.1016/j.bmc.2016.06.036
  • Novel FXR (farnesoid X receptor) modulators: Potential therapies for
           cholesterol gallstone disease
    • Authors: Donna D. Yu; Sreenath S. Andrali; Hongzhi Li; Min Lin; Wendong Huang; Barry M. Forman
      Pages: 3986 - 3993
      Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Donna D. Yu, Sreenath S. Andrali, Hongzhi Li, Min Lin, Wendong Huang, Barry M. Forman
      Metabolic disorders such as diabetes are known risk factors for developing cholesterol gallstone disease (CGD). Cholesterol gallstone disease is one of the most prevalent digestive diseases, leading to considerable financial and social burden worldwide. Ursodeoxycholic acid (UDCA) is the only bile acid drug approved by FDA for the non-surgical treatment of gallstones. However, the molecular link between UDCA and CGD is unclear. Previous data suggest that the farnesoid X receptor (FXR), a bile acid nuclear receptor, may protect against the development of CGD. In studies aimed at identifying the role of FXR, we recently identify a novel chemical tool, 6EUDCA (6-αethyl-ursodeoxycholic acid), a synthetic derivative of UDCA, for studying FXR. We found that 6EUDCA binds FXR stronger than UDCA in a TR-FRET binding assay. This result was supported by computational docking models that suggest 6EUDCA forms a more extensive hydrogen bound network with FXR. Interestingly, neither compound could activate FXR target genes in human nor mouse liver cells, suggesting UDCA and 6EUDCA activate non-genomic signals in an FXR-dependent manner. Overall these studies may lead to the identification of a novel mechanism by which bile acids regulate cell function, and 6EUDCA may be an effective targeted CGD therapeutic.
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      PubDate: 2016-08-18T08:58:06Z
      DOI: 10.1016/j.bmc.2016.06.039
  • Design and synthesis of purine analogues as highly specific ligands for
           FcyB, a ubiquitous fungal nucleobase transporter
    • Authors: Nikolaos Lougiakis; Efthymios-Spyridon Gavriil; Markelos Kairis; Georgia Sioupouli; George Lambrinidis; Dimitra Benaki; Emilia Krypotou; Emmanuel Mikros; Panagiotis Marakos; Nicole Pouli; George Diallinas
      Abstract: Publication date: Available online 22 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Nikolaos Lougiakis, Efthymios-Spyridon Gavriil, Markelos Kairis, Georgia Sioupouli, George Lambrinidis, Dimitra Benaki, Emilia Krypotou, Emmanuel Mikros, Panagiotis Marakos, Nicole Pouli, George Diallinas
      In the course of our study on fungal purine transporters, a number of new 3-deazapurine analogues have been rationally designed, based on the interaction of purine substrates with the Aspergillus nidulans FcyB carrier, and synthesized following an effective synthetic procedure. Certain derivatives have been found to specifically inhibit FcyB-mediated [3H]-adenine uptake. Molecular simulations have been performed, suggesting that all active compounds interact with FcyB through the formation of hydrogen bonds with Asn163, while the insertion of hydrophobic fragments at position 9 and N6 of 3-deazaadenine enhanced the inhibition.
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      PubDate: 2016-09-24T05:12:28Z
      DOI: 10.1016/j.bmc.2016.09.055
  • Insights into tyrosinase inhibition by compounds isolated from Greyia
           radlkoferi Syzsyl using biological activity, molecular docking and gene
           expression analysis
    • Authors: Namrita Lall; Elizabeth Mogapi; Marco Nuno de Canha; Bridget Crampton; Mabatho Nqephe; Ahmed Hussein; Vivek Kumar
      Abstract: Publication date: Available online 22 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Namrita Lall, Elizabeth Mogapi, Marco Nuno de Canha, Bridget Crampton, Mabatho Nqephe, Ahmed Hussein, Vivek Kumar
      Greyia radlkoferi ethanol extract and its five compounds were tested for their inhibitory activity against the mushroom tyrosinase enzyme and melanin production on melanocytes. The crude extract showed significant tyrosinase inhibition with IC50 of 17.96μg/ml. This is the first report of the isolation of these 5 compounds from Greyia radlkoferi. 2’, 4’, 6’-trihydroxydihydrochalcone showed the highest tyrosinase inhibition at 17.70μg/ml (68.48μM), with low toxicity when compared with crude extract. This compound is therefore, a key component in the crude extract, which is responsible for tyrosinase inhibitory activity. The RT-qPCR indicated that the mechanism of action is most likely post transcriptional. Further, the molecular docking study showed that tyrosinase inhibitory activity depends on interaction of the compound with Cu2+ ions at the active site. This is the first report of the tyrosinase inhibitory activity of the G. radlkoferi extract and molecular insights on interaction of its compounds with Cu2+ ions as the driving factor for tyrosinase inhibition. These results suggest that the extract of G. radlkoferi and the compound 2’, 4’, 6’-trihydroxydihydrochalcone have great potential to be further developed as pharmaceutical or cosmetic agents for use against dermatological disorders associated with melanin.
