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CHEMISTRY (597 journals)                  1 2 3 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 6)
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: 31)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 17)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 23)
ACS Macro Letters     Full-text available via subscription   (Followers: 22)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 36)
ACS Nano     Full-text available via subscription   (Followers: 207)
ACS Photonics     Full-text available via subscription   (Followers: 9)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 20)
Acta Chemica Iasi     Open Access   (Followers: 2)
Acta Chimica Sinica     Full-text available via subscription  
Acta Chimica Slovaca     Open Access   (Followers: 1)
Acta Chromatographica     Full-text available via subscription   (Followers: 8)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 5)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 7)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 5)
Advanced Functional Materials     Hybrid Journal   (Followers: 46)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 53)
Advances in Chemical Science     Open Access   (Followers: 12)
Advances in Chemistry     Open Access   (Followers: 11)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Enzyme Research     Open Access   (Followers: 10)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 14)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 16)
Advances in Nanoparticles     Open Access   (Followers: 12)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15)
Advances in Polymer Science     Hybrid Journal   (Followers: 40)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 17)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Science and Technology     Full-text available via subscription   (Followers: 10)
African Journal of Bacteriology Research     Open Access  
African Journal of Chemical Education     Open Access   (Followers: 2)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 7)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
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: 65)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 14)
American Journal of Chemistry     Open Access   (Followers: 24)
American Journal of Plant Physiology     Open Access   (Followers: 12)
American Mineralogist     Full-text available via subscription   (Followers: 12)
Analyst     Full-text available via subscription   (Followers: 44)
Angewandte Chemie     Hybrid Journal   (Followers: 144)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 202)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 1)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 3)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 7)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 12)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 14)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Hybrid Journal  
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 6)
Applied Spectroscopy     Full-text available via subscription   (Followers: 23)
Applied Surface Science     Hybrid Journal   (Followers: 24)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 2)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Atomization and Sprays     Full-text available via subscription   (Followers: 3)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 9)
Biochemistry     Full-text available via subscription   (Followers: 261)
Biochemistry Insights     Open Access   (Followers: 5)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 9)
Bioinspired Materials     Open Access   (Followers: 3)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access  
Biomacromolecules     Full-text available via subscription   (Followers: 18)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 7)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 4)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 108)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 99)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
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   (Followers: 1)
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: 10)
Canadian Mineralogist     Full-text available via subscription   (Followers: 3)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 66)
Catalysis for Sustainable Energy     Open Access   (Followers: 6)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 8)
Catalysis Science and Technology     Free   (Followers: 6)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 7)
Cellulose     Hybrid Journal   (Followers: 6)
Cereal Chemistry     Full-text available via subscription   (Followers: 4)
ChemBioEng Reviews     Full-text available via subscription   (Followers: 1)
ChemCatChem     Hybrid Journal   (Followers: 8)
Chemical and Engineering News     Free   (Followers: 12)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 69)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 22)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 19)
Chemical Reviews     Full-text available via subscription   (Followers: 164)
Chemical Science     Open Access   (Followers: 20)
Chemical Technology     Open Access   (Followers: 15)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 4)
Chemical Week     Full-text available via subscription   (Followers: 7)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 55)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 25)
ChemInform     Hybrid Journal   (Followers: 8)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 6)
Chemistry & Biology     Full-text available via subscription   (Followers: 30)
Chemistry & Industry     Hybrid Journal   (Followers: 5)
Chemistry - A European Journal     Hybrid Journal   (Followers: 128)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 15)
Chemistry and Materials Research     Open Access   (Followers: 16)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 5)
Chemistry in Education     Open Access   (Followers: 8)
Chemistry International     Hybrid Journal   (Followers: 2)
Chemistry Letters     Full-text available via subscription   (Followers: 43)
Chemistry of Materials     Full-text available via subscription   (Followers: 176)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry-Didactics-Ecology-Metrology     Open Access  
ChemistryOpen     Open Access   (Followers: 2)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 2)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 16)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 9)
ChemPlusChem     Hybrid Journal   (Followers: 2)
ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 3)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 10)
Chromatographia     Hybrid Journal   (Followers: 24)
Chromatography Research International     Open Access   (Followers: 7)
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: 10)
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 8)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 3)
Combustion Science and Technology     Hybrid Journal   (Followers: 18)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Composite Interfaces     Hybrid Journal   (Followers: 5)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 2)
Comptes Rendus Chimie     Full-text available via subscription  
Comptes Rendus Physique     Full-text available via subscription   (Followers: 1)
Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 9)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 11)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 10)
Coordination Chemistry Reviews     Full-text available via subscription   (Followers: 2)
Copernican Letters     Open Access  
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 5)
Crystal Structure Theory and Applications     Open Access   (Followers: 3)
CrystEngComm     Full-text available via subscription   (Followers: 10)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Metabolomics     Hybrid Journal   (Followers: 3)
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 15)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 48)
Dalton Transactions     Full-text available via subscription   (Followers: 18)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)
Diamond and Related Materials     Hybrid Journal   (Followers: 11)
Dislocations in Solids     Full-text available via subscription  
Doklady Chemistry     Hybrid Journal  
Drying Technology: An International Journal     Hybrid Journal   (Followers: 3)
Eclética Química     Open Access   (Followers: 1)
Ecological Chemistry and Engineering S     Open Access   (Followers: 3)
Ecotoxicology and Environmental Contamination     Open Access  
Educación Química     Open Access   (Followers: 1)
Education for Chemical Engineers     Hybrid Journal   (Followers: 5)
Elements     Full-text available via subscription   (Followers: 2)
Environmental Chemistry     Hybrid Journal   (Followers: 7)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 4)
Environmental Science & Technology Letters     Full-text available via subscription   (Followers: 5)
Environmental Science : Nano     Partially Free   (Followers: 1)
Environmental Toxicology & Chemistry     Hybrid Journal   (Followers: 19)

        1 2 3 | Last

Journal Cover Bioorganic & Medicinal Chemistry
  [SJR: 1.064]   [H-I: 119]   [108 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0968-0896
   Published by Elsevier Homepage  [3043 journals]
  • Next generation NIR fluorophores for tumor imaging and fluorescence-guided
           surgery: A review
    • Authors: Ashanul Haque; Md. Serajul Haque Faizi; Jahangir Ahmad Rather; Muhammad S. Khan
      Pages: 2017 - 2034
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Ashanul Haque, Md. Serajul Haque Faizi, Jahangir Ahmad Rather, Muhammad S. Khan
      Cancer is a group of diseases responsible for the major causes of mortality and morbidity among people of all ages. Even though medical sciences have made enormous growth, complete treatment of this deadly disease is still a challenging task. Last few decades witnessed an impressive growth in the design and development of near infrared (NIR) fluorophores with and without recognition moieties for molecular recognitions, imaging and image guided surgeries. The present article reviews recently reported NIR emitting organic/inorganic fluorophores that targets and accumulates in organelle/organs specifically for molecular imaging of cancerous cells. Near infrared (NIR probe) with or without a tumor-targeting warhead have been considered and discussed for their applications in the field of cancer imaging. In addition, challenges persist in this area are also delineated in this review.
      Graphical abstract image

      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.061
  • Synthesis of antisense oligonucleotides containing acyclic alkynyl
           nucleoside analogs and their biophysical and biological properties
    • Authors: Aya Ogata; Yusuke Maeda; Yoshihito Ueno
      Pages: 2035 - 2042
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Aya Ogata, Yusuke Maeda, Yoshihito Ueno
      The synthesis of oligonucleotide (ON) analogs, which can be used as antisense molecules, has recently gained much attention. Here, we report the synthesis and properties of an ON analog containing acyclic thymidine and cytidine analogs with a 4-pentyl-1,2-diol instead of the d-ribofuranose moiety. The incorporation of these analogs into the ON improved its nuclease resistance to 3′-exonucleases. Furthermore, it was found that the incorporation of the acyclic thymidine analog into a DNA/RNA duplex accelerates the RNA cleavage of a DNA/RNA duplex by Escherichia coli RNase H.
      Graphical abstract image

      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.01.051
  • Synthesis and anti-inflammatory activity of isoquebecol
    • Authors: Sébastien Cardinal; Pierre-Alexandre Paquet-Côté; Jabrane Azelmat; Corinne Bouchard; Daniel Grenier; Normand Voyer
      Pages: 2043 - 2056
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Sébastien Cardinal, Pierre-Alexandre Paquet-Côté, Jabrane Azelmat, Corinne Bouchard, Daniel Grenier, Normand Voyer
      We report here the synthesis of isoquebecol, an unprecedented constitutional isomer of quebecol, a polyphenolic compound discovered in maple syrup. The methodology used to prepare isoquebecol involves, as key steps, the formation of a dibromoalkene from an α-ketoester precursor, followed by a double Suzuki-Miyaura reaction. The anti-inflammatory activity of isoquebecol was studied on macrophage cells by monitoring its ability to inhibit LPS-induced IL-6 secretion. Results show that this new compound has an improved bioactivity over that of its natural isomer. Precursors and derivatives of quebecol, isoquebecol and model analog 2,3,3-triphenylpropanol were also prepared and tested in this study. Comparison between the three series of compounds led to establishing new SARs concerning the aryl ring substitution pattern on the triarylpropanol scaffold and substructure functionalization.
