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  Subjects -> CHEMISTRY (Total: 846 journals)
    - ANALYTICAL CHEMISTRY (47 journals)
    - CHEMISTRY (597 journals)
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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: 26)
ACS Catalysis     Full-text available via subscription   (Followers: 23)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 15)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 24)
ACS Macro Letters     Full-text available via subscription   (Followers: 18)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 31)
ACS Nano     Full-text available via subscription   (Followers: 155)
ACS Photonics     Full-text available via subscription   (Followers: 6)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 16)
Acta Chemica Iasi     Open Access  
Acta Chimica Sinica     Full-text available via subscription   (Followers: 1)
Acta Chimica Slovaca     Open Access   (Followers: 2)
Acta Chromatographica     Full-text available via subscription   (Followers: 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: 5)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 4)
Advanced Functional Materials     Hybrid Journal   (Followers: 41)
Advanced Science Focus     Free   (Followers: 2)
Advances in Chemical Engineering and Science     Open Access   (Followers: 33)
Advances in Chemical Science     Open Access   (Followers: 10)
Advances in Chemistry     Open Access   (Followers: 7)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 14)
Advances in Drug Research     Full-text available via subscription   (Followers: 21)
Advances in Environmental Chemistry     Open Access   (Followers: 1)
Advances in Enzyme Research     Open Access   (Followers: 4)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 12)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 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: 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: 13)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Science and Technology     Full-text available via subscription   (Followers: 2)
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: 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: 13)
American Mineralogist     Full-text available via subscription   (Followers: 7)
Anadolu University Journal of Science and Technology     Open Access  
Analyst     Full-text available via subscription   (Followers: 41)
Angewandte Chemie     Hybrid Journal   (Followers: 115)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 164)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 1)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 2)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 3)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 7)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 8)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 13)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Full-text available via subscription  
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 5)
Applied Spectroscopy     Full-text available via subscription   (Followers: 22)
Applied Surface Science     Hybrid Journal   (Followers: 20)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 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: 96)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 85)
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: 24)
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: 64)
Catalysis for Sustainable Energy     Open Access   (Followers: 4)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 6)
Catalysis Science and Technology     Free   (Followers: 4)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 5)
Cellulose     Hybrid Journal   (Followers: 4)
Cereal Chemistry     Full-text available via subscription   (Followers: 4)
ChemBioEng Reviews     Full-text available via subscription  
ChemCatChem     Hybrid Journal   (Followers: 5)
Chemical and Engineering News     Free   (Followers: 10)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 61)
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: 136)
Chemical Science     Open Access   (Followers: 18)
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: 26)
ChemInform     Hybrid Journal   (Followers: 4)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 5)
Chemistry & Biology     Full-text available via subscription   (Followers: 30)
Chemistry & Industry     Hybrid Journal   (Followers: 2)
Chemistry - A European Journal     Hybrid Journal   (Followers: 112)
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: 41)
Chemistry of Materials     Full-text available via subscription   (Followers: 137)
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: 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: 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: 16)
Current Research in Chemistry     Open Access   (Followers: 7)
Current Science     Open Access   (Followers: 12)
Dalton Transactions     Full-text available via subscription   (Followers: 17)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 1)
Diamond and Related Materials     Hybrid Journal   (Followers: 12)
Dislocations in Solids     Full-text available via subscription  
Doklady Chemistry     Hybrid Journal  
Drying Technology: An International Journal     Hybrid Journal   (Followers: 3)
Eclética Química     Open Access   (Followers: 1)
Ecological Chemistry and Engineering S     Open Access   (Followers: 2)
Ecotoxicology and Environmental Contamination     Open Access  
Educación Química     Open Access   (Followers: 1)
Education for Chemical Engineers     Hybrid Journal   (Followers: 4)
Elements     Full-text available via subscription  
Environmental Chemistry     Hybrid Journal   (Followers: 5)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 2)

        1 2 3 | Last

Journal Cover Bioorganic & Medicinal Chemistry
  [96 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0968-0896
   Published by Elsevier Homepage  [2970 journals]
  • 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: Available online 27 June 2016
      Source:Bioorganic & Medicinal Chemistry
      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 (KIs of 28.5 – 2954 nM), being highly effective as hCA II (KIs in the range of 0.62 – 12.4 nM) and XII (KIs of 0.54 – 7.11 nM) 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: 2016-06-30T00:29:40Z
       
  • Synthesis and Biological Evaluation of Oblongifolin C Derivatives as c-Met
           Inhibitors
    • Abstract: Publication date: Available online 27 June 2016
      Source:Bioorganic & Medicinal Chemistry
      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: 2016-06-30T00:29:40Z
       
  • Detection of L-alanylaminopeptidase activity in microorganisms using
           fluorogenic self-immolative enzyme substrates
    • Abstract: Publication date: Available online 27 June 2016
      Source:Bioorganic & Medicinal Chemistry
      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: 2016-06-30T00:29:40Z
       
  • “Chemistry and Chemical Biology of Therapeutically Important
           Compounds”
    • Abstract: Publication date: Available online 27 June 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Matthew David Disney



      PubDate: 2016-06-30T00:29:40Z
       
  • Strand-invading linear probe combined with unmodified PNA
    • Abstract: Publication date: Available online 29 June 2016
      Source:Bioorganic & Medicinal Chemistry
      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 100 mM NaCl concentration.
      Graphical abstract image

      PubDate: 2016-06-30T00:29:40Z
       
  • Design, synthesis and biological evaluation of
           N-methyl-N-[(1,2,3-triazol-4-yl)alkyl]propargylamines as novel monoamine
           oxidase B inhibitors
    • Abstract: Publication date: Available online 28 June 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Ornella Di Pietro, Nelson Alencar, Gerard Esteban, Elisabet Viayna, Natalia Szałaj, Javier Vázquez, Jordi Juárez-Jiménez, Irene Sola, Belén Pérez, Montse Solé, Mercedes Unzeta, Diego Muñoz-Torrero, F. Javier Luque
      Different azides and alkynes have been coupled via Cu-catalyzed 1,3-dipolar Huisgen cycloaddition to afford a novel family of N 1- and C 5-substituted 1,2,3-triazole derivatives that feature the propargylamine group typical of irreversible MAO-B inhibitors at the C4-side chain of the triazole ring. All the synthesized compounds were evaluated against human MAO-A and MAO-B. Structureactivity relationships and molecular modelling were utilized to gain insight into the structural and chemical features that enhance the binding affinity and selectivity between the two enzyme isoforms. Several lead compounds, in terms of potency (submicromolar to low micromolar range), MAO-B selective recognition, and brain permeability, were identified. One of these leads (MAO-B IC50 of 3.54 μM, selectivity MAO-B/MAO-A index of 0.036) was further subjected to reversibility and time-dependence inhibition studies, which disclosed a slow and irreversible inhibition of human MAO-B. Overall, the results support the suitability of the 4-triazolylalkyl propargylamine scaffold for exploring the design of multipotent anti-Alzheimer compounds endowed with irreversible MAO-B inhibitory activity.
      Graphical abstract image

