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  Subjects -> CHEMISTRY (Total: 849 journals)
    - ANALYTICAL CHEMISTRY (50 journals)
    - CHEMISTRY (598 journals)
    - CRYSTALLOGRAPHY (22 journals)
    - ELECTROCHEMISTRY (25 journals)
    - INORGANIC CHEMISTRY (42 journals)
    - ORGANIC CHEMISTRY (45 journals)
    - PHYSICAL CHEMISTRY (67 journals)

CHEMISTRY (598 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: 32)
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: 23)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 39)
ACS Nano     Full-text available via subscription   (Followers: 227)
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: 7)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 5)
Advanced Functional Materials     Hybrid Journal   (Followers: 50)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 53)
Advances in Chemical Science     Open Access   (Followers: 13)
Advances in Chemistry     Open Access   (Followers: 14)
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: 15)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 19)
Advances in Nanoparticles     Open Access   (Followers: 14)
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: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 19)
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: 26)
American Journal of Plant Physiology     Open Access   (Followers: 13)
American Mineralogist     Hybrid Journal   (Followers: 13)
Analyst     Full-text available via subscription   (Followers: 38)
Angewandte Chemie     Hybrid Journal   (Followers: 159)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 210)
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: 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: 14)
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: 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: 10)
Biochemistry     Full-text available via subscription   (Followers: 282)
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: 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: 4)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 108)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 93)
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: 2)
Canadian Journal of Chemistry     Hybrid Journal   (Followers: 10)
Canadian Mineralogist     Full-text available via subscription   (Followers: 3)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 67)
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: 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: 12)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 70)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 23)
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: 172)
Chemical Science     Open Access   (Followers: 21)
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: 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: 147)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 15)
Chemistry and Materials Research     Open Access   (Followers: 18)
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: 45)
Chemistry of Materials     Full-text available via subscription   (Followers: 247)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 22)
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: 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)
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: 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: 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: 11)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Metabolomics     Hybrid Journal   (Followers: 5)
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 56)
Dalton Transactions     Full-text available via subscription   (Followers: 19)
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: 4)
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: 2)
Environmental Chemistry     Hybrid Journal   (Followers: 9)
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]   [93 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0960-894X
   Published by Elsevier Homepage  [3042 journals]
  • Progress in the discovery of small molecule modulators of the Cys-loop
           superfamily receptors
    • Authors: Brian A. Sparling; Erin F. DiMauro
      Pages: 3207 - 3218
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Brian A. Sparling, Erin F. DiMauro
      The vertebrate Cys-loop family of ligand-gated ion channels (LGICs) are comprised of nicotinic acetylcholine (nAChR), serotonin type 3 (5-HT3R), γ-aminobutyric acid (GABAAR), and glycine (GlyR) receptors. Here, we review efforts to discover selective small molecules targeting one or more Cys-loop receptors, with a focus on state-of-the-art modulators that have been reported over the past five years. Several highlighted compounds offer robust oral bioavailability and central exposure and have thus been useful in delineating pharmacokinetic/pharmacodynamic relationships in pre-clinical disease models. Others offer high levels of subtype and/or inter-superfamily selectivity and have facilitated understanding of complex SAR and pharmacodynamics.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.04.073
       
  • Diverse heterocyclic scaffolds as dCTP pyrophosphatase 1 inhibitors. Part
           2: Pyridone- and pyrimidinone-derived systems
    • Authors: Sabin Llona-Minguez; Maria Häggblad; Ulf Martens; Lars Johansson; Kristmundur Sigmundsson; Thomas Lundbäck; Olga Loseva; Ann-Sofie Jemth; Bo Lundgren; Annika Jenmalm Jensen; Martin Scobie; Thomas Helleday
      Pages: 3219 - 3225
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Sabin Llona-Minguez, Maria Häggblad, Ulf Martens, Lars Johansson, Kristmundur Sigmundsson, Thomas Lundbäck, Olga Loseva, Ann-Sofie Jemth, Bo Lundgren, Annika Jenmalm Jensen, Martin Scobie, Thomas Helleday
      Two screening campaigns using commercial (Chembridge DiverSET) and proprietary (Chemical Biology Consortium Sweden, CBCS) compound libraries, revealed a number of pyridone- and pyrimidinone-derived systems as inhibitors of the human dCTP pyrophosphatase 1 (dCTPase). In this letter, we present their preliminary structure-activity-relationships (SAR) and ligand efficiency scores (LE and LLE).
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.039
       
  • Synthesis of 6-hydroxyaurone analogues and evaluation of their
           α-glucosidase inhibitory and glucose consumption-promoting activity:
           Development of highly active 5,6-disubstituted derivatives
    • Authors: Hua Sun; Weina Ding; Xiaotong Song; Dong Wang; Mingzhu Chen; Kaili Wang; Yazhou Zhang; Peng Yuan; Ying Ma; Runling Wang; Robert H. Dodd; Yongmin Zhang; Kui Lu; Peng Yu
      Pages: 3226 - 3230
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Hua Sun, Weina Ding, Xiaotong Song, Dong Wang, Mingzhu Chen, Kaili Wang, Yazhou Zhang, Peng Yuan, Ying Ma, Runling Wang, Robert H. Dodd, Yongmin Zhang, Kui Lu, Peng Yu
      A series of 6-hydroxyaurones and their analogues have been synthesized and evaluated for their in vitro α-glucosidase inhibitory and glucose consumption-promoting activity. These compounds exhibited varying degrees of α-glucosidase inhibitory activity, 11 of them showing higher potency than that of the control standard acarbose (IC50 =50.30μM). Surprisingly, analogues devoid of a substituent at C-2 but having an aryl group at C-5 were found to be highly active (e.g., 7f, IC50 =9.88μM). Docking analysis substantiated these findings. The kinetic analysis of compound 7f, the most potent α-glucosidase inhibitor of this study, revealed that it inhibited α-glucosidase in an irreversible and mixed competitive mode. In addition, compounds 7f and 10c exhibited significant glucose consumption promoting activity at 1μM.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.040
       