      Graphical abstract image

      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.01.050
  • Green synthesis of novel spiro-indenoquinoxaline derivatives and their
           cholinesterases inhibition activity
    • Authors: Ammar Maryamabadi; Alireza Hasaninejad; Najmeh Nowrouzi; Gholamhossein Mohebbi
      Pages: 2057 - 2064
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Ammar Maryamabadi, Alireza Hasaninejad, Najmeh Nowrouzi, Gholamhossein Mohebbi
      A convenient synthesis of substituted spiroindenoquinoxalines at mild and green conditions was developed. Multicomponent reaction of substituted phenylene diamines, ninhydrin, malononitrile and N,N′-substituted-2-nitroethene-1,1-diamines produced the target compounds. Twelve new spiroindenoquinoxalines were obtained, and their ability in inhibition of acetyl and butyrylcholinesterases were investigated both in vitro and in silico. All compounds showed moderate level activity against both acetyl and butyrylcholinesterases.
      Graphical abstract image

      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.017
  • Impact of androstane A- and D-ring inversion on 17β-hydroxysteroid
           dehydrogenase type 3 inhibitory activity, androgenic effect and metabolic
    • Authors: Francisco Cortés-Benítez; Jenny Roy; René Maltais; Donald Poirier
      Pages: 2065 - 2073
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Francisco Cortés-Benítez, Jenny Roy, René Maltais, Donald Poirier
      17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a major player in human endocrinology, being one of the most important enzymes involved in testosterone production. To capitalize on the discovery of RM-532-105, a steroidal 17β-HSD3 inhibitor, we explored the effect of its backbone configuration on inhibitory activity, androgenic profile, and metabolic stability. Two modifications that greatly alter the natural shape of steroids, i.e. inversion of the methyl on carbon 13 (13α-CH3 instead of 13β-CH3) and inversion of the hydrogen on carbon 5 (5β-H instead of 5α-H), were tested after the syntheses in 6 steps of 2 isomeric forms (5α/13α-RM-532-105 (6a) and 5β/13β-RM-532-105 (6b), respectively) of the 17β-HSD3 inhibitor RM-532-105 (5α/13β-configurations). For compound 6b, a cis/trans junction of the A/B rings did not significantly alter the inhibitory activity on 17β-HSD3 (IC50 =0.15μM) as well as the liver microsomal stability (16.6% of 6b remaining after 1h incubation) compared to RM-532-105 (IC50 =0.11μM and 14.1% remaining). In contrast, a trans/cis junction of C/D rings reduced the inhibitory activity on 17β-HSD3 (IC50 =1.09μM) but increased the metabolic stability with 29.4% of compound 6a remaining after incubation. The structural modifications represented by compounds 6a and 6b did not change the non-androgenicity profile of an androsterone derivative such as RM-532-105, but slightly increased its cytotoxic activity.
      Graphical abstract image

      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.008
  • 3-Phenylalkyl-2H-chromenes and -chromans as novel rhinovirus infection
    • Authors: Cinzia Conti; Luca Proietti Monaco; Nicoletta Desideri
      Pages: 2074 - 2083
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Cinzia Conti, Luca Proietti Monaco, Nicoletta Desideri
      Following our studies on structure-activity relationships of anti-rhinovirus chromene and chroman derivatives, we designed and synthesized new series of 3-phenylalkyl-2H-chromenes and -chromans bearing differently sized, aliphatic linker chains between the two cycles. The cytotoxicity and the antiviral activity of the new compounds on human rhinovirus (HRV) serotype 1B and 14 infection were evaluated in HeLa cell cultures. Most of the tested compounds interfered with HRV1B multiplication in the micromolar or submicromolar concentrations while HRV14 was less susceptible. 3-[3-(4-Chlorophenyl)propyl]chroman (9c) was selected for preliminary mechanism of action studies due to its potent activity against both serotypes (IC50 of 0.48μM and 1.36μM towards HRV1B and 14, respectively) coupled with high selectivity (SI=206.18 and 73.26, respectively). Results of time of addition/removal studies suggest that 9c, similarly to related derivatives, behaves as a capsid binder interfering with some early events of the HRV1B infectious cycle.
      Graphical abstract image

      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.012
  • Synthesis, hybridization and fluorescence properties of a
           2′-C-pyrene-triazole modified arabino-uridine nucleotide
    • Authors: Pawan Kumar; Pawan K. Sharma; Poul Nielsen
      Pages: 2084 - 2090
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Pawan Kumar, Pawan K. Sharma, Poul Nielsen
      A new pyrene-modified nucleotide monomer is introduced, wherein pyrene is attached to the 2′-position of arabino-uridine through a triazolemethyl linker. When the monomer is introduced into oligonucleotides, very stable DNA duplexes and three way junctions are obtained. An oligonucleotide featuring two modifications in the center shows four-fold increase in the intensity of the pyrene excimer signal on hybridization with an RNA target but not with a DNA target. The new nucleotide monomer has potential in DNA invader probes as well as in RNA targeting and detection.
      Graphical abstract image

      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.011
  • Synthesis and activity of nucleoside-based antiprotozoan compounds
    • Authors: Huu-Anh Tran; Zhaoyan Zheng; Xianghui Wen; Srinivasan Manivannan; Arnaud Pastor; Marcel Kaiser; Reto Brun; Floyd F. Snyder; Thomas G. Back
      Pages: 2091 - 2104
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Huu-Anh Tran, Zhaoyan Zheng, Xianghui Wen, Srinivasan Manivannan, Arnaud Pastor, Marcel Kaiser, Reto Brun, Floyd F. Snyder, Thomas G. Back
      Parasitic protozoa employ a salvage pathway to synthesize purines and generate essential active nucleotides, whereas mammals are capable of their de novo biosynthesis. This difference provides opportunity for the design of potential new antiprotozoan compounds. A series of 47 adenosine analogues was prepared with modifications at the 2-, 6- and 5′-positions, based on the hypothesis that such compounds would serve as substrates for protozoan nucleoside salvage enzymes, while remaining refractory in mammalian cells. The nucleosides were designed to produce toxic metabolites upon cleavage to the corresponding purine base by the parasite. Three 7-deazaguanosine derivatives were prepared with similar objectives. All of these compounds were tested in vitro against T. brucei (African sleeping sickness), T. cruzi (Chagas’ disease), L. donovani (leishmaniasis) and P. falciparum (malaria). In order to determine the therapeutic selectivity indices (SI) of the antiprotozoan nucleosides, their cytotoxicities toward a rat myoblast cell line were also determined. One adenosine derivative proved highly effective against P. falciparum (IC50 =110nM and SI=1010, while a modified guanosine displayed potent activities against L. donovani (IC50 =60nM, SI=2720) and T. brucei (IC50 =130nM, SI=1250), as well as moderate activity against T. cruzi (IC50 =3.4µM, SI=48). These results provide proof of concept for the nucleoside-based antiprotozoan strategy, as well as potential lead compounds for further optimization and validation.
      Graphical abstract image

      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.016
  • Structural insights of SmKDAC8 inhibitors: Targeting Schistosoma
           epigenetics through a combined structure-based 3D QSAR, in vitro and
           synthesis strategy
    • Authors: Flavio Ballante; D. Rajasekhar Reddy; Nancy J. Zhou; Garland R. Marshall
      Pages: 2105 - 2132
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Flavio Ballante, D. Rajasekhar Reddy, Nancy J. Zhou, Garland R. Marshall
      A predictive structure-based 3D QSAR (COMBINEr 2.0) model of the Schistosoma mansoni lysine deacetylase 8 enzyme (SmKDAC8) was developed, validated and used to perform virtual screening (VS) of the NCI Diversity Set V database (1593 compounds). Three external datasets (with congeneric structures to those experimentally resolved in complexes by X-ray and previously reported as SmKDAC8 inhibitors) were employed to compose and validate the most predictive model. Two series characterized by 104 benzodiazepine derivatives (BZDs) and 60 simplified largazole analogs (SLAs), recently reported by our group as human KDAC inhibitors, were tested for their inhibition potency against SmKDAC8 to probe the predictive capability of the quantitative models against compounds with diverse structures. The SmKDAC8 biochemical results confirmed: (1) the benzodiazepine moiety as a valuable scaffold to further investigate when pursuing SmKDAC8 inhibition; (2) the predictive capability of the COMBINEr 2.0 model towards non-congeneric series of compounds, highlighting the most influencing ligand-protein interactions and refining the structure-activity relationships. From the VS investigations, the first 40 top-ranked compounds were obtained and biologically tested for their inhibition potency against SmKDAC8 and hKDACs 1, 3, 6 and 8. Among them, a non-hydroxamic acid benzothiadiazine dioxide derivative (code NSC163639), showed interesting activity and selectivity against SmKDAC8. To further elucidate the structure-activity relationships of NSC163639, two analogs (herein reported as compounds 3 and 4) were synthesized and biologically evaluated. Results suggest the benzothiadiazine dioxide moiety as a promising scaffold to be used in a next step to derive selective SmKDAC8 inhibitors.
