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  Subjects -> CHEMISTRY (Total: 845 journals)
    - ANALYTICAL CHEMISTRY (51 journals)
    - CHEMISTRY (595 journals)
    - CRYSTALLOGRAPHY (21 journals)
    - ELECTROCHEMISTRY (25 journals)
    - INORGANIC CHEMISTRY (41 journals)
    - ORGANIC CHEMISTRY (45 journals)
    - PHYSICAL CHEMISTRY (67 journals)

CHEMISTRY (595 journals)                  1 2 3 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 8)
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: 34)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 18)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 23)
ACS Macro Letters     Full-text available via subscription   (Followers: 24)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 39)
ACS Nano     Full-text available via subscription   (Followers: 244)
ACS Photonics     Full-text available via subscription   (Followers: 11)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 21)
Acta Chemica Iasi     Open Access   (Followers: 2)
Acta Chimica Sinica     Full-text available via subscription   (Followers: 1)
Acta Chimica Slovaca     Open Access   (Followers: 1)
Acta Chromatographica     Full-text available via subscription   (Followers: 9)
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: 8)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 5)
Advanced Functional Materials     Hybrid Journal   (Followers: 51)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 56)
Advances in Chemical Science     Open Access   (Followers: 13)
Advances in Chemistry     Open Access   (Followers: 15)
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: 9)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 16)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 9)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 21)
Advances in Nanoparticles     Open Access   (Followers: 15)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15)
Advances in Polymer Science     Hybrid Journal   (Followers: 41)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 17)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Science and Technology     Full-text available via subscription   (Followers: 12)
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: 67)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 14)
American Journal of Chemistry     Open Access   (Followers: 27)
American Journal of Plant Physiology     Open Access   (Followers: 14)
American Mineralogist     Hybrid Journal   (Followers: 14)
Analyst     Full-text available via subscription   (Followers: 40)
Angewandte Chemie     Hybrid Journal   (Followers: 199)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 218)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 4)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 4)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 8)
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: 15)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Hybrid Journal  
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7)
Applied Spectroscopy     Full-text available via subscription   (Followers: 23)
Applied Surface Science     Hybrid Journal   (Followers: 28)
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: 4)
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: 10)
Biochemistry     Full-text available via subscription   (Followers: 309)
Biochemistry Insights     Open Access   (Followers: 6)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 9)
Bioinspired Materials     Open Access   (Followers: 5)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access   (Followers: 1)
Biomacromolecules     Full-text available via subscription   (Followers: 19)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 6)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 5)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 118)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 91)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 1)
Bitácora Digital     Open Access  
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 2)
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: 3)
Cakra Kimia (Indonesian E-Journal of Applied Chemistry)     Open Access  
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 3)
Canadian Journal of Chemistry     Hybrid Journal   (Followers: 10)
Canadian Mineralogist     Full-text available via subscription   (Followers: 4)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 66)
Catalysis for Sustainable Energy     Open Access   (Followers: 7)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 8)
Catalysis Science and Technology     Free   (Followers: 7)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 8)
Cellulose     Hybrid Journal   (Followers: 7)
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: 14)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 72)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 24)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 20)
Chemical Reviews     Full-text available via subscription   (Followers: 181)
Chemical Science     Open Access   (Followers: 22)
Chemical Technology     Open Access   (Followers: 16)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemical Week     Full-text available via subscription   (Followers: 8)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 58)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 26)
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: 146)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 15)
Chemistry and Materials Research     Open Access   (Followers: 20)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 5)
Chemistry in Education     Open Access   (Followers: 9)
Chemistry International     Hybrid Journal   (Followers: 2)
Chemistry Letters     Full-text available via subscription   (Followers: 44)
Chemistry of Materials     Full-text available via subscription   (Followers: 255)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 22)
Chemistry-Didactics-Ecology-Metrology     Open Access   (Followers: 1)
ChemistryOpen     Open Access   (Followers: 2)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 4)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 15)
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: 2)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 10)
Chromatographia     Hybrid Journal   (Followers: 24)
Clay Minerals     Full-text available via subscription   (Followers: 10)
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: 7)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
Combustion Science and Technology     Hybrid Journal   (Followers: 18)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Composite Interfaces     Hybrid Journal   (Followers: 6)
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: 12)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 9)
Coordination Chemistry Reviews     Full-text available via subscription   (Followers: 3)
Copernican Letters     Open Access   (Followers: 1)
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 5)
Crystal Structure Theory and Applications     Open Access   (Followers: 4)
CrystEngComm     Full-text available via subscription   (Followers: 13)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Metabolomics     Hybrid Journal   (Followers: 5)
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 17)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 61)
Dalton Transactions     Full-text available via subscription   (Followers: 23)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)
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: 4)
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)
EJNMMI Radiopharmacy and Chemistry     Open Access  
Elements     Full-text available via subscription   (Followers: 3)
Environmental Chemistry     Hybrid Journal   (Followers: 7)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 4)
Environmental Science & Technology Letters     Full-text available via subscription   (Followers: 5)

