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  Subjects -> CHEMISTRY (Total: 846 journals)
    - ANALYTICAL CHEMISTRY (47 journals)
    - CHEMISTRY (596 journals)
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CHEMISTRY (596 journals)                  1 2 3 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 4)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 26)
ACS Catalysis     Full-text available via subscription   (Followers: 21)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 14)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 22)
ACS Macro Letters     Full-text available via subscription   (Followers: 18)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 29)
ACS Nano     Full-text available via subscription   (Followers: 153)
ACS Photonics     Full-text available via subscription   (Followers: 6)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 15)
Acta Chemica Iasi     Open Access  
Acta Chimica Sinica     Full-text available via subscription   (Followers: 1)
Acta Chimica Slovaca     Open Access   (Followers: 2)
Acta Chromatographica     Full-text available via subscription   (Followers: 7)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 5)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 5)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 4)
Advanced Functional Materials     Hybrid Journal   (Followers: 40)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 31)
Advances in Chemical Science     Open Access   (Followers: 10)
Advances in Chemistry     Open Access   (Followers: 7)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 14)
Advances in Drug Research     Full-text available via subscription   (Followers: 20)
Advances in Environmental Chemistry     Open Access  
Advances in Enzyme Research     Open Access   (Followers: 3)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 13)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 13)
Advances in Nanoparticles     Open Access   (Followers: 11)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 12)
Advances in Polymer Science     Hybrid Journal   (Followers: 36)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 13)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 12)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Science and Technology     Full-text available via subscription   (Followers: 1)
African Journal of Chemical Education     Open Access   (Followers: 2)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 5)
Afrique Science : Revue Internationale des Sciences et Technologie     Open Access   (Followers: 1)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 1)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
AMB Express     Open Access  
Ambix     Hybrid Journal   (Followers: 2)
American Journal of Applied Sciences     Open Access   (Followers: 26)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 69)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 12)
American Journal of Chemistry     Open Access   (Followers: 23)
American Journal of Plant Physiology     Open Access   (Followers: 12)
American Mineralogist     Full-text available via subscription   (Followers: 7)
Anadolu University Journal of Science and Technology     Open Access  
Analyst     Full-text available via subscription   (Followers: 40)
Angewandte Chemie     Hybrid Journal   (Followers: 107)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 150)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 1)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 2)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 3)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 7)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 8)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 12)
Anti-Infective Agents     Hybrid Journal   (Followers: 2)
Antiviral Chemistry and Chemotherapy     Full-text available via subscription  
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 5)
Applied Spectroscopy     Full-text available via subscription   (Followers: 21)
Applied Surface Science     Hybrid Journal   (Followers: 20)
Arabian Journal of Chemistry     Full-text available via subscription   (Followers: 6)
ARKIVOC     Open Access   (Followers: 1)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 4)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 8)
Biochemistry     Full-text available via subscription   (Followers: 196)
Biochemistry Insights     Open Access   (Followers: 4)
Biochemistry Research International     Open Access   (Followers: 4)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 7)
Bioinspired Materials     Open Access   (Followers: 2)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 1)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access  
Biomacromolecules     Full-text available via subscription   (Followers: 15)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 8)
Biomedical Chromatography     Hybrid Journal   (Followers: 7)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 2)
BioNanoScience     Partially Free   (Followers: 4)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 87)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 76)
Bioorganic Chemistry     Hybrid Journal   (Followers: 9)
Biopolymers     Hybrid Journal   (Followers: 16)
Biosensors     Open Access   (Followers: 1)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 2)
Bitácora Digital     Open Access  
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 3)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 23)
Bulletin of the Korean Chemical Society     Hybrid Journal  
C - Journal of Carbon Research     Open Access   (Followers: 2)
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 3)
Canadian Journal of Chemistry     Full-text available via subscription   (Followers: 6)
Canadian Mineralogist     Full-text available via subscription   (Followers: 3)
Carbohydrate Research     Hybrid Journal   (Followers: 27)
Carbon     Hybrid Journal   (Followers: 61)
Catalysis for Sustainable Energy     Open Access   (Followers: 4)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 6)
Catalysis Science and Technology     Free   (Followers: 4)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 5)
Cellulose     Hybrid Journal   (Followers: 4)
Central European Journal of Chemistry     Hybrid Journal   (Followers: 6)
Cereal Chemistry     Full-text available via subscription   (Followers: 4)
ChemBioEng Reviews     Full-text available via subscription  
ChemCatChem     Hybrid Journal   (Followers: 4)
Chemical and Engineering News     Free   (Followers: 10)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 19)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 15)
Chemical Reviews     Full-text available via subscription   (Followers: 122)
Chemical Science     Open Access   (Followers: 16)
Chemical Technology     Open Access   (Followers: 5)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 4)
Chemical Week     Full-text available via subscription   (Followers: 7)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 53)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 25)
ChemInform     Hybrid Journal   (Followers: 4)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 4)
Chemistry & Biology     Full-text available via subscription   (Followers: 29)
Chemistry & Industry     Hybrid Journal   (Followers: 2)
Chemistry - A European Journal     Hybrid Journal   (Followers: 98)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 11)
Chemistry and Materials Research     Open Access   (Followers: 13)
Chemistry Central Journal     Open Access   (Followers: 5)
Chemistry Education Research and Practice     Free   (Followers: 4)
Chemistry in Education     Open Access   (Followers: 2)
Chemistry International     Hybrid Journal   (Followers: 1)
Chemistry Letters     Full-text available via subscription   (Followers: 42)
Chemistry of Materials     Full-text available via subscription   (Followers: 135)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 8)
Chemistry World     Full-text available via subscription   (Followers: 21)
Chemistry-Didactics-Ecology-Metrology     Open Access  
ChemistryOpen     Open Access   (Followers: 1)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 2)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 14)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 6)
ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 3)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 10)
Chromatographia     Hybrid Journal   (Followers: 25)
Chromatography     Open Access   (Followers: 5)
Chromatography Research International     Open Access   (Followers: 5)
Clay Minerals     Full-text available via subscription   (Followers: 9)
Cogent Chemistry     Open Access  
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 8)
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 6)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
Combustion Science and Technology     Hybrid Journal   (Followers: 17)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 1)
Composite Interfaces     Hybrid Journal   (Followers: 3)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 1)
Comptes Rendus Chimie     Full-text available via subscription  
Comptes Rendus Physique     Full-text available via subscription   (Followers: 1)
Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 10)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 10)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 9)
Coordination Chemistry Reviews     Full-text available via subscription  
Copernican Letters     Open Access  
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 4)
Crystal Structure Theory and Applications     Open Access   (Followers: 2)
CrystEngComm     Full-text available via subscription   (Followers: 6)
Current Catalysis     Hybrid Journal   (Followers: 1)
Current Metabolomics     Hybrid Journal   (Followers: 3)
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 7)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 15)
Current Research in Chemistry     Open Access   (Followers: 7)
Current Trends in Biotechnology and Chemical Research     Open Access   (Followers: 3)
Dalton Transactions     Full-text available via subscription   (Followers: 17)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription  
Diamond and Related Materials     Hybrid Journal   (Followers: 12)
Dislocations in Solids     Full-text available via subscription  
Doklady Chemistry     Hybrid Journal  
Drying Technology: An International Journal     Hybrid Journal   (Followers: 3)
Eclética Química     Open Access   (Followers: 1)
Ecological Chemistry and Engineering S     Open Access   (Followers: 2)
Ecotoxicology and Environmental Contamination     Open Access  
Educación Química     Open Access   (Followers: 1)
Education for Chemical Engineers     Hybrid Journal   (Followers: 4)
Elements     Full-text available via subscription  
Environmental Chemistry     Hybrid Journal   (Followers: 5)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 2)
Environmental Science & Technology Letters     Full-text available via subscription   (Followers: 2)

        1 2 3 | Last

Journal Cover Bioorganic & Medicinal Chemistry
  [87 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0968-0896
   Published by Elsevier Homepage  [2817 journals]
  • Exploring New Chemical Functionalities to Improve Aromatase Inhibition of
           Steroids
    • Abstract: Publication date: Available online 26 April 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Carla L. Varela, Cristina Amaral, Georgina Correia-da-Silva, Saul C. Costa, Rui A. Carvalho, Giosuè Costa, Stefano Alcaro, Natércia A.A. Teixeira, Elisiário J. Tavares-da-Silva, Fernanda M.F. Roleira
      In this work, new potent steroidal aromatase inhibitors both in microsomes and in breast cancer cells have been found. The synthesis of the 3,4-(ethylenedioxy)androsta-3,5-dien-17-one (12), a new steroid containing a heterocycle dioxene fused in the A-ring, led to the discovery of a new reaction for which a mechanism is proposed. New structure-activity relationships were established. Some 5β-steroids, such as compound 4β,5β-epoxyandrostan-17-one (9), showed aromatase inhibitory activity, because they adopt a similar A-ring conformation as those of androstenedione, the natural substrate of aromatase. Moreover, new chemical features to increase planarity were disclosed, specifically the 3α,4α-cyclopropane ring, as in 3α,4α-methylen-5α-androstan-17-one (5) (IC50 = 0.11 μM), and the Δ9-11 double bond in the C-ring, as in androsta-4,9(11)-diene-3,17-dione (13) (IC50 = 0.25 μM). In addition, induced-fit docking (IFD) simulations and site of metabolism (SoM) predictions helped to explain the recognition of new potent steroidal aromatase inhibitors within the enzyme. These insights can be valuable tools for the understanding of the molecular recognition process by the aromatase and for the future design of new steroidal inhibitors.
      Graphical abstract image