      Graphical abstract image

      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.020
  • Identification of a new class of potent Cdc7 inhibitors designed by
           putative pharmacophore model: Synthesis and biological evaluation of
    • Authors: Osamu Kurasawa; Yuya Oguro; Tohru Miyazaki; Misaki Homma; Kouji Mori; Kenichi Iwai; Hideto Hara; Robert Skene; Isaac Hoffman; Akihiro Ohashi; Sei Yoshida; Tomoyasu Ishikawa; Nobuo Cho
      Pages: 2133 - 2147
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Osamu Kurasawa, Yuya Oguro, Tohru Miyazaki, Misaki Homma, Kouji Mori, Kenichi Iwai, Hideto Hara, Robert Skene, Isaac Hoffman, Akihiro Ohashi, Sei Yoshida, Tomoyasu Ishikawa, Nobuo Cho
      Cell division cycle 7 (Cdc7) is a serine/threonine kinase that plays important roles in the regulation of DNA replication process. A genetic study indicates that Cdc7 inhibition can induce selective tumor-cell death in a p53-dependent manner, suggesting that Cdc7 is an attractive target for the treatment of cancers. In order to identify a new class of potent Cdc7 inhibitors, we generated a putative pharmacophore model based on in silico docking analysis of a known inhibitor with Cdc7 homology model. The pharmacophore model provided a minimum structural motif of Cdc7 inhibitor, by which preliminary medicinal chemistry efforts identified a dihydrothieno[3,2-d]-pyrimidin-4(1H)-one scaffold having a heteroaromatic hinge-binding moiety. The structure-activity relationship (SAR) studies resulted in the discovery of new, potent, and selective Cdc7 inhibitors 14a, c, e. Furthermore, the high selectivity of 14c, e for Cdc7 over Rho-associated protein kinase 1 (ROCK1) is discussed by utilizing a docking study with Cdc7 and ROCK2 crystal structures.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.021
  • Investigation on cellular uptake and pharmacodynamics of DOCK2-inhibitory
           peptides conjugated with cell-penetrating peptides
    • Authors: Yusuke Adachi; Kotaro Sakamoto; Tadashi Umemoto; Yasunori Fukuda; Akiyoshi Tani; Taiji Asami
      Pages: 2148 - 2155
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Yusuke Adachi, Kotaro Sakamoto, Tadashi Umemoto, Yasunori Fukuda, Akiyoshi Tani, Taiji Asami
      Protein–protein interaction between dedicator of cytokinesis 2 (DOCK2) and Ras-related C3 botulinum toxin substrate 1 (Rac1) is an attractive intracellular target for transplant rejection and inflammatory diseases. Recently, DOCK2-selective inhibitory peptides have been discovered, and conjugation with oligoarginine cell-penetrating peptide (CPP) improved inhibitory activity in a cell migration assay. Although a number of CPPs have been reported, oligoarginine was only one example introduced to the inhibitory peptides. In this study, we aimed to confirm the feasibility of CPP-conjugation approach for DOCK2-inhibitory peptides, and select preferable sequences as CPP moiety. First, we evaluated cell permeability of thirteen known CPPs and partial sequences of influenza A viral protein PB1-F2 using an internalization assay system based on luciferin–luciferase reaction, and then selected four CPPs with efficient cellular uptake. Among four conjugates of these CPPs and a DOCK2-inhibitory peptide, the inhibitory activity of a novel CPP, PB1-F2 fragment 5 (PF5), conjugate was comparable to oligoarginine conjugate and higher than that of the non-conjugated peptide. Finally, internalization assay revealed that oligoarginine and PF5 increased the cellular uptake of inhibitory peptides to the same extent. Hence, we demonstrated that CPP-conjugation approach is applicable to the development of novel anti-inflammatory drugs based on DOCK2 inhibition by investigating both cellular uptake and bioactivity.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.022
  • Novel pyrrolopyrimidines as Mps1/TTK kinase inhibitors for breast cancer
    • Authors: Yasuro Sugimoto; Dwitiya B. Sawant; Harold A. Fisk; Liguang Mao; Chenglong Li; Somsundaram Chettiar; Pui-Kai Li; Michael V. Darby; Robert W. Brueggemeier
      Pages: 2156 - 2166
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Yasuro Sugimoto, Dwitiya B. Sawant, Harold A. Fisk, Liguang Mao, Chenglong Li, Somsundaram Chettiar, Pui-Kai Li, Michael V. Darby, Robert W. Brueggemeier
      New targeted therapy approaches for certain subtypes of breast cancer, such as triple-negative breast cancers and other aggressive phenotypes, are desired. High levels of the mitotic checkpoint kinase Mps1/TTK have correlated with high histologic grade in breast cancer, suggesting a potential new therapeutic target for aggressive breast cancers (BC). Novel small molecules targeting Mps1 were designed by computer assisted docking analyses, and several candidate compounds were synthesized. These compounds were evaluated in anti-proliferative assays of a panel of 15 breast cancer cell lines and further examined for their ability to inhibit a variety of Mps1-dependent biological functions. The results indicate that the lead compounds have strong anti-proliferative potential through Mps1/TTK inhibition in both basal and luminal BC cell lines, exhibiting IC50 values ranging from 0.05 to 1.0μM. In addition, the lead compounds 1 and 13 inhibit Mps1 kinase enzymatic activity with IC50 values from 0.356μM to 0.809μM, and inhibited Mps1-associated cellular functions such as centrosome duplication and the spindle checkpoint in triple negative breast cancer cells. The most promising analog, compound 13, significantly decreased tumor growth in nude mice containing Cal-51 triple negative breast cancer cell xenografts. Using drug discovery technologies, computational modeling, medicinal chemistry, cell culture and in vivo assays, novel small molecule Mps1/TTK inhibitors have been identified as potential targeted therapies for breast cancers.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.030
  • Synthesis and evaluation of a [18F]BODIPY-labeled caspase-inhibitor
    • Authors: Christian Paul Ortmeyer; Günter Haufe; Katrin Schwegmann; Sven Hermann; Michael Schäfers; Frederik Börgel; Bernhard Wünsch; Stefan Wagner; Verena Hugenberg
      Pages: 2167 - 2176
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Christian Paul Ortmeyer, Günter Haufe, Katrin Schwegmann, Sven Hermann, Michael Schäfers, Frederik Börgel, Bernhard Wünsch, Stefan Wagner, Verena Hugenberg
      BODIPYs (boron dipyrromethenes) are fluorescent dyes which show high stability and quantum yields. They feature the possibility of selective 18F-fluorination at the boron-core. Attached to a bioactive molecule and labeled with [18F]fluorine, the resulting compounds are promising tracers for multimodal imaging in vivo and can be used for PET and fluorescence imaging. A BODIPY containing a phenyl and a hydroxy substituent on boron was synthesized and characterized. Fluorinated and hydroxy substituted dyes were coupled to an isatin-based caspase inhibitor via cycloaddition and the resulting compounds were evaluated in vitro in caspase inhibition assays. The metabolic stability and the formed metabolites were investigated by incubation with mouse liver microsomes and LC-MS analysis. Subsequently the fluorophores were labeled with [18F]fluorine and an in vivo biodistribution study using dynamic PET was performed.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.033
  • Pharmacological evaluation of novel
           (6-aminopyridin-3-yl)(4-(pyridin-2-yl)piperazin-1-yl) methanone
           derivatives as TRPV4 antagonists for the treatment of pain
    • Authors: Naoki Tsuno; Akira Yukimasa; Osamu Yoshida; Shinji Suzuki; Hiromi Nakai; Tomoyuki Ogawa; Motohiro Fujiu; Kenji Takaya; Azusa Nozu; Hiroki Yamaguchi; Hidetoshi Matsuda; Satoko Funaki; Natsue Yamanada; Miki Tanimura; Daiki Nagamatsu; Toshiyuki Asaki; Narumi Horita; Miyuki Yamamoto; Mikie Hinata; Masahiko Soga; Masayuki Imai; Yasuhide Morioka; Toshiyuki Kanemasa; Gaku Sakaguchi; Yasuyoshi Iso
      Pages: 2177 - 2190
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Naoki Tsuno, Akira Yukimasa, Osamu Yoshida, Shinji Suzuki, Hiromi Nakai, Tomoyuki Ogawa, Motohiro Fujiu, Kenji Takaya, Azusa Nozu, Hiroki Yamaguchi, Hidetoshi Matsuda, Satoko Funaki, Natsue Yamanada, Miki Tanimura, Daiki Nagamatsu, Toshiyuki Asaki, Narumi Horita, Miyuki Yamamoto, Mikie Hinata, Masahiko Soga, Masayuki Imai, Yasuhide Morioka, Toshiyuki Kanemasa, Gaku Sakaguchi, Yasuyoshi Iso
      A novel series of (6-aminopyridin-3-yl)(4-(pyridin-2-yl)piperazin-1-yl) methanone derivatives were identified as selective transient receptor potential vanilloid 4 (TRPV4) channel antagonist and showed analgesic effect in Freund’s Complete Adjuvant (FCA) induced mechanical hyperalgesia model in guinea pig and rat. Modification of right part based on the compound 16d which was disclosed in our previous communication led to the identification of compound 26i as a flagship compound. In this paper, we described the details about design, synthesis and structure-activity relationship (SAR) analysis at right and left part of these derivatives (Fig. 1).
