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  Subjects -> CHEMISTRY (Total: 844 journals)
    - ANALYTICAL CHEMISTRY (47 journals)
    - CHEMISTRY (597 journals)
    - CRYSTALLOGRAPHY (22 journals)
    - ELECTROCHEMISTRY (26 journals)
    - INORGANIC CHEMISTRY (41 journals)
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    - PHYSICAL CHEMISTRY (66 journals)

CHEMISTRY (597 journals)                  1 2 3 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 5)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 25)
ACS Catalysis     Full-text available via subscription   (Followers: 25)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 15)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 23)
ACS Macro Letters     Full-text available via subscription   (Followers: 20)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 32)
ACS Nano     Full-text available via subscription   (Followers: 159)
ACS Photonics     Full-text available via subscription   (Followers: 6)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 16)
Acta Chemica Iasi     Open Access  
Acta Chimica Sinica     Full-text available via subscription  
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: 4)
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: 9)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 14)
Advances in Drug Research     Full-text available via subscription   (Followers: 21)
Advances in Enzyme Research     Open Access   (Followers: 4)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 12)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 15)
Advances in Nanoparticles     Open Access   (Followers: 12)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 13)
Advances in Polymer Science     Hybrid Journal   (Followers: 37)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 13)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 13)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Science and Technology     Full-text available via subscription   (Followers: 3)
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: 6)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 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: 115)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 160)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 1)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 2)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 3)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 7)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 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: 24)
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: 2)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 4)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 8)
Biochemistry     Full-text available via subscription   (Followers: 207)
Biochemistry Insights     Open Access   (Followers: 4)
Biochemistry Research International     Open Access   (Followers: 4)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 8)
Bioinspired Materials     Open Access   (Followers: 2)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 1)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access  
Biomacromolecules     Full-text available via subscription   (Followers: 17)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 9)
Biomedical Chromatography     Hybrid Journal   (Followers: 7)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 2)
BioNanoScience     Partially Free   (Followers: 4)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 91)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 81)
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: 62)
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: 4)
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: 20)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 17)
Chemical Reviews     Full-text available via subscription   (Followers: 122)
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: 4)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 5)
Chemistry & Biology     Full-text available via subscription   (Followers: 29)
Chemistry & Industry     Hybrid Journal   (Followers: 2)
Chemistry - A European Journal     Hybrid Journal   (Followers: 109)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 12)
Chemistry and Materials Research     Open Access   (Followers: 14)
Chemistry Central Journal     Open Access   (Followers: 5)
Chemistry Education Research and Practice     Free   (Followers: 4)
Chemistry in Education     Open Access   (Followers: 2)
Chemistry International     Hybrid Journal   (Followers: 1)
Chemistry Letters     Full-text available via subscription   (Followers: 43)
Chemistry of Materials     Full-text available via subscription   (Followers: 138)
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)
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     Open Access   (Followers: 5)
Chromatography Research International     Open Access   (Followers: 5)
Clay Minerals     Full-text available via subscription   (Followers: 9)
Cogent Chemistry     Open Access  
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 8)
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 6)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
Combustion Science and Technology     Hybrid Journal   (Followers: 18)
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: 10)
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: 28)
Dalton Transactions     Full-text available via subscription   (Followers: 17)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 1)
Diamond and Related Materials     Hybrid Journal   (Followers: 12)
Dislocations in Solids     Full-text available via subscription  
Doklady Chemistry     Hybrid Journal  
Drying Technology: An International Journal     Hybrid Journal   (Followers: 3)
Eclética Química     Open Access   (Followers: 1)
Ecological Chemistry and Engineering S     Open Access   (Followers: 2)
Ecotoxicology and Environmental Contamination     Open Access  
Educación Química     Open Access   (Followers: 1)
Education for Chemical Engineers     Hybrid Journal   (Followers: 4)
EDUSAINS     Open Access  
Elements     Full-text available via subscription   (Followers: 1)
Environmental Chemistry     Hybrid Journal   (Followers: 5)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 2)
Environmental Science & Technology Letters     Full-text available via subscription   (Followers: 3)