        1 2 3 | Last

Journal Cover Bioorganic & Medicinal Chemistry Letters
  [SJR: 0.952]   [H-I: 112]   [91 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0960-894X
   Published by Elsevier Homepage  [3051 journals]
  • RNA as a small molecule druggable target
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Noreen F. Rizvi, Graham F. Smith
      Small molecule drugs have readily been developed against many proteins in the human proteome, but RNA has remained an elusive target for drug discovery. Increasingly, we see that RNA, and to a lesser extent DNA elements, show a persistent tertiary structure responsible for many diverse and complex cellular functions. In this digest, we have summarized recent advances in screening approaches for RNA targets and outlined the discovery of novel, drug-like small molecules against RNA targets from various classes and therapeutic areas. The link of structure, function, and small-molecule Druggability validates now for the first time that RNA can be the targets of therapeutic agents.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Cyclotides, a versatile ultrastable micro-protein scaffold for
           biotechnological applications
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Julio A. Camarero
      Cyclotides are fascinating microproteins (≈30–40 residues long) with a unique head-to-tail cyclized backbone, stabilized by three disulfide bonds forming a cystine knot. This unique topology makes them exceptionally stable to chemical, thermal and biological degradation compared to other peptides of similar size. Cyclotides have been also found to be highly tolerant to sequence variability, aside from the conserved residues forming the cystine knot, able to cross cellular membranes and modulate intracellular protein–protein interactions both in vitro and in vivo. These properties make them ideal scaffolds for many biotechnological applications. This article provides and overview of the properties of cyclotides and their applications as molecular imaging agents and peptide-based therapeutics.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Improvement in aqueous solubility achieved via small molecular changes
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Michael A. Walker
      Overcoming poor solubility is a significant issue in drug discovery. The most common solution is to replace carbon atoms with polar heteroatoms such as N and O or by attaching a solubilizing appendage. This approach can lead to other issues such as poor activity and PK or the increased risk for toxicity. However, there are more subtle structural changes which can be employed that lead to an increase in solubility. These include, excising hydrophobic groups which do not efficiently contribute to binding, modifying stereo- and regiochemistry, increasing or decreasing the degree of unsaturation or adding small hydrophobic groups such as fluorine or methyl.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Protective effect of casuarinin against glutamate-induced apoptosis in
           HT22 cells through inhibition of oxidative stress-mediated MAPK
           phosphorylation
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Ji Hoon Song, Ki Sung Kang, You-Kyung Choi
      Glutamate is the major excitatory neurotransmitter in the central nervous system and is involved in oxidative stress during neurodegeneration. In the present study, casuarinin prevented glutamate-induced HT22 murine hippocampal neuronal cell death by inhibiting intracellular reactive oxygen species (ROS) production. Moreover, casuarinin reduced chromatin condensation and annexin-V-positive cell production induced by glutamate. We also confirmed the underlying protective mechanism of casuarinin against glutamate-induced neurotoxicity. Glutamate markedly increased the phosphorylation of extracellular signal regulated kinase (ERK)-1/2 and p38, which are crucial in oxidative stress-mediated neuronal cell death. Conversely, treatment with casuarinin diminished the phosphorylation of ERK1/2 and P38. In conclusion, the results of this study suggest that casuarinin, obtained from natural products, acts as potent neuroprotective agent by suppressing glutamate-mediated apoptosis through the inhibition of ROS production and activation of the mitogen activated protein kinase (MAPK) pathway. Thus, casuarinin can be a potential therapeutic agent in the treatment of neurodegenerative diseases.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Docking based design of diastereoisomeric MTCA as GPIIb/IIIa receptor
           inhibitor
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Xiaozhen Wang, Yuji Wang, Jianhui Wu, Lin Gui, Xiaoyi Zhang, Meiqing Zheng, Yaonan Wang, Shurui Zhao, Ze Li, Ming Zhao, Shiqi Peng
      In GPIIb/IIIa mediated arterial thrombosis platelet activation plays a central role. To discover platelet activation inhibitor the pharmacophores of GPIIb/IIIa receptor inhibitors and anti-thrombotic agents were analyzed. This led to the design of (1R,3S)- and (1S,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acids as GPIIb/IIIa inhibitors. Comparing to (1S,3S)-isomer (1R,3S)-isomer had lower cdocker interaction energy. AFM image showed that the minimal effective concentration of (1S,3S)-isomer and (1R,3S)-isomer inhibiting platelet activation were 10−5 M and 10−6 M, respectively. In vivo 1 μmol/kg of oral (1S,3S)-isomer effectively inhibited the rats to form arterial thrombus and down regulated GPIIb/IIIa expression, but the activities were significantly lower than those of 1 μmol/kg of oral (1R,3S)-isomer. Both (1S,3S)-isomer and (1R,3S)-isomer can be safely used for structural modifications, but (1R,3S)-isomer should be superior to (1S,3S)-isomer.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Design, synthesis and in vitro anti-tuberculosis activity of
           benzo[6,7]cyclohepta[1,2-b]pyridine-1,2,3-triazole derivatives
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Yasodakrishna Sajja, Sowmya Vanguru, Hanmanth Reddy Vulupala, Rajashaker Bantu, Perumal Yogeswari, Dharmarajan Sriram, Lingaiah Nagarapu
      A series of novel benzo[6,7]cyclohepta[1,2-b]pyridine-1,2,3-triazole hybrids (7a–j & 8a–j) have been designed and synthesized in excellent yields by Huisgen’s [3+2] cyclo addition reaction of 3-(azidomethyl)-2-methyl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine (5) with various alkynes 6 in presence of copper sulphate and sodium ascorbate and their structures were confirmed by IR, 1H NMR, 13C NMR and HRMS. The newly synthesized compounds 7a–j & 8a–j were evaluated for their in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC 27294). Among the compounds tested, the compounds 7i and 8g displayed most potent activity with MIC value of 1.56 µg/mL with low cytotoxicity.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Indirubin derivatives protect against endoplasmic reticulum stress-induced
           cytotoxicity and down-regulate CHOP levels in HT22 cells
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Yasuhiro Kosuge, Hiroaki Saito, Tatsuki Haraguchi, Yoshimi Ichimaru, Sachiyo Ohashi, Hiroko Miyagishi, Shunsuke Kobayashi, Kumiko Ishige, Shinichi Miyairi, Yoshihisa Ito
      Indirubin and its derivatives have been reported to exhibit anti-cancer and anti-inflammatory activities. Recently, some of its derived analogs have been shown to have neuroprotective potential. Endoplasmic reticulum (ER) stress has been demonstrated to contribute to the pathogenesis of various neurodegenerative diseases, whereas the effects of indirubin derivatives on ER stress-induced cell death have not been addressed. In the present study, a series of 44 derivatives of indirubin was prepared to search for a novel class of neuroprotective agents against ER stress-induced neuronal death. The MTT reduction assay indicated that tunicamycin (TM), an inducer of ER stress, significantly decreased the viability of hippocampal neuronal HT22 cells. Among the compounds tested, eight showed significant inhibitory activity against TM-induced cell death. Western blot analysis showed that application of these analogs to the cells simultaneously with TM reduced the TM-induced expression of CHOP, an established mediator of ER stress. Our results suggest that the preventive effect of these indirubin derivatives against ER stress-induced neuronal death may be due, at least in part, to attenuation of the CHOP-dependent signaling system.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Preparation, characterization and cytotoxic evaluation of bovine serum
           albumin nanoparticles encapsulating 5-methylmellein: A secondary
           metabolite isolated from Xylaria psidii
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Divya Arora, Amit Kumar, Prasoon Gupta, Gousia Chashoo, Sundeep Jaglan
      In this study, 5-methylmellein (5-MM) loaded bovine serum albumin nanoparticles (BSA NPs) were developed using desolvation technique. The developed nanoparticles were characterized for their mean particle size, polydispersity, zeta potential, loading efficiency, X-ray diffractometry (XRD), differential scanning calorimetry (DSC) and release profile. The developed nanoparticles were spherical in shape under transmission electron microscopy (TEM) and atomic force microscopy (AFM). The developed 5-MM loaded BSA NPs demonstrated a mean particle size with a diameter of 154.95 ± 4.44 nm. The results from XRD and DSC studies demonstrated that the crystal state of the 5-MM was converted to an amorphous state in polymeric matrix. The encapsulation and loading efficiency was found to be 73.26 ± 4.48% and 7.09 ± 0.43%. The in vitro cytotoxicity in human prostate cancer cell line (PC-3), human colon cancer cells (HCT-116) and human breast adenocarcinoma cell line (MCF-7) cells demonstrated enhanced cytotoxicity of 5-MM BSA NPs as compared to native 5-MM after 72-h treatment. The enhancement in cytotoxicity of 5-MM BSA NPs was also supported by increase in cellular apoptosis, mitochondrial membrane potential loss and generation of high reactive oxygen species (ROS). In conclusion, these findings collectively indicated that BSA nanoparticles may serve as promising drug delivery system for improving the efficacy of 5-methylmellein.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Discovery of furan and dihydrofuran-fused tricyclic benzo[d]imidazole
           derivatives as potent and orally efficacious microsomal prostaglandin E
           synthase-1 (mPGES-1) inhibitors: Part-1
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Nagarajan Muthukaman, Macchindra Tambe, Sanjay Deshmukh, Dnyandeo Pisal, Shital Tondlekar, Mahamadhanif Shaikh, Neelam Sarode, Vidya G. Kattige, Monali Pisat, Pooja Sawant, Srinivasa Honnegowda, Vikas Karande, Abhay Kulkarni, Dayanidhi Behera, Satyawan B. Jadhav, Ramchandra R. Sangana, Girish S. Gudi, Neelima Khairatkar-Joshi, Laxmikant A. Gharat
      This letter describes the synthesis and biological evaluation of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as novel mPGES-1 inhibitors, capable of inhibiting an increased PGE2 production in the disease state. Structure-activity optimization afforded many potent mPGES-1 inhibitors having <50 nM potencies in the A549 cellular assay and adequate metabolic stability in liver microsomes. Lead compounds 8l and 8m demonstrated reasonable in vitro pharmacology and pharmacokinetic properties over other compounds. In particular, 8m revealed satisfactory oral pharmacokinetics and bioavailability in multiple species like rat, guinea pig, dog and cynomolgus monkey. In addition, the representative compound 8m showed in vivo efficacy by inhibiting LPS-induced thermal hyperalgesia with an ED50 of 14.3 mg/kg in guinea pig.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Synthesis of 14-deoxy-11,12-didehydroandrographolide analogues as
           potential cytotoxic agents for cholangiocarcinoma
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Sudarat Sombut, Rada Bunthawong, Uthaiwan Sirion, Teerapich Kasemsuk, Pawinee Piyachaturawat, Kanoknetr Suksen, Apichart Suksamrarn, Rungnapha Saeeng
      A series of 14-deoxy-11,12-didehydroandrographolide analogues were synthesized from naturally occurring andrographolide and their cytotoxicity evaluated against nine cancer cell lines including cholangiocarcinoma. Analogues 5a and 5b exhibited the most potent cytotoxicity with ED50s of 3.37 and 3.08 μM on KKU-M213 cell lines and 2.93 and 3.27 μM on KKU-100 cell lines, respectively. Selective cytotoxicity on cholangiocarcinoma cell lines identified in this study highlight the importance of structural modification in the development of drugs for this cancer.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Optimization of a series of heterocycles as survival motor neuron gene
           transcription enhancers
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Sungwoon Choi, Alyssa N. Calder, Eliza H. Miller, Kierstyn P. Anderson, Dawid K. Fiejtek, Anne Rietz, Hongxia Li, Jonathan J. Cherry, Kevin M. Quist, Xuechao Xing, Marcie A. Glicksman, Gregory D. Cuny, Christian L. Lorson, Elliot A. Androphy, Kevin J. Hodgetts
      Spinal muscular atrophy (SMA) is a neurodegenerative disorder that results from mutations in the SMN1 gene, leading to survival motor neuron (SMN) protein deficiency. One therapeutic strategy for SMA is to identify compounds that enhance the expression of the SMN2 gene, which normally only is a minor contributor to functional SMN protein production, but which is unaffected in SMA. A recent high-throughput screening campaign identified a 3,4-dihydro-4-phenyl-2(1H)-quinolinone derivative (2) that increases the expression of SMN2 by 2-fold with an EC50 = 8.3 µM. A structure-activity relationship (SAR) study revealed that the array of tolerated substituents, on either the benzo portion of the quinolinone or the 4-phenyl, was very narrow. However, the lactam ring of the quinolinone was more amenable to modifications. For example, the quinazolinone (9a) and the benzoxazepin-2(3H)-one (19) demonstrated improved potency and efficacy for increase in SMN2 expression as compared to 2.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Two new dammarane-type triterpene saponins from Korean red ginseng and
           their anti-inflammatory effects
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Le Ba Vinh, Yunjeong Lee, Yoo Kyong Han, Jong Seong Kang, Jung Up Park, Young Ran Kim, Seo Young Yang, Young Ho Kim
      Panax ginseng has been the subject of extensive research on potential medicinal materials. The goal of this study was search the chemical constituents and biological activities of processed Panax ginseng, Korean red ginseng. Our efforts led to the isolation eleven compounds (1–11) including two new compounds 1 and 2 from Korean red ginseng using various chromatographic techniques. Chemical structures of isolated compounds were demonstrated by spectroscopic methods (1D-, 2D-NMR, and HR-ESI-MS). The anti-inflammatory effects of the compounds were investigated by inhibiting IL-6 and TNF-α secretion in LPS-activated RAW264.7 cells. Additionally, the effects of the compounds on the expression of COX-2 and iNOS were examined by Western blotting. Compound 1 significantly reduced the level of proinflammatory cytokines IL-6 and TNF-α secretion in LPS-activated RAW264.7 cells and the expression of COX-2 and iNOS inflammatory enzymes in the cells. These results suggested that compound 1, a new ginsenoside might useful in treatment of inflammation.
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      PubDate: 2017-11-16T13:44:04Z
       