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      PubDate: 2016-09-24T05:12:28Z
      DOI: 10.1016/j.bmc.2016.09.054
  • Neuroprotective effects of benzyloxy substituted small molecule monoamine
           oxidase B inhibitors in Parkinson’s disease
    • Authors: Zhimin Wang; Jiajia Wu; Xuelian Yang; Pei Cai; Qiaohong Liu; Kelvin D.G. Wang; Lingyi Kong; Xiaobing Wang
      Abstract: Publication date: Available online 21 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Zhimin Wang, Jiajia Wu, Xuelian Yang, Pei Cai, Qiaohong Liu, Kelvin D.G. Wang, Lingyi Kong, Xiaobing Wang
      The benzyloxy substituted small molecules are well-known highly potent monoamine oxidase B inhibitors, but their therapeutic potential against Parkinson’s disease have not been investigated in detail. In this paper, a series of representative benzyloxy substituted derivatives were synthesized and evaluated for MAO-A/B inhibition. In addition, their neuroprotective effects were investigated in 6-OHDA- and rotenone-treated PC12 cells. It was observed that most of the compounds exhibited a marked increase in survival of PC12 cells which treated with the neurotoxins. Among them, 13 exhibited remarkable and balanced neuroprotective potency. The protective effects of 13 against neurotoxins-induced apoptosis were confirmed with flow cytometry and staining methods. Furthermore, 13 also showed good BBB permeability and low toxicity according to in vitro BBB prediction and in vivo acute toxicity test. The results indicated that 13 is an effective and promising candidate to be further developed as disease-modifying drug for Parkinson’s disease therapy.
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      PubDate: 2016-09-24T05:12:28Z
      DOI: 10.1016/j.bmc.2016.09.050
  • Synthesis and Pin1 inhibitory activity of thiazole derivatives
    • Authors: Hailong Zhao; Guonan Cui; Jing Jin; Xiaoguang Chen; Bailing Xu
      Abstract: Publication date: Available online 21 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Hailong Zhao, Guonan Cui, Jing Jin, Xiaoguang Chen, Bailing Xu
      Pin1 (Protein interacting with NIMA1) is a peptidyl prolyl cis-trans isomerase (PPIase) which specifically catalyze the conformational conversion of the amide bond of pSer/Thr-Pro motifs in its subtrate proteins and is a novel promising anticancer target. A series of new thiazole derivatives were designed and synthesized, and their inhibitory activites were measured agaist human Pin1 using a protease-coupled enzyme assay. Of all the tested compounds, a number of thiazole derivatives bearing an oxalic acid group at 4-position were found to be potent Pin1 inhibitors with IC50 values at low micromolar level. The detailed structure–activity relationships were analyzed and the binding features of compound 10b (IC50 5.38 μM) was predicted using CDOCKER program. The results of this research would provide informative guidance for further optimizing thiazole derivatives as potent Pin1 inhibitors.