        1 2 3 | Last

Journal Cover Bioorganic & Medicinal Chemistry
  [91 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0968-0896
   Published by Elsevier Homepage  [2969 journals]
  • Bortezomib inhibits bacterial and fungal β-carbonic anhydrases
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Claudiu T. Supuran
      Inhibition of the β-carbonic anhydrases (CAs, EC 4.2.1.1) from pathogenic fungi (Cryptococcus neoformans, Candida albicans, Candida glabrata, Malassezia globosa) and bacteria (three isoforms from Mycobacterium tuberculosis, Rv3273, Rv1284 and Rv3588), as well from the insect Drosophila melanogaster (DmeCA) and the plant Flaveria bidentis (FbiCA1) with the boronic acid peptidomimetic proteosome inhibitor bortezomib was investigated. Bortezomib was a micromolar inhibitor of all these enzymes, with K Is ranging between 1.12 and 11.30μM. Based on recent crystallographic data it is hypothesized that the B(OH)2 moiety of the inhibitor is directly coordinated to the zinc ion from the enzyme active site. The class of boronic acids, an under-investigated type of CA inhibitors, may lead to the development of anti-infectives with a novel mechanism of action, based on the pathogenic organisms CA inhibition.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Anion inhibition profiles of the complete domain of the η-carbonic
           anhydrase from Plasmodium falciparum
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Sonia Del Prete, Daniela Vullo, Viviana De Luca, Vincenzo Carginale, Pietro di Fonzo, Sameh M. Osman, Zeid AlOthman, Claudiu T. Supuran, Clemente Capasso
      We have cloned, purified and investigated the catalytic activity and anion inhibition profiles of a full catalytic domain (358 amino acid residues) carbonic anhydrase (CA, EC 4.2.1.1) from Plasmodium falciparum, PfCAdom, an enzyme belonging to the η-CA class and identified in the genome of the malaria-producing protozoa. A truncated such enzyme, PfCA1, containing 235 residues was investigated earlier for its catalytic and inhibition profiles. The two enzymes were efficient catalysts for CO2 hydration: PfCAdom showed a k cat of 3.8×105 s−1 and k cat/K m of 7.2×107 M−1 ×s−1, whereas PfCA showed a lower activity compared to PfCAdom, with a k cat of 1.4×105 s−1 and k cat/K m of 5.4×106 M−1 ×s−1. PfCAdom was generally less inhibited by most anions and small molecules compared to PfCA1. The best PfCAdom inhibitors were sulfamide, sulfamic acid, phenylboronic acid and phenylarsonic acid, which showed K Is in the range of 9–68μM, followed by bicarbonate, hydrogensulfide, stannate and N,N-diethyldithiocarbamate, which were submillimolar inhibitors, with K Is in the range of 0.53–0.97mM. Malaria parasites CA inhibition was proposed as a new strategy to develop antimalarial drugs, with a novel mechanism of action.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Effects of stereochemistry, saturation, and hydrocarbon chain length on
           the ability of synthetic constrained azacyclic sphingolipids to trigger
           nutrient transporter down-regulation, vacuolation, and cell death
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Michael S. Perryman, Jérémie Tessier, Timothy Wiher, Heather O’Donoghue, Alison N. McCracken, Seong M. Kim, Dean G. Nguyen, Grigor S. Simitian, Matheus Viana, Susanne Rafelski, Aimee L. Edinger, Stephen Hanessian
      Constrained analogs containing a 2-hydroxymethylpyrrolidine core of the natural sphingolipids sphingosine, sphinganine, N,N-dimethylsphingosine and N-acetyl variants of sphingosine and sphinganine (C 2-ceramide and dihydro-C 2-ceramide) were synthesized and evaluated for their ability to down-regulate nutrient transporter proteins and trigger cytoplasmic vacuolation in mammalian cells. In cancer cells, the disruptions in intracellular trafficking produced by these sphingolipids lead to cancer cell death by starvation. Structure activity studies were conducted by varying the length of the hydrocarbon chain, the degree of unsaturation and the presence or absence of an aryl moiety on the appended chains, and stereochemistry at two stereogenic centers. In general, cytotoxicity was positively correlated with nutrient transporter down-regulation and vacuolation. This study was intended to identify structural and functional features in lead compounds that best contribute to potency, and to develop chemical biology tools that could be used to isolate the different protein targets responsible for nutrient transporter loss and cytoplasmic vacuolation. A molecule that produces maximal vacuolation and transporter loss is expected to have the maximal anti-cancer activity and would be a lead compound.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Zinc-mediated binding of a low-molecular-weight stabilizer of the host
           anti-viral factor apolipoprotein B mRNA-editing enzyme, catalytic
           polypeptide-like 3G
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Mohamed O. Radwan, Sachiko Sonoda, Tomohiko Ejima, Ayumi Tanaka, Ryoko Koga, Yoshinari Okamoto, Mikako Fujita, Masami Otsuka
      Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G, A3G), is a human anti-virus restriction protein which works deaminase-dependently and -independently. A3G is known to be ubiquitinated by HIV-1 viral infectivity factor (Vif) protein, leading to proteasomal degradation. A3G contains two zinc ions at the N-terminal domain and the C-terminal domain. Four lysine residues, K297, K301, K303, and K334, are known to be required for Vif-mediated A3G ubiquitination and degradation. Previously, we reported compound SN-1, a zinc chelator that increases steady-state expression level of A3G in the presence of Vif. In this study, we prepared Biotin-SN-1, a biotinylated derivative of SN-1, to study the SN-1–A3G interaction. A pull-down assay revealed that Biotin-SN-1 bound A3G. A zinc-abstraction experiment indicated that SN-1 binds to the zinc site of A3G. We carried out a SN-1–A3G docking study using molecular operating environment. The calculations revealed that SN-1 binds to the C-terminal domain through Zn2+, H216, P247, C288, and Y315. Notably, SN-1-binding covers the H257, E259, C288, and C291 residues that participate in zinc-mediated deamination, and the ubiquitination regions of A3G. The binding of SN-1 presumably perturbs the secondary structure between C288 and Y315, leading to less efficient ubiquitination.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Multiantigenic peptide–polymer conjugates as therapeutic vaccines
           against cervical cancer
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Waleed M. Hussein, Tzu-Yu Liu, Zhongfan Jia, Nigel A.J. McMillan, Michael J. Monteiro, Istvan Toth, Mariusz Skwarczynski
      Immunotherapy is one of the most promising strategies for the treatment of cancer. Human papillomavirus (HPV) is responsible for virtually all cases of cervical cancer. The main purpose of a therapeutic HPV vaccine is to stimulate CD8+ cytotoxic T lymphocytes (CTLs) that can eradicate HPV infected cells. HPV oncoproteins E6 and E7 are continuously expressed and are essential for maintaining the growth of HPV-associated tumor cells. We designed polymer-based multi-antigenic formulations/constructs that were comprised of the E6 and E7 peptide epitopes. We developed an N-terminus-based epitope conjugation to conjugate two unprotected peptides to poly tert-butyl acrylate. This method allowed for the incorporation of the two antigens into a polymeric dendrimer in a strictly equimolar ratio. The most effective formulations eliminated tumors in up to 50% of treated mice. Tumor recurrence was not observed up to 3months post initial challenge.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Bacterial versus human sphingosine-1-phosphate lyase (S1PL) in the design
           of potential S1PL inhibitors
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Pol Sanllehí, José-Luis Abad, Josefina Casas, Jordi Bujons, Antonio Delgado
      A series of potential active-site sphingosine-1-phosphate lyase (S1PL) inhibitors have been designed from scaffolds 1 and 2, arising from virtual screening using the X-ray structures of the bacterial (StS1PL) and the human (hS1PL) enzymes. Both enzymes are very similar at the active site, as confirmed by the similar experimental kinetic constants shown by the fluorogenic substrate RBM13 in both cases. However, the docking scoring functions used probably overestimated the weight of electrostatic interactions between the ligands and key active-site residues in the protein environment, which may account for the modest activity found for the designed inhibitors. In addition, the possibility that the inhibitors do not reach the enzyme active site should not be overlooked. Finally, since both enzymes show remarkable structural differences at the access channel and in the proximity to the active site cavity, caution should be taken when designing inhibitors acting around that area, as evidenced by the much lower activity found in StS1PL for the potent hS1PL inhibitor D.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Inhibitors for the bacterial ectonucleotidase Lp1NTPDase from Legionella
           pneumophila
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Amelie Fiene, Younis Baqi, Enas M. Malik, Patrice Newton, Wenjin Li, Sang-Yong Lee, Elizabeth L. Hartland, Christa E. Müller
      Legionella pneumophila is an aerobic, Gram-negative bacterium of the genus Legionella, which constitutes the major causative agent of Legionnaires’ disease. Recently a nucleoside triphosphate diphosphohydrolase (NTPDase) from L. pneumophila was identified and termed Lp1NTPDase; it was found to be a structural and functional homolog of mammalian NTPDases catalyzing the hydrolysis of ATP to ADP and ADP to AMP. Its activity is believed to contribute to the virulence of Legionella pneumophila. Therefore Lp1NTPDase inhibitors are considered as novel antibacterial drugs. However, only weakly potent compounds are available so far. In the present study, a capillary electrophoresis (CE)-based enzyme assay for monitoring the Lp1NTPDase activity was established. The enzymatic reaction was performed in a test tube followed by separation of substrate and products by CE and subsequent quantification by UV analysis. After kinetic characterization of the enzyme, a series of 1-amino-4-ar(alk)ylamino-2-sulfoanthraquinone derivatives structurally related to the anthraquinone dye Reactive Blue 2, a non-selective ecto-NTPDase inhibitor, was investigated for inhibitory activity on Lp1NTPDase using the CE-based enzyme assay. Derivatives bearing a large lipophilic substituent (e.g., fused aromatic rings) in the 4-position of the 1-amino-2-sulfoanthraquinone showed the highest inhibitory activity. Compounds with IC50 values in the low micromolar range were identified. The most potent inhibitor was 1-amino-4-[phenanthrene-9-yl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (28, PSB-16131), with an IC50-value of 4.24μM. It represents the most potent Lp1NTPDase inhibitor described to date. These findings may serve as a starting point for further optimization. Lp1NTPDase inhibition provides a novel approach for the (immuno)therapy of Legionella infections.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Similarities and differences in affinity and binding modes of tricyclic
           pyrimido- and pyrazinoxanthines at human and rat adenosine receptors
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Ewa Szymańska, Anna Drabczyńska, Tadeusz Karcz, Christa E. Müller, Meryem Köse, Janina Karolak-Wojciechowska, Andrzej Fruziński, Jakub Schabikowski, Agata Doroz-Płonka, Jadwiga Handzlik, Katarzyna Kieć-Kononowicz
      A new series of 32 pyrimido- and 5 tetrahydropyrazino[2,1-f]purinediones was obtained and evaluated for their adenosine receptors (ARs) affinities. The 1,3-dibutyl derivative of 9-(4-(2-(dimethylamino)ethoxy)phenyl)-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)-dione was found to be the most potent A1 AR antagonist of the present series, showing selectivity over the other AR subtypes. The structure–activity for the obtained purinediones was established. Docking experiments of the investigated library to homology models of the human and rat A1 and A2A ARs allowed to compare the expected binding modes for selected compounds. The detailed analysis of binding cavities within individual AR subtypes indicated small but significant structural variations that may underlie the observed differences in binding affinities of purinediones at particular subtypes and species.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Synthesis and evaluation of multi-target-directed ligands for the
           treatment of Alzheimer’s disease based on the fusion of donepezil
           and melatonin
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Jin Wang, Zhi-Min Wang, Xue-Mei Li, Fan Li, Jia-Jia Wu, Ling-Yi Kong, Xiao-Bing Wang
      A novel series of compounds obtained by fusing the acetylcholinesterase (AChE) inhibitor donepezil and the antioxidant melatonin were designed as multi-target-directed ligands for the treatment of Alzheimer’s disease (AD). In vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (eqBuChE and hBuChE), and β-amyloid (Aβ) aggregation, and to act as potential antioxidants and biometal chelators. Especially, 4u displayed a good inhibition of AChE (IC50 value of 193nM for eeAChE and 273nM for hAChE), strong inhibition of BuChE (IC50 value of 73nM for eqBuChE and 56nM for hBuChE), moderate inhibition of Aβ aggregation (56.3% at 20μM) and good antioxidant activity (3.28trolox equivalent by ORAC assay). Molecular modeling studies in combination with kinetic analysis revealed that 4u was a mixed-type inhibitor, binding simultaneously to catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4u could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood–brain barrier (BBB). Taken together, these results strongly indicated the hybridization approach is an efficient strategy to identify novel scaffolds with desired bioactivities, and further optimization of 4u may be helpful to develop more potent lead compound for AD treatment.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Identification of the first small-molecule inhibitor of the REV7 DNA
           repair protein interaction
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Marcelo L. Actis, Nigus D. Ambaye, Benjamin J. Evison, Youming Shao, Murugendra Vanarotti, Akira Inoue, Ezelle T. McDonald, Sotaro Kikuchi, Richard Heath, Kodai Hara, Hiroshi Hashimoto, Naoaki Fujii
      DNA interstrand crosslink (ICL) repair (ICLR) has been implicated in the resistance of cancer cells to ICL-inducing chemotherapeutic agents. Despite the clinical significance of ICL-inducing chemotherapy, few studies have focused on developing small-molecule inhibitors for ICLR. The mammalian DNA polymerase ζ, which comprises the catalytic subunit REV3L and the non-catalytic subunit REV7, is essential for ICLR. To identify small-molecule compounds that are mechanistically capable of inhibiting ICLR by targeting REV7, high-throughput screening and structure–activity relationship (SAR) analysis were performed. Compound 1 was identified as an inhibitor of the interaction of REV7 with the REV7-binding sequence of REV3L. Compound 7 (an optimized analog of compound 1) bound directly to REV7 in nuclear magnetic resonance analyses, and inhibited the reactivation of a reporter plasmid containing an ICL in between the promoter and reporter regions. The normalized clonogenic survival of HeLa cells treated with cisplatin and compound 7 was lower than that for cells treated with cisplatin only. These findings indicate that a small-molecule inhibitor of the REV7/REV3L interaction can chemosensitize cells by inhibiting ICLR.
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      PubDate: 2016-08-18T08:58:06Z
       