      PubDate: 2016-06-30T00:29:40Z
       
  • Antioxidant, anticancer activities and mechanistic studies of the flavone
           glycoside diosmin and its oxidovanadium(IV) complex. Interactions with
           bovine serum albumin
    • Abstract: Publication date: Available online 28 June 2016
      Source:Bioorganic & Medicinal Chemistry
      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: 2016-06-30T00:29:40Z
       
  • Synthesis and evaluation of raloxifene derivatives as a selective estrogen
           receptor down-regulator
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
      Author(s): Takuji Shoda, Masashi Kato, Takuma Fujisato, Takashi Misawa, Yosuke Demizu, Hideshi Inoue, Mikihiko Naito, Masaaki Kurihara
      Estrogen receptors (ERs) play a major role in the growth of human breast cancer cells. A selective estrogen receptor down-regulator (SERD) that acts as not only an inhibitor of ligand binding, but also induces the down-regulation of ER, would be useful for the treatment for ER-positive breast cancer. We previously reported that tamoxifen derivatives, which have a long alkyl chain, had the ability to down-regulate ERα. With the aim of expanding range of the currently available SERDs, we designed and synthesized raloxifene derivatives, which had various lengths of the long alkyl chains, and evaluated their SERD activities. All compounds were able to bind ERα, and RC10, which has a decyl group on the amine moiety of raloxifene, was shown to be the most potent compound. Our findings suggest that the ligand core was replaceable, and that the alkyl length was important for controlling SERD activity. Moreover, RC10 showed antagonistic activity and its potency was superior to that of 4,4′-(heptane-4,4-diyl)bis(2-methylphenol) (18), a competitive antagonist of ER without SERD activity. These results provide information that will be useful for the development of promising SERDs candidates.
      Graphical abstract image

      PubDate: 2016-06-13T12:22:31Z
       
  • 2-(Thienothiazolylimino)-1,3-thiazolidin-4-ones inhibit cell division
           cycle 25 A phosphatase
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
      Author(s): Sophie Huber-Villaume, Germain Revelant, Estelle Sibille, Stéphanie Philippot, Angelica Morabito, Sandrine Dunand, Patrick Chaimbault, Denyse Bagrel, Gilbert Kirsch, Stéphanie Hesse, Hervé Schohn
      Cell division cycle dual phosphatases (CDC25) are essential enzymes that regulate cell progression in cell cycle. Three isoforms exist as CDC25A, B and C. Over-expression of each CDC25 enzyme is found in cancers of diverse origins. Thiazolidinone derivatives have been reported to display anti-proliferative activities, bactericidal activities and to reduce inflammation process. New 2-(thienothiazolylimino)-1,3-thiazolidin-4-ones were synthesized and evaluated as inhibitors of CDC25 phosphatase. Among the molecules tested, compound 6 inhibited CDC25A with an IC50 estimated at 6.2±1.0μM. The binding of thiazolidinone derivative 6 onto CDC25A protein was reversible. In cellulo, compound 6 treatment led to MCF7 and MDA-MB-231 cell growth arrest. To our knowledge, it is the first time that such 4-thiazolidinone derivatives are characterized as CDC25 potential inhibitor.
      Graphical abstract image

      PubDate: 2016-06-13T12:22:31Z
       
  • Pyrazolylbenzo[d]imidazoles as new potent and selective inhibitors of
           carbonic anhydrase isoforms hCA IX and XII
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
      Author(s): Satish Kumar, Mariangela Ceruso, Tiziano Tuccinardi, Claudiu T. Supuran, Pawan K. Sharma
      Novel pyrazolylbenzo[d]imidazole derivatives (2a–2f) were designed, synthesized and evaluated against four human carbonic anhydrase isoforms belonging to α family comprising of two cytosolic isoforms hCA I and II as well as two transmembrane tumor associated isoforms hCA IX and XII. Starting from these derivatives that showed high potency but low selectivity in favor of tumor associated isoforms hCA IX and XII, we investigated the impact of removing the sulfonamide group. Thus, analogs 3a–3f without sulfonamide moiety were synthesized and biological assay revealed a good activity as well as an excellent selectivity as inhibitors for tumor associated hCA IX and hCA XII and the same was analyzed by molecular docking studies.
      Graphical abstract image

      PubDate: 2016-06-13T12:22:31Z
       
  • Optimization of the phenylurea moiety in a phosphoinositide 3-kinase
           (PI3K) inhibitor to improve water solubility and the PK profile by
           introducing a solubilizing group and ortho substituents
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
      Author(s): Hatsuo Kawada, Hirosato Ebiike, Masao Tsukazaki, Shun Yamamoto, Kohei Koyama, Mitsuaki Nakamura, Kenji Morikami, Kiyoshi Yoshinari, Miyuki Yoshida, Kotaro Ogawa, Nobuo Shimma, Takuo Tsukuda, Jun Ohwada
      Phosphoinositide 3-kinase (PI3K) is a promising anti-cancer target, because various mutations and amplifications are observed in human tumors isolated from cancer patients. Our dihydropyrrolopyrimidine derivative with a phenylurea moiety showed strong PI3K enzyme inhibitory activity, but its pharmacokinetic property was poor because of lack of solubility. Herein, we report how we improved the solubility of our PI3K inhibitors by introducing a solubilizing group and ortho substituents to break molecular planarity.
      Graphical abstract image

      PubDate: 2016-06-13T12:22:31Z
       
  • Corrigendum to “Purinylpyridinylamino-based DFG-in/αC-helix-out
           B-Raf inhibitors: Applying mutant versus wild-type B-Raf selectivity
           indices for compound profiling” [Bioorg. Med. Chem. 24 (2016)
           2215–2234]
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
      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



      PubDate: 2016-06-13T12:22:31Z
       
  • Novel sulfonamide bearing coumarin scaffolds as selective inhibitors of
           tumor associated carbonic anhydrase isoforms IX and XII
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
      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 tumor 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 antitumor drug acetazolamide. One derivative 2b of series 2 was found to be a better selective inhibitor of hCA IX and XII.
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      PubDate: 2016-06-13T12:22:31Z
       
  • Dihydrochelerythrine and its derivatives: Synthesis and their application
           as potential G-quadruplex DNA stabilizing agents
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
      Author(s): Rajesh Malhotra, Chhanda Rarhi, K.V. Diveshkumar, Rajib Barik, Ruhee D’cunha, Pranab Dhar, Mrinalkanti Kundu, Subrata Chattopadhyay, Subho Roy, Sourav Basu, P.I. Pradeepkumar, Saumen Hajra
      A convenient route was envisaged toward the synthesis of dihydrochelerythrine (DHCHL), 4 by intramolecular Suzuki coupling of 2-bromo-N-(2-bromobenzyl)-naphthalen-1-amine derivative 5 via in situ generated arylborane. This compound was converted to (±)-6-acetonyldihydrochelerythrine (ADC), 3 which was then resolved by chiral prep-HPLC. Efficiency of DHCHL for the stabilization of promoter quadruplex DNA structures and a comparison study with the parent natural alkaloid chelerythrine (CHL), 1 was performed. A thorough investigation was carried out to assess the quadruplex binding affinity by using various biophysical and biochemical studies and the binding mode was explained by using molecular modeling and dynamics studies. Results clearly indicate that DHCHL is a strong G-quadruplex stabilizer with affinity similar to that of the parent alkaloid CHL. Compounds ADC and DHCHL were also screened against different human cancer cell lines. Among the cancer cells, (±)-ADC and its enantiomers showed varied (15–48%) inhibition against human colorectal cell line HCT116 and breast cancer cell line MDA-MB-231 albeit low enantio-specificity in the inhibitory effect; whereas DHCHL showed 30% inhibition against A431 cell line only, suggesting the compounds are indeed cancer tissue specific.
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      PubDate: 2016-06-13T12:22:31Z
       