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      PubDate: 2016-09-24T05:12:28Z
      DOI: 10.1016/j.bmc.2016.09.049
  • A cell-based approach to characterize antimicrobial compounds through
           kinetic dose response
    • Authors: Craig R. MacNair; Jonathan M. Stokes; Shawn French; Cullen L. Myers; Kali R. Iyer; Eric D. Brown
      Abstract: Publication date: Available online 22 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Craig R. MacNair, Jonathan M. Stokes, Shawn French, Cullen L. Myers, Kali R. Iyer, Eric D. Brown
      The rapid spread of antibiotic resistance has created a pressing need for the development of novel drug screening platforms. Herein, we report on the use of cell-based kinetic dose response curves for small molecule characterization in antibiotic discovery efforts. Kinetically monitoring bacterial growth at sub-inhibitory concentrations of antimicrobial small molecules generates unique dose response profiles. We show that clustering of profiles by growth characteristics can classify antibiotics by mechanism of action. Furthermore, changes in growth kinetics have the potential to offer insight into the mechanistic action of novel molecules and can be used to predict off-target effects generated through structure-activity relationship studies. Kinetic dose response also allows for detection of unstable compounds early in the lead development process. We propose that this kinetic approach is a rapid and cost-effective means to gather critical information on antimicrobial small molecules during the hit selection and lead development pipeline.
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      PubDate: 2016-09-24T05:12:28Z
      DOI: 10.1016/j.bmc.2016.09.053
  • Synthesis and Topoisomerases Inhibitory Activity of heteroaromatic
    • Authors: Kyung-Hwa Jeon; Han-Bit Yu; Soo Yeon Kwak; Youngjoo Kwon; Younghwa Na
      Abstract: Publication date: Available online 21 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Kyung-Hwa Jeon, Han-Bit Yu, Soo Yeon Kwak, Youngjoo Kwon, Younghwa Na
      The critical role of nuclear enzyme topoisomerase enzymes during cell proliferation process guided topoisomerases to be one of the major targets for anticancer drug development. We have designed and synthesized 22 heteroaromatic ring incorporated chalcone derivatives substituted with epoxide or thioepoxide. Topoisomerase enzyme inhibitory activity and cytotoxic tests were also conducted to evaluate compounds’ pharmacological efficacy. In the topoisomerase I inhibitory test, compound 1 was most active one, 24% of inhibition at 20 μM, among all the compounds but it was lower than camptothecin. Compounds 9, 11, and 13 inhibited the function of topoisomerase II more strongly than etoposide with almost same magnitude (around 90% and 30% inhibition at 100 and 20 μM, respectively) which were higher than those of etoposide (72% and 18% inhibition). In the cytotoxicity test, compound 9 inhibited T47D cancer cell growth with the IC50 value of 6.61 ± 0.21 μM. On the other hand, compound 13 (IC50: 4.32 ± 0.18 μM) effectively suppressed MDA-MB468 cancer cell growth.
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      PubDate: 2016-09-24T05:12:28Z
      DOI: 10.1016/j.bmc.2016.09.051
  • Not just an antibiotic target: exploring the role of type I signal
           peptidase in bacterial virulence
    • Authors: Shawn Walsh; Arryn Craney; Floyd E. Romesberg
      Abstract: Publication date: Available online 21 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Shawn Walsh, Arryn Craney, Floyd E. Romesberg
      The looming antibiotic crisis has prompted the development of new strategies towards fighting infection. Traditional antibiotics target bacterial processes essential for viability, whereas proposed antivirulence approaches rely on the inhibition of factors that are required only for the initiation and propagation of infection within a host. Although antivirulence compounds have yet to prove their efficacy in the clinic, bacterial signal peptidase I (SPase) represents an attractive target in that SPase inhibitors exhibit broad-spectrum antibiotic activity, but even at sub-MIC doses also impair the secretion of essential virulence factors. The potential consequences of SPase inhibition on bacterial virulence have not been thoroughly examined, and are explored within this review. In addition, we review growing evidence that SPase has relevant biological functions outside of mediating secretion, and discuss how the inhibition of these functions may be clinically significant.