  • Benzo[c][1,2,5]thiadiazole derivatives: A new class of potent Src
           homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
           inhibitors
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Wen-Long Wang, Xiao-Yu Chen, Ya Gao, Li-Xin Gao, Li Sheng, Jingyu Zhu, Lei Xu, Zhen-Zhong Ding, Chao Zhang, Jing-Ya Li, Jia Li, Yu-Bo Zhou
      The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase linked to various kinds of cancers. Consequently, SHP2 has emerged as a promising target for novel anti-cancer agents. Using scaffold-hopping strategy, a series of benzo[c][1,2,5]thiadiazole derivatives was designed from PTP1B inhibitors with 1H-2,3-Dihydroperimidine motif, synthesized and evaluated their biological activities against PTP1B and SHP2. Among them, the representative compound 11g displayed SHP2 inhibitory activity with IC50 of 2.11 ± 0.99 μM, exhibited 2.02-fold and 25-fold selectivity for SHP2 over SHP1 and PTP1B respectively and had no visible activity against TCPTP. These preliminary results could provide a possible opportunity for the development of novel SHP2 inhibitors with optimal potency and improved pharmacological properties.
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      PubDate: 2017-11-16T13:44:04Z
       
  • Potential antimicrobial agents from triazole-functionalized
           2H-benzo[b][1,4]oxazin-3(4H)-ones
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Rajitha Bollu, Saleha Banu, Rajashaker Bantu, A. Gopi Reddy, Lingaiah Nagarapu, K. Sirisha, C. Ganesh Kumar, Shravan Kumar Gunda, Kamal Shaik
      A series of substituted triazole functionalized 2H-benzo[b][1,4]oxazin-3(4H)-ones were synthesized by employing click chemistry and further characterized based on 1H NMR, 13C NMR, IR and mass spectral studies. All the synthesized derivatives were screened for their in vitro antimicrobial activities. Further, molecular docking studies were accomplished to explore the binding interactions between 1,2,3-triazol-4-yl-2H-benzo[b][1,4]oxazin-3(4H)-one and the active site of Staphylococcus aureus (CrtM) dehydrosqualene synthase (PDB ID: 2ZCS). These docking studies revealed that the synthesized derivatives showed high binding energies and strong H-bond interactions with the dehydrosqualene synthase validating the observed antimicrobial activity data. Based on antimicrobial activity and docking studies, the compounds 9c, 9d and 9e were identified as promising antimicrobial leads.
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      PubDate: 2017-11-16T13:44:04Z
       
  • Structure-activity relationships of 2-substituted
           phenyl-N-phenyl-2-oxoacetohydrazonoyl cyanides as novel antagonists of
           exchange proteins directly activated by cAMP (EPACs)
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Zhiqing Liu, Yingmin Zhu, Haiying Chen, Pingyuan Wang, Fang C. Mei, Na Ye, Xiaodong Cheng, Jia Zhou
      Exchange proteins directly activated by cAMP (EPACs) are critical cAMP-dependent signaling pathway mediators that play important roles in cancer, diabetes, heart failure, inflammations, infections, neurological disorders and other human diseases. EPAC specific modulators are urgently needed to explore EPAC’s physiological function, mechanism of action and therapeutic applications. On the basis of a previously identified EPAC specific inhibitor hit ESI-09, herein we have designed and synthesized a novel series of 2-substituted phenyl-N-phenyl-2-oxoacetohydrazonoyl cyanides as potent EPAC inhibitors. Compound 31 (ZL0524) has been discovered as the most potent EPAC inhibitor with IC50 values of 3.6 µM and 1.2  µM against EPAC1 and EPAC2, respectively. Molecular docking of 31 onto an active EPAC2 structure predicts that 31 occupies the hydrophobic pocket in cAMP binding domain (CBD) and also opens up new space leading to the solvent region. These findings provide inspirations for discovering next generation of EPAC inhibitors.
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      PubDate: 2017-11-16T13:44:04Z
       