  • Synthesis, biological evaluation, and physicochemical property assessment
           of 4-substituted 2-phenylaminoquinazolines as Mer tyrosine kinase
           inhibitors
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
      Author(s): Sheng-Biao Wang, Mu-Tian Cui, Xiao-Feng Wang, Emika Ohkoshi, Masuo Goto, De-Xuan Yang, Linna Li, Shoujun Yuan, Susan L. Morris-Natschke, Kuo-Hsiung Lee, Lan Xie
      Current results identified 4-substituted 2-phenylaminoquinazoline compounds as novel Mer tyrosine kinase (Mer TK) inhibitors with a new scaffold. Twenty-one 2,4-disubstituted quinazolines (series 4–7) were designed, synthesized, and evaluated against Mer TK and a panel of human tumor cell lines aimed at exploring new Mer TK inhibitors as novel potential antitumor agents. A new lead, 4b, was discovered with a good balance between high potency (IC50 0.68μM) in the Mer TK assay and antiproliferative activity against MV4-11 (GI50 8.54μM), as well as other human tumor cell lines (GI50 <20μM), and a desirable druglike property profile with low log P value (2.54) and high aqueous solubility (95.6μg/mL). Molecular modeling elucidated an expected binding mode of 4b with Mer TK and necessary interactions between them, thus supporting the hypothesis that Mer TK might be a biologic target of this kind of new active compound.
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      PubDate: 2016-06-13T12:22:31Z
       
  • Synthesis and structure–activity relationships of novel hybrid
           ferrocenyl compounds based on a bicyclic core skeleton for breast cancer
           therapy
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
      Author(s): Changhao Li, Chu Tang, Zhiye Hu, Chenxi Zhao, Chenlu Li, Silong Zhang, Chune Dong, Hai-Bing Zhou, Jian Huang
      Breast cancer is the most frequent cancer in women worldwide, and incidence is increasing year by year. Although current selective estrogen receptor modulators (SERMs) have clear advantages in the treatment of hormone-responsive breast cancer, they are ineffective for ER(−). In this study, we describe the design and synthesis of a series of dual-acting estrogen receptor (ER) and histone deacetylase (HDAC) inhibitors with incorporation of the ferrocenyl moiety, leading to novel hybrid ferrocenyl complexes (FcOBHS–HDACis) for breast cancer therapy. It is worth to note that these ferrocenyl conjugates could not only potently inhibit HDACs and the proliferation of ERα positive (ER(+)) breast cancer cells (MCF-7), but also show significant antiproliferative effect on ER(−) breast cancer cells (MDA-MB-231). Thus, the FcOBHS–HDACi conjugates represent a novel approach to the development of efficiently dual-acting agents for treatment of breast cancer.
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      PubDate: 2016-06-13T12:22:31Z
       
  • Antiplasmodial activities of gold(I) complexes involving functionalized
           N-heterocyclic carbenes
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
      Author(s): Catherine Hemmert, Arba Pramundita Ramadani, Luca Boselli, Álvaro Fernández Álvarez, Lucie Paloque, Jean-Michel Augereau, Heinz Gornitzka, Françoise Benoit-Vical
      A series of twenty five molecules, including imidazolium salts functionalized by N-, O- or S-containing groups and their corresponding cationic, neutral or anionic gold(I) complexes were evaluated on Plasmodium falciparum in vitro and then on Vero cells to determine their selectivity. Among them, eight new compounds were synthesized and fully characterized by spectroscopic methods. The X-ray structures of three gold(I) complexes are presented. Except one complex (18), all the cationic gold(I) complexes show potent antiplasmodial activity with IC50 in the micro- and submicromolar range, correlated with their lipophilicity. Structure–activity relationships enable to evidence a lead-complex (21) displaying a good activity (IC50 =210nM) close to the value obtained with chloroquine (IC50 =514nM) and a weak cytotoxicity.
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      PubDate: 2016-06-13T12:22:31Z
       
  • Triterpene sapogenin–polyarginine conjugates exhibit promising
           antibacterial activity against Gram-positive strains
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
      Author(s): Heiya Na, Xiangpeng Li, Cunbin Zou, Chenhong Wang, Chao Wang, Keliang Liu
      Triterpene sapogenins are a group of biologically active compounds with antibacterial activity. However, the limited solubility and poor bioavailability of triterpene sapogenins restrict their therapeutic application. Polyarginine peptides are small cationic peptides with high affinities for multiple negatively charged cell membranes and possess moderate antibacterial activities. In this study, we designed and synthesized a series of sapogenin–polyarginine conjugates in which the triterpene sapogenin moiety was covalently appended to the positively charged polyarginine via click chemistry. A clear synergistic effect was found, and the conjugates exhibited potent and selective antibacterial activity against Gram-positive strains. Among them, BAc-R3 was the most promising compound, which was also proven to be nontoxic toward mammalian cells as well as stable in plasma. The mechanism of BAc-R3 primarily involves an interaction with the bacterial membrane, similar to that of antimicrobial peptides (AMPs). This scaffold design opens an avenue for the further development of novel antibiotics comprised of the combination of a peptide and a natural product.
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      PubDate: 2016-06-13T12:22:31Z
       
  • Systematic evaluation of methyl ester bioisosteres in the context of
           developing alkenyldiarylmethanes (ADAMs) as non-nucleoside reverse
           transcriptase inhibitors (NNRTIs) for anti-HIV-1 chemotherapy
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
      Author(s): Ayako Hoshi, Takeshi Sakamoto, Jun Takayama, Meiyan Xuan, Mari Okazaki, Tracy L. Hartman, Robert W. Buckheit, Christophe Pannecouque, Mark Cushman
      The alkenyldiarylmethanes (ADAMs) are a class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) targeting HIV-1. Four chemically and metabolically stabilized ADAMs incorporating N-methoxyimidoyl halide replacements of the methyl esters of the lead compound were previously reported. In this study, twenty-five new ADAMs were synthesized in order to investigate the biological consequences of installing nine different methyl ester bioisosteres at three different locations. Attempts to define a universal rank order of methyl ester bioisosteres and discover the ‘best’ one in terms of inhibitory activity versus HIV-1 reverse transcriptase (RT) led to the realization that the potencies are critically dependent on the surrounding structure at each location, and therefore the definition of universal rank order is impossible. This investigation produced several new non-nucleoside reverse transcriptase inhibitors in which all three of the three methyl esters of the lead compound were replaced by methyl ester bioisosteres, resulting in compounds that are more potent as HIV-1 RT inhibitors and antiviral agents than the lead compound itself and are expected to also be more metabolically stable than the lead compound.
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      PubDate: 2016-06-13T12:22:31Z
       