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.047
  • Synthesis of native-like crosslinked duplex RNA and study of its
    • Authors: Kazumitsu Onizuka; Madoka E. Hazemi; Justin M. Thomas; Leanna R. Monteleone; Ken Yamada; Shuhei Imoto; Peter A. Beal; Fumi Nagatsugi
      Pages: 2191 - 2199
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Kazumitsu Onizuka, Madoka E. Hazemi, Justin M. Thomas, Leanna R. Monteleone, Ken Yamada, Shuhei Imoto, Peter A. Beal, Fumi Nagatsugi
      A variety of enzymes have been found to interact with double-stranded RNA (dsRNA) in order to carry out its functions. We have endeavored to prepare the covalently crosslinked native-like duplex RNA, which could be useful for biochemical studies and RNA nanotechnology. In this study, the interstrand covalently linked duplex RNA was formed by a crosslinking reaction between vinylpurine (VP) and the target cytosine or uracil in RNA. We measured melting temperatures and CD spectra to identify the properties of the VP crosslinked duplex RNA. The crosslinking formation increased the thermodynamic stability without disturbing the natural conformation of dsRNA. In addition, a competitive binding experiment with the duplex RNA binding enzyme, ADAR2, showed the crosslinked dsRNA bound the protein with nearly the same binding affinity as the natural dsRNA, confirming that it has finely preserved the natural traits of duplex RNA.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.034
  • Discovery of selective ATP-competitive eIF4A3 inhibitors
    • Authors: Masahiro Ito; Misa Iwatani; Yusuke Kamada; Satoshi Sogabe; Shoichi Nakao; Toshio Tanaka; Tomohiro Kawamoto; Samuel Aparicio; Atsushi Nakanishi; Yasuhiro Imaeda
      Pages: 2200 - 2209
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Masahiro Ito, Misa Iwatani, Yusuke Kamada, Satoshi Sogabe, Shoichi Nakao, Toshio Tanaka, Tomohiro Kawamoto, Samuel Aparicio, Atsushi Nakanishi, Yasuhiro Imaeda
      Eukaryotic initiation factor 4A3 (eIF4A3), an ATP-dependent RNA helicase, is a core component of exon junction complex (EJC). EJC has a variety of roles in RNA metabolism such as translation, surveillance, and localization of spliced RNA. It is worthwhile to identify selective eIF4A3 inhibitors with a view to investigating the functions of eIF4A3 and EJC further to clarify the roles of the ATPase and helicase activities in cells. Our chemical optimization of hit compound 2 culminated in the discovery of ATP-competitive eIF4A3 inhibitor 18 with submicromolar ATPase inhibitory activity and excellent selectivity over other helicases. Hence, compound 18 could be a valuable chemical probe to elucidate the detailed functions of eIF4A3 and EJC.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.035
  • Synthesis of bulky-tailed sulfonamides incorporating
           pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-1(5H)-yl) moieties and
           evaluation of their carbonic anhydrases I, II, IV and IX inhibitory
    • Authors: Mohamed Fares; Radwa A. Eladwy; Alessio Nocentini; Soha R. Abd El Hadi; Hazem A. Ghabbour; Ashraf Abdel-Megeed; Wagdy M. Eldehna; Hatem A. Abdel-Aziz; Claudiu T. Supuran
      Pages: 2210 - 2217
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Mohamed Fares, Radwa A. Eladwy, Alessio Nocentini, Soha R. Abd El Hadi, Hazem A. Ghabbour, Ashraf Abdel-Megeed, Wagdy M. Eldehna, Hatem A. Abdel-Aziz, Claudiu T. Supuran
      Using celecoxib as lead, two novel series of sulfonamides incorporating the pyridotriazolopyrimidine scaffold have been synthesized and evaluated in vitro as inhibitors against four relevant human (h) carbonic anhydrases (CAs, EC, the cytosolic and ubiquitous hCA I and II as well as the transmembrane hCA IV and hCA IX. Most of the reported sulfonamides acted as efficient, low micromolar inhibitors of hCAI, II and IV, whereas they displayed higher efficacy in inhibiting the tumor-associated isoform hCA IX. Many derivates herein reported showed better hCA IX versus hCA II selectivity ratios compared to celecoxib or acetazolamide. Considering isoform IX is a validated target for the diagnosis and treatment of hypoxic tumors, discovery of selective CA IX inhibitors represents a promising step to unveil more effective anticancer therapies.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.037
  • Synthesis of 4-aminotetrahydropyran scaffolds for drug discovery
    • Authors: Andrew Nortcliffe; Gavin D.S. Milne; Daniel Hamza; Christopher J. Moody
      Pages: 2218 - 2225
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Andrew Nortcliffe, Gavin D.S. Milne, Daniel Hamza, Christopher J. Moody
      Functionalised tetrahydropyran scaffolds were prepared using a tethered enol-ether Prins cyclisation and elaborated to show their potential use in library synthesis. The key 4-hydroxytetrahydropyran scaffold could be readily manipulated to the 4-azidotetrahydropyran that could be elaborated via copper catalysed azide-alkyne cycloaddition or by reduction to the amine, to provide sp3-rich scaffolds useful for drug discovery.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.039
  • Development of a novel near-infrared fluorescent theranostic combretastain
           A-4 analogue, YK-5-252, to target triple negative breast cancer
    • Authors: Yali Kong; Jacqueline Smith; Kongwen Li; Jake Cui; John Han; Shujie Hou; Milton L. Brown
      Pages: 2226 - 2233
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Yali Kong, Jacqueline Smith, Kongwen Li, Jake Cui, John Han, Shujie Hou, Milton L. Brown
      The treatment of triple negative breast cancer (TNBC) is a significant challenge to cancer research. The lack of hormone receptors limits the treatment options available to patients with this diagnosis, forcing them to endure prolonged radiation and chemotherapy. Anti-angiogenesis is a chemotherapeutic strategy that targets the vasculature of tumors. Combretastatin A-4 (CA-4) is a well-known vasculature-disrupting agent, which has been shown to effectively kill a variety of cancers through inhibition of tubulin polymerization. Due to its toxicity, small molecule analogues of CA-4 have been sought out. We have designed a novel dual action CA-4 prodrug, YK-5-252, which releases the drug through a disulfide bond cleavage mechanism and contains a near-infrared (NIR) fluorophore, which allows fluorescence monitoring of cleavage. This disulfide linkage causes CA-4 to become effective only when released by glutathione (GSH) reducing the toxicity of the drug while simultaneously releasing the NIR fluorophore. Therefore the prodrug, YK-5-252, represents a novel CA-4 analogue which has reduced toxicity and can be used for theranostics imaging.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.046
  • Identification of a novel hormone sensitive lipase inhibitor with a
           reduced potential of reactive metabolites formation
    • Authors: Tomoko Ogiyama; Mitsuhiro Yamaguchi; Nobuya Kurikawa; Shoko Honzumi; Yuka Yamamoto; Daisuke Sugiyama; Hideo Takakusa; Shin-ichi Inoue
      Pages: 2234 - 2243
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Tomoko Ogiyama, Mitsuhiro Yamaguchi, Nobuya Kurikawa, Shoko Honzumi, Yuka Yamamoto, Daisuke Sugiyama, Hideo Takakusa, Shin-ichi Inoue
      Hormone sensitive lipase (HSL) has emerged as an attractive target for the treatment of dyslipidemia. We previously reported compound 1 as a potent and orally active HSL inhibitor. Although an attractive profile was demonstrated, subsequent studies revealed that compound 1 has a bioactivation liability. The oxygen-carbon linker in compound 1 was identified as being potentially responsible for reactive metabolite formation. By exchanging of this susceptible fragment was feasible, and a benzanilide derivative 6b with a decreased bioactivation liability was obtained. Further modification of the novel benzanilide scaffold resulted in the identification of compound 24b. Compound 24b exhibited potent HSL inhibitory activity (IC50 =2nM) with a significantly reduced bioactivation potential. Oral administration of compound 24b exhibited an antilipolytic effect on rats at 3mg/kg.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.045
  • Rational design and studies of excimer forming novel dual probes to target
    • Authors: O.A. Krasheninina; A.A. Lomzov; V.S. Fishman; D.S. Novopashina; A.G. Venyaminova
      Pages: 2244 - 2250
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): O.A. Krasheninina, A.A. Lomzov, V.S. Fishman, D.S. Novopashina, A.G. Venyaminova
      In this paper, we report structure-based rational design and physico-chemical and biological studies of novel pyrene excimer forming dual probes for visualization of intracellular RNAs. Herein, the probes based on 2′-O-methyl RNA with linkers of different structure and length between pyrene moiety and ribose are studied with respect to their hybridization and spectral properties. We found optimal linkers that provide more intense excimer emission (at ∼480nm) of RNA-bound probes; particularly, the length of the linker arm of the 3′-component of dual probes plays a key role in formation of pyrene excimer. Calculated molecular dynamics trajectories and probability distributions of pyrene-pyrene dimer formation upon hybridization of the dual probes with RNA target are in agreement with the obtained fluorescence spectroscopy data for the corresponding duplexes. Our study demonstrates the excellent binding properties of new dual probes to structured RNA and their feasibility for the visualization of intracellular RNA targets.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.042
  • New derivatives of quinoline-4-carboxylic acid with antiplasmodial
    • Authors: Patrick Hochegger; Johanna Faist; Werner Seebacher; Robert Saf; Pascal Mäser; Marcel Kaiser; Robert Weis
      Pages: 2251 - 2259
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Patrick Hochegger, Johanna Faist, Werner Seebacher, Robert Saf, Pascal Mäser, Marcel Kaiser, Robert Weis