      PubDate: 2016-04-28T10:46:53Z
       
  • Design, Synthesis, Structure-Activity Relationships, and Docking Studies
           of Pyrazole-Containing Derivatives as a Novel Series of Potent Glucagon
           Receptor Antagonists
    • Abstract: Publication date: Available online 26 April 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Shuangjie Shu, Xiaoqing Cai, Jia Li, Yang Feng, Antao Dai, Jiang Wang, Dehua Yang, Ming-Wei Wang, Hong Liu
      Glucagon receptor antagonists possess a great potential for treatment of type 2 diabetes mellitus. A series of pyrazole-containing derivatives were designed, synthesized and evaluated by biological assays as glucagon receptor antagonists. Most of the compounds exhibited good in vitro efficacy. Two of them, compounds 17f and 17k, displayed relatively potent antagonist effects on glucagon receptors with IC50 values of 3.9 and 3.6 μM, respectively. The possible binding modes of 17f and 17k with the cognate receptor were explored by molecular docking simulation.
      Graphical abstract image

      PubDate: 2016-04-28T10:46:53Z
       
  • Synthesis and evaluation of duocarmycin SA analogs incorporating the
           methyl
           1,2,8,8a-tetrahydrocyclopropa[c]imidazolo[4,5-e]indol-4-one-6-carboxylate
           (CImI) alkylation subunit
    • Abstract: Publication date: Available online 26 April 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Prem B. Chanda, Kristopher E. Boyle, Daniel M. Brody, Vyom Shukla, Dale L. Boger
      The design, synthesis, and evaluation of methyl 1,2,8,8a-tetrahydrocyclopropa[c]imidazolo[4,5-e]indol-4-one-6-carboxylate (CImI) derivatives are detailed representing analogs of duocarmycin SA and yatakemycin containing an imidazole replacement for the fused pyrrole found in the DNA alkylation subunit.
      Graphical abstract image

      PubDate: 2016-04-28T10:46:53Z
       
  • Synthesis and biological evaluation of 1,2-dithiol-3-thiones and
           pyrrolo[1,2-a]pyrazines as novel hypoxia inducible factor-1 (HIF-1)
           inhibitor
    • Abstract: Publication date: Available online 26 April 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Young Hun Lee, Jung Min Lee, Sang Geon Kim, Yong Sup Lee
      Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor which is strongly associated with tumor survival, progression, and therapeutic resistance. Accordingly, it has been suggested that the inhibition of the HIF-1 pathway can suppress tumor, and it has become an important therapeutic target. In present study, oltipraz, its metabolite M2, and their derivatives were synthesized and evaluated as HIF-1α inhibitors. Among the synthesized, benzyl-substituted pyrrolo[1,2-a]pyrazine 2g most potently inhibited HIF-1α protein accumulation (81% at 10 μM) and VEGF, GLUT-1 transcription (77% and 92% at 10 μM, respectively).
      Graphical abstract image

      PubDate: 2016-04-28T10:46:53Z
       
  • Hydraphiles Enhance Antimicrobial Potency Against Escherichia coli,
           Pseudomonas aeruginosa, and Bacillus subtilis
    • Abstract: Publication date: Available online 27 April 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Mohit B. Patel, Evan C. Garrad, Ariel Stavri, Michael R. Gokel, Saeedeh Negin, Joseph W. Meisel, Zachary Cusumano, George W. Gokel
      Hydraphiles are synthetic amphiphiles that form ion-conducting pores in liposomal membranes. These pores exhibit open-close behavior when studied by planar bilayer conductance techniques. In previous work, we showed that when co-administered with various antibiotics to the DH5α strain of E. coli, they enhanced the drug’s potency. We report here potency enhancements at low concentrations of hydraphiles for the structurally and mechanistically unrelated antibiotics erythromycin, kanamycin, rifampicin, and tetracycline against Gram negative E. coli (DH5α and K-12) and Pseudomonas aeruginosa, as well as Gram positive Bacillus subtilis. Earlier work suggested that potency increases correlated to ion transport function. The data presented here comport with the function hydraphiles to enhance membrane permeability in addition to, or instead of, their known function as ion conductors.
      Graphical abstract image

      PubDate: 2016-04-28T10:46:53Z
       
  • Capture of endogenously biotinylated proteins from Pseudomonas aeruginosa
           displays unexpected downregulation of LiuD upon iron nutrition
    • Abstract: Publication date: Available online 26 April 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Farnusch Kaschani, Qing Wei, Jozef Dingemans, Renier A.L. van der Hoorn, Pierre Cornelis, Markus Kaiser
      The uptake and storage but also removal of excess iron are of utmost importance to microorganisms since surplus levels of iron may lead to the formation of reactive oxygen species. Therefore, iron homeostasis is generally tightly regulated by the ferric uptake regulator (Fur), a global iron regulator acting as a transcriptional repressor. While detecting biotinylated proteins in labelling experiments, we discovered that the endogenously biotinylated protein LiuD differentially accumulated upon iron treatment. LiuD represents the αsubunit of the methylcrotonyl‐CoA‐carboxylase (MCCase), an enzyme from the leucine/isovalerate utilization pathway. Real-time PCR transcription analysis revealed that the observed lower levels of LiuD biotinylation could be traced back to lower LiuD protein levels via a transcriptional repression of liuABCDE expression that however does not seem to be mediated by Fur. In accordance with LiuD’s role for the leucine/isovalerate utilization pathway and its protein level regulation by nutritional iron levels, we found that wild-type P. aeruginosa did not grow in the presence of iron if the medium contained only leucine as a carbon source. Conversely, iron stimulated the growth when glucose was used as a carbon source. Our study thus demonstrates the complexities of iron-regulated bacterial growth in Pseudomonas aeruginosa.
      Graphical abstract image

      PubDate: 2016-04-28T10:46:53Z
       
  • The 5-aromatic hydantoin-3-acetate derivatives as inhibitors of the tumour
           multidrug resistance efflux pump P-glycoprotein (ABCB1): Synthesis,
           crystallographic and biological studies
    • Abstract: Publication date: Available online 26 April 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Ewa Żesławska, Annamária Kincses, Gabriella Spengler, Wojciech Nitek, Karolina Wyrzuc, Katarzyna Kieć-Kononowicz, Jadwiga Handzlik
      A series of arylpiperazine derivatives of hydantoin-3-acetate, including previously obtained 5,5-diphenylhydantoin (1-7) and new-synthesized spirofluorene-hydantoin derivatives (8-12), were investigated in the search for new inhibitors of the tumour multidrug resistance (MDR) efflux pump P-glycoprotein (P-gp, ABCB1) overexpressed in mouse T-lymphoma cells. Synthesis of new compounds (8-12) was performed. Crystal structures of two compounds (8 and 11) were determined by X-ray diffraction method. The conformations of the investigated molecules (8 and 11) in the crystalline samples are different. The bent conformation seems to be more favourable for biological activity than the extended one. The efflux pump inhibitory properties of the compounds 1-12 were evaluated in the fluorescence uptake assay using rhodamine 123 dye in mouse T-lymphoma model in vitro. Their cytotoxic action was examined, too. All compounds with methyl acetate moiety displayed high potency to inhibit the MDR efflux pump. The most active compound, methyl 2-(1-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-5,5-diphenylhydantoin-3-yl)acetate (5), was tested at 1/10 of verapamil concentration displayed the 9-fold higher P-gp inhibitory action.
      Graphical abstract image

      PubDate: 2016-04-28T10:46:53Z
       
  • Novel sulfonamide bearing coumarin scaffolds as selective inhibitors of
           tumour associated carbonic anhydrase isoforms IX and XII
    • Abstract: Publication date: Available online 26 April 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Navneet Chandak, Mariangela Ceruso, Claudiu T. Supuran, Pawan K. Sharma
      Four novel scaffolds consisting of total 24 compounds (1a-1o, 2a-2c, 3a-3c and 4a-4c) bearing aromatic sulfonamide and coumarin moieties connected through various linkers were synthesized in order to synergize the inhibition potential of both the moieties against four selected human carbonic anhydrase isoforms (hCA I, II, IX & XII). All compounds were found to be potent inhibitors of tumour associated hCA IX & XII while at the same time required large amounts to inhibit off-targeted housekeeping hCA I & II. Selectivity was more pronounced against hCA II over I, and hCA XII over IX. Results were compared with antitumour drug acetazolamide. One derivative 2b of series 2 was found to be a better selective inhibitor of hCA IX and XII.
      Graphical abstract image

      PubDate: 2016-04-28T10:46:53Z
       
  • Synthesis and characterization of a fluorescent probe for
           α-tocopherol suitable for fluorescence microscopy
    • Abstract: Publication date: Available online 26 April 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Mikel Ghelfi, Lynn Ulatowski, Danny Manor, Jeffrey Atkinson
      Previously prepared fluorescent derivatives of α-tocopherol have shown tremendous utility in both in vitro exploration of the mechanism of ligand transfer by the α-tocopherol transfer protein (α-TTP) and the intracellular transport of α-tocopherol in cells and tissues. We report here the synthesis of a 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) containing α-tocopherol analogue having extended conjugation with an alkenyl thiophene group that extends the absorption and emission maxima to longer wavelengths (λex = 571 nm and λem= 583 nm). The final fluorophore thienyl-ene-BODIPY-α-tocopherol, 2, binds to recombinant human α-TTP with a K d = 8.7 ± 1.1 nM and is a suitable probe for monitoring the secretion of α-tocopherol from cultured Mcf7#189 cells.
      Graphical abstract image