  • The discovery of novel and selective fatty acid binding protein 4
           inhibitors by virtual screening and biological evaluation
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Yang Zhou, Tao Nie, Yan Zhang, Ming Song, Kuai Li, Mengxiao Ding, Ke Ding, Donghai Wu, Yong Xu
      Adipocyte fatty acid binding protein (AFABP, FABP4) has been proven to be a potential therapeutic target for diabetes, atherosclerosis and inflammation-related diseases. In this study, a series of new scaffolds of small molecule inhibitors of FABP4 were identified by virtual screening and were validated by a bioassay. Fifty selected compounds were tested, which led to the discovery of seven hits. Structural similarity-based searches were then performed based on the hits and led to the identification of one high affinity compound 33b (K i = 0.29±0.07μM, ΔT m =8.5°C). This compound’s effective blockade of inflammatory response was further validated by its ability to suppress pro-inflammatory cytokines induced by lipopolysaccharide (LPS) stimulation. Molecular dynamics simulation (MD) and mutagenesis studies validated key residues for its inhibitory potency and thus provide an important clue for the further development of drugs.
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      PubDate: 2016-08-18T08:58:06Z
       
  • Steric structure–activity relationship of cyproheptadine derivatives
           as inhibitors of histone methyltransferase Set7/9
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Takashi Fujiwara, Kasumi Ohira, Ko Urushibara, Akihiro Ito, Minoru Yoshida, Misae Kanai, Aya Tanatani, Hiroyuki Kagechika, Tomoya Hirano
      Set7/9 is a histone lysine methyltransferase, but it is also thought to be involved in a wide variety of pathophysiological functions. We previously identified cyproheptadine, which has a characteristic butterfly-like molecular conformation with bent tricyclic dibenzosuberene and chair-form N-methylpiperidine moieties, as a Set7/9 inhibitor. In this work, we synthesized several derivatives in order to examine the steric structure–inhibitory activity relationship. We found that even a small change of molecular shape due to reduction or replacement of the 10,11-olefinic bond of the tricyclic ring generally resulted in a drastic decrease of the inhibitory activity. Our results should be useful not only for development of more potent and selective inhibitors, but also for the construction of novel inhibitor scaffolds.
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      PubDate: 2016-08-18T08:58:06Z
       
  • Robust design of some selective matrix metalloproteinase-2 inhibitors over
           matrix metalloproteinase-9 through in silico/fragment-based lead
           identification and de novo lead modification: Syntheses and biological
           assays
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Nilanjan Adhikari, Amit K. Halder, Sumana Mallick, Achintya Saha, Kishna D. Saha, Tarun Jha
      Broad range of selectivity possesses serious limitation for the development of matrix metalloproteinase-2 (MMP-2) inhibitors for clinical purposes. To develop potent and selective MMP-2 inhibitors, initially multiple molecular modeling techniques were adopted for robust design. Predictive and validated regression models (2D and 3D QSAR and ligand-based pharmacophore mapping studies) were utilized for estimating the potency whereas classification models (Bayesian and recursive partitioning analyses) were used for determining the selectivity of MMP-2 inhibitors over MMP-9. Bayesian model fingerprints were used to design selective lead molecule which was modified using structure-based de novo technique. A series of designed molecules were prepared and screened initially for inhibitions of MMP-2 and MMP-9, respectively, as these are designed followed by other MMPs to observe the broader selectivity. The best active MMP-2 inhibitor had IC50 value of 24nM whereas the best selective inhibitor (IC50 =51nM) showed at least 4 times selectivity to MMP-2 against all tested MMPs. Active derivatives were non-cytotoxic against human lung carcinoma cell line—A549. At non-cytotoxic concentrations, these inhibitors reduced intracellular MMP-2 expression up to 78% and also exhibited satisfactory anti-migration and anti-invasive properties against A549 cells. Some of these active compounds may be used as adjuvant therapeutic agents in lung cancer after detailed study.
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      PubDate: 2016-08-18T08:58:06Z
       
  • Development of ethynyl-2′-deoxyuridine chemical probes for cell
           proliferation
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Carrie J. Lovitt, David H. Hilko, Vicky M. Avery, Sally-Ann Poulsen
      A common method of evaluating cellular proliferation is to label DNA with chemical probes. 5-Ethynyl-2′-deoxyuridine (EdU) is a widely utilized chemical probe for labeling DNA, and upon incorporation, EdU treatment of cells is followed by a reaction with a small molecule fluorescent azide to allow detection. The limitations when using EdU include cytotoxicity and a reliance on nucleoside active transport mechanisms for entry into cells. Here we have developed six novel EdU pro-labels that consist of EdU modified with variable lipophilic acyl ester moieties. This pro-label:chemical probe relationship parallels the prodrug:drug relationship that is employed widely in medicinal chemistry. EdU and EdU pro-labels were evaluated for their labeling efficacy and cytotoxicity. Several EdU pro-label analogues incorporate into DNA at a similar level to EdU, suggesting that nucleoside transporters can be bypassed by the pro-labels. These EdU pro-labels also had reduced toxicity compared to EdU.
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      PubDate: 2016-08-18T08:58:06Z
       
  • Discovery and optimization of a series of imidazo[4,5-b]pyrazine
           derivatives as highly potent and exquisitely selective inhibitors of the
           mesenchymal–epithelial transition factor (c-Met) protein kinase
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Fei Zhao, Jing Zhang, Leduo Zhang, Yu Hao, Chen Shi, Guangxin Xia, Jianxin Yu, Yanjun Liu
      Aberrant c-Met activation has been implicated in multiple tumor oncogenic processes and drug resistance. In this study, a series of imidazo[4,5-b]pyrazine derivatives was designed and synthesized, and their inhibitory activities were evaluated in vitro. Structure–activity relationship (SAR) was investigated systematically and docking analysis was performed to elucidate the binding mode, leading to the identification of the most promising compound 1D-2 which exhibited significant inhibitory effect on both enzymatic (IC50 =1.45nM) and cellular (IC50 =24.7nM in H1993 cell line) assays, as well as exquisite selectivity and satisfactory metabolic stability in human and rat liver microsomes.
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      PubDate: 2016-08-18T08:58:06Z
       