  • Antiproliferative activity and apoptosis inducing effects of nitric oxide
           donating derivatives of evodiamine
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
      Author(s): Nan Zhao, Kang-tao Tian, Ke-guang Cheng, Tong Han, Xu Hu, Da-hong Li, Zhan-lin Li, Hui-ming Hua
      The first series of nitric oxide donating derivatives of evodiamine were designed and prepared. NO releasing ability of all target derivatives was evaluated in BGC-823, Bel-7402 and L-02 cells. The cytotoxicity was evaluated against three human tumor cell lines (Bel-7402, A549 and BGC-823) and normal human liver cells L-02. The nitrate derivatives 11a and 11b only exhibited moderate activity and furoxan-based derivatives 13a–c, 14a and 14b showed promising activity. 13c showed good cytotoxic selectivity between tumor and normal liver cells and was further investigated for its apoptotic properties on human hepatocarcinoma Bel-7402 cells. The molecular mode of action revealed that 13c caused cell-cycle arrest at S phase and induced apoptosis in Bel-7402 cells through mitochondria-related caspase-dependent pathways.
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      PubDate: 2016-06-13T12:22:31Z
       
  • Stable and biocompatible cystine knot peptides from the marine sponge
           Asteropus sp.
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
      Author(s): Mingzhi Su, Huayue Li, Haibo Wang, Eun La Kim, Hyung Sik Kim, Eun-Hee Kim, Jaewon Lee, Jee H. Jung
      Two new cystine knot peptides, asteropsins F (ASPF) and G (ASPG), were isolated from the marine sponge Asteropus sp. ASPF and ASPG are composed of 33 and 32 amino acids, respectively, and contain six cysteines which are involved in three disulfide bonds. They shared the characteristic features of the asteropsin family, such as, N-terminal pyroglutamate modification, incorporation of cis prolines, and the unique anionic profile, which distinguish them from other knottin families. Tertiary structures of the peptides were determined by high resolution NMR. ASPF and ASPG were found to be remarkably resistant not only to digestive enzymes (chymotrypsin, pepsin, elastase, and trypsin) but also to thermal degradation. In addition, these peptides were pharmacologically inert; non-hemolytic to human and fish red blood cells, non-stimulatory to murine macrophage cells, and nontoxic in vitro or in vivo. These observations support their stability and biocompatibility as suitable carrier scaffolds for the design of oral peptide drug.
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      PubDate: 2016-06-13T12:22:31Z
       
  • Bismuth(III) complexes with 2-acetylpyridine- and
           2-benzoylpyridine-derived hydrazones: Antimicrobial and cytotoxic
           activities and effects on the clonogenic survival of human solid tumor
           cells
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
      Author(s): Isabella P. Ferreira, Elisa D.L. Piló, Angel A. Recio-Despaigne, Jeferson G. Da Silva, Jonas P. Ramos, Lucas B. Marques, Pedro H.D.M. Prazeres, Jacqueline A. Takahashi, Elaine M. Souza-Fagundes, Willian Rocha, Heloisa Beraldo
      Complexes [Bi(2AcPh)Cl2]·0.5H2O (1), [Bi(2AcpClPh)Cl2] (2), [Bi(2AcpNO2Ph)Cl2] (3), [Bi(2AcpOHPh)Cl2]·2H2O (4), [Bi(H2BzPh)Cl3]·2H2O (5), [Bi(H2BzpClPh)Cl3] (6), [Bi(2BzpNO2Ph)Cl2]·2H2O (7) and [Bi(H2BzpOHPh)Cl3]·2H2O (8) were obtained with 2-acetylpyridine phenylhydrazone (H2AcPh), its -para-chloro-phenyl- (H2AcpClPh), -para-nitro-phenyl (H2AcpNO2Ph) and -para-hydroxy-phenyl (H2AcpOHPh) derivatives, as well as with the 2-benzoylpyridine phenylhydrazone analogues (H2BzPh, H2BzpClPh, H2BzpNO2Ph, H2BzpOHPh). Upon coordination to bismuth(III) antibacterial activity against Gram-positive and Gram-negative bacterial strains significantly improved except for complex (4). The cytotoxic effects of the compounds under study were evaluated on HL-60, Jurkat and THP-1 leukemia, and on MCF-7 and HCT-116 solid tumor cells, as well as on non-malignant Vero cells. In general, 2-acetylpyridine-derived hydrazones proved to be more potent and more selective as cytotoxic agents than the corresponding 2-benzoylpyridine-derived counterparts. Exposure of HCT-116 cells to H2AcpClPh, H2AcpNO2Ph and complex (3) led to 99% decrease of the clonogenic survival. The IC50 values of these compounds were three-fold smaller when cells were cultured in soft-agar (3D) than when cells were cultured in monolayer (2D), suggesting that they constitute interesting scaffolds, which should be considered in further studies aiming to develop new drug candidates for the treatment of colon cancer.
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      PubDate: 2016-06-13T12:22:31Z
       
  • Novel free fatty acid receptor 1 (GPR40) agonists based on
           1,3,4-thiadiazole-2-carboxamide scaffold
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
      Author(s): Mikhail Krasavin, Alexey Lukin, Nikolay Zhurilo, Alexey Kovalenko, Ihor Zahanich, Sergey Zozulya, Daniel Moore, Irina G. Tikhonova
      Free fatty acid receptor 1 (FFA1), previously known as GPR40 is a G protein-coupled receptor and a new target for treatment of type 2 diabetes. Two series of FFA1 agonists utilizing a 1,3,4-thiadiazole-2-caboxamide scaffold were synthetized. Both series offered significant improvement of the potency compared to the previously described 1,3,4-thiadiazole-based FFA1 agonists and high selectivity for FFA1. Molecular docking predicts new aromatic interactions with the receptor that improve agonist potency. The most potent compounds from both series were profiled for in vitro ADME properties (plasma and metabolic stability, Log D, plasma protein binding, hERG binding and CYP inhibition). One series suffered very rapid degradation in plasma and in presence of mouse liver microsomes. However, the other series delivered a lead compound that displayed a reasonable ADME profile together with the improved FFA1 potency.
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      PubDate: 2016-06-13T12:22:31Z
       
  • Design, synthesis and biological evaluation of novel
           tetrahydroisoquinoline quaternary derivatives as peripheral κ-opioid
           receptor agonists
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
      Author(s): Ting Guo, Zongjie Gan, Jie Chen, Dechuan Wang, Ling He, Qiao Song, Yungen Xu
      A novel series of tetrahydroisoquinoline quaternary derivatives 4 were synthesized as peripheral κ-opioid receptor agonists. All the target compounds were evaluated in κ-opioid receptor binding assays, and compounds 4l, 4m, and 4n exhibited high affinity for κ-opioid receptor. Furthermore, compound 4l (κK i =0.94nM) produced potent antinociceptive activity in the mouse acetic acid-induced writhing assay, with lower sedative side effects than the parent compound MB-1c.
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      PubDate: 2016-06-13T12:22:31Z
       