  • Discovery of a highly potent, selective and novel CDK9 inhibitor as an
           anticancer drug candidate
    • Authors: Yongtao Li; Qingxiang Guo; Chao Zhang; Zhi Huang; Tianqi Wang; Xin Wang; Xiang Wang; Guangwei Xu; Yanhua Liu; Shengyong Yang; Yan Fan; Rong Xiang
      Pages: 3231 - 3237
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Yongtao Li, Qingxiang Guo, Chao Zhang, Zhi Huang, Tianqi Wang, Xin Wang, Xiang Wang, Guangwei Xu, Yanhua Liu, Shengyong Yang, Yan Fan, Rong Xiang
      A series of novel hybrid structure derivatives, containing both LEE011 and Cabozantinib pharmacophore, were designed, synthesized and evaluated. Surprisingly, a compound 4d was discovered that highly exhibited effective and selective activity of CDK9 inhibition with IC50 =12nM. It effectively induced apoptosis in breast and lung cancer cell lines at nanomolar level. Molecular docking of 4d to ATP binding site of CDK9 kinase demonstrated a new hydrogen bonding between F atom of 4-(3-fluorobenzyloxy) group and ASN116 residue, compared with the positive control, LEE011. The compound 4d could block the cell cycle both in G0/G1 and G2/M phase to prevent the proliferation and differentiation of cancer cells. Mice bared-breast cancer treated with compound 4d showed significant suppression of cancer with low toxicity. Taken together, this novel compound 4d could be a promising drug candidate for clinical application.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.041
       
  • Antitumor activity of resveratrol is independent of Cu(II) complex
           formation in MCF-7 cell line
    • Authors: Priscylla Andrade Volkart; Rodrigo Benedetti Gassen; Bettina Mühlen Nogueira; Bárbara Nery Porto; José Eduardo Vargas; André Arigony Souto
      Pages: 3238 - 3242
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Priscylla Andrade Volkart, Rodrigo Benedetti Gassen, Bettina Mühlen Nogueira, Bárbara Nery Porto, José Eduardo Vargas, André Arigony Souto
      Resveratrol (Rsv) is widely reported to possess anticarcinogenic properties in a plethora of cellular and animal models having limited toxicity toward normal cells. In the molecular level, Rsv can act as a suppressive agent for several impaired signaling pathways on cancer cells. However, Fukuhara and Miyata have shown a non-proteic reaction of Rsv, which can act as a prooxidant agent in the presence of copper (Cu), causing cellular oxidative stress accompanied of DNA damage. After this discovery, the complex Rsv-Cu was broadly explored as an antitumor mechanism in multiples tumor cell lines. The aim of the study is to explore the anticarcinogenic behavior of resveratrol–Cu(II) complex in MCF-7 cell line. Selectivity of Rsv binding to Cu ions was analyzed by HPLC and UV–VIS. The cells were enriched with concentrations of 10 and 50µM CuSO4 solution and treated with 25µM of Rsv. Copper uptake after enrichment of cells, as its intracellular distribution in MCF-7 line, was scanned by ICP-MS and TEM-EDS. Cell death and intracellular ROS production were determined by flow cytometry. Different from the extracellular model, no relationship of synergy between Rsv–Cu(II) and reactive oxidative species (ROS) production was detected in vitro. ICP-MS revealed intracellular copper accumulation to both chosen concentrations (0.33±0.09 and 1.18±0.13ppb) but there is no promotion of cell death by Rsv–Cu(II) complex. In addition, significant attenuation of ROS production was detected when cells were exposed to CuSO4 after Rsv treatment, falling from 7.54% of ROS production when treated only with Rsv to 3.07 and 2.72% with CuSO4. Based on these findings antitumor activity of resveratrol when in copper ions presence, is not mediated by Rsv-Cu complex formation in MCF-7 human cell line, suggesting that the antitumoral reaction is dependent of a cancer cellular model.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.036
       
  • Design and optimization of highly-selective, broad spectrum fungal CYP51
           inhibitors
    • Authors: Christopher M. Yates; Edward P. Garvey; Sammy R. Shaver; Robert J. Schotzinger; William J. Hoekstra
      Pages: 3243 - 3248
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Christopher M. Yates, Edward P. Garvey, Sammy R. Shaver, Robert J. Schotzinger, William J. Hoekstra
      While the orally-active azoles such as fluconazole and posaconazole are effective antifungal agents, they potently inhibit a broad range of off-target human cytochrome P450 enzymes (CYPs) leading to various safety issues (e.g., drug-drug interactions, liver, and reproductive toxicities). Recently we described the rationally-designed, antifungal agent VT-1161 that is more selective for fungal CYP51 than related human CYP enzymes such as CYP3A4. Herein, we describe the use of a homology model of Aspergillus fumigatus to design and optimize a novel series of highly selective, broad spectrum fungal CYP51 inhibitors. This series includes the oral antifungal VT-1598 that exhibits excellent potency against yeast, dermatophyte, and mold fungal pathogens.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.037
       