  • Simple and accurate single base resolution analysis of
           5-hydroxymethylcytosine by catalytic oxidative bisulfite sequencing using
           micelle incarcerated oxidants
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Seketsu Fukuzawa, Saori Takahashi, Kazuo Tachibana, Shoji Tajima, Isao Suetake
      Oxidation of 5-methylcytosine (5mC) is catalyzed by ten-eleven translocation (TET) enzymes to produce 5-hydroxymethylcytosine (5hmC) and following oxidative products. The oxidized nucleotides were shown to be the intermediates for DNA demethylation, as the nucleotides are removed by base excision repair system initiated by thymine DNA glycosylase. A simple and accurate method to determine initial oxidation product 5hmC at single base resolution in genomic DNA is necessary to understand demethylation mechanism. Recently, we have developed a new catalytic oxidation reaction using micelle-incarcerated oxidants to oxidize 5hmC to form 5-formylcytosine (5fC), and subsequent bisulfite sequencing can determine the positions of 5hmC in DNA. In the present study, we described the optimization of the catalytic oxidative bisulfite sequencing (coBS-seq), and its application to the analysis of 5hmC in genomic DNA at single base resolution in a quantitative manner. As the oxidation step showed quite low damage on genomic DNA, the method allows us to down scale the sample to be analyzed.
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      PubDate: 2016-08-18T08:58:06Z
       
  • Synthesis and anticancer potential of novel xanthone derivatives with
           3,6-substituted chains
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Chaomei Liu, Mei Zhang, Zhenhuan Zhang, Steven B. Zhang, Shanmin Yang, Amy Zhang, Liangjie Yin, Steven Swarts, Sadasivan Vidyasagar, Lurong Zhang, Paul Okunieff
      In an effort to develop new drug candidates with enhanced anticancer activity, our team synthesized and assessed the cytotoxicity of a series of novel xanthone derivatives with two longer 3,6-disubstituted amine carbonyl methoxy side chains on either benzene ring in selected human cancer cell lines. An MTT assay revealed that a set of compounds with lower IC50 values than the positive control, 5-FU, exhibited greater anticancer effects. The most potent derivative (XD8) exhibited anticancer activity in MDA-MB-231, PC-3, A549, AsPC-1, and HCT116 cells lines with IC50 values of 8.06, 6.18, 4.59, 4.76, and 6.09μM, respectively. Cell cycle analysis and apoptosis activation suggested that the mechanism of action of these derivatives includes cell cycle regulation and apoptosis induction.
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      PubDate: 2016-08-18T08:58:06Z
       
  • Functional foldamers that target bacterial membranes: The effect of
           charge, amphiphilicity and conformation
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Yogita Patil-Sen, Sarah R. Dennison, Timothy J. Snape
      By varying the molecular charge, shape and amphiphilicity of a series of conformationally distinct diarylureas it is possible to control the levels of phospholipid membrane lysis using membranes composed of bacterial lipid extracts. From the data obtained, it appears as though the lysis activity observed is not due to charge, conformation or amphiphilicity in isolation, but that surface aggregation, H-bonding and other factors may also play a part. The work provides evidence that this class of foldamer possesses potential for optimisation into new antibacterial agents.
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      PubDate: 2016-08-18T08:58:06Z
       
  • Design and comparative anticonvulsant activity assessment of CNS-active
           alkyl-carbamoyl imidazole derivatives
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Hafiz Mawasi, David Bibi, Meir Bialer
      A novel series of carbamoyl derivatives of alkylimidazole has been designed and their anticonvulsant activity was comparatively evaluated in the mice- and rats-maximal-electroshock (MES), subcutaneous-metrazol (scMet) seizure tests and the mice-6Hz psychomotor (6Hz) models. The ten new designed molecules contain in their chemical structure imidazole, alkyl side-chain and carbamate as three potential active moieties. In spite of the close structural features of the carbamoyl imidazole derivatives only compounds 7, 8, 13 and 16 were active at the MES test with ED50 values ranging from 12 to 20mg/kg coupled with high protective index (PI=TD50/ED50) values of 4.1–7.3 after ip administration to rats. A similar phenomenon was observed in mice where compounds 7, 8, 9, 12 had MES-ED50 values of 14–26mg/kg. Compounds 7 and 13 also demonstrated anticonvulsant activity in the 6Hz model with ED50 values of 32 and 44mg/kg, respectively. As the most active entities, compounds 7, 8 followed by 13 and 16, thus offer an optimal efficacy–safety profile and consequently, might be promising candidates for development as new antiepileptics.
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      PubDate: 2016-08-18T08:58:06Z
       
  • Design, synthesis, molecular docking and biological evaluation of
           thiophen-2-iminothiazolidine derivatives for use against Trypanosoma cruzi
           
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): E.F. Silva-Júnior, E.P.S. Silva, P.H.B. França, J.P.N. Silva, E.O. Barreto, E.B. Silva, R.S. Ferreira, C.C. Gatto, D.R.M. Moreira, J.L. Siqueira-Neto, F.J.B. Mendonça-Júnior, M.C.A. Lima, J.H. Bortoluzzi, M.T. Scotti, L. Scotti, M.R. Meneghetti, T.M. Aquino, J.X. Araújo-Júnior
      In this study, we designed and synthesized a series of thiophen-2-iminothiazolidine derivatives from thiophen-2-thioureic with good anti-Trypanosoma cruzi activity. Several of the final compounds displayed remarkable trypanocidal activity. The ability of the new compounds to inhibit the activity of the enzyme cruzain, the major cysteine protease of T. cruzi, was also explored. The compounds 3b, 4b, 8b and 8c were the most active derivatives against amastigote form, with significant IC50 values between 9.7 and 6.03μM. The 8c derivative showed the highest potency against cruzain (IC50 =2.4μM). Molecular docking study showed that this compound can interact with subsites S1 and S2 simultaneously, and the negative values for the theoretical energy binding (E b =−7.39kcal·mol−1) indicates interaction (via dipole–dipole) between the hybridized sulfur sp3 atom at the thiazolidine ring and Gly66. Finally, the results suggest that the thiophen-2-iminothiazolidines synthesized are important lead compounds for the continuing battle against Chagas disease.
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      PubDate: 2016-08-18T08:58:06Z
       
  • Discovery of a potent and highly selective transforming growth factor
           β receptor-associated kinase 1 (TAK1) inhibitor by structure based
           drug design (SBDD)
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Terushige Muraoka, Mitsuaki Ide, Kenji Morikami, Machiko Irie, Mitsuaki Nakamura, Takaaki Miura, Takayuki Kamikawa, Masamichi Nishihara, Hirotaka Kashiwagi
      A novel thienopyrimidinone analog was discovered as a potent and highly selective TAK1 inhibitor using the SBDD approach. TAK1 plays a key role in inflammatory and immune signaling, so TAK1 is considered to be an attractive molecular target for the treatment of human diseases (inflammatory disease, cancer, etc.). After the hit compound had been obtained, our modifications successfully increased TAK1 inhibitory activity and solubility, but metabolic stability was still unsatisfactory. To improve metabolic stability, we conducted metabolic identification. Although the obtained metabolite was fortunately a potent TAK1 inhibitor, its kinase selectivity was low. Subsequently, to achieve high kinase selectivity, we used SBDD to follow two strategies: one targeting unique amino acid residues in TAK1, especially the combination of Ser111 and Asn114; the other decreasing the interaction with Tyr106 at the hinge position in TAK1. As expected, our designed compound showed an excellent kinase selectivity profile in both an in-house and a commercially available panel assay of over 420 kinases and also retained its potent TAK1 inhibitory activity (TAK1 IC50 =11nM).
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      PubDate: 2016-08-18T08:58:06Z
       