  • The identification of a novel lead class for phosphodiesterase 2
           inhibition by fragment-based drug design
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Ashley B. Forster, Pravien Abeywickrema, Jaime Bunda, Christopher D. Cox, Tamara D. Cabalu, Melissa Egbertson, John Fay, Krista Getty, Dawn Hall, Maria Kornienko, Jun Lu, Gopal Parthasarathy, John Reid, Sujata Sharma, William D. Shipe, Sean M. Smith, Stephen Soisson, Shawn J. Stachel, Hua-Poo Su, Deping Wang, Richard Berger
      We have identified a novel PDE2 inhibitor series using fragment-based screening. Pyrazolopyrimidine fragment 1, while possessing weak potency (Ki = 22.4 μM), exhibited good binding efficiencies (LBE = 0.49, LLE = 4.48) to serve as a start for structure-based drug design. With the assistance of molecular modeling and X-ray crystallography, this fragment was developed into a series of potent PDE2 inhibitors with good physicochemical properties. Compound 16, a PDE2 selective inhibitor, was identified that exhibited favorable rat pharmacokinetic properties.
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      PubDate: 2017-11-16T13:44:04Z
       
  • Phenoxypropanolamine derivatives as selective inhibitors of the 20S
           proteasome β1 and β5 subunits
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Anna A. Hovhannisyan, The Hien Pham, Dominique Bouvier, Xiao Tan, SiAmmar Touhar, Gevorg G. Mkryan, Ashot M. Dallakyan, Chahrazade El Amri, Gagik S. Melikyan, Michèle Reboud-Ravaux, Michelle Bouvier-Durand
      New series of thiophene-containing phenoxypropanolamines were synthesized and evaluated for their potency to inhibit the three proteolytic activities of the mammalian 20S proteasome. Noticeable inhibition of both ChT-L and PA activities was obtained with three compounds: one with unsubstituted phenoxypropanolamine group (7) and the two others with a p-Cl-substituted group (4 and 9). For three other compounds (3, 8 and 10), ChT-L activity alone was significantly inhibited. In silico docking performed on the β5 and β1 subunits bearing the respective ChT-L and PA catalytic sites showed features common to poses associated with active compounds. These features may constitute a selectivity criterion for structure-guided inhibitor design.
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      PubDate: 2017-11-16T13:44:04Z
       
  • Challenges in the development of an M4 PAM preclinical candidate: The
           discovery, SAR, and biological characterization of a series of
           azetidine-derived tertiary amides
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): James C. Tarr, Michael R. Wood, Meredith J. Noetzel, Bruce J. Melancon, Atin Lamsal, Vincent B. Luscombe, Alice L. Rodriguez, Frank W. Byers, Sichen Chang, Hyekyung P. Cho, Darren W. Engers, Carrie K. Jones, Colleen M. Niswender, Michael W. Wood, Nicholas J. Brandon, Mark E. Duggan, P. Jeffrey Conn, Thomas M. Bridges, Craig W. Lindsley
      Herein we describe the continued optimization of M4 positive allosteric modulators (PAMs) within the 5-amino-thieno[2,3-c]pyridazine series of compounds. In this letter, we disclose our studies on tertiary amides derived from substituted azetidines. This series provided excellent CNS penetration, which had been challenging to consistently achieve in other amide series. Efforts to mitigate high clearance, aided by metabolic softspot analysis, were unsuccessful and precluded this series from further consideration as a preclinical candidate. In the course of this study, we found that potassium tetrafluoroborate salts could be engaged in a tosyl hydrazone reductive cross coupling reaction, a previously unreported transformation, which expands the synthetic utility of the methodology.
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      PubDate: 2017-11-16T13:44:04Z
       
  • Synthesis and biological evolution of hydrazones derived from
           4-(trifluoromethyl)benzohydrazide
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Martin Krátký, Szilvia Bősze, Zsuzsa Baranyai, Jiřina Stolaříková, Jarmila Vinšová
      Reflecting the known biological activity of isoniazid-based hydrazones, seventeen hydrazones of 4-(trifluoromethyl)benzohydrazide as their bioisosters were synthesized from various benzaldehydes and aliphatic ketones. The compounds were screened for their in vitro activity against Mycobacterium tuberculosis, nontuberculous mycobacteria (M. avium, M. kansasii), bacterial and fungal strains. The most antimicrobial potent derivatives were also investigated for their cytostatic and cytotoxic properties against three cell lines. Camphor-based molecule, 4-(trifluoromethyl)-N′-(1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)benzohydrazide, exhibited the highest and selective inhibition of M. tuberculosis with the minimum inhibitory concentration (MIC) of 4 µM, while N′-(4-chlorobenzylidene)-4-(trifluoromethyl)benzohydrazide was found to be superior against M. kansasii (MIC = 16 µM). N′-(5-Chloro-2-hydroxybenzylidene)-4-(trifluoromethyl)benzohydrazide showed the lowest MIC values for gram-positive bacteria including methicillin-resistant Staphylococcus aureus as well as against two fungal strains of Candida glabrata and Trichophyton mentagrophytes within the range of ≤0.49–3.9 µM. The convenient substitution of benzylidene moiety at the position 4 or the presence of 5-chloro-2-hydroxybenzylidene scaffold concomitantly with a sufficient lipophilicity are essential for the noticeable antimicrobial activity. This 5-chlorosalicylidene derivative avoided any cytotoxicity on two mammalian cell cultures (HepG2, BMMΦ) up to the concentration of 100 µM, but it affected the growth of MonoMac6 cells.
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      PubDate: 2017-11-16T13:44:04Z
       
  • Synthesis and evaluation of analogues of the tuberculosis drug bedaquiline
           containing heterocyclic B-ring units
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Peter J. Choi, Hamish S. Sutherland, Amy S.T. Tong, Adrian Blaser, Scott G. Franzblau, Christopher B. Cooper, Manisha U. Lotlikar, Anna M. Upton, Jerome Guillemont, Magali Motte, Laurence Queguiner, Koen Andries, Walter Van den Broeck, William A. Denny, Brian D. Palmer
      Analogues of bedaquiline where the phenyl B-unit was replaced with monocyclic heterocycles of widely differing lipophilicity (thiophenes, furans, pyridines) were synthesised and evaluated. While there was an expected broad positive correlation between lipophilicity and anti-TB activity, the 4-pyridyl derivatives appeared to have an additional contribution to antibacterial potency. The majority of the compounds were (desirably) more polar and had higher rates of clearance than bedaquiline, and showed acceptable oral bioavailability, but there was only limited (and unpredictable) improvement in their hERG liability.
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      PubDate: 2017-11-16T13:44:04Z
       
  • Proapoptotic modification of substituted isoindolinones as MDM2-p53
           inhibitors
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Tatyana A. Grigoreva, Daria S. Novikova, Alexey V. Petukhov, Maxim A. Gureev, Alexander V. Garabadzhiu, Gerry Melino, Nickolai A. Barlev, Vyacheslav G. Tribulovich
      A series of novel amino acid ester derivatives of 2,3-substituted isoindolinones was synthesized and evaluated for p53-mediated apoptotic activity. The rationale for augmentation of the target activity of 2,3-substituted isoindolinones was based on the introduction of new fragments in the structure of the inhibitor that would provide additional binding sites in the hydrophobic cavity of MDM2. To select for the anticipated modifications we employed molecular docking. Synthesized molecules were evaluated for their ability to induce apoptosis in two cancer cell lines and their derivatives with different status of p53 (colorectal HCT116 and osteosarcoma U2OS cells) by Annexin V staining. The target activity was estimated using high-content imaging system Operetta. Valine and phenylglycine ester derivatives were identified as potentially active MDM2-p53 inhibitors.
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      PubDate: 2017-11-16T13:44:04Z
       