  • Optimization of a novel series of potent and orally bioavailable GPR119
           agonists
    • Authors: Tomoaki Koshizawa; Toshiharu Morimoto; Gen Watanabe; Toshiaki Watanabe; Nao Yamasaki; Yoshikazu Sawada; Tomoaki Fukuda; Ayumu Okuda; Kimiyuki Shibuya; Tadaaki Ohgiya
      Pages: 3249 - 3253
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Tomoaki Koshizawa, Toshiharu Morimoto, Gen Watanabe, Toshiaki Watanabe, Nao Yamasaki, Yoshikazu Sawada, Tomoaki Fukuda, Ayumu Okuda, Kimiyuki Shibuya, Tadaaki Ohgiya
      We describe the discovery and optimization of a novel series of furo[3,2-d]pyrimidines as G protein-coupled receptor 119 agonists. Agonistic activity of 4 (EC50 =129nM) was improved by replacing the intramolecular hydrogen bond between the fluorine atom and the aniline hydrogen in the head moiety with a covalent C-C bond to enhance conformational restriction, which consequently gave a lead compound 12 (EC50 =53nM). Optimized compound 26, which was identified by the further optimization of 12, exhibited potent activity (EC50 =42nM) with improved clearance in liver microsomes and induced a 33% reduction in blood glucose area under the curve at a dose of 10mg/kg in an oral glucose tolerance test in C57BL/6N mice.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.034
       
  • The structural requirements of histone deacetylase inhibitors: SAHA
           analogs modified at the C5 position display dual HDAC6/8 selectivity
    • Authors: Ahmed T. Negmeldin; Mary Kay H. Pflum
      Pages: 3254 - 3258
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Ahmed T. Negmeldin, Mary Kay H. Pflum
      Histone deacetylase (HDAC) proteins have emerged as important targets for anti-cancer drugs, with four small molecules approved for use in the clinic. Suberoylanilide hydroxamic acid (Vorinostat, SAHA) was the first FDA-approved HDAC inhibitor for cancer treatment. However, SAHA inhibits most of the eleven HDAC isoforms. To understand the structural requirements of HDAC inhibitor selectivity and develop isoform selective HDAC inhibitors, SAHA analogs modified in the linker at the C5 position were synthesized and tested for potency and selectivity. C5-modified SAHA analogs displayed dual selectivity to HDAC6 and HDAC8 over HDAC 1, 2, and 3, with only a modest reduction in potency. These findings are consistent with prior work showing that modification of the linker region of SAHA can alter isoform selectivity. The observed HDAC6/8 selectivity of C5-modified SAHA analogs provide guidance toward development of isoform selective HDAC inhibitors and more effective anti-cancer drugs.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.033
       
  • Introduction of fluorine to phenyl group of
           4-(2-pyrimidinylamino)benzamides leading to a series of potent hedgehog
           signaling pathway inhibitors
    • Authors: Minhang Xin; Liandi Zhang; Jun Wen; Han Shen; Xinge Zhao; Qiu Jin; Feng Tang
      Pages: 3259 - 3263
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Minhang Xin, Liandi Zhang, Jun Wen, Han Shen, Xinge Zhao, Qiu Jin, Feng Tang
      In present study, a novel series of fluorine containing 4-(2-pyrimidinylamino)benzamide analogues were designed and synthesized. The hedgehog (Hh) signaling inhibitory activities for these compounds were evaluated by a luciferase reporter method. The preliminary SAR was discussed and many compounds showed potent Hh signaling inhibitory activities. Compound 15h displayed the most potent inhibitory activity, with an IC50 of 0.050nM. This paper finds the introduction of fluorine to the 4-(2-pyrimidinylamino)benzamide scaffold can lead to a novel series of potent Hh signaling pathway inhibitors.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.030
       
  • Chimeric analogs of human β-defensin 1 and θ-defensin disrupt
           pre-established bacterial biofilms
    • Authors: Basil Mathew; Sudar Olli; Ankeeta Guru; Ramakrishanan Nagaraj
      Pages: 3264 - 3266
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Basil Mathew, Sudar Olli, Ankeeta Guru, Ramakrishanan Nagaraj
      Antibiofilm activity of several human defensin analogs that have the ability to kill planktonic bacteria, against pre-established biofilms of Escherichia coli MG1655 and Staphylococcus aureus NCTC 8530 were examined. Linear and linear fatty acylated analogs did not show any activity while disulfide constrained analogs disrupted pre-established S. aureus biofilms. Chimeric analogs of human β-defensin 1 and θ-defensin, hBTD-1 and [d]hBTD-1 were highly active against S. aureus biofilms. Among the analogs tested, only the d-enantiomer [d]hBTD-1 showed activity against E. coli biofilm. Our study provides insights into the structural requirements for the eradication of pre-established biofilms in defensin analogs.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.031
       