  • Binding mode prediction of aplysiatoxin, a potent agonist of protein
           kinase C, through molecular simulation and structure–activity study
           on simplified analogs of the receptor-recognition domain
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Yoshiki Ashida, Ryo C. Yanagita, Chise Takahashi, Yasuhiro Kawanami, Kazuhiro Irie
      Aplysiatoxin (ATX) is a naturally occurring tumor promoter isolated from a sea hare and cyanobacteria. ATX binds to, and activates, protein kinase C (PKC) isozymes and shows anti-proliferative activity against human cancer cell lines. Recently, ATX has attracted attention as a lead compound for the development of novel anticancer drugs. In order to predict the binding mode between ATX and protein kinase Cδ (PKCδ) C1B domain, we carried out molecular docking simulation, atomistic molecular dynamics simulation in phospholipid membrane environment, and structure–activity study on a simple acyclic analog of ATX. These studies provided the binding model where the carbonyl group at position 27, the hydroxyl group at position 30, and the phenolic hydroxyl group at position 20 of ATX were involved in intermolecular hydrogen bonding with the PKCδ C1B domain, which would be useful for the rational design of ATX derivatives as anticancer lead compounds.
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      PubDate: 2016-08-18T08:58:06Z
       
  • Structure elucidation of anti-methicillin resistant Staphylococcus aureus
           (MRSA) flavonoids from balsam poplar buds
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): François Simard, Charles Gauthier, Jean Legault, Serge Lavoie, Vakhtang Mshvildadze, André Pichette
      There is nowadays an urgent need for developing novel generations of antibiotic agents due to the increased resistance of pathogenic bacteria. As a rich reservoir of structurally diverse compounds, plant species hold promise in this regard. Within this framework, we isolated a unique series of antibacterial flavonoids, named balsacones N–U, featuring multiple cinnamyl chains on the flavan skeleton. The structures of these compounds, isolated as racemates, were determined using extensive 1D and 2D NMR analysis in tandem with HRMS. Balsacones N–U along with previously isolated balsacones A–M were evaluated for their antibacterial activity against clinical isolates of methicillin resistant Staphylococcus aureus (MRSA). Several of the tested balsacones were potent anti-MRSA agents showing MIC values in the low micromolar range. Structure–activity relationships study highlighted some important parameters involved in the antibacterial activity of balsacones such as the presence of cinnamyl and cinnamoyl chains at the C-3 and C-8 positions of the flavan skeleton, respectively. These results suggest that balsacones could represent a potential novel class of naturally occurring anti-MRSA agents.
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      PubDate: 2016-08-18T08:58:06Z
       
  • Synthesis and properties of peptide nucleic acid labeled at the N-terminus
           with HiLyte Fluor 488 fluorescent dye
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Dziyana Hnedzko, Dennis W. McGee, Eriks Rozners
      Fluorescently labeled peptide nucleic acids (PNAs) are important tools in fundamental research and biomedical applications. However, synthesis of labeled PNAs, especially using modern and expensive dyes, is less explored than similar preparations of oligonucleotide dye conjugates. Herein, we present a simple procedure for labeling of the PNA N-terminus with HiLyte Fluor 488 as the last step of solid phase PNA synthesis. A minimum excess of 1.25equiv of activated carboxylic acid achieved labeling yields close to 90% providing a good compromise between the price of dye and the yield of product and significant improvement over previous literature procedures. The HiLyte Fluor 488-labeled PNAs retained the RNA binding ability and in live cell fluorescence microscopy experiments were brighter and significantly more photostable than PNA labeled with carboxyfluorescein. In contrast to fluorescein-labeled PNA, the fluorescence of PNAs labeled with HiLyte Fluor 488 was independent of pH in the biologically relevant range of 5–8. The potential of HiLyte Fluor 488-labeling for studies of PNA cellular uptake and distribution was demonstrated in several cell lines.
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      PubDate: 2016-08-18T08:58:06Z
       
  • Synthesis and in vitro reactivation study of isonicotinamide derivatives
           of 2-(hydroxyimino)-N-(pyridin-3-yl)acetamide as reactivators of Sarin and
           VX inhibited human acetylcholinesterase (hAChE)
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Hitendra N. Karade, G. Raviraju, B.N. Acharya, Aditya Kapil Valiveti, Uma Bhalerao, Jyotiranjan Acharya
      Previously (Karade et al., 2014), we have reported the synthesis and in vitro evaluation of bis-pyridinium derivatives of pyridine-3-yl-(2-hydroxyimino acetamide), as reactivators of sarin and VX inhibited hAChE. Few of the molecules showed superior in vivo protection efficacy (mice model) (Kumar et al., 2014; Swami et al., 2016) in comparison to 2-PAM against DFP and sarin poisoning. Encouraged by these results, herein we report the synthesis and in vitro evaluation of isonicotinamide derivatives of pyridine-3-yl-(2-hydroxyimino acetamide) (4a–4d) against sarin and VX inhibited erythrocyte ghost hAChE. Reactivation kinetics of these compounds was studied and the determined kinetic parameters were compared with that of commercial reactivators viz. 2-PAM and obidoxime. In comparison to 2-PAM and obidoxime, oxime 4a and 4b exhibited enhanced reactivation efficacy toward sarin inhibited hAChE while oxime 4c showed far greater reactivation efficacy toward VX inhibited hAChE. The acid dissociation constant and IC50 values of these oximes were determined and correlated with the observed reactivation potential.
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      PubDate: 2016-08-18T08:58:06Z
       
  • Synthesis of alanyl nucleobase amino acids and their incorporation into
           proteins
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Poulami Talukder, Larisa M. Dedkova, Andrew D. Ellington, Petro Yakovchuk, Jaebum Lim, Eric V. Anslyn, Sidney M. Hecht
      Proteins which bind to nucleic acids and regulate their structure and functions are numerous and exceptionally important. Such proteins employ a variety of strategies for recognition of the relevant structural elements in their nucleic acid substrates, some of which have been shown to involve rather subtle interactions which might have been difficult to design from first principles. In the present study, we have explored the preparation of proteins containing unnatural amino acids having nucleobase side chains. In principle, the introduction of multiple nucleobase amino acids into the nucleic acid binding domain of a protein should enable these modified proteins to interact with their nucleic acid substrates using Watson-Crick and other base pairing interactions. We describe the synthesis of five alanyl nucleobase amino acids protected in a fashion which enabled their attachment to a suppressor tRNA, and their incorporation into each of two proteins with acceptable efficiencies. The nucleobases studied included cytosine, uracil, thymine, adenine and guanine, i.e. the major nucleobase constituents of DNA and RNA. Dihydrofolate reductase was chosen as one model protein to enable direct comparison of the facility of incorporation of the nucleobase amino acids with numerous other unnatural amino acids studied previously. The Klenow fragment of DNA polymerase I was chosen as a representative DNA binding protein whose mode of action has been studied in detail.
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      PubDate: 2016-08-18T08:58:06Z
       
  • Introduction of perfluoroalkyl chain into the esterifying moiety of
           bacteriochlorophyll c in the green sulfur photosynthetic bacterium
           Chlorobaculum tepidum by pigment biosynthesis
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Yoshitaka Saga, Hayato Yamashita, Keiya Hirota
      The green sulfur photosynthetic bacterium Chlorobaculum (Cba.) tepidum was grown in liquid cultures containing perfluoro-1-decanol, 1H,1H,2H,2H-heptadecafluoro-1-decanol [CF3(CF2)7(CH2)2OH] or 1H,1H-nonadecafluoro-1-decanol [CF3(CF2)8CH2OH], to introduce rigid and fluorophilic chains into the esterifying moiety of light-harvesting bacteriochlorophyll (BChl) c. Exogenous 1H,1H,2H,2H-heptadecafluoro-1-decanol was successfully attached to the 172-carboxy group of bacteriochlorophyllide (BChlide) c in vivo: the relative ratio of the unnatural BChl c esterified with this perfluoroalcohol over the total BChl c was 10.3%. Heat treatment of the liquid medium containing 1H,1H,2H,2H-heptadecafluoro-1-decanol with β-cyclodextrin before inoculation increased the relative ratio of the BChl c derivative esterified with this alcohol in the total BChl c in Cba. tepidum. In a while, 1H,1H-nonadecafluoro-1-decanol was not attached to BChlide c in Cba. tepidum, which was grown by its supplementation. These results suggest that the rigidity close to the hydroxy group of the esterifying alcohol is not suitable for the recognition by the BChl c synthase called BchK in Cba. tepidum. The unnatural BChl c esterified with 1H,1H,2H,2H-heptadecafluoro-1-decanol participated in BChl c self-aggregates in chlorosomes.
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      PubDate: 2016-08-18T08:58:06Z
       