  • Resveratrol analogues like piceatannol are potent antioxidants as
           quantitatively demonstrated through the high scavenging ability against
           reactive oxygen species and methyl radical
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Yoshimi Sueishi, Risako Nii, Naru Kakizaki
      Resveratrol (RSV) analogues have attracted much attention because of the expected health functions including antioxidant activities. We have carried out a quantitative determination of the scavenging abilities of six trans-RSV analogues against various reactive oxygen species and methyl radical (hydroxyl radical, superoxide, alkoxyl radical, peroxyl radical, methyl radical, and singlet oxygen). RSV analogues are in general more potent scavenger than the parent RSV. Furthermore, piceatannol (PIC) having two OH groups in the ortho position of resveratrol was found to show 11 times higher scavenging ability against peroxyl radical than parent resveratrol. With the aid of previous theoretical studies, the enhanced antioxidant ability was interpreted based on the effects of substituent that modifies the original resveratrol structure and function.
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      PubDate: 2017-11-16T13:44:04Z
       
  • Acacetin inhibits neuronal cell death induced by 6-hydroxydopamine in
           cellular Parkinson’s disease model
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Sang Min Kim, Yong Joo Park, Myoung-Sook Shin, Ha-Ryong Kim, Min Jae Kim, Sang Hun Lee, Seung Pil Yun, Seung-Hwan Kwon
      Acacetin (5,7-dihydroxy-4′-methoxyflavone), a flavonoid compound isolated from Flos Chrysanthemi Indici, chrysanthemum, safflower, and Calamintha and Linaria species has been shown to have anti-cancer activity, indicating its potential clinical value in cancer treatment. In this study, we sought to study the potentials of acacetin in preventing human dopaminergic neuronal death via inhibition of 6-hydroxydopamine (6-OHDA)-induced neuronal cell death in the SH-SY5Y cells. Our results suggest that acacetin was effective in preventing 6-OHDA-induced neuronal cell death through regulation of mitochondrial-mediated cascade apoptotic cell death. Pretreatment with acacetin significantly inhibited neurotoxicity and neuronal cell death through reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) dysfunction. Acacetin also markedly acted on key molecules in apoptotic cell death pathways and reduced phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinases (PI3K)/Akt, and glycogen synthase kinase-3beta (GSK-3β). These results suggested that acacetin could inhibit 6-OHDA-induced neuronal cell death originating from ROS-mediated cascade apoptosis pathway. Thus, the results of our study suggest that acacetin is a potent therapeutic agent for PD progression.
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      PubDate: 2017-11-16T13:44:04Z
       
  • Synthesis and biological evaluation of thiazole derivatives as GPR119
           agonists
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Hyojin Kim, Suk Joon Cho, Minjin Yoo, Seung Kyu Kang, Kwang Rok Kim, Hwan Hee Lee, Jin Sook Song, Sang Dal Rhee, Won Hoon Jung, Jin Hee Ahn, Jae-Kyung Jung, Kwan-Young Jung
      A series of 4-(phenoxymethyl)thiazole derivatives was synthesized and evaluated for their GPR119 agonistic effect. Several 4-(phenoxymethyl)thiazoles with pyrrolidine-2,5-dione moieties showed potent GPR119 agonistic activities. Among them, compound 27 and 32d showed good in vitro activity with an EC50 value of 49 nM and 18 nM, respectively with improved human and rat liver microsomal stability compare with MBX-2982. Compound 27 & 32d did not exhibit significant CYP inhibition, hERG binding, and cytotoxicity. Moreover, these compounds lowered the glucose excursion in mice in an oral glucose-tolerance test.
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      PubDate: 2017-11-16T13:44:04Z
       
  • Imidazo[1,2-a]pyridin-6-yl-benzamide analogs as potent RAF inhibitors
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Aaron Smith, Zhi-Jie Ni, Daniel Poon, Zilin Huang, Zheng Chen, Qiong Zhang, Laura Tandeske, Hanne Merritt, Kevin Shoemaker, John Chan, Susan Kaufman, Kay Huh, Jeremy Murray, Brent A. Appleton, Sandra W. Cowan-Jacob, Clemens Scheufler, Takanori Kanazawa, Johanna M. Jansen, Darrin Stuart, Cynthia M. Shafer
      A series of imidazo[1,2-a]pyridin-6-yl-benzamide analogs was designed as inhibitors of B-RAFV600E. Medicinal chemistry techniques were employed to explore the SAR for this series and improve selectivity versus P38 and VEGFR2.
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      PubDate: 2017-11-16T13:44:04Z
       
  • Azolylthioacetamides as a potent scaffold for the development of
           metallo-β-lactamase inhibitors
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Yang Xiang, Ya-Nan Chang, Ying Ge, Joon S. Kang, Yi-Lin Zhang, Xiao-Long Liu, Peter Oelschlaeger, Ke-Wu Yang
      In an effort to develop new inhibitors of metallo-β-lactamases (MβLs), twenty-eight azolylthioacetamides were synthesized and assayed against MβLs. The obtained benzimidazolyl and benzioxazolyl substituted 1–19 specifically inhibited the enzyme ImiS, and 10 was found to be the most potent inhibitor of ImiS with an IC50 value of 15 nM. The nitrobenzimidazolyl substituted 20–28 specifically inhibited NDM-1, with 27 being the most potent inhibitor with an IC50 value of 170 nM. Further studies with 10, 11, and 27 revealed a mixed inhibition mode with competitive and uncompetitive inhibition constants in a similar range as the IC50 values. These inhibitors resulted in a 2–4-fold decrease in imipenem MIC values using E. coli cells producing ImiS or NDM-1. While the source of uncompetitive (possibly allosteric) inhibition remains unclear, docking studies indicate that 10 and 11 may interact orthosterically with Zn2 in the active site of CphA, while 27 could bridge the two Zn(II) ions in the active site of NDM-1 via its nitro group.
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      PubDate: 2017-11-16T13:44:04Z
       
  • Novel highly selective peroxisome proliferator-activated receptor δ
           (PPARδ) modulators with pharmacokinetic properties suitable for
           once-daily oral dosing
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Bharat Lagu, Arthur F. Kluge, Ross A. Fredenburg, Effie Tozzo, Ramesh S. Senaiar, Mahaboobi Jaleel, Sunil K. Panigrahi, Nirbhay K. Tiwari, Narasimha R. Krishnamurthy, Taisuke Takahashi, Michael A. Patane
      Optimization of benzamide PPARδ modulator 1 led to (E)-6-(2-((4-(furan-2-yl)-N-methylbenzamido)methyl)phenoxy)-4-methylhex-4-enoic acid (18), a potent selective PPARδ modulator with significantly improved exposure in multiple species following oral administration.
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      PubDate: 2017-11-16T13:44:04Z
       
  • Repurposing Hsp90 inhibitors as antibiotics targeting histidine kinases
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Chau D. Vo, Hanna L. Shebert, Shannon Zikovich, Rebecca A. Dryer, Tony P. Huang, Lindsey J. Moran, Juno Cho, Douglas R. Wassarman, Bryn E. Falahee, Peter D. Young, Garrick H. Gu, James F. Heinl, John W. Hammond, Taylor N. Jackvony, Thomas E. Frederick, Jimmy A. Blair
      To address the growing need for new antimicrobial agents, we explored whether inhibition of bacterial signaling machinery could inhibit bacterial growth. Because bacteria rely on two-component signaling systems to respond to environmental changes, and because these systems are both highly conserved and mediated by histidine kinases, inhibiting histidine kinases may provide broad spectrum antimicrobial activity. The histidine kinase ATP binding domain is conserved with the ATPase domain of eukaryotic Hsp90 molecular chaperones. To find a chemical scaffold for compounds that target histidine kinases, we leveraged this conservation. We screened ATP competitive Hsp90 inhibitors against CckA, an essential histidine kinase in Caulobacter crescentus that controls cell growth, and showed that the diaryl pyrazole is a promising scaffold for histidine kinase inhibition. We synthesized a panel of derivatives and found that they inhibit the histidine kinases C. crescentus CckA and Salmonella PhoQ but not C. crescentus DivJ; and they inhibit bacterial growth in both Gram-negative and Gram-positive bacterial strains.
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      PubDate: 2017-11-16T13:44:04Z
       