  • Bioactive new withanolides from the cultured soft coral Sinularia brassica
    • Authors: Chiung-Yao Huang; Atallah F. Ahmed; Jui-Hsin Su; Ping-Jyun Sung; Tsong-Long Hwang; Pei-Lun Chiang; Chang-Feng Dai; Chih-Chuang Liaw; Jyh-Horng Sheu
      Pages: 3267 - 3271
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Chiung-Yao Huang, Atallah F. Ahmed, Jui-Hsin Su, Ping-Jyun Sung, Tsong-Long Hwang, Pei-Lun Chiang, Chang-Feng Dai, Chih-Chuang Liaw, Jyh-Horng Sheu
      Continuing study of the ethyl acetate (EtOAc) extract of the cultured soft coral Sinularia brassica afforded five new withanolides, sinubrasolides H–L (1–5). The structures of the new compounds were elucidated on the basis of spectroscopic analysis. The cytotoxicities of new compounds 1–5 and a known compound sinubrasolide A (6) against the proliferation of a limited panel of cancer cell lines were assayed. The anti-inflammatory activities of compounds 1–6 were evaluated by measuring their ability to suppress N-formyl-methionyl-leucyl-phenyl-alanine/cytochalasin B (fMLP/CB)-induced superoxide anion generation and elastase release in human neutrophils.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.029
       
  • Design, synthesis and SAR of a novel series of heterocyclic
           phenylpropanoic acids as GPR120 agonists
    • Authors: Xuqing Zhang; Chaozhong Cai; Michael Winters; Michele Wells; Mark Wall; James Lanter; Zhihua Sui; Jingyuan Ma; Aaron Novack; Imad Nashashibi; Yuanping Wang; Wen Yan; Arthur Suckow; Hong Hua; Austin Bell; Peter Haug; Wilma Clapper; Celia Jenkinson; Joseph Gunnet; James Leonard; William V. Murray
      Pages: 3272 - 3278
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Xuqing Zhang, Chaozhong Cai, Michael Winters, Michele Wells, Mark Wall, James Lanter, Zhihua Sui, Jingyuan Ma, Aaron Novack, Imad Nashashibi, Yuanping Wang, Wen Yan, Arthur Suckow, Hong Hua, Austin Bell, Peter Haug, Wilma Clapper, Celia Jenkinson, Joseph Gunnet, James Leonard, William V. Murray
      A novel series of 5-membered heterocycle-containing phenylpropanoic acid derivatives was discovered as potent GPR120 agonists with low clearance, high oral bioavailability and in vivo antidiabetic activity in rodents.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.028
       
  • 2-Chlorophenyl-substituted benzofuro[3,2-b]pyridines with enhanced
           topoisomerase inhibitory activity: The role of the chlorine substituent
    • Authors: Til Bahadur Thapa Magar; Tara Man Kadayat; Hwa-Jong Lee; Seojeong Park; Ganesh Bist; Aarajana Shrestha; Youngjoo Kwon; Eung-Seok Lee
      Pages: 3279 - 3283
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Til Bahadur Thapa Magar, Tara Man Kadayat, Hwa-Jong Lee, Seojeong Park, Ganesh Bist, Aarajana Shrestha, Youngjoo Kwon, Eung-Seok Lee
      A new series of 2-chloropheny-substituted benzofuro[3,2-b]pyridines were designed, synthesized, and evaluated for topoisomerase I and II inhibition and antiproliferative activity. Compounds 17–19, 23, 24, 26, and 27 exhibited excellent topo II inhibitory activity. A systematic structure-activity relationship study revealed the important role of chlorine substitution in the strong topoisomerase inhibitory activity.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.025
       
  • Spacer structure and hydrophobicity influences transfection activity of
           novel polycationic gemini amphiphiles
    • Authors: Pavel A. Puchkov; Irina A. Kartashova; Elena V. Shmendel; Anastasya S. Luneva; Nina G. Morozova; Marina A. Zenkova; Mikhail A. Maslov
      Pages: 3284 - 3288
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Pavel A. Puchkov, Irina A. Kartashova, Elena V. Shmendel, Anastasya S. Luneva, Nina G. Morozova, Marina A. Zenkova, Mikhail A. Maslov
      Three novel polycationic gemini amphiphiles with different spacers were developed and evaluated in terms of their physiochemical properties and transfection efficiencies. Cationic liposomes formed by these amphiphiles and the helper lipid DOPE were able to successfully condense DNA, as shown by gel mobility shift and ethidium bromide intercalation assays. Transfection activity of the liposomes was superior to Lipofectamine® 2000 and was dependent on spacer structure, hydrophobicity, and nucleic acid type (pDNA or siRNA). We demonstrated that the cationic liposomes 2X6/DOPE and 2X7/DOPE are potential non-toxic vehicles for gene delivery.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.026
       
  • Cyclic tetrapeptide HDAC inhibitors as potential therapeutics for spinal
           muscular atrophy: Screening with iPSC-derived neuronal cells
    • Authors: Jiun-I Lai; Luke J. Leman; Sherman Ku; Chris J. Vickers; Christian A. Olsen; Ana Montero; M. Reza Ghadiri; Joel M. Gottesfeld
      Pages: 3289 - 3293
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Jiun-I Lai, Luke J. Leman, Sherman Ku, Chris J. Vickers, Christian A. Olsen, Ana Montero, M. Reza Ghadiri, Joel M. Gottesfeld
      Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder that is caused by inactivating mutations in the Survival of motor neuron 1 (SMN1) gene, resulting in decreased SMN protein expression. Humans possess a paralog gene, SMN2, which contains a splicing defect in exon 7 leading to diminished expression of full-length, fully functional SMN protein. Increasing SMN2 expression has been a focus of therapeutic development for SMA. Multiple studies have reported the efficacy of histone deacetylase inhibitors (HDACi) in this regard. However, clinical trials involving HDACi have been unsatisfactory, possibly because previous efforts to identify HDACi to treat SMA have employed non-neuronal cells as the screening platform. To address this issue, we generated an SMA-patient specific, induced pluripotent stem cell (iPSC) derived neuronal cell line that contains homogenous Tuj1+neurons. We screened a small library of cyclic tetrapeptide HDACi using this SMA neuronal platform and discovered compounds that elevate SMN2 expression by an impressive twofold or higher. These candidates are also capable of forming gems intranuclearly in SMA neurons, demonstrating biological activity. Our study identifies new potential HDACi therapeutics for SMA screened using a disease-relevant SMA neuronal cellular model.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.027
       