      PubDate: 2016-04-28T10:46:53Z
       
  • Antileishmanial Activity of new Thiophene-indole Hybrids: Design,
           Synthesis, Biological and Cytotoxic Evaluation, and Chemometric Studies
    • Abstract: Publication date: Available online 26 April 2016
      Source:Bioorganic & Medicinal Chemistry
      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 10.0 μg/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 3.2 μg/mL. Demonstrating that all of the compounds were less toxic than the reference drugs, even at the highest evaluated concentration (400 μg/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/lipophylicity, 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: 2016-04-28T10:46:53Z
       
  • 6-Oxooxazolidine-quinazolines as noncovalent inhibitors with the potential
           to target mutant forms of EGFR
    • Abstract: Publication date: Available online 23 April 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Jiaan Shao, En Chen, Ke Shu, Wenteng Chen, Guolin Zhang, Yongping Yu
      Despite the remarkable benefits of gefitinib, the clinical efficacy is eventually diminished due to the acquired point mutations in the EGFR (T790M). To address this unmet medical need, we demonstrated a strategy to prepare a hybrid analogue consisting of the oxooxazolidine ring and the quinazoline scaffold and provided alternative noncovalent inhibitors targeting mutant forms of EGFR. Most of the derivatives displayed moderate to good anti-proliferative activity against gefitinib-resistant NCI-H1975. Some of them exhibited potent EGFR kinase inhibitory activities, especially on EGFR T790M and EGFR L858R kinases. SAR studies led to the identification of a hit 9a that can target both of the most common EGFR mutants: L858R and T790M. Also, 9a displayed weaker inhibitory against cancer cell lines with low level of EGFR expression and good chemical stability under different pH conditions. The work presented herein showed the potential for developing noncovalent inhibitors targeting EGFR mutants.
      Graphical abstract image

      PubDate: 2016-04-24T13:55:31Z
       
  • Analysis of the aplyronine A-induced protein–protein interaction
           between actin and tubulin by surface plasmon resonance
    • Abstract: Publication date: Available online 24 April 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Yuichiro Hirayama, Kota Yamagishi, Tomohiro Suzuki, Hirokazu Kawagishi, Masaki Kita, Hideo Kigoshi
      The antitumor macrolide aplyronine A induces protein–protein interaction (PPI) between actin and tubulin to exert highly potent biological activities. The interactions and binding kinetics of these molecules were analyzed by the surface plasmon resonance with biotinylated aplyronines or tubulin as ligands. Strong binding was observed for tubulin and actin with immobilized aplyronine A. These PPIs were almost completely inhibited by one equivalent of either aplyronine A or C, or mycalolide B. In contrast, a non-competitive actin-depolymerizing agent, latrunculin A, highly accelerated their association. Significant binding was also observed for immobilized tubulin with an actin–aplyronine A complex, and the dissociation constant K D was 1.84 μM. Our method could be used for the quantitative analysis of the PPIs between two polymerizing proteins stabilized with small agents. © 2016 Elsevier Science. All rights reserved
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      PubDate: 2016-04-24T13:55:31Z
       
  • Exploring the 2- and 5-positions of the pyrazolo[4,3-d]pyrimidin-7-amino
           scaffold to target human A1 and A2A adenosine receptors
    • Abstract: Publication date: Available online 23 April 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Lucia Squarcialupi, Matteo Falsini, Daniela Catarzi, Flavia Varano, Marco Betti, Katia Varani, Fabrizio Vincenzi, Diego Dal Ben, Catia Lambertucci, Rosaria Volpini, Vittoria Colotta
      A new series of 7-aminopyrazolo[4,3-d]pyrimidine derivatives (1-31) were synthesized to evaluate some structural modifications at the 2- and 5- positions aimed at shifting affinity towards the human (h) A2A adenosine receptor (AR) or both hA2A and hA1 ARs. The most active compounds were those featured by a 2-furyl or 5-methylfuran-2-yl moiety at position 5, combined with a benzyl or a substituted-benzyl group at position 2. Several of these derivatives (22-31) displayed nanomolar affinity for the hA2A AR (Ki= 3.62-57 nM) and slightly lower for the hA1 ARs, thus showing different degrees (3-22 fold) of hA2A versus hA1 selectivity. In particular, the 2-(2-methoxybenzyl)-5-(5-methylfuran-2-yl) derivative 25 possessed the highest hA2A and hA1 AR affinities (Ki= 3.62 nM and 18 nM, respectively) and behaved as potent antagonist at both these receptors (cAMP assays). Its 2-(2-hydroxybenzyl) analog 26 also showed a high affinity for the hA2A AR (Ki= 5.26 nM) and was 22-fold selective versus the hA1 subtype. Molecular docking investigations performed at the hA2A AR crystal structure and at a homology model of the hA1 AR allowed us to represent the hypothetical binding mode of our derivatives and to rationalize the observed SARs.
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      PubDate: 2016-04-24T13:55:31Z
       
  • Studies on phenothiazines: New microtubule-interacting compounds with
           phenothiazine A-ring as potent antineoplastic agents
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Alina Ghinet, Iuliana-Monica Moise, Benoît Rigo, Germain Homerin, Amaury Farce, Joëlle Dubois, Elena Bîcu
      New phenothiazine derivatives 6–20 have been designed, synthesized and evaluated in vitro for their ability to inhibit tubulin polymerization and antiproliferative activity against 60 cancer cell lines, including several multi-drug resistant (MDR) tumor cell lines. The phenothiazine unit may successfully replace the classical 3,4,5-trimethoxyphenyle A ring of parent combretastatin A-4 or phenstatin, confirming previous studies. The most promising structural modulations have been realized on the B ring, the 2′-fluoro-4′-methoxy substitution in compound 6 and the 2′-trifluoromethyl-4′-methoxy substitution in compound 7 providing the best antitubulin and antitumor activity in the current study. Compounds 6–8 and 16 exhibited more important cell growth inhibition than parent phenstatin 2 on human colon Duke’s type D, colorectal adenocarcinoma COLO 205 and on human kidney adenocarcinoma A498 cell lines. 10-Methylphenothiazine derivatives 19 and 20 did not show biological activity but exerted bright fluorescence and solvatochromism effects. These molecules deserve further chemical efforts in order to provide valuable tools for biophysical studies.
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      PubDate: 2016-04-20T13:51:13Z
       
  • Synthesis and molecular docking of
           N′-arylidene-5-(4-chlorophenyl)-1-(3,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbohydrazides
           as novel hypoglycemic and antioxidant dual agents
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Eduardo Hernández-Vázquez, Sandybel Salgado-Barrera, Juan José Ramírez-Espinosa, Samuel Estrada-Soto, Francisco Hernández-Luis
      Herein, the design and synthesis of 10 novel N′-arylidene pyrazole-3-carbohydrazides are described. Compounds were pretended to act as dual agents against diabetes and oxidative stress, two correlated pathologies involved in metabolic syndrome development and progression. The antioxidant capacity was evaluated by means of DPPH and FRAP in vitro assays. It was found that compounds bearing a hydroxyl group at 4-position of the hydrazone moiety are potent antioxidant entities, being compound 3g (a syringaldehyde derivative) the most active compound. In addition, the in vivo hypoglycemic effect of the analogues was determined. With regard to the above, the cinnamaldehyde derivatives showed a scarce biological activity, while the 4-hydroxy analogues showed the higher glycemia reduction at 7h after administration. Interestingly, the most potent antioxidants 3b and 3g also were of the most active compounds in reducing the plasma glucose, reaching 80% of reduction in the case of 3g. Molecular docking binding poses conducted to a plausible interpretation of the biological outcomes and a possible interaction between a hydroxy group and Asn287 of CB1R was proposed as an important feature for enhancing the observed activity.
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      PubDate: 2016-04-20T13:51:13Z
       
  • Design, synthesis and biological evaluation of LBM-A5 derivatives as
           potent P-glycoprotein-mediated multidrug resistance inhibitors
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Yuxiang Wu, Miaobo Pan, Yuxuan Dai, Baomin Liu, Jian Cui, Wei Shi, Qianqian Qiu, Wenlong Huang, Hai Qian
      A novel series of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) inhibitors with triazol-N-phenethyl-tetrahydroisoquinoline or triazol-N-ethyl-tetrahydroisoquinoline scaffold were designed and synthesized via click chemistry. Most of the synthesized compounds showed higher reversal activity than verapamil (VRP). Among them, the most potent compound 4 showed a comparable activity with the known potent P-gp inhibitor WK-X-34 with lower cytotoxicity toward K562 cells (IC50 >100μM). Compared with VRP, compound 4 exhibited more potency in increasing drug accumulation in K562/A02 MDR cells. Moreover, compound 4 could significantly reverse MDR in a dose-dependent manner and also persist longer chemo-sensitizing effect than VRP with reversibility. Further mechanism studies revealed that compound 4 could remarkably increase the intracellular accumulation of Adriamycin (ADM) in K562/A02 cells as well as inhibit rhodamine-123 (Rh123) efflux from the cells. These results suggested that compound 4 may represent a promising candidate for developing P-gp-mediated MDR inhibitors.
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      PubDate: 2016-04-20T13:51:13Z
       