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      PubDate: 2016-09-24T05:12:28Z
      DOI: 10.1016/j.bmc.2016.09.048
  • Synthesis and Biological Evaluation of Furocoumarin Derivatives on Melanin
           Synthesis in Murine B16 Cells for the Treatment of Vitiligo
    • Authors: Chao Niu; Guang Xian Pang; Gen Li; Jun Dou; Li Fei Nie; Helimay Himit; Madina Kabas; Haji Akber Aisa
      Abstract: Publication date: Available online 23 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Chao Niu, Guang Xian Pang, Gen Li, Jun Dou, Li Fei Nie, Helimay Himit, Madina Kabas, Haji Akber Aisa
      Furocoumarins, isolated from Psoralen corylifolia L., were found to be the most effective drug in the treatment of vitiligo nowadays. Twenty-five furocoumarin derivatives were thus designed and synthesized in order to improve the melanogenesis in B16 cells for the first time. Among them, twenty-three compounds were more potent than the positive control (8-MOP), the commonly used drug for vitiligo in clinic. Noticeably, compounds 6m (350.5%) and 6p (313.1%) based on the scaffold of 6k (2H-benzofuro[2,3-h]chromen-2-one) were nearly 3-fold stronger than 8-MOP (114.50%). The in vitro melanin synthesis evaluation of these structurally diverse analogues had also led to an outline of structure-activity relationship.
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      PubDate: 2016-09-24T05:12:28Z
      DOI: 10.1016/j.bmc.2016.09.056
  • Syntheses and mucosal adjuvant activity of simplified oleanolic acid
           saponins possessing cinnamoyl ester
    • Authors: Tatsuya Shirahata; Takayuki Nagai; Nozomu Hirata; Masaki Yokoyama; Tatsuya Katsumi; Naruki Konishi; Takashi Nishino; Kazuishi Makino; Haruki Yamada; Eisuke Kaji; Hiroaki Kiyohara; Yoshinori Kobayashi
      Abstract: Publication date: Available online 22 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Tatsuya Shirahata, Takayuki Nagai, Nozomu Hirata, Masaki Yokoyama, Tatsuya Katsumi, Naruki Konishi, Takashi Nishino, Kazuishi Makino, Haruki Yamada, Eisuke Kaji, Hiroaki Kiyohara, Yoshinori Kobayashi
      A series of new simplified oleanolic acid saponins with a glycosyl ester moiety at C28, were efficiently prepared. Furthermore, the effect of nasal administration of the synthetic oleanolic acid saponins on the nasal anti-influenza virus antibody titer against secondary nasal inoculation of the influenza split vaccine was examined. The result revealed cinnamoyl saponin as a suitable candidate vaccine adjuvant.
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      PubDate: 2016-09-24T05:12:28Z
      DOI: 10.1016/j.bmc.2016.09.052
  • Design, Synthesis, and Evaluation of Novel Porcupine Inhibitors Featuring
           a Fused 3-ring System Based on the “Reversed” Amide Scaffold
    • Authors: Zhixiang Xu; Xiangxiang Xu; Ruadhan O’Laoi; Haikuo Ma; Jiyue Zheng; Shuaishuai Chen; Lusong Luo; Zhilin Hu; Sudan He; Jiajun Li; Hongjian Zhang; Xiaohu Zhang
      Abstract: Publication date: Available online 17 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Zhixiang Xu, Xiangxiang Xu, Ruadhan O’Laoi, Haikuo Ma, Jiyue Zheng, Shuaishuai Chen, Lusong Luo, Zhilin Hu, Sudan He, Jiajun Li, Hongjian Zhang, Xiaohu Zhang
      The Wnt signaling pathway is an essential signal transduction pathway which leads to the regulation of cellular processes such as proliferation, differentiation and migration. Aberrant Wnt signaling is known to have an association with multiple cancers. Porcupine is an enzyme that catalyses the addition of palmitoleate to a serine residue in Wnt proteins, a process which is required for the secretion of Wnt proteins. Here we report the synthesis and structure-activity-relationship of the novel porcupine inhibitors based on a “reversed” amide scaffold. The leading compound 53 was as potent as the clinical compound LGK974 in a cell based STF reporter gene assay. Compound 53 potently inhibited the secretion of Wnt3A, therefore was confirmed to be a porcupine inhibitor. Furthermore, compound 53 showed excellent chemical and plasma stabilities. However, the clearance of compound 53 in liver microsomal tests was moderate to high, and the solubility of compound 53 was suboptimal. Collective efforts toward further optimization of this novel tricyclic template to develop better porcupine inhibitors will be subsequently undertaken and reported in due course.