  • Discovery of BMS-961955, an allosteric inhibitor of the hepatitis C virus
           NS5B polymerase
    • Authors: Barbara Zhizhen Zheng; Stanley V. D'Andrea; Umesh Hanumegowda; Jay O. Knipe; Kathy Mosure; Xiaoliang Zhuo; Julie A. Lemm; Mengping Liu; Karen L. Rigat; Ying-Kai Wang; Hua Fang; Chris Poronsky; Jingfang Cutrone; Dauh-Rurng Wu; Pirama Nayagam Arunachalam; T.J. Balapragalathan; Arunachalam Arumugam; Arvind Mathur; Nicholas A. Meanwell; Min Gao; Susan B. Roberts; John F. Kadow
      Pages: 3294 - 3300
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Barbara Zhizhen Zheng, Stanley V. D'Andrea, Umesh Hanumegowda, Jay O. Knipe, Kathy Mosure, Xiaoliang Zhuo, Julie A. Lemm, Mengping Liu, Karen L. Rigat, Ying-Kai Wang, Hua Fang, Chris Poronsky, Jingfang Cutrone, Dauh-Rurng Wu, Pirama Nayagam Arunachalam, T.J. Balapragalathan, Arunachalam Arumugam, Arvind Mathur, Nicholas A. Meanwell, Min Gao, Susan B. Roberts, John F. Kadow
      The synthesis, structure-activity relationship (SAR) data, and further optimization of the metabolic stability and pharmacokinetic (PK) properties for a previously disclosed class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors are described. These efforts led to the discovery of BMS-961955 as a viable contingency backup to beclabuvir which was recently approved in Japan for the treatment of HCV as part of a three drug, single pill combination marketed as XimencyTM.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.024
       
  • Anti-diabetic xanthones from the bark of Garcinia xanthochymus
    • Authors: Chi N. Nguyen; Binh T.D. Trinh; Toan B. Tran; Le-Thu T. Nguyen; Anna K. Jäger; Lien-Hoa D. Nguyen
      Pages: 3301 - 3304
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Chi N. Nguyen, Binh T.D. Trinh, Toan B. Tran, Le-Thu T. Nguyen, Anna K. Jäger, Lien-Hoa D. Nguyen
      An ethyl acetate extract the bark of Garcinia xanthochymus exhibited strong inhibition towards α-glucosidase and PTP1B with IC50 values of 0.3±0.1μg/mL and 2.3±0.4μg/mL, respectively. Chemical constituents of the extract were therefore examined, and two new compounds, xanthochymusxanthones A (1) and B (2), along with ten known xanthones (3–12), were isolated. Their structures were determined using spectroscopic methods, mainly 1D and 2D NMR. Inhibitory activity of the isolated compounds was then tested, and subelliptenone F (12) showed significant effect towards α-glucosidase with IC50 value of 4.1±0.3μM (compared with acarbose, IC50 =900.0±3.0μM) whilst xanthochymusxanthone B (2) exhibited remarkable activity towards PTP1B with IC50 value of 8.0±0.6μM (compared with RK682, IC50 =4.4±0.3μM).
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.021
       
  • Bioactivity-guided isolation of chemical constituents against H2O2-induced
           neurotoxicity on PC12 from Cimicifuga dahurica (Turcz.) Maxim.
    • Authors: Chongning Lv; Fan Yang; Rulan Qin; Zheyuan Qi; Wanrong Zhou; Jincai Lu
      Pages: 3305 - 3309
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Chongning Lv, Fan Yang, Rulan Qin, Zheyuan Qi, Wanrong Zhou, Jincai Lu
      Three new compounds (1, 6, 9), with six known compounds (2–5, 7–8) were obtained from water-soluble extract of Cimicifuga dahurica (Turcz.) Maxim. by bioactivity-guided isolation. Their structures were elucidated by chemical and spectral analysis, including 1D, 2D NMR data and HRESIMS. H2O2-induced neurotoxicity on PC12 cells model were conducted to evaluate the neuro-protective capability of these compounds. The piscidic acid derivatives compounds 4–7 showed marked neuro-protective effect at certain concentration.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.020
       
  • Synthesis and anthelmintic activity of arctigenin derivatives against
           Dactylogyrus intermedius in goldfish
    • Authors: Yang Hu; Lei Liu; Guang-Lu Liu; Xiao Tu; Gao-Xue Wang; Fei Ling
      Pages: 3310 - 3316
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Yang Hu, Lei Liu, Guang-Lu Liu, Xiao Tu, Gao-Xue Wang, Fei Ling
      To control the parasitic disease of Dactylogyrus intermedius, a series of new arctigenin derivatives were designed, synthesized and tested in our study. The anthelmintic activity of most of the derivatives ranged from 1 to 10mg/L. Compared to traditional drug praziquantel (EC50 =2.69mg/L), ether derivatives 2g and 2h exhibited slightly higher anti-parasitic activity, with the EC50 values of 2.48 and 1.52mg/L, respectively. Furthermore, the arctigenin-imidazole hybrids 4a and 4b also removed D. intermedius effectively, with the EC50 values of 2.13 and 2.07mg/L, respectively. The structure-activity relationship analysis indicated that four carbon atoms length of linker and imidazole substitute group could significantly increase the anthelmintic activity, and reduced the toxicity. Through the scanning electron microscope observation, compounds 4a and 4b caused the D. intermedius tegumental damage such as intensive wrinkles, holes and nodular structures. Overall, the structural optimization analysis of arctigenin suggested that 4a and 4b can be used for preventing and controlling Dactylogyrus infections and considered as promising lead compounds for the development of commercial drugs.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.023
       