  • Synthesis of asymmetric zinc(II) phthalocyanines with two different
           functional groups & spectroscopic properties and photodynamic
           activity for photodynamic therapy
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Meltem Göksel
      Zinc(II) phthalocyanine containing [2-(tert-butoxycarbonyl)amino]ethoxy and iodine groups (A and B), as well as their deprotected mono-amino and tri-iodine zinc(II) phthalocyanine (2) were obtained. This structure surrounds by substituents with functional groups. From this perspective it can be used a starting material for many reactions and applications, such as sonogashira coupling, carbodiimide coupling. An example of a first diversification reaction of this compound was obtained with conjugation of a biotin. Asymmetrically biotin conjugated and heavy atom bearing zinc(II) phthalocyanine (3) were synthesized characterized for the first time and photophysical, photochemical and photobiological properties of these phthalocyanines were compared in this study.
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      PubDate: 2016-08-18T08:58:06Z
       
  • Design, synthesis, and evaluation of Trolox-conjugated amyloid-β
           C-terminal peptides for therapeutic intervention in an in vitro model of
           Alzheimer’s disease
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Takuya Arai, Akiko Ohno, Mori Kazunori, Taeko Kakizawa, Hiroshi Kuwata, Toshihiko Ozawa, Motoko Shibanuma, Shuntaro Hara, Seiichi Ishida, Masaaki Kurihara, Naoki Miyata, Hidehiko Nakagawa, Kiyoshi Fukuhara
      Two hallmarks of Alzheimer’s disease (AD) observed in the brains of patients with the disease include oxidative injury and deposition of protein aggregates comprised of amyloid-β (Aβ) variants. To inhibit these toxic processes, we synthesized antioxidant-conjugated peptides comprised of Trolox and various C-terminal motifs of Aβ variants, TxAβ x – n (x =34, 36, 38, 40; n =40, 42, 43). Most of these compounds were found to exhibit anti-aggregation activities. Among them, TxAβ36–42 significantly inhibited Aβ1–42 aggregation, showed potent antioxidant activity, and protected SH-SY5Y cells from Aβ1–42-induced cytotoxicity. Thus, this method represents a promising strategy for developing multifunctional AD therapeutic agents.
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      PubDate: 2016-08-18T08:58:06Z
       
  • Synthesis and biological evaluation of 3-substituted
           5-benzylidene-1-methyl-2-thiohydantoins as potent NADPH oxidase (NOX)
           inhibitors
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Yun Soo Bae, Sun Choi, Jung Jae Park, Jung Hee Joo, Minghua Cui, Hyunsung Cho, Won Jae Lee, Sang Hyup Lee
      We report the synthesis of novel 3-substituted 5-benzylidene-1-methyl-2-thiohydantoins 3, and their biological evaluation using NADPH oxidase (NOX) 1 and 4. Based on structural and pharmacophore analyses of known inhibitors such as hydroxypyrazole 2, we envisioned interesting 2-thiohydantoin compounds, 3-substituted 5-benzylidene-1-methyl-2-thiohydantoins 3 that would be expected to well match the structural features in 2. Efficient synthesis of eighteen target compounds 3 were achieved through the synthetic pathway of 4 → 11 → 3, established after consideration of several plausible synthetic pathways. The inhibitory activities of compounds 3 against NOX 1 and 4 were measured, with some of the target compounds showing similar or higher activities compared with reference 2; in particular, compounds 3bz, 3cz, and 3ez were found to be promising inhibitors of both NOX 1 and 4 with modest isozyme selectivities, which highlights the significance of the 2-thiohydantoin substructure for inhibition of NOX 1 and 4. This marks the first time these compounds have been applied to the inhibition of NOX enzymes.
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      PubDate: 2016-08-18T08:58:06Z
       