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      PubDate: 2016-09-20T13:35:09Z
      DOI: 10.1016/j.bmc.2016.09.041
  • Investigation of Bombesin peptide as a targeting ligand for the gastrin
           releasing peptide (GRP) receptor
    • Authors: Anjuman Ara Begum; Peter M. Moyle; Istvan Toth
      Abstract: Publication date: Available online 16 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Anjuman Ara Begum, Peter M. Moyle, Istvan Toth
      Gastrin releasing peptide (GRP) receptor (GRPR), a bombesin family receptor, is overexpressed in many cancers including breast, prostate, pancreatic and lung. The targeting of therapeutics to GRPR can be achieved using the full-length (14 amino acid) GRP analogue Bombesin (BBN) or the truncated BBN(6-14) sequence, both of which bind GRPR with high affinity and specificity. In this study, we have investigated the level of GRPR expression in various cancerous (Caco-2, HeLa, LNCap, MDA-MB-231, and PC-3) and non-cancerous (WPMY-1) cell lines using a western blotting approach. Such information is currently lacking in the literature, and is therefore of importance for the in vitro assessment of GRPR targeted therapeutics. Of the cell lines assessed, the PC-3 (prostate cancer) and Caco-2 (colon cancer) cell lines demonstrated the highest and lowest levels of GRPR expression respectively. Using this information, we further investigated the cellular uptake of carboxyfluorescein-labelled BBN and BBN(6-14) peptides by flow cytometry and confocal microscopy using cell lines that express GRPR (Caco-2, HeLa, PC-3). The uptake of each of these peptides was similar, suggesting that the shorter BBN(6-14) peptide is sufficient for GRPR targeting. Further, the uptake of these peptides could be inhibited by competition with unlabelled BBN peptides, suggesting their cellular uptake is GRPR-mediated, while the level of BBN uptake (as measured by flow cytometry) was found to be directly proportional to the level of GRPR expression. Overall, the information obtained from these studies provides useful information for the in vitro assessment of GRPR targeted therapeutics.
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      PubDate: 2016-09-20T13:35:09Z
      DOI: 10.1016/j.bmc.2016.09.039
  • Sobetirome Prodrug Esters with Enhanced Blood-Brain Barrier Permeability
    • Authors: Andrew T. Placzek; Skylar J. Ferrara; Meredith D. Hartley; Hannah S. Sanford-Crane; James M. Meinig; Thomas S. Scanlan
      Abstract: Publication date: Available online 16 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Andrew T. Placzek, Skylar J. Ferrara, Meredith D. Hartley, Hannah S. Sanford-Crane, James M. Meinig, Thomas S. Scanlan
      There is currently great interest in developing drugs that stimulate myelin repair for use in demyelinating diseases such as multiple sclerosis. Thyroid hormone plays a key role in stimulating myelination during development and also controls the expression of important genes involved in myelin repair in adults. Because endogenous thyroid hormone in excess lacks a generally useful therapeutic index, it is not used clinically for indications other than hormone replacement; however, selective thyromimetics such as sobetirome offer a therapeutic alternative. Sobetirome is the only clinical-stage thyromimetic that is known to cross the blood-brain-barrier (BBB) and we endeavored to increase the BBB permeability of sobetirome using a prodrug strategy. Ester prodrugs of sobetirome were prepared based on literature reports of improved BBB permeability with other carboxylic acid containing drugs and BBB permeability was assessed in vivo. One sobetirome prodrug, ethanolamine ester 11, was found to distribute more sobetirome to the brain compared to an equimolar peripheral dose of unmodified sobetirome. In addition to enhanced brain levels, prodrug 11 displayed lower sobetirome blood levels and a brain/serum ratio that was larger than that of unmodified sobetirome. Thus, these data indicate that an ester prodrug strategy applied to sobetirome can deliver increased concentrations of the active drug to the central nervous system (CNS), which may prove useful in the treatment of CNS disorders.