  • SAR and characterization of non-substrate isoindoline urea inhibitors of
           nicotinamide phosphoribosyltransferase (NAMPT)
    • Authors: Michael L. Curtin; H. Robin Heyman; Richard F. Clark; Bryan K. Sorensen; George A. Doherty; T. Matthew Hansen; Robin R. Frey; Kathy A. Sarris; Ana L. Aguirre; Anurupa Shrestha; Noah Tu; Kevin Woller; Marina A. Pliushchev; Ramzi F. Sweis; Min Cheng; Julie L. Wilsbacher; Peter J. Kovar; Jun Guo; Dong Cheng; Kenton L. Longenecker; Diana Raich; Alla V. Korepanova; Nirupama B. Soni; Mikkel A. Algire; Paul L. Richardson; Violeta L. Marin; Ilaria Badagnani; Anil Vasudevan; F. Greg Buchanan; David Maag; Gary G. Chiang; Chris Tse; Michael R. Michaelides
      Pages: 3317 - 3325
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Michael L. Curtin, H. Robin Heyman, Richard F. Clark, Bryan K. Sorensen, George A. Doherty, T. Matthew Hansen, Robin R. Frey, Kathy A. Sarris, Ana L. Aguirre, Anurupa Shrestha, Noah Tu, Kevin Woller, Marina A. Pliushchev, Ramzi F. Sweis, Min Cheng, Julie L. Wilsbacher, Peter J. Kovar, Jun Guo, Dong Cheng, Kenton L. Longenecker, Diana Raich, Alla V. Korepanova, Nirupama B. Soni, Mikkel A. Algire, Paul L. Richardson, Violeta L. Marin, Ilaria Badagnani, Anil Vasudevan, F. Greg Buchanan, David Maag, Gary G. Chiang, Chris Tse, Michael R. Michaelides
      Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.018
       
  • Design, synthesis and biological evaluation of novel indolin-2-ones as
           potent anticancer compounds
    • Authors: Andong Zhou; Lei Yan; Fangfang Lai; Xiaoguang Chen; Masuo Goto; Kuo-Hsiung Lee; Zhiyan Xiao
      Pages: 3326 - 3331
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Andong Zhou, Lei Yan, Fangfang Lai, Xiaoguang Chen, Masuo Goto, Kuo-Hsiung Lee, Zhiyan Xiao
      The indolin-2-one core is a privileged structure for antitumor agents, especially kinase inhibitors. Twenty-three novel indolin-2-ones were designed by molecular dissection of the anticancer drug indirubin. Seventeen of them exhibited significant inhibition against the tested cell lines, and two of them (1c and 1h) showed IC50 values at the submicromolar level against HCT-116 cells. Compounds 1c and 2c were also potent inhibitors of the triple-negative breast cancer (TNBC) cell line MDA-MB-231. Flow cytometry was utilized to explore the antitumor mechanism of 1c and 2c with MDA-MB-231 cells, and distinct effects were observed on 2c. Furthermore, immunocytochemical examination of 1c suggested a destabilization of microtubules, which was significantly different from the effect of IM, an indirubin derivative.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.019
       
  • Design and synthesis of a novel inhibitor of T. Viride chitinase through
           an in silico target fishing protocol
    • Authors: Giorgio Maccari; Davide Deodato; Diego Fiorucci; Francesco Orofino; Giuseppina I. Truglio; Carolina Pasero; Riccardo Martini; Filomena De Luca; Jean-Denis Docquier; Maurizio Botta
      Pages: 3332 - 3336
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Giorgio Maccari, Davide Deodato, Diego Fiorucci, Francesco Orofino, Giuseppina I. Truglio, Carolina Pasero, Riccardo Martini, Filomena De Luca, Jean-Denis Docquier, Maurizio Botta
      In the last ten years, we identified and developed a new therapeutic class of antifungal agents, the macrocyclic amidinoureas. These compounds are active against several Candida species, including clinical isolates resistant to currently available antifungal drugs. The mode of action of these molecules is still unknown. In this work, we developed an in-silico target fishing procedure to identify a possible target for this class of compounds based on shape similarity, inverse docking procedure and consensus score rank-by-rank. Chitinase enzyme emerged as possible target. To confirm this hypothesis a novel macrocyclic derivative has been produced, specifically designed to increase the inhibition of the chitinase. Biological evaluation highlights a stronger enzymatic inhibition for the new derivative, while its antifungal activity drops probably because of pharmacokinetic issues. Collectively, our data suggest that chitinase represent at least one of the main target of macrocyclic amidinoureas.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.016
       