  • Discovery of a novel covalent non-β-lactam inhibitor of the
           metallo-β-lactamase NDM-1
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
      Author(s): Tony Christopeit, Anastasia Albert, Hanna-Kirsti S. Leiros
      The inhibition of metallo-β-lactamases (MBL) can prevent the hydrolysis of β-lactam antibiotics and hence is a promising strategy for the treatment of antibiotic resistant infections. In this study, we present a novel reversible covalent inhibitor of the clinically relevant MBL New Delhi metallo-β-lactamase 1 (NDM-1). Electrospray ionization-mass spectrometry (ESI-MS) and single site directed mutagenesis were used to show that the inhibitor forms a covalent bond with Lys224 in the active site of NDM-1. The inhibitor was further characterized using an enzyme inhibition assay, a surface plasmon resonance (SPR) based biosensor assay and covalent docking. The determined inhibition constant (K I ∗) was 580nM and the inhibition constant for the initial complex (K I) was 76μM. To our knowledge, this inhibitor is the first example for a reversible covalent non-β-lactam inhibitor targeting NDM-1 and a promising starting point for the design of potent covalent inhibitors.
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      PubDate: 2016-06-13T12:22:31Z
       
  • Design, synthesis and anticonvulsant activity of new hybrid compounds
           derived from N-phenyl-2-(2,5-dioxopyrrolidin-1-yl)-propanamides and
           -butanamides
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
      Author(s): Krzysztof Kamiński, Anna Rapacz, Barbara Filipek, Jolanta Obniska
      The focused library of 21 new N-phenyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide, 2-(3-methyl-2,5-dioxopyrrolidin-1-yl)propanamide, and 2-(2,5-dioxopyrrolidin-1-yl)butanamide derivatives as potential new hybrid anticonvulsant agents was synthesized. These hybrid molecules were obtained as close analogs of previously described N-benzyl derivatives and fuse the chemical fragments of clinically relevant antiepileptic drugs such as ethosuximide, levetiracetam, and lacosamide. The initial anticonvulsant screening was performed in mice (ip) using the ‘classical’ maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests, as well as in the six-Hertz (6Hz) model of pharmacoresistant limbic seizures. Applying the rotarod test, the acute neurological toxicity was determined. The broad spectra of activity across the preclinical seizure models in mice (ip) displayed compounds 4, 5, 11, and 19. The most favorable anticonvulsant properties demonstrated 4 (ED50 MES=96.9mg/kg, ED50 scPTZ=75.4mg/kg, ED50 6Hz=44.3mg/kg) which showed TD50 =335.8mg/kg in the rotarod test that yielded satisfying protective indexes (PI MES=3.5, PI scPTZ=4.4, PI 6Hz=7.6). Consequently, compound 4 revealed comparable or better safety profile than model antiepileptic drugs (AEDs): ethosuximide, lacosamide, and valproic acid. In the in vitro assays, compound 4 was observed as relatively effective binder to the neuronal voltage-sensitive sodium and diltiazem site of L-type calcium channels.
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      PubDate: 2016-06-13T12:22:31Z
       
  • Discovery of new [1,4]dioxino[2,3-f]quinazoline-based inhibitors of EGFR
           including the T790M/L858R mutant
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
      Author(s): Xuemei Qin, Zhipeng Li, Leifu Yang, Peng Liu, Liming Hu, Chengchu Zeng, Zhiyong Pan
      A novel series of 2,3-dihydro-[1,4]dioxino[2,3-f]quinazoline derivatives were designed, synthesized and evaluated as reversible and noncovalent epidermal growth factor receptor (EGFR) inhibitors. Most of the compounds exhibited good potency against EGFRwt and some showed moderate to excellent potency against EGFRT790M/L858R mutant. The half-maximal inhibitory concentration (IC50) values of twenty-one compounds against EGFRwt were less than 50nM, and those of six compounds were less than 10nM. The IC50 values of eleven compounds against EGFRT790M/L858R were less than 100nM. Among these, compound b1 displayed the most potent inhibitory activity against EGFRwt (IC50 =2.0nM) and EGFRT790M/L858R (IC50 =6.9nM). Compounds with excellent inhibitory activities against EGFRwt and EGFRT790M/L858R kinase inhibitory activities showed good antiproliferative activities against H358 and A549 cells. Docking study was performed to position compound b1 into the EGFR active pocket to determine the probable binding conformation.
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      PubDate: 2016-06-13T12:22:31Z
       
  • Development of hydroxy-based sphingosine kinase inhibitors and
           anti-inflammation in dextran sodium sulfate induced colitis in mice
    • Abstract: Publication date: 15 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14
      Author(s): Meiyang Xi, Jun Ge, Xiaojian Wang, Chenbin Sun, Tianqi Liu, Liang Fang, Qiong Xiao, Dali Yin
      Sphingosine kinase (SphK)-catalyzed production of sphingosine-1-phosphate (S1P) regulates cell growth, survival and proliferation as well as inflammatory status in animals. In recent study we reported the N′-(3-(benzyloxy)benzylidene)-3,4,5-trihydroxybenzohydrazide scaffold as a potent SphK inhibitor. As a continuation of these efforts, 51 derivatives were synthesized and evaluated by SphK1/2 inhibitory activities for structure–activity relationship (SAR) study. Among them, 33 was identified as the most potent SphK inhibitor. Potency of 33 was also observed to efficiently decrease SphK1/2 expression in human colorectal cancer cells (HCT116) and significantly inhibit dextran sodium sulfate (DSS)-induced colitis as well as the decreased expression of interleukin (IL)-6 and cyclooxygenase-2 (COX-2) in mouse models. Collectively, 33 was validated as an effective SphK inhibitor, which can be served as anti-inflammatory agent to probably treat inflammatory bowel diseases in human.
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      PubDate: 2016-06-13T12:22:31Z
       