  • Inhibitory effect of moschamine isolated from Carthamus tinctorius on
           LPS-induced inflammatory mediators via AP-1 and STAT1/3 inactivation in
           RAW 264.7 macrophages
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): A-ra Jo, Hee-soo Han, Seunghwan Seo, Ji-Sun Shin, Jae Yeol Lee, Hyoung Ja Kim, Kyung-Tae Lee
      Seeds of Carthamus tinctorius L. (Compositae) have been used in Korean traditional medicines for the treatment of cardiovascular and bone diseases. In this study, we investigated the anti-inflammatory effects of known serotonin derivatives (1–9) isolated from the ethyl acetate (EtOAc) soluble fraction from the seeds of C. tinctorius. Compound 2, identified as moschamine, most potently inhibited lipopolysaccharide (LPS)-induced production of prostaglandin E2 (PGE2) and nitric oxide (NO) in RAW 264.7 macrophages. Moschamine concentration-dependently inhibited LPS-induced PGE2 and NO production in RAW 264.7 macrophages. Consistent with these findings, moschamine suppressed the protein and mRNA levels of cyclooxygenase-2 (COX-2), microsomal prostaglandin E2 synthase (mPGES)-1, and inducible NO synthase (iNOS), interleukin (IL)-6, and IL-1β. In addition, pretreatment of moschamine significantly inhibited LPS-stimulated the transcriptional activity of activator protein-1 (AP-1) and the phosphorylation of signal transducer and activator of transcription (STAT)1/3 in RAW 264.7 macrophages. Moreover, moschamine inhibited LPS-induced the phosphorylation of p38 mitogen-activated protein kinase (p38) and extracellular signal-regulated kinase (ERK), but it had no effect on c-Jun N-terminal kinase (JNK). These results suggest that the mechanism of anti-inflammatory activity of moschamine is associated with the downregulation of COX-2, mPGES-1, iNOS, IL-6, and IL-1β expression through the suppression of AP-1 and STAT1/3 activation in LPS-induced RAW 264.7 macrophages.
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      PubDate: 2017-11-16T13:44:04Z
       
  • Discovery of DS28120313 as a potent orally active hepcidin production
           inhibitor: Design and optimization of novel 4,6-disubstituted indazole
           derivatives
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Takeshi Fukuda, Riki Goto, Toshihiro Kiho, Kenjiro Ueda, Sumie Muramatsu, Masami Hashimoto, Anri Aki, Kengo Watanabe, Naoki Tanaka
      Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis, and its inhibition could be a favorable strategy for treating anemia of chronic disease (ACD). Here, we report the design, synthesis and structure–activity relationships (SAR) of a series of 4,6-disubstituted indazole compounds as hepcidin production inhibitors. The optimization study of multi-kinase inhibitor 1 led to the design of a potent and bioavailable hepcidin production inhibitor, 32 (DS28120313), which showed serum hepcidin-lowering effects in an interleukin-6-induced acute inflammatory mouse model.
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      PubDate: 2017-11-16T13:44:04Z
       
  • Additive effect of heparin on the photoinactivation of Escherichia coli
           using tricationic P-porphyrins
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Jin Matsumoto, Kou Suzuki, Hidekazu Uezono, Kaho Watanabe, Masahide Yasuda
      Polycationic porphyrins have received substantial attention in developing singlet oxygen-sensitizers for biological use such as in the photoinactivation of bacteria and photodynamic therapy (PDT) of tumor cells because they have strong binding affinities for DNA and proteins. However, these strong cellular interactions can retard elimination of the drug after PDT. Therefore, the studies on the interactions of porphyrins with other molecules present much interest, in order to modulate the sensitizers’ activity or even remove them from the human body after PDT. Here, we studied the additive effect of heparin on the photoinactivation by polycationic porphyrins using Escherichia coli as a model cell. Tricationic P-porphyrin sensitizers substituted with an N-alkylpyridinium group (alkyl = pentyl (1a), hexyl (1b), and heptyl (1c)) or N-hexylammonium (1d) as the axial ligand were used. Additionally, dicationic Sb-porphyrin substituted with an N-hexylpyridinium group (1e) was prepared. We studied the additive effect of heparin on the photoinactivation of E. coli by 1a–1e. The bactericidal activities were evaluated using the half-life (T 1/2 in min) of E. coli and the minimum effective concentrations ([P]) of the porphyrin sensitizers. In the absence of heparin, the [P] values were determined to be 0.4–0.5 μM for 1a−1c and 2.0 μM for 1d−1e. The bactericidal activity of 1a−1c was completely retarded by the addition of heparin (1.0 μM). However, the addition of heparin (1.0 μM) could not completely retard the bactericidal activity of 1d−1e whose [P] values were relatively large. It is suggested that tricationic 1a−1c adsorbed onto the anionic heparin through electrostatic interactions. The adsorption of 1 on heparin disturbs the uptake of 1 into E. coli cells. Thus, the addition of heparin was found to be a useful method for retarding photoinactivation.
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      PubDate: 2017-11-16T13:44:04Z
       
  • Discovery and structure-activity-relationship study of novel
           conformationally restricted indane analogues for mutant isocitric
           dehydrogenase 1 (IDH1) inhibitors
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Qiangang Zheng, Shuai Tang, Xianlei Fu, Ziqi Chen, Yan Ye, Xiaojing Lan, Lei Jiang, Ying Huang, Jian Ding, Meiyu Geng, Min Huang, Huixin Wan
      The discovery and optimization of various of indane amides as mutant IDH1 inhibitors via structure-based rational design were reported. The optimal compounds demonstrated both potent inhibition in IDH1R132H enzymatic activity and 2HG production in IDH1 mutant HT1080 cell line, favorable PK properties and great selectivity against IDH1wt and IDH2R140Q.
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      PubDate: 2017-11-16T13:44:04Z
       
  • Macrocyclic pyrrolobenzodiazepine dimers as antibody-drug conjugate
           payloads
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Andrew F. Donnell, Yong Zhang, Erik M. Stang, Donna D. Wei, Andrew J. Tebben, Heidi L. Perez, Gretchen M. Schroeder, Chin Pan, Chetana Rao, Robert M. Borzilleri, Gregory D. Vite, Sanjeev Gangwar
      Macrocyclic pyrrolobenzodiazepine dimers were designed and evaluated for use as antibody-drug conjugate payloads. Initial structure–activity exploration established that macrocyclization could increase the potency of PBD dimers compared with non-macrocyclic analogs. Further optimization overcame activity-limiting solubility issues, leading to compounds with highly potent (picomolar) activity against several cancer cell lines. High levels of in vitro potency and specificity were demonstrated with an anti-mesothelin conjugate.
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      PubDate: 2017-11-16T13:44:04Z
       