  • Inhibitory effect of flavonoids on human glutaminyl cyclase
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Manman Li, Yao Dong, Xi Yu, Yongdong Zou, Yizhi Zheng, Xianzhang Bu, Junmin Quan, Zhendan He, Haiqiang Wu
      Glutaminyl cyclase (QC) plays an important role in the pathogenesis of Alzheimer’s disease (AD) and can be a potential target for the development of novel anti-AD agents. However, the study of QC inhibitors are still less. Here, phenol-4′ (R1-), C5-OH (R2-) and C7-OH (R3-) modified apigenin derivatives were synthesized as a new class of human QC (hQC) inhibitors. The efficacy investigation of these compounds was performed by spectrophotometric assessment and the structure–activity relationship (SAR) was evaluated. Molecular docking was also carried out to analyze the binding mode of the synthesized flavonoid to the active site of hQC.
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      PubDate: 2016-04-20T13:51:13Z
       
  • Synthesis, identification, and biological activity of metabolites of two
           novel selective S1P1 agonists
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Qiong Xiao, Jing Jin, Xiaojian Wang, Jinping Hu, Meiyang Xi, Yulin Tian, Dali Yin
      SYL927 and SYL930 are selective S1P1 agonists under preclinical development. However, during their pharmacokinetic studies we detected two metabolites in rat blood that were tentatively identified as monohydroxylated metabolites of SYL927 and SYL930 based on LC–MS/MS data. In this study, we designed and synthesized possible monohydroxylated products 6a–e and used them as references to confirm the structures of the two metabolites detected by LC–MS/MS. We also evaluated the in vitro and in vivo biological activities of these two metabolites.
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      PubDate: 2016-04-20T13:51:13Z
       
  • Orally bioavailable pyridine and pyrimidine-based Factor XIa inhibitors:
           Discovery of the methyl N-phenyl carbamate P2 prime group
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): James R. Corte, Tianan Fang, Donald J.P. Pinto, Michael J. Orwat, Alan R. Rendina, Joseph M. Luettgen, Karen A. Rossi, Anzhi Wei, Vidhyashankar Ramamurthy, Joseph E. Myers, Steven Sheriff, Rangaraj Narayanan, Timothy W. Harper, Joanna J. Zheng, Yi-Xin Li, Dietmar A. Seiffert, Ruth R. Wexler, Mimi L. Quan
      Pyridine-based Factor XIa (FXIa) inhibitor (S)-2 was optimized by modifying the P2 prime, P1, and scaffold regions. This work resulted in the discovery of the methyl N-phenyl carbamate P2 prime group which maintained FXIa activity, reduced the number of H-bond donors, and improved the physicochemical properties compared to the amino indazole P2 prime moiety. Compound (S)-17 was identified as a potent and selective FXIa inhibitor that was orally bioavailable. Replacement of the basic cyclohexyl methyl amine P1 in (S)-17 with the neutral p-chlorophenyltetrazole P1 resulted in the discovery of (S)-24 which showed a significant improvement in oral bioavailability compared to the previously reported imidazole (S)-23. Additional improvements in FXIa binding affinity, while maintaining oral bioavailability, was achieved by replacing the pyridine scaffold with either a regioisomeric pyridine or pyrimidine ring system.
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      PubDate: 2016-04-20T13:51:13Z
       
  • Development of 99mTc-labeled asymmetric urea derivatives that target
           prostate-specific membrane antigen for single-photon emission computed
           tomography imaging
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Hiroyuki Kimura, Sotaro Sampei, Daiko Matsuoka, Naoya Harada, Hiroyuki Watanabe, Kenji Arimitsu, Masahiro Ono, Hideo Saji
      Prostate-specific membrane antigen (PSMA) is expressed strongly in prostate cancers and is, therefore, an attractive diagnostic and radioimmunotherapeutic target. In contrast to previous reports of PMSA-targeting 99mTc-tricarbonyl complexes that are cationic or lack a charge, no anionic 99mTc-tricarbonyl complexes have been reported. Notably, the hydrophilicity conferred by both cationic and anionic charges leads to rapid hepatobiliary clearance, whereas an anionic charge might better enhance renal clearance relative to a cationic charge. Therefore, an improvement in rapid clearance would be expected with either cationic or anionic charges, particularly anionic charges. In this study, we designed and synthesized a novel anionic 99mTc-tricarbonyl complex ([99mTc]TMCE) and evaluated its use as a single-photon emission computed tomography (SPECT) imaging probe for PSMA detection. Direct synthesis of [99mTc]TMCE from dimethyl iminodiacetate, which contains both the asymmetric urea and succinimidyl moiety important for PSMA binding, was performed using our microwave-assisted one-pot procedure. The chelate formation was successfully achieved even though the precursor included a complicated bioactive moiety. The radiochemical yield of [99mTc]TMCE was 12–17%, with a radiochemical purity greater than 98% after HPLC purification. [99mTc]TMCE showed high affinity in vitro, with high accumulation in LNCaP tumors and low hepatic retention in biodistribution and SPECT/CT studies. These findings warrant further evaluation of [99mTc]TMCE as an imaging agent and support the benefit of this strategy for the design of other PSMA imaging probes.
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      PubDate: 2016-04-20T13:51:13Z
       
  • N-Indolylglycosides bearing modifications at the glucose C6-position as
           sodium-dependent glucose co-transporter 2 inhibitors
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Kuang-Feng Chu, Chun-Hsu Yao, Jen-Shin Song, Chiung-Tong Chen, Teng-Kuang Yeh, Tsung-Chih Hsieh, Chung-Yu Huang, Min-Hsien Wang, Szu-Huei Wu, Wei-En Chang, Yu-Sheng Chao, Jinq-Chyi Lee
      Suppression of glucose reabsorption through the inhibition of sodium-dependent glucose co-transporter 2 (SGLT2) is a promising therapeutic approach for the treatment of type 2 diabetes. To investigate the effect of C6-substitution on inhibition of SGLT2 by N-indolylglucosides, a small library of 6-triazole, 6-amide, 6-urea, and 6-thiourea N-indolylglycosides were synthesized and tested. A detailed structure–activity relationship (SAR) study culminated in the identification of 6-amide derivatives 6a and 6o as potent SGLT2 inhibitors, which were further tested for inhibitory activity against SGLT1. The data obtained indicated that 6a and 6o are mildly to moderately selective for SGLT2 over SGLT1. Both compounds were also evaluated in a urinary glucose excretion test and pharmacokinetic study; 6a was found capable of inducing urinary glucose excretion in normal SD rats.
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      PubDate: 2016-04-20T13:51:13Z
       
  • Short cationic lipopeptides as effective antibacterial agents: Design,
           physicochemical properties and biological evaluation
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Fazren Azmi, Alysha G. Elliott, Nirmal Marasini, Soumya Ramu, Zyta Ziora, Angela M. Kavanagh, Mark A.T. Blaskovich, Matthew A. Cooper, Mariusz Skwarczynski, Istvan Toth
      The spread of drug-resistant bacteria has imparted a sense of urgency in the search for new antibiotics. In an effort to develop a new generation of antibacterial agents, we have designed de novo charged lipopeptides inspired by natural antimicrobial peptides. These short lipopeptides are composed of cationic lysine and hydrophobic lipoamino acids that replicate the amphiphilic properties of natural antimicrobial peptides. The resultant lipopeptides were found to self-assemble into nanoparticles. Some were effective against a variety of Gram-positive bacteria, including strains resistant to methicillin, daptomycin and/or vancomycin. The lipopeptides were not toxic to human kidney and liver cell lines and were highly resistant to tryptic degradation. Transmission electron microscopy analysis of bacteria cells treated with lipopeptide showed membrane-damage and lysis with extrusion of cytosolic contents. With such properties in mind, these lipopeptides have the potential to be developed as new antibacterial agents against drug-resistant Gram-positive bacteria.
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      PubDate: 2016-04-20T13:51:13Z
       
  • Purinylpyridinylamino-based DFG-in/αC-helix-out B-Raf inhibitors:
           Applying mutant versus wild-type B-Raf selectivity indices for compound
           profiling
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Longbin Liu, Matthew R. Lee, Joseph L. Kim, Douglas A. Whittington, Howard Bregman, Zihao Hua, Richard T. Lewis, Matthew W. Martin, Nobuko Nishimura, Michele Potashman, Kevin Yang, Shuyan Yi, Karina R. Vaida, Linda F. Epstein, Carol Babij, Manory Fernando, Josette Carnahan, Mark H. Norman
      One of the challenges for targeting B-RafV600E with small molecule inhibitors had been achieving adequate selectivity over the wild-type protein B-RafWT, as inhibition of the latter has been associated with hyperplasia in normal tissues. Recent studies suggest that B-Raf inhibitors inducing the ‘DFG-in/αC-helix-out’ conformation (Type IIB) likely will exhibit improved selectivity for B-RafV600E. To explore this hypothesis, we transformed Type IIA inhibitor (1) into a series of Type IIB inhibitors (sulfonamides and sulfamides 4–6) and examined the SAR. Three selectivity indices were introduced to facilitate the analyses: the B-RafV600E/B-RafWT biochemical (bS), cellular (cS) selectivity, and the phospho-ERK activation (pA). Our data indicates that α-branched sulfonamides and sulfamides show higher selectivities than the linear derivatives. We rationalized this finding based on analysis of structural information from the literature and provided evidence for a monomeric B-Raf-inhibitor complex previously hypothesized to be responsible for the desired B-RafV600E selectivity.
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      PubDate: 2016-04-20T13:51:13Z
       