  • Editorial board
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13




      PubDate: 2016-06-13T12:22:31Z
       
  • Design, synthesis, and biological evaluation of a novel series of
           peripheral-selective noradrenaline reuptake inhibitors—Part 2
    • Abstract: Publication date: 15 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14
      Author(s): Tomoya Yukawa, Ikuo Fujimori, Taku Kamei, Yoshihisa Nakada, Nobuki Sakauchi, Masami Yamada, Yusuke Ohba, Hiroyuki Ueno, Maiko Takiguchi, Masako Kuno, Izumi Kamo, Hideyuki Nakagawa, Yasushi Fujioka, Tomoko Igari, Yuji Ishichi, Tetsuya Tsukamoto
      Peripherally selective inhibition of noradrenaline reuptake is a novel mechanism for the treatment of stress urinary incontinence to overcome adverse effects associated with central action. Herein, we describe our medicinal chemistry approach to discover peripheral-selective noradrenaline reuptake inhibitors to avert the risk of P-gp-mediated DDI at the blood–brain barrier. We observed that steric shielding of the hydrogen-bond acceptors and donors (HBA and HBD) of compound 1 reduced the multidrug resistance protein 1 (MDR1) efflux ratio; however, the resulting compound 6, a methoxyacetamide derivative, was mainly metabolized by CYP2D6 and CYP2C19 in the in vitro phenotyping study, implying the risk of PK variability based on the genetic polymorphism of the CYPs. Replacement of the hydrogen atom with a deuterium atom in a strategic, metabolically hot spot led to compound 13, which was mainly metabolized by CYP3A4. To our knowledge, this study represents the first report of the effect of deuterium replacement for a major metabolic enzyme. The compound 13, N-{[(6S,7R)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-[(2H 3)methyloxy]acetamide hydrochloride, which exhibited peripheral NET selective inhibition at tested doses in rats, increased urethral resistance in a dose-dependent manner.
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      PubDate: 2016-06-13T12:22:31Z
       
  • Discovery of novel 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine
           derivatives as γ-secretase modulators (Part 2)
    • Abstract: Publication date: 15 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14
      Author(s): Takafumi Takai, Tatsuki Koike, Minoru Nakamura, Yuichi Kajita, Toshiro Yamashita, Naohiro Taya, Tetsuya Tsukamoto, Tomomichi Watanabe, Koji Murakami, Tomoko Igari, Makoto Kamata
      γ-Secretase modulators (GSMs), which lower pathogenic amyloid beta (Aβ) without affecting the production of total Aβ or Notch signal, have emerged as a potential therapeutic agent for Alzheimer’s disease (AD). A novel series of 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine derivatives was discovered and characterized as GSMs. Optimization of substituents at the 8-position of the core scaffold using ligand-lipophilicity efficiency (LLE) as a drug-likeness guideline led to identification of various types of high-LLE GSMs. Phenoxy compound (R)-17 exhibited especially high LLE as well as potent in vivo Aβ42-lowering effect by single administration. Furthermore, multiple oral administration of (R)-17 significantly reduced soluble and insoluble brain Aβ42, and ameliorated cognitive deficit in novel object recognition test (NORT) using Tg2576 mice as an AD model.
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      PubDate: 2016-06-13T12:22:31Z
       
  • A combined ligand- and structure-based approach for the identification of
           rilmenidine-derived compounds which synergize the antitumor effects of
           doxorubicin
    • Abstract: Publication date: 15 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14
      Author(s): Jelica Vucicevic, Tatjana Srdic-Rajic, Marco Pieroni, Jonne M.M. Laurila, Vladimir Perovic, Sabrina Tassini, Elisa Azzali, Gabriele Costantino, Sanja Glisic, Danica Agbaba, Mika Scheinin, Katarina Nikolic, Marco Radi, Nevena Veljkovic
      The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I1-type imidazoline receptors (I1-IR) was recently found to have cytotoxic effects on cultured cancer cell lines. However, due to its pharmacological effects resulting also from α2-adrenoceptor activation, rilmenidine cannot be considered a suitable anticancer drug candidate. Here, we report the identification of novel rilmenidine-derived compounds with anticancer potential and devoid of α2-adrenoceptor effects by means of ligand- and structure-based drug design approaches. Starting from a large virtual library, eleven compounds were selected, synthesized and submitted to biological evaluation. The most active compound 5 exhibited a cytotoxic profile similar to that of rilmenidine, but without appreciable affinity to α2-adrenoceptors. In addition, compound 5 significantly enhanced the apoptotic response to doxorubicin, and may thus represent an important tool for the development of better adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers.
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      PubDate: 2016-06-13T12:22:31Z
       
  • Structure–activity relationships of dibenzoylhydrazines for the
           inhibition of P-glycoprotein-mediated quinidine transport
    • Abstract: Publication date: 15 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14
      Author(s): Ken-ichi Miyata, Yoshiaki Nakagawa, Yasuhisa Kimura, Kazumitsu Ueda, Miki Akamatsu
      We previously demonstrated that dibenzoylhydrazines (DBHs) are not only P-glycoprotein (P-gp) substrates, but also inhibitors. In the present study, we evaluated the inhibition of P-gp-mediated quinidine transport by two series of DBHs and performed a classical QSAR analysis and docking simulation in order to investigate the mechanisms underlying P-gp substrate/inhibitor recognition. The results of the QSAR analysis identified the hydrophobic factor as the most important for inhibitory activities, while electronic and steric effects also influenced the activities. The different substituent effects observed in each series suggested the different binding modes of each series of DBHs, which was supported by the results of the docking simulation.
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      PubDate: 2016-06-13T12:22:31Z
       
  • New trans dichloro (triphenylphosphine)platinum(II) complexes containing
           N-(butyl),N-(arylmethyl)amino ligands: Synthesis, cytotoxicity and
           mechanism of action
    • Abstract: Publication date: 1 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
      Author(s): Lisa Dalla Via, Aída Nelly García-Argáez, Enzo Agostinelli, Daniela Belli Dell’Amico, Luca Labella, Simona Samaritani
      Some new platinum(II) complexes have been prepared, of general formula trans-[PtCl2(PPh3){NH(Bu)CH2Ar}], where the dimension of the Ar residue in the secondary amines has been varied from small phenyl to large pyrenyl group. The obtained complexes, tested in vitro towards a panel of human tumor cell lines showed an interesting antiproliferative effect on both cisplatin-sensitive and -resistant cells. For the most cytotoxic derivative 2a the investigation on the mechanism of action highlighted the ability to induce apoptosis on resistant cells and interestingly, to inhibit the catalytic activity of topoisomerase II.
      Graphical abstract image

      PubDate: 2016-06-13T12:22:31Z
       
  • Editorial board
    • Abstract: Publication date: 15 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14




      PubDate: 2016-06-13T12:22:31Z
       
  • Structure–activity relationship of lipid core peptide-based Group A
           Streptococcus vaccine candidates
    • Abstract: Publication date: 15 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14
      Author(s): Amy Chan, Waleed M. Hussein, Khairunnisa Abdul Ghaffar, Nirmal Marasini, Ahmed Mostafa, Sharareh Eskandari, Michael R. Batzloff, Michael F. Good, Mariusz Skwarczynski, Istvan Toth
      Infection with Group A Streptococcus (GAS) can result in a range of different illnesses, some of which are fatal. Currently, our efforts to develop a vaccine against GAS focuses on the lipid core peptide (LCP) system, a subunit vaccine containing a lipoamino acid (LAA) moiety which allows the stimulation of systemic antibody activity. In the present study, a peptide (J14) representing the B-cell epitope from the GAS M protein was incorporated alongside a universal T-helper epitope (P25) in four LCP constructs of different spatial orientation or LAA lengths. Through structure–activity studies, it was discovered that while the alteration of the LCP orientation had a weaker effect on immunostimulation, increasing the LAA side chain length within the construct increased antibody responses in murine models. Furthermore, the mice immunised with the lead LCP construct were also able to maintain antibody activity throughout the course of five months. These findings highlight the importance of LAA moieties in the development of intranasal peptide vaccines and confirmed that its side chain length has an effect on the immunogenicity of the structure.
      Graphical abstract image