  • Discovery and structure–activity relationship study of
           1,3,6-trisubstituted 1,4-diazepane-7-ones as novel human kallikrein 7
           inhibitors
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Hidenobu Murafuji, Hiroki Sakai, Megumi Goto, Seiichi Imajo, Hajime Sugawara, Tsuyoshi Muto
      Compound 1, composed of a 1,3,6-trisubstituted 1,4-diazepane-7-one, was discovered as a novel human kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme, SCCE) inhibitor, and its derivatives were synthesized and evaluated. Structure–activity relationship studies of the amidoxime unit and benzoic acid part of this new scaffold led to the identification of 25 and 34, which were more potent than the hit compound, 1. The X-ray co-crystal structure of compound 25 and human KLK7 revealed the characteristic interactions and enabled explanations of the structure–activity relationship.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • 6-Substituted quinolines as RORγt inverse agonists
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): J. Kent Barbay, Maxwell D. Cummings, Marta Abad, Glenda Castro, Kevin D. Kreutter, David A. Kummer, Umar Maharoof, Cynthia Milligan, Rachel Nishimura, Joan Pierce, Celine Schalk-Hihi, John Spurlino, Virginia M. Tanis, Maud Urbanski, Hariharan Venkatesan, Aihua Wang, Craig Woods, Ronald Wolin, Xiaohua Xue, James P. Edwards, Anne M. Fourie, Kristi Leonard
      We identified 6-substituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). The synthesis of this class of RORγt modulators is reported, and optimization of the substituents at the quinoline 6-position that produced compounds with high affinity for the receptor is detailed. This effort identified molecules that act as potent, full inverse agonists in a RORγt-driven cell-based reporter assay. The X-ray crystal structures of two full inverse agonists from this chemical series bound to the RORγt ligand binding domain are disclosed, and we highlight the interaction of a hydrogen-bond acceptor on the 6-position substituent of the inverse agonist with Glu379:NH as a conserved binding contact.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Synthesis, anticancer, structural, and computational docking studies of
           3-benzylchroman-4-one derivatives
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Lalitha Simon, Abdul Ajees Abdul Salam, S. Madan Kumar, T. Shilpa, K.K. Srinivasan, K. Byrappa
      A series of 3-Benzylchroman-4-ones were synthesized and screened for anticancer activity by MTT assay. The compounds were evaluated against two cancerous cell lines BT549 (human breast carcinoma), HeLa (human cervical carcinoma), and one noncancerous cell line vero (normal kidney epithelial cells). 3b was found to be the most active molecule against BT549 cells (IC50 = 20.1 µM) and 3h against HeLa cells (IC50 = 20.45 µM). 3b also exhibited moderate activity against HeLa cells (IC50 = 42.8 µM). The molecular structures of 3h and 3i were solved by single crystal X-ray crystallographic technique. Additionally, the molecular docking studies between the tumour suppressor protein p53 with the lead compound 3h, which exhibited better anticancer activity against HeLa cells was examined.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Polyhydroxylated azetidine iminosugars: Synthesis, glycosidase inhibitory
           activity and molecular docking studies
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Pravin P. Lawande, Vyankat A. Sontakke, Navanath M. Kumbhar, Tanay R. Bhagwat, Sougata Ghosh, Vaishali S. Shinde
      An efficient and practical strategy for the synthesis of unknown azetidine iminosugars (2S,3R,4S)-2-((R)-1,2-dihydroxyethyl)-3-hydroxy-4-(hydroxymethyl)azetidine 2, (2S,3r,4R)-3-hydroxy-2,4-bis(hydroxymethyl)azetidine 3 and (2S,3R,4S)-3-hydroxy-4-(hydroxymethyl)-N-methylazetidine-2-carboxylic acid 4, starting from the d-glucose has been reported. The methodology involves preparation of the 3-amino-N-benzyloxycarbonyl-3-deoxy-6-O-tert-butyldimethylsillyl-1,2-O-isopropylidene-α-d-glucofuranose 9, which was converted to the C-5-OMs derivative 11. Intramolecular nucleophilic displacement of the C-5-OMs group with in situ generated 3-amino functionality provided the required key azetidine ring skeletons 10 with additional hydroxymethyl group. Removal of 1,2-acetonide protection, followed by reduction and hydrogenolysis afforded azetidine iminosugar 2. Alternatively, removal of 1,2-acetonide group and chopping of C1-anomeric carbon gave C2-aldehyde that on reduction or oxidation followed by hydrogenolysis gave 2,4-bis(hydroxymethyl) azetidine iminosugars 3 and N-methylazetidine-2-carboxylic acid 4 respectively. The glycosidase inhibitory activity of 2–4 iminosugars was screened against various glycosidase enzymes and compared with a standard miglitol. Amongst synthesized targets, the compound 2 was found to be more potent amyloglucosidase inhibitor than miglitol. These results were supported by molecular docking studies.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Synthesis and anti-HCV activity of a series of
           β-d-2′-deoxy-2′-dibromo nucleosides and their corresponding
           phosphoramidate prodrugs
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Zhe Chen, Bryan D. Cox, Ethel C. Garnier-Amblard, Tamara R. McBrayer, Steven J. Coats, Raymond F. Schinazi, Franck Amblard
      Several β-d-2′-deoxy-2′-substituted nucleoside analogs have displayed potent and selective anti-HCV activities and some of them have reached human clinical trials. In that regard, we report herein the synthesis of a series of 2′-deoxy,2′-dibromo substituted U, C, G and A nucleosides 10a–d and their corresponding phosphoramidate prodrugs 13a–d. The synthesized nucleosides 10a–d and prodrugs 13a–d were evaluated for their inhibitory activity against HCV as well as cellular toxicity. The results showed that the most potent compound was prodrug 13a, which exhibited micromolar inhibitory activity (EC50 = 1.5 ± 0.8 µM) with no observed toxicity. In addition, molecular modeling and free energy perturbation calculations for the 5′-triphosphate formed from 13a and related 2′-modified nucleotides are discussed.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Design, synthesis, and biological evaluation of
           pyrrolobenzodiazepine-containing hypoxia-activated prodrugs
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Peter S. Dragovich, Fabio Broccatelli, Jinhua Chen, Peter Fan, Hoa Le, Weiguang Mao, Thomas H. Pillow, Andrew G. Polson, John Wai, Zijin Xu, Hui Yao, Donglu Zhang
      The ability of various pyrrolobenzodiazepine(PBD)-containing cytotoxic compounds to function as hypoxia-activated prodrugs was assessed. These molecules incorporated a 1-methyl-2-nitro-1H-imidazole hypoxia-activated trigger (present in the clinically evaluated compound TH-302) in a manner that masked a reactive imine moiety required for cytotoxic activity. Incubation of the prodrugs with cytochrome P450-reductase under normoxic and hypoxic conditions revealed that some, but not all, were efficient substrates for the enzyme. In these experiments, prodrugs derived from PBD-monomers underwent rapid conversion to the parent cytotoxic compounds under low-oxygen conditions while related PBD-dimers did not. The ability of a given prodrug to function as an efficient cytochrome P450-reductase substrate correlated with the ratio of cytotoxic potencies measured for the compound against NCI460 cells under normoxic and hypoxic conditions.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Compound design guidelines for evading the efflux and permeation barriers
           of Escherichia coli with the oxazolidinone class of antibacterials: Test
           case for a general approach to improving whole cell Gram-negative activity
           