  • PNA monomers fully compatible with standard Fmoc-based solid-phase
           synthesis of pseudocomplementary PNA
    • Authors: Toru Sugiyama; Genki Hasegawa; Chie Niikura; Keiko Kuwata; Yasutada Imamura; Yosuke Demizu; Masaaki Kurihara; Atsushi Kittaka
      Pages: 3337 - 3341
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Toru Sugiyama, Genki Hasegawa, Chie Niikura, Keiko Kuwata, Yasutada Imamura, Yosuke Demizu, Masaaki Kurihara, Atsushi Kittaka
      Here we report the synthesis of new PNA monomers for pseudocomplementary PNA (pcPNA) that are fully compatible with standard Fmoc chemistry. The thiocarbonyl group of the 2-thiouracil (sU) monomer was protected with the 4-methoxy-2-methybenzyl group (MMPM), while the exocyclic amino groups of diaminopurine (D) were protected with Boc groups. The newly synthesized monomers were incorporated into a 10-mer PNA oligomer using standard Fmoc chemistry for solid-phase synthesis. Oligomerization proceeded smoothly and the HPLC and MALDI-TOF MS analyses indicated that there was no remaining MMPM on the sU nucleobase. The new PNA monomers reported here would facilitate a wide range of applications, such as antigene PNAs and DNA nanotechnologies.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.015
       
  • Dioscin suppresses TGF-β1-induced epithelial-mesenchymal transition and
           suppresses A549 lung cancer migration and invasion
    • Authors: Won-Chul Lim; Hyunhee Kim; Young-Joo Kim; Kyung-Chul Choi; In Ho Lee; Ki Heon Lee; Mi Kyung Kim; Hyeonseok Ko
      Pages: 3342 - 3348
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Won-Chul Lim, Hyunhee Kim, Young-Joo Kim, Kyung-Chul Choi, In Ho Lee, Ki Heon Lee, Mi Kyung Kim, Hyeonseok Ko
      Epithelial-to-mesenchymal transition (EMT), an important cellular process, occurs during cancer development and progression, has a crucial role in metastasis by enhancing the motility of tumor cells. Dioscin is a polyphenolic component isolated from Phyllanthus amarus, which exhibits a wide range of pharmacological and physiological activities, such as anti-tumor, anti-inflammatory, anti-obesity, anti-fungal, and anti-viral activities. However, the possible role of dioscin in the EMT is unclear. We investigated the suppressive effect of dioscin on the EMT. Transforming growth factor-beta 1 (TGF-β1) is known to induce EMT in a number of cancer cell types and promote lung adenocarcinoma migration and invasion. To verify the inhibitory role of dioscin in lung cancer migration and invasion, we investigated the use of dioscin as inhibitors of TGF-β1-induced EMT in A549 lung cancer cells in vitro. Here, we found that dioscin prominently increased expression of the epithelial marker E-cadherin and expression of the mesenchymal marker N-cadherin and Snail during the TGF-β1-induced EMT. In addition, dioscin inhibited the TGF-β1-induced increase in cell migration and invasion of A549 lung cancer cells. Also, dioscin remarkably inhibited TGF-β1-regulated activation of MMP-2/9, Smad2, and p38. Taken together, our findings provide new evidence that dioscin suppresses lung cancer migration, and invasion in vitro by inhibiting the TGF-β1-induced EMT.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.014
       
  • A small-molecule screen identifies the antitrypanosomal agent suramin and
           analogues NF023 and NF449 as inhibitors of STAT5a/b
    • Authors: Angela Berg; Thorsten Berg
      Pages: 3349 - 3352
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Angela Berg, Thorsten Berg
      The transcription factor STAT5a is a potential target for tumor therapy. We present a fluorescence polarization-based, high-throughput screen of chemical libraries containing natural products and known bioactive molecules, for the identification of small-molecule inhibitors of the STAT5a SH2 domain. This screen identified suramin, a drug used to treat African trypanosomiasis, and its analogues NF023 and NF449 as inhibitors of the SH2 domains of STAT5a/b. Our data extend the known in vitro targets of suramin and analogues to include members of the STAT protein family.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.012
       
  • Novel 3-fluoro-6-methoxyquinoline derivatives as inhibitors of bacterial
           DNA gyrase and topoisomerase IV
    • Authors: Mark J. Mitton-Fry; Steven J. Brickner; Judith C. Hamel; Rose Barham; Lori Brennan; Jeffrey M. Casavant; Xiaoyuan Ding; Steven Finegan; Joel Hardink; Thuy Hoang; Michael D. Huband; Meghan Maloney; Anthony Marfat; Sandra P. McCurdy; Dale McLeod; Chakrapani Subramanyam; Michael Plotkin; Usa Reilly; John Schafer; Gregory G. Stone; Daniel P. Uccello; Todd Wisialowski; Kwansik Yoon; Richard Zaniewski; Christopher Zook
      Pages: 3353 - 3358
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Mark J. Mitton-Fry, Steven J. Brickner, Judith C. Hamel, Rose Barham, Lori Brennan, Jeffrey M. Casavant, Xiaoyuan Ding, Steven Finegan, Joel Hardink, Thuy Hoang, Michael D. Huband, Meghan Maloney, Anthony Marfat, Sandra P. McCurdy, Dale McLeod, Chakrapani Subramanyam, Michael Plotkin, Usa Reilly, John Schafer, Gregory G. Stone, Daniel P. Uccello, Todd Wisialowski, Kwansik Yoon, Richard Zaniewski, Christopher Zook
      Novel (non-fluoroquinolone) inhibitors of bacterial type II topoisomerases (NBTIs) are an emerging class of antibacterial agents. We report an optimized series of cyclobutylaryl-substituted NBTIs. Compound 14 demonstrated excellent activity both in vitro (S. aureus MIC90 =0.125μg/mL) and in vivo (systemic and tissue infections). Enhanced inhibition of Topoisomerase IV correlated with improved activity in S. aureus strains with mutations conferring resistance to NBTIs. Compound 14 also displayed an improved hERG IC50 of 85.9μM and a favorable profile in the anesthetized guinea pig model.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.009
       