      PubDate: 2016-06-13T12:22:31Z
       
  • The influence of halogen substituents on the biological properties of
           sulfur-containing flavonoids
    • Abstract: Publication date: 15 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14
      Author(s): Lucian Gabriel Bahrin, Laura Gabriela Sarbu, Henning Hopf, Peter G. Jones, Cornelia Babii, Marius Stefan, Mihail Lucian Birsa
      A series of halogen-substituted tricyclic flavonoids containing a 1,3-dithiol-2-ylium moiety has been synthesized from the corresponding 3-dithiocarbamic flavanones. The influence of halogen substituents on the antibacterial properties of the tricyclic flavonoids has been investigated against Staphylococcus aureus and Escherichia coli. On going from fluorine to iodine, these compounds exhibit good to excellent inhibitory properties against both Gram-positive and Gram-negative pathogens. These results suggest that size is the main factor for the change in potency rather than polarity/electronics.
      Graphical abstract image

      PubDate: 2016-06-13T12:22:31Z
       
  • Thiazolo[3,2-a]benzimidazol-3(2H)-one derivatives:
           Structure–activity relationships of selective nucleotide
           pyrophosphatase/phosphodiesterase1 (NPP1) inhibitors
    • Abstract: Publication date: 15 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14
      Author(s): Sang-Yong Lee, Arianna Perotti, Steven De Jonghe, Piet Herdewijn, Theodor Hanck, Christa E. Müller
      Ecto-nucleotide pyrophosphatase/phosphodiesterase1 (NPP1) is the most important member of the NPP family, which consists of seven closely related proteins (NPP1–NPP7). This glycoprotein is a membrane-associated or secreted enzyme, which catalyzes the hydrolysis of a wide range of phosphodiester bonds, e.g., in nucleoside triphosphates, dinucleotides and nucleotide sugars. NPP1 plays a crucial role in various physiological functions including bone mineralization, soft-tissue calcification, and insulin receptor signaling. Recently, an upregulated expression of NPP1 has been observed in astrocytic brain cancers. Therefore, NPP1 has been proposed as a novel drug target for the treatment of glioblastoma. Despite their therapeutic potential, only few NPP1 inhibitors have been reported to date, which are in most cases non- or only moderately selective. The best investigated NPP1 inhibitors so far are nucleotide derivatives and analogs, however they are not orally bioavailable due to their high polarity. We identified thiazolo[3,2-a]benzimidazol-3(2H)-one derivatives as a new class of NPP1 inhibitors with drug-like properties. Among the 25 derivatives investigated in the present study, 2-[(5-iodo-2-furanyl)methylene]thiazolo[3,2-a]benzimidazol-3(2H)-one (17) was found to be the most potent NPP1 inhibitor with a K i value of 467nM versus ATP as a substrate and an un-competitive mechanism of inhibition. Compound 17 did not inhibit other human ecto-nucleotidases, including NTPDase1 (CD39), NTPDases2-3, NPP2, NPP3, tissue-nonspecific alkaline phosphatase (TNAP), and ecto-5′-nucleotidase (eN, CD73), and is thus highly selective for NPP1.
      Graphical abstract image

      PubDate: 2016-06-13T12:22:31Z
       
  • New bifunctional antioxidant/σ1 agonist ligands: Preliminary
           chemico-physical and biological evaluation
    • Abstract: Publication date: 15 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14
      Author(s): Emanuela Arena, Ivana Cacciatore, Laura S. Cerasa, Hasan Turkez, Valeria Pittalà, Lorella Pasquinucci, Agostino Marrazzo, Carmela Parenti, Antonio Di Stefano, Orazio Prezzavento
      We previously reported bifunctional sigma-1 (σ1) ligands endowed with antioxidant activity (1 and 2). In the present paper, pure enantiomers (R)-1 and (R)-2 along with the corresponding p-methoxy (6, 11), p-fluoro derivatives (7, 12) were synthesized. σ1 and σ2 affinities, antioxidant properties, and chemico-physical profiles were evaluated. Para derivatives, while maintaining strong σ1 affinity, displayed improved σ1 selectivity compared to the parent compounds 1 and 2. In vivo evaluation of compounds 1, 2, (R)-1, 7, and 12 showed σ1 agonist pharmacological profile. Chemico-physical studies revealed that amides 2, 11 and 12 were more stable than corresponding esters 1, 6 and 7 under our experimental conditions. Antioxidant properties were exhibited by fluoro derivatives 7 and 12 being able to increase total antioxidant capacity (TAC). Our results underline that p-substituents have an important role on σ1 selectivity, TAC, chemical and enzymatic stabilities. In particular, our data suggest that new very selective compounds 7 and 12 could be promising tools to investigate the disorders in which σ1 receptor dysfunction and oxidative stress are contemporarily involved.
      Graphical abstract image

      PubDate: 2016-06-13T12:22:31Z
       
  • Efficient protein knockdown of HaloTag-fused proteins using hybrid
           molecules consisting of IAP antagonist and HaloTag ligand
    • Abstract: Publication date: 15 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14
      Author(s): Shusuke Tomoshige, Yuichi Hashimoto, Minoru Ishikawa
      We previously reported a protein knockdown system for HaloTag-fused proteins using hybrid small molecules consisting of alkyl chloride, which binds covalently to HaloTag, linked to BE04 (2), a bestatin (3) derivative with an affinity for cellular inhibitor of apoptosis protein 1 (cIAP1, a kind of ubiquitin ligase). This system addressed several limitations of prior protein knockdown technology, and was applied to degrade two HaloTag-fused proteins. However, the degradation activity of these hybrid small molecules was not potent. Therefore, we set out to improve this system. We report here the design, synthesis and biological evaluation of novel hybrid compounds 4a and 4b consisting of alkyl chloride linked to IAP antagonist MV1 (5). Compounds 4a and 4b were confirmed to reduce the levels of HaloTag-fused tumor necrosis factor α (HaloTag-TNFα), HaloTag-fused cell division control protein 42 (HaloTag-Cdc42), and unfused HaloTag protein in living cells more potently than did BE04-linked compound 1b. Analysis of the mode of action revealed that the reduction of HaloTag-TNFα is proteasome-dependent, and is also dependent on the linker structure between MV1 (5) and alkyl chloride. These compounds appear to induce ubiquitination at the HaloTag moiety of HaloTag-fused proteins. Our results indicate that these newly synthesized MV1-type hybrid compounds, 4a and 4b, are efficient tools for protein knockdown for HaloTag-fused proteins.
      Graphical abstract image