  • Editorial board
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10




      PubDate: 2016-04-20T13:51:13Z
       
  • Towards understanding the unbound state of drug compounds: Implications
           for the intramolecular reorganization energy upon binding
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Nicolas Foloppe, I-Jen Chen
      There has been an explosion of structural information for pharmaceutical compounds bound to biological targets, but the conformations and dynamics of compounds free in solution are poorly characterized, if at all. Yet, knowledge of the unbound state is essential to understand the fundamentals of molecular recognition, including the much debated conformational intramolecular reorganization energy of a compound upon binding (ΔE Reorg). Also, dependable observation of the unbound compounds is important for ligand-based drug discovery, e.g. with pharmacophore modelling. Here, these questions are addressed with long (⩾0.5μs) state-of-the-art molecular dynamics (MD) simulations of 26 compounds (including 7 approved drugs) unbound in explicit solvent. These compounds were selected to be chemically diverse, with a range of flexibility, and good quality bioactive X-ray structures. The MD-simulated free compounds are compared to their bioactive structure and conformers generated with ad hoc sampling in vacuo or with implicit generalized Born (GB) aqueous solvation models. The GB conformational models clearly depart from those obtained in explicit solvent, and suffer from conformational collapse almost as severe as in vacuo. Thus, the global energy minima in vacuo or with GB are not suitable representations of the unbound state, which can instead be extensively sampled by MD simulations. Many, but not all, MD-simulated compounds displayed some structural similarity to their bioactive structure, supporting the notion of conformational pre-organization for binding. The ligand–protein complexes were also simulated in explicit solvent, to estimate ΔE Reorg as an enthalpic difference ΔH Reorg between the intramolecular energies in the bound and unbound states. This fresh approach yielded ΔH Reorg values⩽6kcal/mol for 18 out of 26 compounds. For three particularly polar compounds 15⩽ΔH Reorg ⩽20kcal/mol, supporting the notion that ΔH Reorg can be substantial. Those large ΔH Reorg values correspond to a redistribution of electrostatic interactions upon binding. Overall, the study illustrates how MD simulations offer a promising avenue to characterize the unbound state of medicinal compounds.
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      PubDate: 2016-04-20T13:51:13Z
       
  • Tumour-specific cytotoxicity and structure–activity relationships of
           novel
           1-[3-(2-methoxyethylthio)propionyl]-3,5-bis(benzylidene)-4-piperidones
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Mohammad Hossain, Umashankar Das, Naoki Umemura, Hiroshi Sakagami, Jan Balzarini, Erik De Clercq, Masami Kawase, Jonathan R. Dimmock
      A series of 1-acyl-3,5-bis(benzylidene)-4-piperidones 3–7 were designed and synthesized as novel cytotoxic agents. These compounds displayed potent cytotoxic properties towards human Molt4/C8, CEM, HSC-2, HSC-3 and HSC-4 neoplasms and also to murine L1210 cells. The majority of the compounds have sub-micromolar or very low micromolar IC50 and CC50 values and are significantly more potent than the reference alkylating drug melphalan. Evaluation of these compounds against non-malignant HGF and HPLF cells revealed the tumour-specific toxicity. In particular, 3e emerged as a promising lead cytotoxic agent which caused apoptosis and PARP1 cleavage in HSC-2 cells.
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      PubDate: 2016-04-20T13:51:13Z
       
  • Synthesis and evaluation of novel opioid ligands with a C-homomorphinan
           skeleton
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Kyoko Ishikawa, Yusuke Mochizuki, Shigeto Hirayama, Toru Nemoto, Kenichiro Nagai, Kennosuke Itoh, Hideaki Fujii
      As the reports about C-homomorphinans with the seven-membered C-ring are much fewer than those of morphinan derivatives with a six-membered C-ring, we attempted to synthesize C-homomorphinan derivatives and to evaluate their opioid activities. C-Homomorphinan 5 showed sufficient binding affinities to the opioid receptors. C-Homomorphinan derivatives possessing the δ address moiety such as indole (NTI-type), quinoline, or benzylidene (BNTX-type) functionalities showed the strongest binding affinities for the δ receptor among the three types of opioid receptors, which indicated that the C-homomorphinan skeleton sufficiently functions as a message-part in the ligand. Although NTI-type compound 8 and quinoline compound 9 with C-homomorphinan scaffold exhibited lower affinities and selectivities for the δ receptor than the corresponding morphinan derivatives did, both the binding affinity and selectivity for the δ receptor of BNTX-type compound 12 with a seven-membered C-ring were improved compared with the corresponding compounds with a six-membered C-ring including BNTX itself. BNTX-Type compound 12 was the most selective δ receptor antagonist among the tested compounds.
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      PubDate: 2016-04-20T13:51:13Z
       
  • The Cu/ligand stoichiometry effect on the coordination behavior of aroyl
           hydrazone with copper(II): Structure, anticancer activity and anticancer
           mechanism
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): JunGang Deng, Yi Gou, Wei Chen, Xiang Fu, Hang Deng
      In an effort to better understand the biological efficacy of the tridentate aroyl hydrazone Cu(II) complexes, three Cu(II) complexes of acetylpyridine benzoyl hydrazone (HL), [Cu(L)(NO3) (H2O)]·H2O (C1), [Cu(L)2] (C2) and [Cu(L)(HL)]·(NO3)(Sas) (C3) (Sas=salicylic acid) were synthesized and characterized. X-ray crystal structures and infrared (IR) spectra of the complexes reveal that the L− ligand of C1 and C2 are predominantly in the enolate resonance form, while one L− ligand in C3 is represented enolate resonance form and the other HL ligand exhibits keto resonance form. All Cu(II) complexes showed significantly more anticancer activity than the ligand alone. Interestingly, the Cu complexes where the ligand/metal ratio was 1:1 (C1) rather than 2:1 (C2 and C3) had higher antitumor efficacy. Moreover, the 1:1 Cu/ligand complex, C1, promotes A549 cell apoptosis possibly through the intrinsic reactive oxygen species (ROS) mediated mitochondrial pathway, accompanied by the regulation of Bcl-2 family proteins.
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      PubDate: 2016-04-20T13:51:13Z
       
  • Acetylcholinesterase and carbonic anhydrase inhibitory properties of novel
           urea and sulfamide derivatives incorporating dopaminergic 2-aminotetralin
           scaffolds
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Bünyamin Özgeriş, Süleyman Göksu, Leyla Polat Köse, İlhami Gülçin, Ramin Ekhteiari Salmas, Serdar Durdagi, Ferhan Tümer, Claudiu T. Supuran
      In the present study a series of urea and sulfamide compounds incorporating the tetralin scaffolds were synthesized and evaluated for their acetylcholinesterase (AChE), human carbonic anhydrase (CA, EC 4.2.1.1) isoenzyme I, and II (hCA I and hCA II) inhibitory properties. The urea and their sulfamide analogs were synthesized from the reactions of 2-aminotetralins with N,N-dimethylcarbamoyl chloride and N,N-dimethylsulfamoyl chloride, followed by conversion to the corresponding phenols via O-demethylation with BBr3. The novel urea and sulfamide derivatives were tested for inhibition of hCA I, II and AChE enzymes. These derivatives exhibited excellent inhibitory effects, in the low nanomolar range, with K i values of 2.61–3.69nM against hCA I, 1.64–2.80nM against hCA II, and in the range of 0.45–1.74nM against AChE. In silico techniques such as, atomistic molecular dynamics (MD) and molecular docking simulations, were used to understand the scenario of the inhibition mechanism upon approaching of the ligands into the active site of the target enzymes. In light of the experimental and computational results, crucial amino acids playing a role in the stabilization of the enzyme–inhibitor adducts were identified.
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      PubDate: 2016-04-20T13:51:13Z
       
  • Synthesis and anticancer activity of some 5-fluoro-2′-deoxyuridine
           phosphoramidates
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Marta Lewandowska, Piotr Ruszkowski, Kinga Chojnacka, Natalia Kleczewska, Marcin Hoffmann, Karol Kacprzak, Lech Celewicz
      Two series of novel 4-chlorophenyl N-alkyl phosphoramidates of 3′-O-(t-butoxycarbonyl)-5-fluoro-2′-deoxyuridine (3′-BOC-FdU) (9a–9j) and 5-fluoro-2′-deoxyuridine (FdU) (10a–10j) were synthesized by means of phosphorylation of 3′-BOC-FdU (4) with 4-chlorophenyl phosphoroditriazolide (7), followed by a reaction with the appropriate amine. Phosphoramidates 9a–9j were converted to the corresponding 10a–10j by removal of the 3′-t-butoxycarbonyl protecting group (BOC) under acidic conditions. The synthesized phosphoramidates 9a–9j and 10a–10j were evaluated for their cytotoxic activity in five human cancer cell lines: cervical (HeLa), nasopharyngeal (KB), breast (MCF-7), liver (HepG2), osteosarcoma (143B) and normal human dermal fibroblast cell line (HDF) using the sulforhodamine B (SRB) assay. Two phosphoramidates 9b and 9j with the N-ethyl and N-(methoxy-(S)-alaninyl) substituents, respectively, displayed remarkable activity in all the investigated cancer cells, and the activity was considerably higher than that of the parent nucleoside 4 and FdU. Among phosphoramidates 10a–10j compound 10c with the N-(2,2,2-trifluoroethyl) substituent showed the highest activity. Phosphoramidate 10c was more active than the FdU in all the cancer cell lines tested.
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      PubDate: 2016-04-20T13:51:13Z
       