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      PubDate: 2016-09-20T13:35:09Z
      DOI: 10.1016/j.bmc.2016.09.038
  • Design, Synthesis and Biological Evaluation of Potential Antibacterial
    • Authors: Alaa Sweidan; Marylene Chollet-Krugler; Pierre van de Weghe; Ali Chokr; Sophie Tomasi; Martine Bonnaure-Mallet; Latifa Bousarghin
      Abstract: Publication date: Available online 17 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Alaa Sweidan, Marylene Chollet-Krugler, Pierre van de Weghe, Ali Chokr, Sophie Tomasi, Martine Bonnaure-Mallet, Latifa Bousarghin
      Novel butyrolactone analogues were designed and synthesized based on the known lichen antibacterial compounds, lichesterinic acids (B-10 and B-11), by substituting different functional groups on the butyrolactone ring trying to enhance its activity. All synthesized butyrolactone analogues were evaluated for their in vitro antibacterial activity against Streptococcus gordonii. Among the derivatives, B-12 and B-13 had the lowest MIC of 9.38 μg/mL where they have shown to be stronger bactericidals, by 2-3 times, than the reference antibiotic, doxycycline. These two compounds were then checked for their cytotoxicity against human gingival epithelial cell lines, Ca9-22, and macrophages, THP-1, by MTT and LDH assays which confirmed their safety against the tested cell lines. A preliminary study of the structure-activity relationships unveiled that the functional groups at the C4 position had an important influence on the antibacterial activity. An optimum length of the alkyl chain at the C5 position registered the best antibacterial inhibitory activity however as its length increased the bactericidal effect increased as well. This efficiency was attained by a carboxyl group substitution at the C4 position indicating the important dual role contributed by these two substituents which might be involved in their mechanism of action.
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      PubDate: 2016-09-20T13:35:09Z
      DOI: 10.1016/j.bmc.2016.09.040
  • Quinazolinone derivatives: synthesis and comparison of inhibitory
           mechanisms on α-glucosidase
    • Authors: Mankun Wei; Wei-Ming Chai; Rui Wang; Qin Yang; Zhihong Deng; Yiyuan Peng
      Abstract: Publication date: Available online 17 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Mankun Wei, Wei-Ming Chai, Rui Wang, Qin Yang, Zhihong Deng, Yiyuan Peng
      In this study, eight quinazolinone derivatives were designed and synthesized. Their inhibitory activities on α-glucosidase were assessed in vitro. Two compounds: 2-(4-chlorophenyl)-quinazolin-4(3H)-one (CQ) and 2-(4-bromophenyl)-quinazolin-4(3H)-one (BQ) were found to be potent inhibitors of α-glucosidase with IC50 values of 12.5 ± 0.1 μM and 15.6 ± 0.2 μM, respectively. Spectroscopy methods were performed to analyze the inhibitory mechanisms of both compounds on α-glucosidase. The results revealed that they reversibly inhibited α-glucosidase in a non-competitive manner. CQ and BQ could statically quench the fluorescence spectra by formation of an inhibitor-α-glucosidase complex. The interaction between CQ and α-glucosidase depended on hydrogen bonds, electrostatic and hydrophobic force, while the driving force of the binding between BQ and the enzyme was hydrophobic. The docking results showed that BQ was less active than CQ against α-glucosidase because of its weaker interaction with the enzyme. In brief, the quinazolinone derivatives identified in this work were potentially promising candidates for developing as novel anti-diabetic agents.