      New analogues of the recently published compound DDD107498 were prepared. Their activities were examined in vitro against the chloroquine-sensitive NF54 strain. The most active were also tested against the multiresistant K1 strain of Plasmodium falciparum. A couple of the newly synthesized compounds showed promising antiplasmodial activity and selectivity. A single compound showed adequate reduction of parasitaemia (98.1%) in mice infected with Plasmodium berghei. Survival time was doubled compared to control. The results of the biological tests of the novel compounds were compared with the activities of drugs in use. Structure-activity relationships were discussed.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.043
  • Role of the sugar moiety on the opioid receptor binding and conformation
           of a series of enkephalin neoglycopeptides
    • Authors: Mònica Rosa; Verónica Gonzalez-Nunez; Katherine Barreto-Valer; Filipa Marcelo; Julia Sánchez-Sánchez; Luis P. Calle; Juan C. Arévalo; Raquel E. Rodríguez; Jesús Jiménez-Barbero; Gemma Arsequell; Gregorio Valencia
      Pages: 2260 - 2265
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Mònica Rosa, Verónica Gonzalez-Nunez, Katherine Barreto-Valer, Filipa Marcelo, Julia Sánchez-Sánchez, Luis P. Calle, Juan C. Arévalo, Raquel E. Rodríguez, Jesús Jiménez-Barbero, Gemma Arsequell, Gregorio Valencia
      Glycosylation by simple sugars is a drug discovery alternative that has been explored with varying success for enhancing the potency and bioavailability of opioid peptides. Long ago we described two O-glycosides having either β-Glucose and β-Galactose of (d-Met2, Pro5)-enkephalinamide showing one of the highest antinociceptive activities known. Here, we report the resynthesis of these two analogs and the preparation of three novel neoglycopeptide derivatives (α-Mannose, β-Lactose and β-Cellobiose). Binding studies to cloned zebrafish opioid receptors showed very small differences of affinity between the parent compound and the five glycopeptides thus suggesting that the nature of the carbohydrate moiety plays a minor role in determining the binding mode. Indeed, NMR conformational studies, combined with molecular mechanics calculations, indicated that all glycopeptides present the same major conformation either in solution or membrane-like environment. The evidences provided here highlight the relevance for in vivo activity of the conjugating bond between the peptide and sugar moieties in opioid glycopeptides.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.052
  • Design, synthesis and in vitro activity of 1,4-disubstituted piperazines
           and piperidines as triple reuptake inhibitors
    • Authors: Suresh Paudel; Srijan Acharya; Goo Yoon; Kyeong-Man Kim; Seung Hoon Cheon
      Pages: 2266 - 2276
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Suresh Paudel, Srijan Acharya, Goo Yoon, Kyeong-Man Kim, Seung Hoon Cheon
      Monoamine transporters regulate the concentration of monoamine neurotransmitters, which are essential for vital physiological processes, and their dysfunction can cause several central nervous system diseases. Monoamine transporters currently appear to be the potential target in the management of these disorders. In this study, homologation and bioisosterism techniques have been used in the designing of new 1,4-disubstituted piperazines and piperidines. These derivatives were synthesized and evaluated as potential triple reuptake inhibitors for studying the structure-activity relationships. The most advanced compound, 1-(4-(5-benzhydryl-1H-tetrazol-1-yl)butyl)-4-(3-phenylpropyl)piperazine (2i), was able to inhibit monoamine neurotransmitter reuptake in an in vitro test (IC50 =158.7nM for 5-HT, 99nM for NE and 97.5nM for DA). These novel potent triple reuptake inhibitor-based 1,4-disubstituted piperazine and piperidine scaffolds deserve further systematic optimization and pharmacological evaluation.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.051
  • Oligo-aspartic acid conjugates with
           benzo[c][2,6]naphthyridine-8-carboxylic acid scaffold as picomolar
           inhibitors of CK2
    • Authors: Jürgen Vahter; Kaido Viht; Asko Uri; Erki Enkvist
      Pages: 2277 - 2284
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Jürgen Vahter, Kaido Viht, Asko Uri, Erki Enkvist
      Structurally diverse inhibitors of the protein kinase CK2 are required for regulation of this ubiquitous protein to establish biological roles of the enzyme which catalyzes the phosphorylation of a vast number of substrate proteins. In this article we disclose a series of new bisubstrate inhibitors of CK2 that are structurally represented by the oligo(l-Asp) peptide conjugates of benzo[c][2,6]naphthyridine-8-carboxylic acid. This fragment originated from CX-4945, the first in class inhibitor taken to clinical trials. The most potent conjugates possessed two-digit picomolar affinity and clear selectivity for CK2α in a panel of 140 protein kinases. Labeling of the inhibitors with a fluorescent dye yielded probes for a fluorescence anisotropy-based binding/displacement assay which can be used for analysis of CK2 and precise determination of affinity of the highly potent (tight-binding) CK2-targeting inhibitors.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.055
  • Total synthesis and antileukemic evaluations of the phenazine 5,10-dioxide
           natural products iodinin, myxin and their derivatives
    • Authors: Elvar Örn Viktorsson; Bendik Melling Grøthe; Reidun Aesoy; Misbah Sabir; Simen Snellingen; Anthony Prandina; Ove Alexander Høgmoen Åstrand; Tore Bonge-Hansen; Stein Ove Døskeland; Lars Herfindal; Pål Rongved
      Pages: 2285 - 2293
      Abstract: Publication date: 1 April 2017
      Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 7
      Author(s): Elvar Örn Viktorsson, Bendik Melling Grøthe, Reidun Aesoy, Misbah Sabir, Simen Snellingen, Anthony Prandina, Ove Alexander Høgmoen Åstrand, Tore Bonge-Hansen, Stein Ove Døskeland, Lars Herfindal, Pål Rongved
      A new efficient total synthesis of the phenazine 5,10-dioxide natural products iodinin and myxin and new compounds derived from them was achieved in few steps, a key-step being 1,6-dihydroxyphenazine di-N-oxidation. Analogues prepared from iodinin, including myxin and 2-ethoxy-2-oxoethoxy derivatives, had fully retained cytotoxic effect against human cancer cells (MOLM-13 leukemia) at atmospheric and low oxygen level. Moreover, iodinin was for the first time shown to be hypoxia selective. The structure-activity relationship for leukemia cell death induction revealed that the level of N-oxide functionality was essential for cytotoxicity. It also revealed that only one of the two phenolic functions is required for activity, allowing the other one to be modified without loss of potency.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.02.058
  • Diverse size approach to incorporate and extend highly fluorescent
           unnatural nucleotides into DNA
    • Authors: Binh Huy Le; Ja Choon Koo; Han Na Joo; Young Jun Seo
      Abstract: Publication date: Available online 23 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Binh Huy Le, Ja Choon Koo, Han Na Joo, Young Jun Seo
      We have prepared a series of size-diverse unnatural nucleotides containing fluorescent (dApyrTP, dUpyrTP, dUantTP, dUthiTP) and quencher (dUazoTP) units, as well as nucleotides presenting small functional groups (dAethTP, dAoctTP, dUethTP, dUiodTP), all based on deoxyadenosine and deoxyuridine, and examined their suitability for use in enzymatic incorporation and extension into DNA. We observed a size-dependence of the incorporation and extension capability (following the order dUiodTP = dUethTP = dUthiTP > dUazoTP > dUpyrTP > dUantTP) during primer extension. This result was supported by circular dichroism (CD) spectra, which revealed a trend in the different B-form DNA structures depending on the size of the unit at the 5-position of the deoxyuridine (dUiodTP > dUethTP > dUthiTP > dUpyrTP), obtained from the PCR products. Interestingly, dUthiTP could be incorporated and extended into long DNA strands during primer extension and even PCR amplification, with CD spectroscopy confirming a stable secondary B-form duplex DNA structure. We observed full-length extension products even when combining dUthiTP with a template containing 24 continuous dA units during the primer extension. Thus, we believe that dUthiTP is a promising fluorescent nucleotide for a diverse range of biological applications requiring multiple incorporation and extension directly without disruption of B-form DNA structures.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.03.045
  • Ester-to-Amide Rearrangement of Ethanolamine-Derived Prodrugs of
           Sobetirome with Increased Blood-Brain Barrier Penetration
    • Authors: Skylar J. Ferrara; J. Matthew Meinig; Andrew T. Placzek; Tapasree Banerji; Peter McTigue; Meredith D. Hartley; Hannah S. Sanford-Crane; Tania Banerji; Dennis Bourdette; Thomas S. Scanlan
      Abstract: Publication date: Available online 23 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Skylar J. Ferrara, J. Matthew Meinig, Andrew T. Placzek, Tapasree Banerji, Peter McTigue, Meredith D. Hartley, Hannah S. Sanford-Crane, Tania Banerji, Dennis Bourdette, Thomas S. Scanlan
      Current therapeutic options for treating demyelinating disorders such as multiple sclerosis (MS) do not stimulate myelin repair, thus creating a clinical need for therapeutic agents that address axonal remyelination. Thyroid hormone is known to play an important role in promoting developmental myelination and repair, and CNS permeable thyromimetic agents could offer an increased therapeutic index compared to endogenous thyroid hormone. Sobetirome is a clinical stage thyromimetic that has been shown to have promising activity in preclinical models related to MS and X-linked adrenoleukodystrophy (X-ALD), a genetic disease that involves demyelination. Here we report a new series of sobetirome prodrugs containing ethanolamine-based promoieties that were found to undergo an intramolecular O,N acyl migration to form the pharmacologically relevant amide species. Several of these systemically administered prodrugs deliver more sobetirome to the brain compared to unmodified sobetirome. Pharmacokinetic properties of the parent drug sobetirome and amidoalcohol prodrug 3 are described and prodrug 3 was found to be more potent than sobetirome in target engagement in the brain from systemic dosing.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.03.047