  • Synthesis and evaluation of 4-hydroxyl aurone derivatives as
           multifunctional agents for the treatment of Alzheimer’s disease
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Yan Li, Xiaoming Qiang, Li Luo, Yuxing Li, Ganyuan Xiao, Zhenghuai Tan, Yong Deng
      A series of 4-hydroxyl aurone derivatives were designed synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer’s disease. The results demonstrated that most of the derivatives exhibited good multifunctional properties. Among them, compound 14e displayed good inhibitory activities of self- and Cu2+-induced Aβ 1–42 aggregation with 99.2% and 84.0% at 25μM, respectively, and high antioxidant activity with a value 1.90-fold of Trolox. In addition, 14e also showed remarkable inhibitory activities of both monoamine oxidase A and B with IC50 values of 0.271μM and 0.393μM, respectively. However the 6-methoxyl aurones 15a–c revealed excellent selectivity toward MAO-B. Furthermore, the representative compounds 14e and 15b displayed good metal-chelating abilities and blood–brain barrier (BBB) permeabilities in vitro.
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      PubDate: 2016-04-20T13:51:13Z
       
  • Biological evaluation of synthetic α,β-unsaturated carbonyl
           based cyclohexanone derivatives as neuroprotective novel inhibitors of
           acetylcholinesterase, butyrylcholinesterase and amyloid-β aggregation
           
    • Abstract: Publication date: 15 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 10
      Author(s): Gao-Feng Zha, Cheng-Pan Zhang, Hua-Li Qin, Ibrahim Jantan, Muhammad Sher, Muhammad Wahab Amjad, Muhammad Ajaz Hussain, Zahid Hussain, Syed Nasir Abbas Bukhari
      A series of new α,β-unsaturated carbonyl-based cyclohexanone derivatives was synthesized by simple condensation method and all compounds were characterized by using various spectroscopic techniques. New compounds were evaluated for their effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These compounds were also screened for in vitro cytotoxicity and for inhibitory activity for self-induced Aβ1–42 aggregation. The effect of these compounds against amyloid β-induced cytotoxicity was also investigated. The findings of in vitro experiment revealed that most of these compounds exhibited potent inhibitory activity against AChE and self-induced Aβ1–42 aggregation. The compound 3o exhibited best AChE (IC50 =0.037μM) inhibitory potential. Furthermore, compound 3o disassembled the Aβ fibrils produced by self-induced Aβ aggregation by 76.6%. Compounds containing N-methyl-4-piperidone linker, showed high acetylcholinesterase and self-induced Aβ aggregation inhibitory activities as compared to reference drug donepezil. The pre-treatment of cells with synthetic compounds protected them against Aβ-induced cell death by up to 92%. Collectively, these findings suggest that some compounds from this series have potential to be promising multifunctional agents for AD treatment and our study suggest the cyclohexanone derivatives as promising new inhibitors for AChE and BuChE, potentially useful to treat neurodegenerative diseases.
      Graphical abstract image

      PubDate: 2016-04-20T13:51:13Z
       
  • Design, synthesis, assessment, and molecular docking of novel
           pyrrolopyrimidine (7-deazapurine) derivatives as non-nucleoside hepatitis
           C virus NS5B polymerase inhibitors
    • Abstract: Publication date: 1 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 9
      Author(s): Mosaad S. Mohamed, Amira I. Sayed, Mohammed A. Khedr, Sameh H. Soror
      Hepatitis C virus (HCV) infection is highly persistent and presents an unmet medical need requiring more effective treatment options. This has spurred intensive efforts to discover novel anti-HCV agents. The RNA-dependent RNA polymerase (RdRp), NS5B of HCV, constitutes a selective target for drug discovery due to its absence in human cells; also, it is the centerpiece for viral replication. Here, we synthesized novel pyrrole, pyrrolo[2,3-d]pyrimidine and pyrrolo[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives. The non-toxic doses of these compounds on Huh 7.5 cell line were determined and their antiviral activity against HCVcc genotype 4a was examined. Compounds 7j, 7f, 5c, 12i and 12f showed significant anti HCV activity. The percent of reduction for the non-toxic doses of 7j, 7f, 5c, 12i and 12f were 90%, 76.7±5.8%, 73.3±5.8%, 70% and 63.3±5.8%, respectively. The activity of these compounds was interpreted by molecular docking against HCV NS5B polymerase enzyme.
      Graphical abstract image

      PubDate: 2016-04-12T02:01:27Z
       
  • Design, synthesis, and biological evaluation of
           arylpiperazine–benzylpiperidines with dual serotonin and
           norepinephrine reuptake inhibitory activities
    • Abstract: Publication date: 1 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 9
      Author(s): Suresh Paudel, Srijan Acharya, Kyeong-Man Kim, Seung Hoon Cheon
      The limitations of established serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake inhibitors necessitate the development of safer and more effective therapeutic agents. Based on the structures of 4-benzylpiperidine carboxamides and trazodone, arylpiperazine–benzylpiperidines with chemical scaffolds different from those of marketed drugs were designed, synthesized, and evaluated for their neurotransmitter reuptake inhibitory activities. The majority of the synthesized compounds showed greater NE than 5-HT reuptake inhibition. The activities were even greater than those of the standard drug, venlafaxine hydrochloride were. The derivatives with a three-carbon linker showed better activities than the derivatives with a two-carbon linker. Among the newly synthesized compounds, 2d exhibited the strongest reuptake inhibition of the neurotransmitters (IC50 =0.38μM for NE and 1.18μM for 5-HT). The biological activity data demonstrate that arylpiperazine–benzylpiperidines have the potential to be developed as a new class of therapeutic agents to treat neuropsychiatric and neurodegenerative disorders.
      Graphical abstract image

      PubDate: 2016-04-12T02:01:27Z
       
  • Synthesis, anti-inflammatory, analgesic, COX-1/2 inhibition activities and
           molecular docking study of pyrazoline derivatives
    • Abstract: Publication date: 1 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 9
      Author(s): Maged A. Abdel-Sayed, Said M. Bayomi, Magda A. El-Sherbeny, Naglaa I. Abdel-Aziz, Kamal Eldin H. ElTahir, George S.G. Shehatou, Alaa A.-M. Abdel-Aziz
      Design, synthesis and pharmacological activities of a group of 1,3,5-trisubstituted pyrazolines were reported. The chemical structures of the synthesized compounds have been assigned on the basis of IR, MS, 1H NMR, and 13C NMR spectral analyses. The synthesized 1,3,5-trisubstituted pyrazoline derivatives were evaluated in vivo for anti-inflammatory, analgesic activities and in vitro for COX-1/2 inhibition assay. Among the tested compounds, derivatives 4h, 6e, 7a, 7e, and 9 showed more potent anti-inflammatory and analgesic activities than the reference drug celecoxib. On the basis of their higher activities in the in vivo studies compared with celecoxib, the five compounds 4h, 6e, 7a, 7e and 9 were selected to test their inhibitory activities against ovine COX-1/2 using an in vitro cyclooxygenase inhibition assay. Docking study of compounds 7a, 7e and 9 into the COX-2 binding site revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.
      Graphical abstract image

      PubDate: 2016-04-12T02:01:27Z
       
  • Synthesis and evaluation of 6-(3-[18F]fluoro-2-hydroxypropyl)-substituted
           2-pyridylbenzothiophenes and 2-pyridylbenzothiazoles as potential PET
           tracers for imaging Aβ plaques
    • Abstract: Publication date: 1 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 9
      Author(s): Byoung Se Lee, So Young Chu, Hye Rim Kwon, Chansoo Park, Uthaiwan Sirion, Damian Brockschnieder, Thomas Dyrks, Seung Jun Oh, Jae Seung Kim, Dae Yoon Chi
      3-[18F]Fluoro-2-hydroxypropyl substituted compounds were synthesized and evaluated as novel 18F-labeled PET tracers for imaging Aβ plaque in a living brain. All compounds exhibited high binding affinities toward the synthetic Aβ1–42 aggregate and/or Alzheimer’s disease brain homogenate. In the microPET study with normal mice, the 3-[18F]fluoro-2-hydroxypropyl substituted compounds resulted in fast brain washout by reducing the lipophilicities of the compounds. Intriguingly, (S)-configured PET tracers, (S)-[18F]1b and (S)-[18F]1c, exhibited a 2.8 and 4.0-fold faster brain washout rate at a peak/30min in the mouse brain than the corresponding (R)-configured PET tracers despite there being no meaningful difference in binding affinities toward Aβ plaque. A further evaluation of (S)-[18F]1c with healthy rhesus monkeys also revealed excellent clearance from the frontal cortex with ratios of 7.0, 16.0, 30.0 and 49.0 at a peak/30, 60, 90, and 120min, respectively. These results suggest that (S)-[18F]1c may be a potential PET tracer for imaging Aβ plaque in a living brain.
      Graphical abstract image