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      PubDate: 2016-09-20T13:35:09Z
      DOI: 10.1016/j.bmc.2016.09.042
  • Synthesis and Structure–Activity Relationships of 1-Benzylindane
           Derivatives as Selective Agonists for Estrogen Receptor Beta
    • Authors: Shigeru Yonekubo; Nobuhiko Fushimi; Takashi Miyagi; Osamu Nakanishi; Kenji Katsuno; Motoyasu Ozawa; Chiaki Handa; Noritaka Furuya; Hideyuki Muranaka
      Abstract: Publication date: Available online 20 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Shigeru Yonekubo, Nobuhiko Fushimi, Takashi Miyagi, Osamu Nakanishi, Kenji Katsuno, Motoyasu Ozawa, Chiaki Handa, Noritaka Furuya, Hideyuki Muranaka
      The estrogen receptor beta (ERβ) selective agonist is considered a promising candidate for the treatment of estrogen deficiency symptoms in ERβ-expressing tissues, without the risk of breast cancer, and multiple classes of compounds have been reported as ERβ selective agonists. Among them, 6-6 bicyclic ring-containing structures (e.g., isoflavone phytoestrogens) are regarded as one of the cyclized analogues of isobutestrol 5b, and suggest that other cyclized scaffolds comprising 5-6 bicyclic rings could also act as selective ERβ ligands. In this study, we evaluated the selective ERβ agonistic activity of 1-(4-hydroxybenzyl)indan-5-ol 7a and studied structure–activity relationship (SAR) of its derivatives. Some functional groups improved the properties of 7a; introduction of a nitrile group on the indane-1-position resulted in higher selectivity for ERβ (12a), and further substitution with a fluoro or a methyl group to the pendant phenyl ring was also preferable (12b, d, and e). Subsequent chiral resolution of 12a identified that R -12a has a superior profile over S -12a. This is comparable to diarylpropionitrile (DPN) 5c, one of the promising selective ERβ agonists and indicates that this indane-based scaffold has the potential to provide better ERβ agonistic probes.
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      PubDate: 2016-09-20T13:35:09Z
      DOI: 10.1016/j.bmc.2016.09.047
  • Design, synthesis and evaluation of anti-CD123 antibody drug conjugates
    • Authors: Bin Li; Weiyu Zhao; Xinfu Zhang; Junfeng Wang; Xiao Luo; Sharyn D. Baker; Craig T. Jordan; Yizhou Dong
      Abstract: Publication date: Available online 17 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Bin Li, Weiyu Zhao, Xinfu Zhang, Junfeng Wang, Xiao Luo, Sharyn D. Baker, Craig T. Jordan, Yizhou Dong
      Leukemia stem cells (LSCs) account for the development of drug resistance and increased recurrence rate in acute myeloid leukemia (AML) patients. Targeted drug delivery to leukemia stem cells remains a major challenge in AML chemotherapy. Overexpressed interleukin-3 receptor alpha chain, CD123, on the surface of leukemia stem cells was reported to be a potential target in AML treatment. Here, we designed and developed an antibody drug conjugate by integrating anti-CD123 antibody with a chemotherapeutic agent, Camptothecin (CPT), via a disulfide linker (CD123-CPT). The linker is biodegradable in the presence of Glutathione (GSH, a endogenous component in cells), which leads to release of CPT. Anti-CD123 antibody conjugates showed significant higher cellular uptake in CD123-overexpressed tumor cells. More importantly, CD123-CPT demonstrated potent inhibitory effects on CD123-overexpressed tumor cells. Consequently, these results provide a promising targeted chemotherapeutical strategy for AML treatment.
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      PubDate: 2016-09-20T13:35:09Z
      DOI: 10.1016/j.bmc.2016.09.043
  • A facile stereoselective synthesis of dispiro-indeno
           pyrrolidine/pyrrolothiazole-thiochroman hybrids and evaluation of their
           antimycobacterial, anticancer and AchE inhibitory activities
    • Authors: Chelliah Bharkavi Sundaravel Vivek Kumar Mohamed Ashraf Ali Hasnah Osman
      Abstract: Publication date: Available online 19 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Chelliah Bharkavi, Sundaravel Vivek Kumar, Mohamed Ashraf Ali, Hasnah Osman, Shanmugam Muthusubramanian, Subbu Perumal
      A facile stereoselective synthesis of novel dispiro indeno pyrrolidine/pyrrolothiazole-thiochroman hybrids has been achieved by 1,3-dipolar cycloaddition of azomethine ylides, generated in situ from ninhydrin and sarcosine/thiaproline, on a series of 3-benzylidenethiochroman-4-ones. The synthesised compounds were screened for their antimycobacterial, anticancer and AchE inhibition activities. Compound 4l (IC50 1.07 μM) has been found to exhibit the most potent antimycobacterial activity compared to cycloserine (12 times), pyrimethamine (37 times) and ethambutol (IC50 < 1.56 μM) and 6l (IC50 = 2.87 μM) is more active than both cycloserine (4 times) and pyrimethamine (12 times). Three compounds, 4a, 6b and 6i, display good anticancer activity against CCRF-CEM cell lines. Compounds 6g and 4g display maximum AchE inhibitory activity with IC50 values of 1.10 and 1.16 μmol/L respectively.