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Andrew Spaulding, Khuloud Takrouri, Pornachandran Mahalingam, Dillon C. Cleary, Harold D. Cooper, Paola Zucchi, Westley Tear, Bilyana Koleva, Penny J. Beuning, Elizabeth B. Hirsch, James B. Aggen
      Previously we reported the results from an effort to improve Gram-negative antibacterial activity in the oxazolidinone class of antibiotics via a systematic medicinal chemistry campaign focused entirely on C-ring modifications. In that series we set about testing if the efflux and permeation barriers intrinsic to the outer membrane of Escherichia coli could be rationally overcome by designing analogs to reside in specific property limits associated with Gram-negative activity: i) low MW (<400), ii) high polarity (clogD7.4 <1), and iii) zwitterionic character at pH 7.4. Indeed, we observed that only analogs residing within these limits were able to overcome these barriers. Herein we report the results from a parallel effort where we explored structural changes throughout all three rings in the scaffold for the same purpose. Compounds were tested against a diagnostic MIC panel of Escherichia coli and Staphylococcus aureus strains to determine the impact of combining structural modifications in overcoming the OM barriers and in bridging the potency gap between the species. The results demonstrated that distributing the charge-carrying moieties across two rings was also beneficial for avoidance of the outer membrane barriers. Importantly, analysis of the structure-permeation relationship (SPR) obtained from this and the prior study indicated that in addition to MW, polarity, and zwitterionic character, having ≤4 rotatable bonds is also associated with evasion of the OM barriers. These combined results provide the medicinal chemist with a framework and strategy for overcoming the OM barriers in GNB in antibacterial drug discovery efforts.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Discovery and evaluation of Cav3.1-selective T-type calcium channel
           blockers
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Olivier Bezençon, Luboš Remeň, Sylvia Richard, Catherine Roch, Melanie Kessler, Richard Moon, Jacques Mawet, Eric A. Ertel, Thomas Pfeifer, Bruno Capeleto
      We identified and characterized a series of pyrazole amides as potent, selective Cav3.1-blockers. This series culminated with the identification of pyrazole amides 5a and 12d, with excellent potencies and/or selectivities toward the Cav3.2- and Cav3.3-channels. This compound displays poor DMPK properties, making its use difficult for in vivo applications. Nevertheless, this compound as well as analogous ones are well-suited for in vitro studies.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Discovery and evaluation of Cav3.2-selective T-type calcium channel
           blockers
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Olivier Bezençon, Luboš Remeň, Sylvia Richard, Catherine Roch, Melanie Kessler, Eric A. Ertel, Richard Moon, Jacques Mawet, Thomas Pfeifer, Bruno Capeleto
      We identified and characterized a series of pyrrole amides as potent, selective Cav3.2-blockers. This series culminated with the identification of pyrrole amides 13b and 26d, with excellent potencies and/or selectivities toward the Cav3.1- and Cav3.3-channels. These compounds display poor physicochemical and DMPK properties, making their use difficult for in vivo applications. Nevertheless, they are well-suited for in vitro studies.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Discovery of a class of diheteroaromatic amines as orally bioavailable
           CDK1/4/6 inhibitors
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Yan Fu, Shuai Tang, Yi Su, Xiaojing Lan, Yan Ye, Chuantao Zha, Lei Li, Jianhua Cao, Yi Chen, Lei Jiang, Ying Huang, Jian Ding, Meiyu Geng, Min Huang, Huixin Wan
      The discovery of a class of diheteroaromatic amines based on LY2835219 as cyclin-dependent kinase (CDK1/4/6) inhibitors was described. The series was found to have much more improved CDK1 inhibition and potent in vitro anti-proliferative effects against cancer cell lines. The synthesis and structure–activity relationship studies of these compounds were reported. One promising compound was selected to evaluate as a novel lead compound after in vitro and in vivo profiling.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Delphinidin inhibits BDNF-induced migration and invasion in SKOV3 ovarian
           cancer cells
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Won-Chul Lim, Hyunhee Kim, Young-Joo Kim, Seung-Ho Park, Ji-Hye Song, Ki Heon Lee, In Ho Lee, Yoo-Kyung Lee, Kyeong A. So, Kyung-Chul Choi, Hyeonseok Ko
      Brain-derived neurotrophic factor (BDNF), the TrkB ligand, is associated with aggressive malignant behavior, including migration and invasion, in tumor cells and a poor prognosis in patients with various types of cancer. Delphinidin is a diphenylpropane-based polyphenolic ring structure-harboring compound, which exhibits a wide range of pharmacological activities, anti-tumor, anti-oxidant, anti-inflammatory, anti-angiogenic and anti-mutagenic activity. However, the possible role of delphinidin in the cancer migration and invasion is unclear. We investigated the suppressive effect of delphinidin on the cancer migration and invasion. Thus, we found that BDNF enhanced cancer migration and invasion in SKOV3 ovarian cancer cell. To exam the inhibitory role of delphinidin in SKOV3 ovarian cancer migration and invasion, we investigated the use of delphinidin as inhibitors of BDNF-induced motility and invasiveness in SKOV3 ovarian cancer cells in vitro. Here, we found that delphinidin prominently inhibited the BDNF-induced increase in cell migration and invasion of SKOV3 ovarian cancer cells. Furthermore, delphinidin remarkably inhibited BDNF-stimulated expression of MMP-2 and MMP-9. Also, delphinidin antagonized the phosphorylation of Akt and nuclear translocation of NF-κB permitted by the BDNF in SKOV3 ovarian cancer cells. Taken together, our findings provide new evidence that delphinidin suppressed the BDNF-induced ovarian cancer migration and invasion through decreasing of Akt activation.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • The synthesis of 2,3,6-trisubstituted 1-oxo-1,2-dihydroisoquinolines as
           potent CRTh2 antagonists
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Xianhai Huang, Ashwin Rao, Wei Zhou, Robert Aslanian, Ravi Nargund, Alexei Buevich, Li-Kang Zhang, Hongchen Qiu, Xiaoxin Yang, Charles G. Garlisi, Craig Correll, Anandan Palani
      New synthetic methods were developed for the preparation of 2,3,6-trisubstituted 1-oxo-1,2-dihydroisoquinolines as CRTh2 antagonists. The isoquinolinone core could be constructed before the introduction of substitution groups or synthesized through a catalytic intramolecular cyclization reaction with desired substitution groups properly installed. These synthetic strategies have helped to accelerate the SAR development of this series, and potent lead compounds were identified in both the CRTh2 receptor binding assay and the CD11b biomarker assay.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Concise syntheses and HCV NS5B polymerase inhibition of (2′R)-3 and
           (2′S)-2′-ethynyluridine-10 and related nucleosides
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Frank Bennett, Alexei V. Buevich, Hsueh-Cheng Huang, Vinay Girijavallabhan, Angela D. Kerekes, Yuhua Huang, Asra Malikzay, Elizabeth Smith, Eric Ferrari, Mary Senior, Rebecca Osterman, Lingyan Wang, Jun Wang, Haiyan Pu, Quang T. Truong, Paul Tawa, Stephane L. Bogen, Ian W. Davies, Ann E. Weber
      (2′R)-Ethynyl uridine 3, and its (2′S)-diastereomer 10, are synthesised in a divergent fashion from the inexpensive parent nucleoside. Both nucleoside analogues are obtained from a total of 5 simple synthetic steps and 3 trivial column chromatography purifications. To evaluate their effectiveness against HCV NS5B polymerase, the nucleosides were converted to their respective 5′-O-triphosphates. Subsequently, this lead to the discovery of the 2′-β-ethynyl 18 and -propynyl 20 nucleotides having significantly improved potency over Sofosbuvir triphosphate 24.
      Graphical abstract image

      PubDate: 2017-11-16T13:44:04Z
       
  • Corrigendum to “A novel intestinal-restricted FXR agonist” [Bioorg Med
           Chem Lett 27 (2017) 3386–3390]
    • Abstract: Publication date: 1 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 23
      Author(s): Hong Wang, Zhou Zhao, Jiyu Zhou, Yitong Guo, Guangji Wang, Haiping Hao, Xiaowei Xu


      PubDate: 2017-11-16T13:44:04Z
       
 
 
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