      PubDate: 2016-04-12T02:01:27Z
       
  • Synthesis and evaluation of novel angiotensin II receptor 1 antagonists as
           anti-hypertension drugs
    • Abstract: Publication date: 1 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 9
      Author(s): Xiaolu Bao, Weibo Zhu, Ruijing Zhang, Caihong Wen, Li Wang, Yijia Yan, Hesheng Tang, Zhilong Chen
      Three new angiotensin II receptor 1 antagonists, 1, 2 and 3 were designed, synthesized and evaluated. The AT1 receptor-binding assays in vitro showed that all the synthesized compounds had nanomolar affinity for the AT1 receptor. From which compound 3 was found to be the most potent ligands with an IC50 value of 2.67±0.23nM. Biological evaluation in vivo revealed that all the compounds could cause significant decrease on MBP in a dose dependent manner in spontaneously hypertensive rats, and compound 3 especially showed an efficient and long-lasting effect in reducing blood pressure, whose maximal response lowered 41mmHg of MBP at 10mg/kg and 62mmHg at 15mg/kg after oral administration, the significant anti-hypertensive effect lasted beyond 12h, which is better than the reference compound losartan. The pharmacokinetic experiments showed that compound 3 could be absorbed efficiently and metabolized smoothly both in blood and in tissues in Wistar rats. The acute toxicity assay suggested that it has low toxicity with the LD50 value of 2974.35mg/kg. These results demonstrate that compound 3 is a potent angiotensin AT1 receptor antagonist which could be considered as a novel anti-hypertension candidate and deserved for further investigation.
      Graphical abstract image

      PubDate: 2016-04-12T02:01:27Z
       
  • Design, synthesis and anti-HIV-1 evaluation of hydrazide-based
           peptidomimetics as selective gelatinase inhibitors
    • Abstract: Publication date: 1 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 9
      Author(s): Liang Yang, Ping Wang, Ji-Feng Wu, Liu-Meng Yang, Rui-Rui Wang, Wei Pang, Yong-Gang Li, Yue-Mao Shen, Yong-Tang Zheng, Xun Li
      As our ongoing work on research of gelatinase inhibitors, an array of hydrazide-containing peptidomimetic derivatives bearing quinoxalinone as well as spiro-heterocyclic backbones were designed, synthesized, and assayed for their in vitro enzymatic inhibitory effects. The results demonstrated that both the quinoxalinone (series I and II) and 1,4-dithia-7-azaspiro[4,4]nonane-based hydrazide peptidomimetics (series III) displayed remarkably selectivity towards gelatinase A as compared to APN, with IC50 values in the micromole range. Structure–activity relationships were herein briefly discussed. Given evidences have validated that gelatinase inhibition may be contributable to the therapy of HIV-1 infection, all the target compounds were also submitted to the preliminary in vitro anti-HIV-1 evaluation. It resulted that gelatinase inhibition really has positive correlation with anti-HIV-1 activity, especially compounds 4m and 7h, which gave enhanced gelatinase inhibition in comparison with the positive control LY52, and also decent anti-HIV-1 potencies. The FlexX docking results provided a straightforward insight into the binding pattern between inhibitors and gelatinase, as well as the selective inhibition towards gelatinase over APN. Collectively, our research encouraged potent gelatinase inhibitors might be used in the development of anti-HIV-1 agents. And else, compounds 4m and 7h might be promising candidates to be considered for further chemical optimization.
      Graphical abstract image

      PubDate: 2016-04-12T02:01:27Z
       
  • Acridin-3,6-dialkyldithiourea hydrochlorides as new photosensitizers for
           photodynamic therapy of mouse leukemia cells
    • Abstract: Publication date: 1 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 9
      Author(s): A. Cisáriková, Z. Barbieriková, L. Janovec, J. Imrich, L. Hunáková, Z. Bačová, H. Paulíková
      Acridin-3,6-dialkyldithiourea hydrochlorides (AcrDTUs) have been evaluated as a new group of photosensitizers (PSs) for photodynamic antitumor therapy (PDT). Mouse leukemia cells L1210 were used for testing of AcrDTUs as the new PSs. The irradiation (UV-A light (365nm), 1.05J/cm2) increased cytotoxicity of all derivatives against L1210 cells more than ten times. The highest photocytotoxicity was found for propyl-AcrDTU with IC50 =0.48±0.03μM after 48h incubation. A generation of the superoxide radical anion upon UV-A irradiation of propyl-AcrDTU was confirmed by in situ photochemical EPR experiments. To explain a mechanism of photocytotoxic action of AcrDTUs, an intracellular distribution of propyl-AcrDTU has been studied. It was found that AcrDTU in non-irradiated cells was not present in their nucleus but in the lysosomes and partly in the mitochondria, and sequestration of propyl-AcrDTU was dependent on pH in lysosomes. After irradiation, the cell death was induced by oxidative damage of lysosomal and mitochondrial membranes. Concerning the cell cycle, flow cytometry after PDT with propyl-AcrDTU showed a significant increase of the cells in the subG0 phase. Observed signs of necrosis, apoptosis, and autophagy indicate that PDT/AcrDTU leads to multiple cell death types (caspase independent apoptosis, necrosis, and autophagy).
      Graphical abstract image

      PubDate: 2016-04-12T02:01:27Z
       
  • Design, synthesis, and evaluation of hinge-binder tethered
           1,2,3-triazolylsalicylamide derivatives as Aurora kinase inhibitors
    • Abstract: Publication date: 1 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 9
      Author(s): Yunkyung Jeong, Jooyeon Lee, Jae-Sang Ryu
      A series of hinge-binder tethered 1,2,3-triazolylsalicylamide derivatives were designed, synthesized, and evaluated for the Aurora kinase inhibitory activities. The novel hinge-binder tethered 1,2,3-triazolylsalicylamide scaffold was effectively assembled by Cu(I)-catalyzed azide–alkyne 1,3-dipolar cycloaddition (CuAAC). A variety of alkynes with hinge binders were used to search proper structures–binding relationship to the hinge region. The synthesized 1,2,3-triazolylsalicylamide derivatives showed significant Aurora kinase inhibitory activity. In particular, 8a inhibited Aurora A kinase with an IC50 value of 0.284μM, whereas 8m inhibited Aurora B kinase with an IC50 value of 0.364μM.
      Graphical abstract image

      PubDate: 2016-04-12T02:01:27Z
       
  • Development of a 3′-amino linker with high conjugation activity and
           its application to conveniently cross-link blunt ends of a duplex
    • Abstract: Publication date: 1 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 9
      Author(s): Keiko Kowata, Naoshi Kojima, Yasuo Komatsu
      The 2-aminoethyl carbamate linker (ssH linker) exhibits high activity in modifying the 5′-termini of oligonucleotides; however, the ssH linker is not appropriate for 3′-terminal modification because it undergoes intramolecular trans-acylation under heat–aqueous ammonia conditions. We developed an N-(2-aminoethyl)carbamate linker (revH linker), in which the carbamate is oriented in the reverse direction relative to that in 2-aminoethyl carbamate. The revH linker was tolerant to heat–alkaline conditions and retained its high reactivity in conjugation with exogenous molecules. The 3′-revH linker was efficiently linked with the 5′-ssH linker at the termini of complementary double strands with a bifunctional molecule, producing a synthetic loop structure. An anti-microRNA oligonucleotide (AMO) was prepared from the chemical ligation of three-stranded 2′-O-methyl RNAs, and the AMO with two alkyl loops exhibited high inhibition activity toward miRNA function. The revH linker is not only useful for 3′-terminal modification of oligonucleotides but also expands the utility range in combination with the 5′-ssH linker.
      Graphical abstract image

      PubDate: 2016-04-12T02:01:27Z
       
  • Synthesis and antitumor activity evaluation of a novel combi-nitrosourea
           prodrug: Designed to release a DNA cross-linking agent and an inhibitor of
           O6-alkylguanine-DNA alkyltransferase
    • Abstract: Publication date: 1 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 9
      Author(s): Guohui Sun, Na Zhang, Lijiao Zhao, Tengjiao Fan, Shufen Zhang, Rugang Zhong
      The drug resistance of CENUs induced by O6-alkylguanine-DNA alkyltransferase (AGT), which repairs the O6-alkylated guanine and subsequently inhibits the formation of dG–dC cross-links, hinders the application of CENU chemotherapies. Therefore, the discovery of CENU analogs with AGT inhibiting activity is a promising approach leading to novel CENU chemotherapies with high therapeutic index. In this study, a new combi-nitrosourea prodrug 3-(3-(((2-amino-9H-purin-6-yl)oxy)methyl)benzyl)-1-(2-chloroethyl)-1-nitrosourea (6), designed to release a DNA cross-linking agent and an inhibitor of AGT, was synthesized and evaluated for its antitumor activity and ability to induce DNA interstrand cross-links (ICLs). The results indicated that 6 exhibited higher cytotoxicity against mer+ glioma cells compared with ACNU, BCNU, and their respective combinations with O6-benzylguanine (O6-BG). Quantifications of dG–dC cross-links induced by 6 were performed using HPLC–ESI-MS/MS. Higher levels of dG–dC cross-link were observed in 6-treated human glioma SF763 cells (mer+), whereas lower levels of dG–dC cross-link were observed in 6-treated calf thymus DNA, when compared with the groups treated with BCNU and ACNU. The results suggested that the superiority of 6 might result from the AGT inhibitory moiety, which specifically functions in cells with AGT activity. Molecular docking studies indicated that five hydrogen bonds were formed between the O6-BG analogs released from 6 and the five residues in the active pocket of AGT, which provided a reasonable explanation for the higher AGT-inhibitory activity of 6 than O6-BG.
      Graphical abstract image