  • Synthesis and biological evaluation of Oblongifolin C derivatives as c-Met
           inhibitors
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Liping Wang, Rong Wu, Wenwei Fu, Yuanzhi Lao, Changwu Zheng, Hongsheng Tan, Hongxi Xu
      Oblongifolin C, one of the polyprenylated benzoylphloroglucinol natural products (PPAPs) isolated from the fruits of Garcinia yunnanensis Hu, was recently discovered to be a potent anti-tumor agent. A collection of 12 derivatives with modifications on the benzophenone moieties were synthesized and tested for c-Met kinase inhibition and cytotoxicity against the HepG2, Miapaca-2, HCC827, Hela, A549, AGS, and HT-29 cell lines in vitro. An oxidized derivative, 10, was found to possess strong inhibition and anti-migration properties in the HCC827 cell line and serves as a potential lead compound for the development of new anticancer drugs. In addition, structure–activity relationships (SAR) were also evaluated to provide key information for future anticancer drug development.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Strand-invading linear probe combined with unmodified PNA
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Hiroyuki Asanuma, Rie Niwa, Mariko Akahane, Keiji Murayama, Hiromu Kashida, Yukiko Kamiya
      Efficient strand invasion by a linear probe to fluorescently label double-stranded DNA has been implemented by employing a probe and unmodified PNA. As a fluorophore, we utilized ethynylperylene. Multiple ethynylperylene residues were incorporated into the DNA probe via a d-threoninol scaffold. The ethynylperylene did not significantly disrupt hybridization with complementary DNA. The linear probe self-quenched in the absence of target DNA and did not hybridize with PNA. A gel-shift assay revealed that linear probe and PNA combination invaded the central region of double-stranded DNA upon heat-shock treatment to form a double duplex. To further suppress the background emission and increase the stability of the probe/DNA duplex, a probe containing anthraquinones as well as ethynylperylene was synthesized. This probe and PNA invader pair detected an internal sequence in a double-stranded DNA with high sensitivity when heat shock treatment was used. The probe and PNA pair was able to invade at the terminus of a long double-stranded DNA at 40°C at 100mM NaCl concentration.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Synthesis
           4-[2-(2-mercapto-4-oxo-4H-quinazolin-3-yl)-ethyl]-benzenesulfonamides with
           subnanomolar carbonic anhydrase II and XII inhibitory properties
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Murat Bozdag, Ahmed M. Alafeefy, Fabrizio Carta, Mariangela Ceruso, Abdul-Malek S. Al-Tamimi, Abdulla A. Al-Kahtani, Fatmah A.S. Alasmary, Claudiu T. Supuran
      Condensation of substituted anthranilic acids with 4-isothiocyanatoethyl-benzenesulfonamide led to series of heterocyclic benzenesulfonamides incorporating 2-mercapto-quinazolin-4-one tails. These sulfonamides were investigated as inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isozymes), as well as hCA XII (a transmembrane, tumor-associated enzyme also involved in glaucoma-genesis). The new sulfonamides acted as medium potency inhibitors of hCA I (K Is of 28.5–2954nM), being highly effective as hCA II (K Is in the range of 0.62–12.4nM) and XII (K Is of 0.54–7.11nM) inhibitors. All substitution patterns present in these compounds (e.g., halogens, methyl and methoxy moieties, in positions 6, 7 and/or 8 of the 2-mercapto-quinazolin-4-one ring) led to highly effective hCA II/XII inhibitors. These compounds should thus be of interest as preclinical candidates in pathologies in which the activity of these enzymes should be inhibited, such as glaucoma (CA II and XII as targets) or some tumors in which the activity of isoforms CA II and XII is dysregulated.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Antioxidant, anticancer activities and mechanistic studies of the flavone
           glycoside diosmin and its oxidovanadium(IV) complex. Interactions with
           bovine serum albumin
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Luciana Naso, Valeria R. Martínez, Luis Lezama, Clarisa Salado, María Valcarcel, Evelina G. Ferrer, Patricia A.M. Williams
      The natural antioxidant flavonoid diosmin, found in citric fruits, showed low antioxidant properties among other flavonoids due to its structural characteristics and low cytotoxicity against lung (A549) and breast (T47D, SKBR3 and MDAMB231) cancer cell lines. The anticancer behavior has been improved by the metal complex generated with the flavonoid and the oxidovanadium(IV) ion. This new complex, [VO(dios)(OH)3]Na5·6H2O (VOdios), has been synthesized and characterized both in solid and solution states. The interaction of the metal ion through the sugar moiety of diosmin precluded the improvement of the antioxidant effects. However, the cell-killing effects tested in human lung A549 and breast T47D, SKBR3 and MDAMB231 cancer cell lines, were enhanced by complexation. The anti-proliferative effects on the human lung cancer cell line were accompanied by cellular ROS generation and an increase in cytoplasm condensation. The breast cancer cell lines did not produce caspase3/7 activation, mitochondrial potential reduction and ROS generation. Therefore, a non-apoptotic form of cell death in a caspase- and oxidative stress-independent manner has been proposed. The protein binding ability has been monitored by the quenching of tryptophan emission in the presence of the compounds using bovine serum albumin (BSA) as a model protein. Both compounds could be distributed and transported in vivo and the complex displayed stronger binding affinity and higher contributions to the hydrogen bond and van der Waals forces.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Detection of l-alanylaminopeptidase activity in microorganisms using
           fluorogenic self-immolative enzyme substrates
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Marie Cellier, Arthur L. James, Jonathan Lowe, Sylvain Orenga, John D. Perry, Ari K. Rasul, Stephen P. Stanforth
      A series of fluorogenic enzymatic substrates that incorporate a self-immolative spacer were synthesised for the purpose of identifying l-alanylaminopeptidase activity in microorganisms in agar media. These substrates resulted in the generation of fluorescent microorganism colonies with Gram-negative microorganisms.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Synthesis, antiproliferative and pro-apoptotic activity of 2-phenylindoles
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Patrick M. Kelly, Sandra A. Bright, Darren Fayne, Jade K. Pollock, Daniela M. Zisterer, D. Clive Williams, Mary J. Meegan
      Breast cancer is the second most common cancer worldwide after lung cancer with the vast majority of early stage breast cancers being hormone-dependent. One of the major therapeutic advances in the clinical treatment of breast cancer has been the introduction of selective estrogen receptor modulators (SERMs). We describe the design and synthesis of novel SERM type ligands based on the 2-arylindole scaffold to selectively target the estrogen receptor in hormone dependent breast cancers. Some of these novel compounds are designed as bisindole type structures, while others are conjugated to a cytotoxic agent based on combretastatin A4 (CA4) which is a potent inhibitor of tubulin polymerisation. The indole compounds synthesised within this project such as 31 and 86 demonstrate estrogen receptor (ER) binding and strong antiproliferative activity in the ER positive MCF-7 breast cancer cell line with IC50 values of 2.71μM and 1.86μM respectively. These active compounds induce apoptotic activity in MCF-7 cells with minimal effects on normal peripheral blood cells. Their strong anti-cancer effect is likely mediated by the presence of two ER binding ligands for 31 and an ER binding ligand combined with a cytotoxic agent for 86.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Oxa-Pictet–Spengler reaction as key step in the synthesis of novel
           σ receptor ligands with 2-benzopyran structure
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Inga Knappmann, Dirk Schepmann, Bernhard Wünsch
      The Oxa-Pictet–Spengler reaction of methyl 3-hydroxy-4-phenylbutanoate (8) was explored to obtain novel σ receptor ligands. 1-Acyl protected piperidone ketals 10 and 11 reacted with phenylethanol 8 to yield spirocyclic compounds. Aliphatic aldehyde acetals 19 provided 1,3-disubstituted 2-benzopyrans 20 with high cis-diastereoselectivity. The intramolecular Oxa-Pictet–Spengler reaction of 24 led to the tricyclic compound 25. The spirocyclic compounds 18 show high σ1 affinity (K i 20–26nM) and σ1/σ2 selectivity (>9-fold), when a large substituent (n-octyl, benzyl, phenylpropyl) is attached to the piperidine N-atom. Opening of the piperidine ring to yield aminoethyl (22, 23) or aminomethyl derivatives (21) resulted in reduced σ1 affinity and σ1/σ2 selectivity.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Antibacterial and anticancer activity of a series of novel peptides
           incorporating cyclic tetra-substituted Cα amino acids
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Rickey P. Hicks
      Eleven antimicrobial peptides (AMP) based on the incorporation of cyclic tetra substituted Cα amino acids, as well as other unnatural amino acids were designed, synthesized and screened for in vitro activity against 18 strains of bacteria as well as 12 cancer cell lines. The AMPs discussed herein are derived from the following peptide sequence: Ac-GF(X)G(X)B(X)G(X)F(X)G(X)GB(X)BBBB-amide, X=any one of the following residues, A5c, A6c, Tic or Oic and B=any one of the following residues, Arg, Lys, Orn, Dpr or Dab. A diversity of in vitro inhibitory activity was observed for these AMPs. Several analogs exhibited single digit μM activity against drug resistant bacteria including; multiple drug resistant Mycobacterium tuberculosis, extremely drug resistant Mycobacterium tuberculosis and MRSA. The physicochemical properties of the basic amino acid residues incorporated into these AMPs seem to play a major role in defining antibacterial activity. Overall hydrophobicity seems to play a limited role in defining antibacterial activity. The ESKAPE pathogens were used to compare the activity of these AMPs to another family of synthetic AMPs incorporating the unnatural amino acids Tic and Oic. In most cases similarly substituted members of both families exhibited similar inhibitory activity against the ESKAPE pathogens. In specific cases differences in activity as high as 15 fold were observed between analogs. In addition four of these AMPs exhibited promising IC50 (<7.5μM) values against 12 different and diverse cancer cell lines. Five other AMPs exhibited promising IC50 (<7.5μM) values against selected cancer cell lines.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Synthesis and biological evaluation of analogues of the potent ADAM8
           inhibitor cyclo(RLsKDK) for the treatment of inflammatory diseases and
           cancer metastasis
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Victor Yim, Anaïs F.M. Noisier, Kuo-yuan Hung, Jörg W. Bartsch, Uwe Schlomann, Margaret A. Brimble
      The metalloproteinase ADAM8 serves as a pivotal catalyst in the development of inflammatory diseases and cancer metastasis. The cyclic peptide cyclo(RLsKDK) has been shown to inhibit the enzymatic activity of ADAM8 with high specificity and potency. Herein we report a structure–activity relationship (SAR) study of cyclo(RLsKDK) that involves the synthesis and biological evaluation of the lead compound and structural analogues thereof. This study provides insight into the ligand–receptor interactions that govern the binding of cyclo(RLsKDK) to the ADAM8 disintegrin domain and represents a stepping stone for the development of new treatments for inflammatory diseases and cancer metastasis.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Synthesis and potent antiprotozoal activity of mono/di amidino
           2-anilinobenzimidazoles versus Plasmodium falciparum and Trypanosoma
           brucei rhodesiense
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Cigdem Karaaslan, Marcel Kaiser, Reto Brun, Hakan Göker
      A series of mono and dicationic new 2-anilinobenzimidazole carboxamidines were prepared in a four step process starting from 4-amino-3-nitrobenzonitrile and corresponding o-phenylenediamines. Their antiparasitic activity against Plasmodium falciparum (P. falciparum) and Trypanosoma brucei rhodesiense (T.b. rhodesiense) were evaluated in vitro. Some of the dicationic compounds (10,12,14) showed equal or very close activity against T.b. rhodesiense with melarsoprol and also showed promising activity against P. falciparum as compared to chloroquine. Among the monocationic derivatives compound 21 exhibited best inhibitory activity against P. falciparum.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Design, synthesis, and mode of action studies of a mitomycin tetramer
           inducing double activations with a single probe
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Hyoung Rae Kim, Yeon Kyeong Park, Sang Hyup Lee
      We report design, synthesis, and mechanistic studies of a new mitomycin tetramer 9 along with a new mitomycin dimer 10. Mitomycin 9 is a tetramer connected by the disulfide linker 11, and easily undergoes disulfide cleavage to provide two dimeric structures 9r that each contains a single thiol probe for activations. So, tetramer 9 as a precursor of 9r was specifically targeted to undergo double activations with a single probe. A tetramer 9 was synthesized using 1 and key intermediate 11, and a dimer 10 was synthesized from 1 and diamine 12. Activation studies revealed that 9 underwent effective double activations with a single probe by nucleophiles while the reference 10 did not. Evaluations of DNA ISC formations showed that 9 generated substantial levels of DNA ISC by nucleophilic activation while the references 10 and 2 did not. The effectiveness of 9 in activation and formation of DNA ISC per probe was verified by comparing with dimers 5–8 of double activations with two probes. These findings highlighted the role of a single thiol in 9r and demonstrated the intended double activations with a single probe, which marks the first case in mitomycin studies.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Kinetic and structural insights into the binding of histone deacetylase 1
           and 2 (HDAC1, 2) inhibitors
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Florence F. Wagner, Michel Weïwer, Stefan Steinbacher, Adrian Schomburg, Peter Reinemer, Jennifer P. Gale, Arthur J. Campbell, Stewart L. Fisher, Wen-Ning Zhao, Surya A. Reis, Krista M. Hennig, Méryl Thomas, Peter Müller, Martin R. Jefson, Daniel M. Fass, Stephen J. Haggarty, Yan-Ling Zhang, Edward B. Holson
      The structure–activity and structure–kinetic relationships of a series of novel and selective ortho-aminoanilide inhibitors of histone deacetylases (HDACs) 1 and 2 are described. Different kinetic and thermodynamic selectivity profiles were obtained by varying the moiety occupying an 11Å channel leading to the Zn2+ catalytic pocket of HDACs 1 and 2, two paralogs with a high degree of structural similarity. The design of these novel inhibitors was informed by two ligand-bound crystal structures of truncated hHDAC2. BRD4884 and BRD7232 possess kinetic selectivity for HDAC1 versus HDAC2. We demonstrate that the binding kinetics of HDAC inhibitors can be tuned for individual isoforms in order to modulate target residence time while retaining functional activity and increased histone H4K12 and H3K9 acetylation in primary mouse neuronal cell culture assays. These chromatin modifiers, with tuned binding kinetic profiles, can be used to define the relation between target engagement requirements and the pharmacodynamic response of HDACs in different disease applications.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Dideoxy nucleoside triphosphate (ddNTP) analogues: Synthesis and
           polymerase substrate activities of pyrrolidinyl nucleoside triphosphates
           (prNTPs)
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Chandrasekhar Reddy Gade, Manjusha Dixit, Nagendra K. Sharma
      The dideoxynucleoside triphosphates (ddNTPs) terminate the bio-polymerization of DNA and become essential chemical component of DNA sequencing technology which is now basic tool for molecular biology research. In this method the radiolabeled or fluorescent dye labeled ddNTP analogues are being used for DNA sequencing by detection of the terminated DNA fragment after single labeled ddNTP incorporation into DNA under PCR conditions. This report describes the syntheses of rationally designed novel amino-functionalized ddNTP analogue such as Pyrrolidine nucleoside triphosphates (prNTPs), and their polymerase activities with DNA polymerase by LC–MS and Gel-electrophoretic techniques. The Mass and PAGE analyses strongly support the incorporation of prNTPs into DNA oligonucleotide with Therminator DNA polymerase as like control substrate ddNTP. As resultant the DNA oligonucleotide are functionalized as amine group by prNTP incorporation with polymerase. Hence prNTPs provide opportunities to prepare demandable conjugated DNA with other biomolecules/dyes/fluorescence molecule without modifying nucleobase structure.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Synthesis and biological investigation of new equatorial (β)
           stereoisomers of 3-aminotropane arylamides with atypical antipsychotic
           profile
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Jacek Stefanowicz, Tomasz Słowiński, Martyna Zofia Wróbel, Franciszek Herold, Anna Edyta Gomółka, Anna Wesołowska, Magdalena Jastrzębska-Więsek, Anna Partyka, Marta Andres-Mach, Stanisław Jerzy Czuczwar, Jarogniew Jacek Łuszczki, Mirosław Zagaja, Agata Siwek, Gabriel Nowak, Maria Żołnierek, Tomasz Bączek, Szymon Ulenberg, Mariusz Belka, Jadwiga Turło
      A series of novel 3β-aminotropane derivatives containing a 2-naphthalene or a 2-quinoline moiety was synthesised and evaluated for their affinity for 5-HT1A, 5-HT2A and D2 receptors. Their affinity for the receptors was in the nanomolar to micromolar range. p-Substitution (6c, 6f, 6i, 6l, 6o), as well as substitution with chlorine atoms (6g, 6h, 6i), led to a significant increase in binding affinity for D2 receptors with compounds 6f (K i =0.6nM), 6c and 6i (K i =0.4nM), having the highest binding affinities. m-Substituted derivatives were the most promising ligands in terms of 5-HT2A receptor binding affinity whereas 2-quinoline derivatives (10a, 10b) displayed the highest affinity for 5-HT1AR and were the most selective ligands with K i =62.7nM and K i =30.5nM, respectively. Finally, the selected ligands 6b, 6d, 6e, 6g, 6h, 6k, 6n and 6o, with triple binding activity for the D2, 5-HT1A and 5-HT2A receptors, were subjected to in vivo tests, such as those for induced hypothermia, climbing behaviour and the head twitch response, in order to determine their pharmacological profile. The tested ligands presented neither agonist nor antagonist properties for the 5-HT1A receptors in the induced hypothermia and lower lip retraction (LLR) tests. All tested compounds displayed antagonistic activity against 5-HT2A, with 6n and 6o being the most active. Four (6b, 6k, 6n and 6o) out of eight tested compounds could be classified as D2 antagonists. Additionally, evaluation of metabolic stability was performed for selected ligands, and introduction of halogen atoms into the benzene ring of 6h, 6k, 6n and 6o improved their metabolic stability. The project resulted in the selection of the lead compounds 6n and 6o, which had antipsychotic profiles, combining dopamine D2-receptor and 5-HT2A antagonism and metabolic stability.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Small molecule non-peptide inhibitors of botulinum neurotoxin serotype E:
           Structure–activity relationship and a pharmacophore model
    • 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.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Novel FXR (farnesoid X receptor) modulators: Potential therapies for
           cholesterol gallstone disease
    • 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.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Editorial board
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18