  • Small Molecules Inhibit STAT3 Activation, Autophagy, and Cancer Cell
           Anchorage-Independent Growth
    • Authors: Donghui Zhou; Maya Z. Springer; David Xu; Degang Liu; Andy Hudmon; Kay F. Macleod; Samy O. Meroueh
      Abstract: Publication date: Available online 23 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Donghui Zhou, Maya Z. Springer, David Xu, Degang Liu, Andy Hudmon, Kay F. Macleod, Samy O. Meroueh
      Triple-negative breast cancers (TNBCs) lack the signature targets of other breast tumors, such as HER2, estrogen receptor, and progesterone receptor. These aggressive basal-like tumors are driven by a complex array of signaling pathways that are activated by multiple driver mutations. Here we report the discovery of 6 (KIN-281), a small molecule that inhibits multiple kinases including maternal leucine zipper kinase (MELK) and the non-receptor tyrosine kinase bone marrow X-linked (BMX) with single-digit micromolar IC50s. Several derivatives of 6 were synthesized to gain insight into the binding mode of the compound to the ATP binding pocket. Compound 6 was tested for its effect on anchorage-dependent and independent growth of MDA-MB-231 and MDA-MB-468 breast cancer cells. The effect of 6 on BMX prompted us to evaluate its effect on STAT3 phosphorylation and DNA binding. The compound’s inhibition of cell growth led to measurements of survivin, Bcl-XL, p21WAF1/CIP1, and cyclin A2 levels. Finally, LC3B-II levels were quantified following treatment of cells with 6 to determine whether the compound affected autophagy, a process that is known to be activated by STAT3. Compound 6 provides a starting point for the development of small molecules with polypharmacology that can suppress TNBC growth and metastasis.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.03.048
  • Design and Synthesis of Quinazolinones as EGFR inhibitors to Overcome EGFR
           Resistance Obstacle
    • Authors: Harun M. Patel; Rahul Pawara; Azim Ansari; Malleshappa Noolvi; Sanjay Surana
      Abstract: Publication date: Available online 23 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Harun M. Patel, Rahul Pawara, Azim Ansari, Malleshappa Noolvi, Sanjay Surana
      The epidermal growth factor receptor (EGFR) T790M mutant is found in about 50% of clinically acquired resistance to gefitinib among patients with non-small cell lung cancer (NSCLC). New derivatives of 4(3H)-quinazolinones were synthesized and evaluated for their inhibitory activity against NSCLC. The results of the study demonstrated that compound 79, 7-chloro-3-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)-2-phenylquinazolin-4(3H)-one was found to be the most potent compounds of the series with IC50 value of 0.031 μM against mutant T790M/L858R EGFR. Compounds 15, 51, 73, 75, 78, 79 and 96 were less potent against A549 (WT EGFR and k-Ras mutation) and HT-29 (non-special gene type) cells, showing a high safety index. The obtained results showed that compounds 15, 51, 73, 75, 78, 79 and 96 could be the promising template to overcome drug resistance mediated by the EGFR T790 Mutant.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.03.039
  • Corrigendum to “Synthesis and biological activity of
           2,5-diaryl-3-methylpyrimido[4,5-c]quinolin-1(2H)-one derivatives”
           [Bioorg. Med. Chem. 15 (2007) 2434–2440]
    • Authors: Kamel Metwally; Omar Aly; Enayat Aly; Abhijit Banerjee; Rudravajhala Ravindra; Susan Bane
      Abstract: Publication date: Available online 22 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Kamel Metwally, Omar Aly, Enayat Aly, Abhijit Banerjee, Rudravajhala Ravindra, Susan Bane

      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.03.025
  • Rapid screening the potential mechanism-based inhibitors of CYP3A4 from
           Tripterygium wilfordi based on computer approaches combined with in vitro
    • Authors: Lili Wang; Yue Hai; Lijun An; Junxiu Chen; Rongjia Liang; Xin He
      Abstract: Publication date: Available online 22 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Lili Wang, Yue Hai, Lijun An, Junxiu Chen, Rongjia Liang, Xin He
      CYP3A4 is the main human metabolizing enzyme, and many clinically relevant drug/herb-drug interactions (DDIs/HDIs) involving CYP3A4 are due to mechanism-based inhibition. In this study, pharmacophore model together with molecular docking (MD) are used to rapidly screen the potential CYP3A4 mechanism-based inhibitors from Tripterygium wilfordii, and in vitro experiments are conducted to validate the computational data. The results showed that the rate of computational prediction could be improved based on a combination of pharmacophore model and MD, and a combination of computational approaches might be a useful tool to identify potential mechanism-based inhibitor of CYP3A4 from herbal medicines.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.03.037
  • Facile access to pseudo-thio-1,2-dimannoside, a new glycomimetic DC-SIGN
    • Authors: Alice Tamburrini; Silvia Achilli; Francesca Vasile; Sara Sattin; Corinne Vivès; Cinzia Colombo; Franck Fieschi; Anna Bernardi
      Abstract: Publication date: Available online 22 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Alice Tamburrini, Silvia Achilli, Francesca Vasile, Sara Sattin, Corinne Vivès, Cinzia Colombo, Franck Fieschi, Anna Bernardi
      The synthesis and conformational analysis of pseudo-thio-1,2-dimannoside are described. This molecule mimics mannobioside (Manα(1,2)Man) and is an analog of pseudo-1,2-dimannoside, with expected increased stability to enzymatic hydrolysis. A short and efficient synthesis was developed based on an epoxide ring-opening reaction by a mannosyl thiolate, generated in situ from the corresponding thioacetate. NMR-NOESY studies supported by MM3∗ calculations showed that the pseudo-thio-1,2-dimannoside shares the conformational behavior of the pseudo-1,2-dimannoside and is a structural mimic of the natural disaccharide. Its affinity for DC-SIGN was measured by SPR and found to be comparable to the corresponding O-linked analogue, offering good opportunities for further developments.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.03.046
  • Synthesis and biological activity of novel tert-amylphenoxyalkyl
           (homo)piperidine derivatives as histamine H3R ligands
    • Authors: Kamil Kuder; Dorota Łażewska; Maria Kaleta; Gniewomir Latacz; Tim Kottke; Agnieszka Olejarz; Tadeusz Karcz; Andrzej Fruziński; Katarzyna Szczepańska; Janina Karolak-Wojciechowska; Holger Stark; Katarzyna Kieć-Kononowicz
      Abstract: Publication date: Available online 21 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Kamil Kuder, Dorota Łażewska, Maria Kaleta, Gniewomir Latacz, Tim Kottke, Agnieszka Olejarz, Tadeusz Karcz, Andrzej Fruziński, Katarzyna Szczepańska, Janina Karolak-Wojciechowska, Holger Stark, Katarzyna Kieć-Kononowicz
      As a continuation of our search for novel histamine H3 receptor ligands a series of twenty new tert-amyl phenoxyalkylamine derivatives (2-21) was synthesized. Compounds of four to eight carbon atoms spacer alkyl chain were evaluated on their binding properties at human histamine H3 receptor (hH3R). The highest affinities were observed for pentyl derivatives 6-8 (Ki= 8.8 – 23.4 nM range) and among them piperidine derivative 6 with Ki=8.8 nM. Structures 6, 7 were also classified as antagonists in cAMP accumulation assay (with EC50 = 157 and 164 nM, respectively). Moreover, new compounds were also evaluated for anticonvulsant activity in Antiepileptic Screening Program (ASP) at National Institute of Neurological Disorders and Stroke (USA). Seven compounds (2-4, 9, 11, 12 and 20) showed anticonvulsant activity at maximal electroshock (MES) test in the dose of 30 mg/kg at 0.5 h. In the subcutaneous pentetrazole (scMET) test compound 4 showed protection at 100 and 300 mg/kg dose at mice, however compounds showed high neurotoxicity in rotarod test at used doses. Also, molecular modeling studies were undertaken, to explain affinity of compounds at hH3R (taking into the consideration X-ray analysis of compound 18). In order to estimate “drug-likeness” of selected compounds in silico and experimental evaluation of lipophilicity, metabolic stability and cytotoxicity was performed.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.03.031
  • Synthesis and hyperpolarisation of eNOS substrates for quantification of
           NO production by 1H-NMR spectroscopy
    • Authors: Fernando Fernandez Diaz-Rullo; Francesco Zamberlan; Ryan E. Mewis; Marianna Fekete; Lionel Broche; Lesley A. Cheyne; Sergio Dall'Angelo; Simon B. Duckett; Dana Dawson; Matteo Zanda
      Abstract: Publication date: Available online 21 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Fernando Fernandez Diaz-Rullo, Francesco Zamberlan, Ryan E. Mewis, Marianna Fekete, Lionel Broche, Lesley A. Cheyne, Sergio Dall'Angelo, Simon B. Duckett, Dana Dawson, Matteo Zanda
      Hyperpolarization enhances the intensity of the NMR signals of a molecule, whose in vivo metabolic fate can be monitored by MRI with higher sensitivity. SABRE is a hyperpolarization technique that could potentially be used to image nitric oxide (NO) production in vivo. This would be very important, because NO dysregulation is involved in several pathologies, including cardiovascular ones. The nitric oxide synthase (NOS) pathway leads to NO production via conversion of l-arginine into l-citrulline. NO is a free radical gas with a short half-life in vivo (≈ 5 s), therefore direct NO quantification is challenging. An indirect method – based on quantifying conversion of an l-Arg- to L-Cit-derivative by 1H-NMR spectroscopy – is herein proposed. A small library of pyridyl containing L-Arg derivatives was designed and synthesized. In vitro tests showed that compounds 4a-j and 11a-c were better or equivalent substrates for the eNOS enzyme (NO2 - production = 19-46 μM) than native L-Arg (NO2 - production = 25 μM). Enzymatic conversion of L-Arg to L-Cit derivatives could be monitored by 1H-NMR. The maximum hyperpolarization achieved by SABRE reached 870-fold NMR signal enhancement, which opens up exciting future perspectives of using these molecules as hyperpolarized MRI tracers in vivo.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.03.041
  • Metabolite diversification by cultivation of the endophytic fungus