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      PubDate: 2016-09-20T13:35:09Z
  • Tyrosyl-DNA phosphodiesterase inhibitors: Progress and potential
    • Authors: Sergey S. Laev; Nariman F. Salakhutdinov; Olga I. Lavrik
      Abstract: Publication date: Available online 20 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Sergey S. Laev, Nariman F. Salakhutdinov, Olga I. Lavrik
      DNA topoisomerases are essential during transcription and replication. The therapeutic mechanism of action of topoisomerase inhibitors is enzyme poisoning rather than catalytic inhibition. Tyrosyl-DNA phosphodiesterases 1 or 2 were found as DNA repair enzymes hydrolyzing the covalent bond between the tyrosyl residue of topoisomerases I or II and the 3’- or 5’-phosphate groups in DNA, respectively. Tyrosyl-DNA phosphodiesterase 1 is a key enzyme in DNA repair machinery and a promising target for antitumor and neurodegenerative therapy. Inhibitors of tyrosyl-DNA phosphodiesterase 1 could act synergistically with topoisomerase I inhibitors and thereby potentiate the effects of topoisomerase I poisons. Tyrosyl-DNA phosphodiesterase 2 is an enzyme that specifically repairs DNA damages induced by topoisomerase II poisons and causes resistance to these drugs. Selective inhibition of tyrosyl-DNA phosphodiesterase 2 may be a novel approach to overcome intrinsic or acquired resistance to topoisomerase II-targeted drug therapy. Thus, agents that inhibit tyrosyl-DNA phosphodiesterases 1 and 2 have many applications in biochemical and physiological research and they have the potential to become anticancer and antiviral drugs. The structures, mechanism of action and therapeutic rationale of tyrosyl-DNA phosphodiesterase inhibitors and their development for combinations with topoisomerase inhibitors and DNA damaging agents are discussed.
      Graphical abstract image

      PubDate: 2016-09-20T13:35:09Z
      DOI: 10.1016/j.bmc.2016.09.045
  • Synthesis and antimicrobial activity of small cationic amphipathic
           aminobenzamide marine natural product mimics and evaluation of relevance
           against clinical isolates including ESBL-CARBA multi-resistant bacteria
    • Authors: Elizaveta M. Igumnova; Ekaterina Mishchenko; Tor Haug; Hans-Matti Blencke; Johanna U. Ericson Sollid; Elizabeth G. Aarag Fredheim; Silje Lauksund; Klara Stensvåg; Morten B. Strøm
      Abstract: Publication date: Available online 20 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Elizaveta M. Igumnova, Ekaterina Mishchenko, Tor Haug, Hans-Matti Blencke, Johanna U. Ericson Sollid, Elizabeth G. Aarag Fredheim, Silje Lauksund, Klara Stensvåg, Morten B. Strøm
      A library of small aminobenzamide derivatives was synthesised to explore a cationic amphipathic motif found in marine natural antimicrobials. The most potent compound E23 displayed minimal inhibitory concentrations (MICs) of 0.5 – 2 μg/ml against several Gram-positive bacterial strains, including methicillin resistant Staphylococcus epidermidis (MRSE). E23 was also potent against 275 clinical isolates including Staphylococcus aureus, Enterococcus spp., Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae, as well as methicillin-resistant S. aureus (MRSA), vancomycin-resistant enterococci (VRE), and ESBL-CARBA multi-resistant Gram-negative bacteria. The study demonstrates how structural motifs found in marine natural antimicrobials can be a valuable source for making novel antimicrobial lead-compounds.
      Graphical abstract image

      PubDate: 2016-09-20T13:35:09Z
      DOI: 10.1016/j.bmc.2016.09.046
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