      PubDate: 2016-04-12T02:01:27Z
       
  • Synthesis of 4-substituted nipecotic acid derivatives and their evaluation
           as potential GABA uptake inhibitors
    • Abstract: Publication date: 1 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 9
      Author(s): Tim Hellenbrand, Georg Höfner, Thomas Wein, Klaus T. Wanner
      In this study, we disclose the design and synthesis of novel 4-susbtituted nipecotic acid derivatives as inhibitors of the GABA transporter mGAT1. Based on molecular modeling studies the compounds are assumed to adopt a binding pose similar to that of the potent mGAT1 inhibitor nipecotic acid. As substitution in 4-position should not cause an energetically unfavorable orientation of nipecotic acid as it is the case for N-substituted derivatives this is expected to lead to highly potent binders. For the synthesis of novel 4-substituted nipecotic acid derivatives a linear synthetic strategy was employed. As a key step, palladium catalyzed cross coupling reactions were used to attach the required biaryl moieties to the ω-position of the alkenyl- or alkynyl spacers of varying length in the 4-position of the nipecotic acid scaffold. The resulting amino acids were characterized with respect to their binding affinities and inhibitory potencies at mGAT1. Though the biological activities found were generally insignificant to poor, two compounds, one of which possesses a reasonable binding affinity for mGAT1, rac-57, the other a notable inhibitory potency at mGAT4, rac-84, both displaying a slight subtype selectivity for the individual transporters, could be identified.
      Graphical abstract image

      PubDate: 2016-04-12T02:01:27Z
       
  • Tetrahydroprotoberberine alkaloids with dopamine and σ receptor
           affinity
    • Abstract: Publication date: 1 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 9
      Author(s): Satishkumar Gadhiya, Sudharshan Madapa, Thomas Kurtzman, Ian L. Alberts, Steven Ramsey, Nagavara-Kishore Pillarsetty, Teja Kalidindi, Wayne W. Harding
      Two series of analogues of the tetrahydroprotoberberine (THPB) alkaloid (±)-stepholidine that (a) contain various alkoxy substituents at the C10 position and, (b) were de-rigidified with respect to (±)-stepholidine, were synthesized and evaluated for affinity at dopamine and σ receptors in order to evaluate effects on D3 and σ2 receptor affinity and selectivity. Small n-alkoxy groups are best tolerated by D3 and σ2 receptors. Among all compounds tested, C10 methoxy and ethoxy analogues (10 and 11 respectively) displayed the highest affinity for σ2 receptors as well as σ2 versus σ1 selectivity and also showed the highest D3 receptor affinity. De-rigidification of stepholidine resulted in decreased affinity at all receptors evaluated; thus the tetracyclic THPB framework is advantageous for affinity at dopamine and σ receptors. Docking of the C10 analogues at the D3 receptor, suggest that an ionic interaction between the protonated nitrogen atom and Asp110, a H-bond interaction between the C2 phenol and Ser192, a H-bond interaction between the C10 phenol and Cys181 as well as hydrophobic interactions of the aryl rings to Phe106 and Phe345, are critical for high affinity of the compounds.
      Graphical abstract image

      PubDate: 2016-04-12T02:01:27Z
       
  • Design, synthesis and biological evaluation of
           5-amino-4-(1H-benzoimidazol-2-yl)-phenyl-1,2-dihydro-pyrrol-3-ones as
           inhibitors of protein kinase FGFR1
    • Abstract: Publication date: 1 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 9
      Author(s): A.A. Gryshchenko, S.S. Tarnavskiy, K.V. Levchenko, V.G. Bdzhola, G.P. Volynets, A.G. Golub, T.P. Ruban, K.V. Vygranenko, L.L. Lukash, S.M. Yarmoluk
      Fibroblast growth factor receptor 1 (FGFR1) plays an important role in tumorigenesis and is therefore an attractive target for anticancer therapy. Using molecular docking approach we have identified inhibitor of FGFR1 belonging to 5-amino-4-(1H-benzoimidazol-2-yl)-phenyl-1,2-dihydro-pyrrol-3-ones with IC50 value of 3.5μM. A series of derivatives of this chemical scaffold has been synthesized and evaluated for inhibition of FGFR1 kinase activity. It was revealed that the most promising compounds 5-amino-1-(3-hydroxy-phenyl)-4-(6-methyl-1H-benzoimidazol-2-yl)-1,2-dihydro-pyrrol-3-one and 5-amino-4-(1H-benzoimidazol-2-yl)-1-(3-hydroxy-phenyl)-1,2-dihydro-pyrrol-3-one inhibit FGFR1 with IC50 values of 0.63 and 0.32μM, respectively, and posses antiproliferative activity against KG1 myeloma cell line with IC50 values of 5.6 and 9.3μM. Structure–activity relationships have been studied and binding mode of this chemical class has been proposed.
      Graphical abstract image

      PubDate: 2016-04-12T02:01:27Z
       
  • Editorial board
    • Abstract: Publication date: 1 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 9




      PubDate: 2016-04-12T02:01:27Z
       
  • Investigation of human flap structure-specific endonuclease 1 (FEN1)
           activity on primer-template models and exploration of a substrate-based
           FEN1 inhibitor
    • Abstract: Publication date: 1 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 9
      Author(s): Sai Ba, Hao Zhang, Jasmine Yiqin Lee, Haixia Wu, Ruijuan Ye, Dejian Huang, Tianhu Li
      Flap structure-specific endonuclease 1 (FEN1) is one of the enzymes that involve in Eukaryotic DNA replication and repair. Recent studies have proved that FEN1 is highly over-expressed in various types of cancer cells and is a drug target. However, a limited number of FEN1 inhibitors has been identified and approved. Herein, we investigate the catalytic activity of FEN1, and propose a substrate-based inhibitor. As a consequence, one of the phosphorothioate-modified substrates is proved to exhibit the most efficient inhibitory effect in our in vitro examinations. A novelly-designed substrate-based FEN1 inhibitor was accordingly constructed and determined a remarkable IC50 value.
      Graphical abstract image

      PubDate: 2016-04-12T02:01:27Z
       
  • Exploration of the P3 region of PEXEL peptidomimetics leads to a potent
           inhibitor of the Plasmodium protease, plasmepsin V
    • Abstract: Publication date: 1 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 9
      Author(s): Michelle Gazdik, Kate E. Jarman, Matthew T. O’Neill, Anthony N. Hodder, Kym N. Lowes, Helene Jousset Sabroux, Alan F. Cowman, Justin A. Boddey, Brad E. Sleebs
      The use of arginine isosteres is a known strategy to overcome poor membrane permeability commonly associated with peptides or peptidomimetics that possess this highly polar amino acid. Here, we apply this strategy to peptidomimetics that are potent inhibitors of the malarial protease, plasmepsin V, with the aim of enhancing their activity against Plasmodium parasites, and exploring the structure–activity relationship of the P3 arginine within the S3 pocket of plasmepsin V. Of the arginine isosteres trialled in the P3 position, we discovered that canavanine was the ideal and that this peptidomimetic potently inhibits plasmepsin V, efficiently blocks protein export and inhibits parasite growth. Structure studies of the peptidomimetics bound to plasmepsin V provided insight into the structural basis for the enzyme activity observed in vitro and provides further evidence why plasmepsin V is highly sensitive to substrate modification.
      Graphical abstract image

      PubDate: 2016-04-12T02:01:27Z
       
  • Synthetic approaches to the 2014 new drugs
    • Abstract: Publication date: 1 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 9
      Author(s): Andrew C. Flick, Hong X. Ding, Carolyn A. Leverett, Robert E. Kyne, Kevin K.-C. Liu, Sarah J. Fink, Christopher J. O’Donnell
      New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition and also serve as leads for designing future new drugs. This annual review covers the synthesis of thirty-seven NCEs that were approved for the first time in 2014 and one drug which was approved in 2013 and was not covered in a previous edition of this review.
      Graphical abstract image

      PubDate: 2016-04-12T02:01:27Z
       
  • Discovery of novel pyrrole-based scaffold as potent and orally
           bioavailable free fatty acid receptor 1 agonists for the treatment of type
           2 diabetes
    • Abstract: Publication date: 1 May 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 9
      Author(s): Zheng Li, Miaobo Pan, Xin Su, Yuxuan Dai, Mian Fu, Xingguang Cai, Wei Shi, Wenlong Huang, Hai Qian
      The free fatty acid receptor 1 (FFA1) has gained significant interest as a novel antidiabetic target. Most of FFA1 agonists reported in the literature bearing a common biphenyl scaffold, which was crucial for toxicity verified by the researchers of Daiichi Sankyo. Herein, we describe the systematic exploration of non-biphenyl scaffold and further chemical modification of the optimal pyrrole scaffold. All of these efforts led to the identification of compound 11 as a potent and orally bioavailable FFA1 agonist without the risk of hypoglycemia. Further molecular modeling studies promoted the understanding of ligand-binding pocket and might help to design more promising FFA1 agonists.
      Graphical abstract image

      PubDate: 2016-04-12T02:01:27Z
       
 
 
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