           Dothideomycete sp. in halogen containing media: Cultivation of terrestrial
           fungus in seawater
    • Authors: Kanchana Wijesekera; Chulabhorn Mahidol; Somsak Ruchirawat; Prasat Kittakoop
      Abstract: Publication date: Available online 20 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Kanchana Wijesekera, Chulabhorn Mahidol, Somsak Ruchirawat, Prasat Kittakoop
      The endophytic fungus, Dothideomycete sp. CRI7, isolated from the terrestrial plant, Tiliacora triandra, was salt tolerant, capable of growing in the culture medium prepared from seawater; salts in seawater did not have any effects on the fungal growth. Metabolite productions of the fungus CRI7 cultivated in media prepared from seawater (MSW), prepared from deionized water supplemented with potassium bromide (MKBr) or potassium iodide (MKI), and prepared from deionized water (MDW) were investigated. It was found that the cultivation of the fungus CRI7 in MKBr and MSW enabled the fungus to produce nine new metabolites (1-9). The production of an azaphilone, austdiol (10), of the fungus CRI7 grown in MDW was 0.04g/L, which was much lower than that grown in MSW, MKBr, and MKI media which provided the yields of 0.5, 0.9, and 1.2 g/L, respectively, indicating that halogen salts significantly enhanced the production of the polyketide 10. The cultivation of terrestrial fungi in media containing halogen salts could therefore be useful for the metabolite diversification by one strain-many compounds (OSMAC) approach. Moreover, the isolated polyketides had significant biosynthetic relationship, suggesting that the cultivation of fungi in halogen containing media could provide the insights into certain polyketide biosynthesis. One of the isolated compounds exhibited antibacterial activity with the MIC value of 100 μg/mL.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.03.040
  • Design, Synthesis and Anti-tumor Activity Study of Novel Histone
           Deacetylase Inhibitors Containing Isatin-based Caps and
           O-phenylenediamine-based Zinc Binding Groups
    • Authors: Shuai Gao; Jie Zang; Qianwen Gao; Xuewu Liang; Qinge Ding; Xiaoyang Li; Wenfang Xu; C. James Chou; Yingjie Zhang
      Abstract: Publication date: Available online 19 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Shuai Gao, Jie Zang, Qianwen Gao, Xuewu Liang, Qinge Ding, Xiaoyang Li, Wenfang Xu, C. James Chou, Yingjie Zhang
      As a hot topic of epigenetic studies, histone deacetylases (HDACs) are related to lots of diseases, especially cancer. Further researches indicated that different HDAC isoforms played various roles in a wide range of tumor types. Herein a novel series of HDAC inhibitors with isatin-based caps and o-phenylenediamine-based zinc binding groups have been designed and synthesized through scaffold hopping strategy. Among these compounds, the most potent compound 9n exhibited similar if not better HDAC inhibition and antiproliferative activities against multiple tumor cell lines compared with the positive control entinostat (MS-275). Additionally, compared with MS-275 (IC50 values for HDAC1, 2 and 3 were 0.163, 0.396 and 0.605 µM, respectively), compound 9n with IC50 values of 0.032, 0.256 and 0.311 µM for HDAC1, 2 and 3 respectively, showed a moderate HDAC1 selectivity.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.03.036
  • Discovery of a series of 1,3,4-oxadiazole-2(3H)-thione derivatives
           containing piperazine skeleton as potential FAK inhibitors
    • Authors: Juan Sun; Shen-Zhen Ren; Xiao-Yuan Lu; Jing-Jing Li; Fa-Qian Shen; Chen Xu; Hai-Liang Zhu
      Abstract: Publication date: Available online 19 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Juan Sun, Shen-Zhen Ren, Xiao-Yuan Lu, Jing-Jing Li, Fa-Qian Shen, Chen Xu, Hai-Liang Zhu
      Focal adhesion kinase (FAK) is an important drug target that plays a fundamental role in mediating signal transduction system. We report herein the discovery of a novel class of 1,3,4-oxadiazole-2(3H)-thione derivatives containing piperazine skeleton with improved potency toward FAK. All of the 17 new synthesized compounds were assayed for the anticancer activities against four cancer cells, HepG2, Hela, SW116 and BGC823. Because of the combination of 1,4-benzodioxan, 1,3,4-oxadiazole and piperazine ring, most of them exhibited remarkable antitumor activities. Notably, compound 5m showed the most potent biological activities (IC50=5.78 μM for HepG2, and IC50=47.15 μM for SW1116), and its anti-FAK inhibitory activity (IC50=0.78 μM) was also the best. Computational docking studies also showed that compound 5m has interaction with FAK key residues in the active site.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.03.038
  • PIFA–BF3·OEt2 mediated intramolecular regioselective domino cyclization
           of ynamides: A novel method for the synthesis of
    • Authors: Winai Ieawsuwan; Somsak Ruchirawat
      Abstract: Publication date: Available online 19 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Winai Ieawsuwan, Somsak Ruchirawat
      The transition metal-free intramolecular regioselective domino cyclization of N-Boc protected ynamides has been developed to provide the corresponding tetrahydroisoquinoline-oxazo-2(3H)-ones in moderate to good yields.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.03.034
  • Indole-TEMPO conjugates alleviate ischemia-reperfusion injury via
           attenuation of oxidative stress and preservation of mitochondrial function
    • Authors: Wei Bi; Yue Bi; Xiang Gao; Pengfei Li; Shanshan Hou; Yanrong Zhang; Cathy Bammert; Steffen Jockusch; Thomas D. Legalley; K. Michael Gibson; Lanrong Bi
      Abstract: Publication date: Available online 19 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Wei Bi, Yue Bi, Xiang Gao, Pengfei Li, Shanshan Hou, Yanrong Zhang, Cathy Bammert, Steffen Jockusch, Thomas D. Legalley, K. Michael Gibson, Lanrong Bi
      Mitochondrial oxidative damage contributes to a wide range of pathologies including ischemia/ reperfusion injury. Accordingly, protecting mitochondria from oxidative damage should possess therapeutic relevance. In the present study, we have designed and synthesized a series of novel indole-TEMPO conjugates that manifested good anti-inflammatory properties in a murine model of xylene-induced ear edema. We have demonstrated that these compounds can protect cells from simulated ischemia/reperfusion (s-I/R)-induced reactive oxygen species (ROS) overproduction and mitochondrial dysfunction. Furthermore, we have demonstrated that indole-TEMPO conjugates can attenuate organ damage induced in rodents via intestinal I/R injury. We therefore propose that the pharmacological profile and mechanism of action of these indole-TEMPO conjugates involve convergent roles, including the ability to decrease free radical production via lipid peroxidation which couples to an associated decrease in ROS-mediated activation of the inflammatory process. We further hypothesize that the protective effects of indole-TEMPO conjugates partially reside in maintaining optimal mitochondrial function.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.03.033
  • Design and synthesis of bicyclic acetals as Beta Secretase (BACE1)
    • Authors: Riccardo Innocenti; Elena Lenci; Gloria Menchi; Alberto Pupi; Andrea Trabocchi
      Abstract: Publication date: Available online 18 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Riccardo Innocenti, Elena Lenci, Gloria Menchi, Alberto Pupi, Andrea Trabocchi
      Taking advantage of the structural similarity between aspartic proteases, small-molecule peptidomimetic inhibitors that already showed activity towards Secreted Aspartic Protease 2 as anti-Candida agents and HIV protease inhibitors were exploited as potential BACE1 inhibitors. A focused library of 6,8-dioxa-3-azabicyclo[3.2.1]-octane peptidomimetic scaffolds was synthesized and assayed towards BACE1 enzyme, resulting in the identification of a thiolactam-containing hit compound possessing IC50 in the low micromolar range, and confirming the bicyclic acetal portion as a potential transition state analogue in the interaction with catalytic aspartic acid residues
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.03.030
  • Comparative assessment of a 99mTc labeled H1299.2-HYNIC peptide bearing
           two different co-ligands for tumor-targeted imaging
    • Authors: Seyedeh Atekeh; Torabizadeh Seyed Mohammad Abedi Zoreh Noaparsat Seyed Jalal
      Abstract: Publication date: Available online 18 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Seyedeh Atekeh Torabizadeh, Seyed Mohammad Abedi, Zoreh Noaparsat, Seyed Jalal Hosseinimehr
      Peptides are a class of targeting agents that bind to cancer-specific cell surfaces. Since they specifically target cancer cells, they could be used as molecular imaging tools. In this study, the 15-mer peptide Ac-H1299.2 (YAAWPASGAWTGTAP) was conjugated with HYNIC via lysine amino acid on C-terminus and labeled with 99mTc using tricine and EDDA/tricine as the co-ligands. These radiotracers were evaluated for potential utilization in diagnostic imaging of ovarian cancer cells (SKOV-3). The cell-specificity of these radiolabeled peptides was determined based on their binding on an ovarian cancer cell line (SKOV-3), and displaying a low affinity for lung adenocarcinoma cell line (A549) and breast cancer cell line (MCF7). Biodistribution studies were conducted in normal mice as well as in nude mice bearing SKOV-3 ovarian cancer xenografts. HYNIC-peptides was labeled with 99mTc with more than 99% efficiency and showed high stability in buffer and serum. We observed nanomolar binding affinities for both radiolabeled peptides. The tumor uptakes were 3.27% ± 0.46% and 1.55% ± 0.20% for tricine and 2.34 ± 0.18% and 1.09% ± 0.18% for EDDA/tricine at 1 and 4 h after injection, respectively. A higher tumor to background ratio and lower radioactivity in the blood were observed for EDDA/tricine co-ligands, leading to clear tumor visualization in imaging with injection of this peptide. This new 99mTc-labeled peptide selectively targeted ovarian cancer and introduction of a (EDDA/tricine) as a co-ligand improved the pharmacokinetics of 99mTc-labeled H1299.2 for tumor imaging in animals.