      PubDate: 2016-06-13T12:22:31Z
       
  • 2-Aryl-8-aza-3-deazaadenosine analogues of
           5′-O-[N-(salicyl)sulfamoyl]adenosine: Nucleoside antibiotics that
           block siderophore biosynthesis in Mycobacterium tuberculosis
    • Abstract: Publication date: 15 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14
      Author(s): Anna Krajczyk, Joanna Zeidler, Piotr Januszczyk, Surendra Dawadi, Helena I. Boshoff, Clifton E. Barry, Tomasz Ostrowski, Courtney C. Aldrich
      A series of 5′-O-[N-(salicyl)sulfamoyl]-2-aryl-8-aza-3-deazaadenosines were designed to block mycobactin biosynthesis in Mycobacterium tuberculosis (Mtb) through inhibition of the essential adenylating enzyme MbtA. The synthesis of the 2-aryl-8-aza-3-deazaadenosine nucleosides featured sequential copper-free palladium-catalyzed Sonogashira coupling of a precursor 4-cyano-5-iodo-1,2,3-triazolonucleoside with terminal alkynes and a Minakawa–Matsuda annulation reaction. These modified nucleosides were shown to inhibit MbtA with apparent K i values ranging from 6.1 to 25nM and to inhibit Mtb growth under iron-deficient conditions with minimum inhibitory concentrations ranging from 12.5 to >50μM.
      Graphical abstract image

      PubDate: 2016-06-13T12:22:31Z
       
  • Synthesis and evaluation of biphenyl derivatives as potential
           downregulators of VEGF protein secretion and telomerase-related gene
           expressions
    • Abstract: Publication date: 15 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14
      Author(s): María Sánchez-Peris, Eva Falomir, Juan Murga, Miguel Carda, J. Alberto Marco
      A group of 47 biphenyl functionalized compounds, prepared by means of Suzuki couplings, has been investigated for their cytotoxicity on two tumoral cell lines (HT-29 and MCF-7) and one non tumoral cell line (HEK-293). 29 selected compounds have been investigated for their ability to inhibit the production of the vascular endothelial growth factor (VEGF). Subsequently, the capacity of the compounds to downregulate the expression of the VEGF, h-TERT and c-Myc genes, the two latter involved in the control of the activation of telomerase, has also been determined.
      Graphical abstract image

      PubDate: 2016-06-13T12:22:31Z
       
  • Synthesis and biological activity of pyrazole analogues of the
           staurosporine aglycon K252c
    • Abstract: Publication date: 15 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14
      Author(s): Yannick J. Esvan, Francis Giraud, Elisabeth Pereira, Virginie Suchaud, Lionel Nauton, Vincent Théry, Lyubov G. Dezhenkova, Dmitry N. Kaluzhny, Vsevolod N. Mazov, Alexander A. Shtil, Fabrice Anizon, Pascale Moreau
      A derivative of the staurosporine aglycon (K252c), in which the lactam ring was replaced by a pyrazole moiety, was synthesized. The resulting indolopyrazolocarbazole (3) inhibited Pim isoforms 1–3 whereas it did not impair the activity of two known targets of K252c, protein kinase C isoforms α and γ. Compound 3 exhibited moderate cytotoxic activity toward human leukemia and colon carcinoma cell lines (K562 and HCT116), strongly suggesting that this new scaffold deserves further investigations for treatment of malignancies associated with Pim activity.
      Graphical abstract image

      PubDate: 2016-06-13T12:22:31Z
       
  • Identification, characterization, kinetics, and molecular docking of
           flavonoid constituents from Archidendron clypearia (Jack.) Nielsen leaves
           and twigs
    • Abstract: Publication date: 15 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14
      Author(s): Nguyen Phuong Thao, Bui Thi Thuy Luyen, Jang Hoon Kim, Ah Reum Jo, Nguyen Tien Dat, Phan Van Kiem, Chau Van Minh, Young Ho Kim
      In our search for natural soluble epoxide hydrolase (sEH) inhibitors from plants, we found that the methanolic extract of the leaves and twigs of Archidendron clypearia (Jack.) Nielsen (Fabaceae) significantly inhibits sEH in vitro. In a phytochemical investigation of the water layer of A. clypearia, we isolated two new chalcones, clypesides A–B (1–2), 13 flavonoid derivatives (3–15) and established their structures based on an extensive 1D and 2D NMR, CD data, and MS analysis. All of the flavonoid derivatives inhibited sEH enzymatic activity in a dose-dependent manner, with IC50 values ranging from 10.0±0.4 to 30.1±2.1μM. A kinetic analysis of compounds 4, 8–10, 12, 13, and 15 revealed that the compounds 8–10 were non-competitive, 4, 13, and 15 were mixed-type, and 12 was competitive inhibitors. Additionally, molecular docking increased our understanding of their receptor-ligand binding. These results demonstrated that flavonoid derivatives from A. clypearia are potential sEH inhibitors.
      Graphical abstract image

      PubDate: 2016-06-13T12:22:31Z
       
  • Discovery and preliminary structure–activity relationship studies on
           tecomaquinone I and tectol as novel farnesyltransferase and plasmodial
           inhibitors
    • Abstract: Publication date: 15 July 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14
      Author(s): Melissa M. Cadelis, Marie-Lise Bourguet-Kondracki, Joëlle Dubois, Alexis Valentin, David Barker, Brent R. Copp
      Biological screening of a library of synthesized benzo[c]chromene-7,10-dione natural products against human farnesyltransferase (FTase) has identified tecomaquinone I (IC50 of 0.065±0.004μM) as being one of the more potent natural product inhibitors identified to date. Anti-plasmodial screening of the same library against a drug-resistant strain of Plasmodium falciparum identified the structurally-related dichromenol tectol as a moderately active growth inhibitor with an IC50 3.44±0.20μM. Two novel series of analogues, based on the benzo[c]chromene-7,10-dione scaffold, were subsequently synthesized, with one analogue exhibiting farnesyltransferase inhibitory activity in the low micromolar range. A preliminary structure–activity relationship (SAR) study has identified different structural requirements for anti-malarial activity in comparison to FTase activities for these classes of natural products. Our results identify tecomaquinone I as a novel scaffold from which more potent inhibitors of human and parasitic FTase could be developed.
      Graphical abstract image

      PubDate: 2016-06-13T12:22:31Z
       
  • Identification, synthesis and evaluation of SARS-CoV and MERS-CoV 3C-like
           protease inhibitors
    • Abstract: Publication date: Available online 12 May 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Vathan Kumar, Kian-Pin Tan, Ying-Ming Wang, Sheng-Wei Lin, Po-Huang Liang
      Severe acute respiratory syndrome(SARS) led to a life-threatening form of atypical pneumonia in late 2002. Following that, Middle East Respiratory Syndrome (MERS-CoV) has recently emerged, killing about 36% of patients infected globally, mainly in Saudi Arabia and South Korea. Based on a scaffold we reported for inhibiting neuraminidase (NA), we synthesized the analogues and identified compounds with low micromolar inhibitory activity against 3CLpro of SARS-CoV and MERS-CoV. Docking studies show that a carboxylate present at either R1 or R4 destabilizes the oxyanion hole in the 3CLpro. Interestingly, 3f, 3g and 3m could inhibit both NA and 3CLpro and serve as a starting point to develop broad-spectrum antiviral agents.
      Graphical abstract image

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

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

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

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

      PubDate: 2016-05-14T22:55:23Z
       
 
 
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