      PubDate: 2016-08-18T08:58:06Z
       
  • Dual and antagonic therapeutic effects of sulfated glycans
    • 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.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Antileishmanial activity of new thiophene–indole hybrids: Design,
           synthesis, biological and cytotoxic evaluation, and chemometric studies
    • 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.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
  • Anti-inflammatory properties of pterocarpanquinone LQB-118 in mice
    • Abstract: Publication date: 15 September 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 18
      Author(s): Ingred G. Riça, Chaquip D. Netto, Magdalena N. Rennó, Paula A. Abreu, Paulo R.R. Costa, Alcides J.M. da Silva, Moisés C.M. Cavalcante
      Pterocarpanquinone (+/−)-LQB-118 presents antineoplastic and antiparasitic properties and also shows great inhibitory effect on TNF-α release in vitro. Here, its anti-inflammatory activity was evaluated in a lipopolysaccharide (LPS)-induced lung inflammation model in C57BL/6 mice. LPS inhalation induced a marked neutrophil infiltration to the lungs which was reduced by intraperitoneal treatment with (+/−)-LQB-118 in a similar manner to that of dexamethasone and even better than that of acetylsalicylic acid. Moreover, (+/−)-LQB-118 administration resulted in decrease of NF-κB activation and KC level in lungs, with a pronounced inhibitory effect on TNF-α release, measured in bronchoalveolar lavage fluid. Trying to understand the anti-inflammatory mechanism by which (+/−)-LQB-118 acts, we performed a molecular modeling analysis, including docking to estrogen receptors α and β. Results suggested that (+/−)-LQB-118 may bind to both receptors, with a similar orientation to 17-β-estradiol. Together, these results showed that (+/−)-LQB-118 exhibits an anti-inflammatory effect, most likely by inhibiting TNF-α release and NF-κB activation, which may be related to the estrogen receptor binding.
      Graphical abstract image

      PubDate: 2016-08-18T08:58:06Z
       
 
 
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