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      PubDate: 2017-03-25T11:40:02Z
  • Do spiroindolines have the potential to replace vesamicol as lead compound
           for the development of radioligands targeting the vesicular acetylcholine
    • Authors: Marcel Lindemann; Winnie Deuther-Conrad; Rares Moldovan; Kondapalli Venkata Gowri Chandra Sekhar; Peter Brust; Barbara Wenzel
      Abstract: Publication date: Available online 18 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Marcel Lindemann, Winnie Deuther-Conrad, Rares Moldovan, Kondapalli Venkata Gowri Chandra Sekhar, Peter Brust, Barbara Wenzel
      The vesicular acetylcholine transporter (VAChT) is an important target for in vivo imaging of neurodegenerative processes using positron emission tomography (PET). So far the development of VAChT PET radioligands is based on the single known lead compound vesamicol. In this study we investigated a recently published spiroindoline based compound class (Sluder et al., 2012), which was suggested to have potential in the development of VAChT ligands. Therefore, we synthesized a small series of N,N-substituted spiro[indoline-3,4′-piperidine] derivatives and determined their in vitro binding affinities toward the VAChT. In order to investigate the selectivity, the off-target binding toward σ1 and σ2 receptors was determined. The compounds possessed VAChT affinities with K i values in the range of 39–376nM. Binding affinities toward the σ1 and σ2 receptors are in a similar range indicating that the strong structural difference between the spiroindolines and vesamicol did not improve the selectivity. The observed potential to additionally bind to σ receptors let us assume that the herein investigated spiroindolines are not suitable to replace vesamicol as lead compound for the development of VAChT ligands.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.03.028
  • C-2 (E)-4-(Styryl)aniline Substituted Diphenylpyrimidine Derivatives
           (Sty-DPPYs) as Specific Kinase Inhibitors Targeting Clinical Resistance
           related EGFRT790M Mutant
    • Authors: Anran Song; Jianbin Zhang; Yang Ge; Changyuan Wang; Qiang Meng; Zeyao Tang; Jinyong Peng; Kexin Liu; Yanxia Li; Xiaodong Ma
      Abstract: Publication date: Available online 18 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Anran Song, Jianbin Zhang, Yang Ge, Changyuan Wang, Qiang Meng, Zeyao Tang, Jinyong Peng, Kexin Liu, Yanxia Li, Xiaodong Ma
      With the aim to overcome the drug resistance induced by the EGFR T790M mutation (EGFRT790M), herein, a family of diphenylpyrimidine derivatives (Sty-DPPYs) bearing a C-2 (E)-4-(styryl)aniline functionality were designed and synthesized as potential EGFRT790M inhibitors. Among them, the compound 10e displayed strong potency against the EGFRT790M enzyme, with the IC50 of 11.0 nM. Compound 10e also showed a higher SI value (SI = 49.0) than rociletinib (SI = 21.4), indicating its less side effect. In addition, compound 10e could effectively inhibit the proliferation of H1975 cells harboring the EGFRT790M mutation, within the concentration of 2.91 μM. Significantly, compound 10e has low toxicity against the normal HBE cell (IC50 = 22.48 μM). This work provided new insights into the discovery of potent and selective inhibitor against EGFRT790M over wild-type (EGFRWT)
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.03.032
  • Inhibition of Malassezia globosa carbonic anhydrase with phenols
    • Authors: Yeganeh Entezari Heravi; Silvia Bua; Alessio Nocentini; Sonia Del Prete; Ali Akbar Saboury; Hassan Sereshti; Clemente Capasso; Paola Gratteri; Claudiu T. Supuran
      Abstract: Publication date: Available online 18 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Yeganeh Entezari Heravi, Silvia Bua, Alessio Nocentini, Sonia Del Prete, Ali Akbar Saboury, Hassan Sereshti, Clemente Capasso, Paola Gratteri, Claudiu T. Supuran
      A panel of 22 phenols was investigated as inhibitors of the β-class carbonic anhydrase (CAs, EC from the fungal parasite Malassezia globosa (MgCA), a validated anti-dandruff drug target. The displayed inhibitory activities were compared to the ones previously reported against the off-target widely distributed human (h) isoforms hCA I and II. All tested phenols possessed a better efficacy in inhibiting MgCA than the clinically used sulfonamide acetazolamide, with KIs in the range of 2.5 and 65.0μM. A homology-built model of MgCA was also used for understanding the binding mode of phenols to the fungal enzyme. Indeed, a wide network of hydrogen bonds and hydrophobic interactions between the phenol and active site residues were evidenced. The OH moiety of the inhibitor was observed anchored to the zinc-coordinated water, also making hydrogen bonds with Ser48 and Asp49. The diverse substituents at the phenolic scaffold were observed to interact with different portions of the hydrophobic pocket according to their nature and position. Considering the effective MgCA inhibitory properties of phenols, beside to the rather low inhibition against the off-target hCA I and II, this class of compounds might be of considerable interest in the cosmetics field as potential anti-dandruff drugs.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.03.026
  • Synthesis and carbonic anhydrase inhibition of a series of SLC-0111
    • Authors: Fabrizio Carta; Daniela Vullo; Sameh M. Osman; Zeid AlOthman; Claudiu T. Supuran
      Abstract: Publication date: Available online 18 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Fabrizio Carta, Daniela Vullo, Sameh M. Osman, Zeid AlOthman, Claudiu T. Supuran
      SLC-0111 is a sulfonamide carbonic anhydrase (CA, EC inhibitor (CAI) in Phase I/II clinical trials for the treatment of advanced hypoxic tumors complicated with metastases. Its antitumor effects are due to inhibition of the enzymatic activity of CA IX, an isoform predominantly found in tumors/metastases, but it also reduces the cancer stem cells population. Here we report the synthesis of analogs of SLC-0111, both of the sulfanilamide and metanilamide series, which possess diverse substitution patterns at the terminal ureido-phenyl moiety, thus including one or more halogens, trifluoromethyl, perchloro-/perfluorophenyl groups instead of the 4-fluorophenyl present in SLC-0111. Most of the sulfanilamide ureido derivatives were highly effective inhibitors of the tumor associated isoform and some showed selective CA IX/XII inhibitory profiles. Most of the sulfanilamide ureido derivatives were highly effective and in some cases selective CA IX/XII inhibitors, whereas the metanilamide ureido derivatives were less effective as transmembrane CA isoforms inhibitors. Structure activity relationship for this class of sulfonamides is discussed in detail.
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      PubDate: 2017-03-25T11:40:02Z
      DOI: 10.1016/j.bmc.2017.03.027
  • Covalently linked kanamycin – ciprofloxacin hybrid antibiotics as a tool
           to fight bacterial resistance
    • Authors: Michal Shavit; Varvara Pokrovskaya; Valery Belakhov; Timor Baasov
      Abstract: Publication date: Available online 16 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Michal Shavit, Varvara Pokrovskaya, Valery Belakhov, Timor Baasov
      To address the growing problem of antibiotic resistance, a set of 12 hybrid compounds that covalently link fluoroquinolone (ciprofloxacin) and aminoglycoside (kanamycin A) antibiotics were synthesized, and their activity was determined against both Gram-negative and Gram-positive bacteria, including resistant strains. The hybrids were antagonistic relative to the ciprofloxacin, but were substantially more potent than the parent kanamycin against Gram-negative bacteria, and overcame most dominant resistance mechanisms to aminoglycosides. Selected hybrids were 42-640 fold poorer inhibitors of bacterial protein synthesis than the parent kanamycin, while they displayed similar inhibitory activity to that of ciprofloxacin against DNA gyrase and topoisomerase IV enzymes. The hybrids showed significant delay of resistance development in both E. coli and B. subtilis in comparison to that of component drugs alone or their 1:1 mixture. More generally, the data suggest that an antagonistic combination of aminoglycoside-fluoroquinolone hybrids can lead to new compounds that slowdown/prevent the emergence of resistance.
      Graphical abstract image

      PubDate: 2017-03-18T07:00:26Z
      DOI: 10.1016/j.bmc.2017.02.068
  • Corrigendum to “Antiplasmodial phloroglucinol derivatives from Syncarpia
           glomulifera” [Bioorg. Med. Chem. 24 (2016) 2544–2548]
    • Authors: Qingxi Su; Seema Dalal; Michael Goetz; Maria B. Cassera; David G.I. Kingston
      Abstract: Publication date: Available online 9 March 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Qingxi Su, Seema Dalal, Michael Goetz, Maria B. Cassera, David G.I. Kingston

      PubDate: 2017-03-18T07:00:26Z
      DOI: 10.1016/j.bmc.2017.02.062
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