  • Synthesis of MeON-neoglycosides of digoxigenin with 6-deoxy- and
           2,6-dideoxy-d-glucose derivatives and their anticancer activity
    • Authors: Dong-dong Wang; Xiao-san Li; Yu-zhou Bao; Jie Liu; Xiao-kun Zhang; Xin-sheng Yao; Xue-Long Sun; Jin-Shan Tang
      Pages: 3359 - 3364
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Dong-dong Wang, Xiao-san Li, Yu-zhou Bao, Jie Liu, Xiao-kun Zhang, Xin-sheng Yao, Xue-Long Sun, Jin-Shan Tang
      Cardiac glycosides show anticancer activities and their deoxy-sugar chains are vital for their anticancer effects. In order to study the structure-activity relationship (SAR) of cardiac glycosides toward cancers and get more potent anticancer agents, a series of MeON-neoglycosides of digoxigenin was synthesized and evaluated. First, ten 6-deoxy- and 2,6-dideoxy-d-glucopyranosyl donors were synthesized starting from methyl α-d-glucopyranoside and 2-deoxy-d-glucose. Meanwhile, the digoxigenin was obtained by acidic hydrolysis of commercially available digoxin as glycosyl acceptor. Then, a 22-member MeON-neoglycoside library of digoxigenin was successfully synthesized by neoglycosylation method. Finally, the induction of Nur77 expression and its translocation from the nucleus to cytoplasm together with cytotoxicity of these MeON-neoglycosides were evaluated. The SAR analysis revealed that C3 glycosylation is required for their induction of Nur77 expression. Moreover, some MeON-neoglycosides (2b and 8b) could significant induce the expression of Nur77 and its translocation from the nucleus to cytoplasm. However, these compounds showed no inhibitory effects on the proliferation of cancer cells, suggesting that they may not induce apoptosis of NIH-H460 cancer cells and their underlying potential and application toward cancer cells deserves future study.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.008
       
  • Design, synthesis and herbicidal activity study of aryl 2,6-disubstituted
           sulfonylureas as potent acetohydroxyacid synthase inhibitors
    • Authors: Wei Wei; Shaa Zhou; Dandan Cheng; Yuxin Li; Jingbo Liu; Yongtao Xie; Yonghong Li; Zhengming Li
      Pages: 3365 - 3369
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Wei Wei, Shaa Zhou, Dandan Cheng, Yuxin Li, Jingbo Liu, Yongtao Xie, Yonghong Li, Zhengming Li
      A series of sulfonylurea derivatives containing a 2,6-disubstituted aryl moiety were designed, synthesized and evaluated for their herbicidal activities. Most of these compounds showed excellent inhibitory rates against both monocotyledonous and dicotyledonous weeds, especially 10a, 10h and 10i. They exhibited equivalent or superior herbicidal efficiency than commercial chlorsulfuron at the dosage of 15g/ha and the preliminary SAR was summarized. In order to illuminate the molecular mechanism of several potent compounds, their apparent inhibition constant (K i app) of Arabidopsis thaliana acetohydroxyacid synthase (AHAS) were determined and the results confirmed that these compounds were all potent AHAS inhibitors. 10i have a K i app of 11.5nM, which is about 4 times as potent as chlorsulfuron (52.4nM).
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.007
       
  • Synthesis and biological evaluation of 5-fatty-acylamido-1, 3,
           4-thiadiazole-2-thioglycosides
    • Authors: Srikanth Vudhgiri; Dhevendar Koude; Dileep Kumar Veeragoni; Sunil Misra; R.B.N. Prasad; Ram Chandra Reddy Jala
      Pages: 3370 - 3373
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Srikanth Vudhgiri, Dhevendar Koude, Dileep Kumar Veeragoni, Sunil Misra, R.B.N. Prasad, Ram Chandra Reddy Jala
      In the present study, the synthesis of 1, 3, 4-thiadiazole-based thioglycosides were accomplished in good yields with employing a convergent synthetic route. The starting material 5-amino-1, 3, 4-thiadiazole-2-thiol and followed by a series of 5-fatty-acylamido-1, 3, 4-thiadiazole-2-thiols (4a–4j) were synthesized with different fatty acid chlorides. The glycosylation of compounds 4a–4j were achieved with trichloroacetimidate methodology. Antimicrobial and cytotoxicity activities of title compounds were evaluated. Among the entire compounds lauric acid and myristic acid derivatives showed good and moderate antimicrobial activity. In case of cytotoxicity results of compounds 8a–8j and 9a–9j, the acetate protected short chain (C6:0, C8:0, C10:0) compounds and the free hydroxyl long chain saturated (C16:0, C18:0) and unsaturated (C18:1, C22:1) compounds exhibited good activity against different cancer cell lines. Further, the free hydroxyl compounds 9a, 9c–9j did not show any toxicity towards normal CHO-K1 cell line whereas acylated compounds 8a–8j exhibited toxicity.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.004
       
  • Synthesis and biological evaluation of caffeic acid derivatives as potent
           inhibitors of α-MSH-stimulated melanogenesis
    • Authors: Hyeju Jo; Minho Choi; Jaeuk Sim; Mayavan Viji; Siyuan Li; Young Hee Lee; Youngsoo Kim; Seung-Yong Seo; Yuanyuan Zhou; Kiho Lee; Wun-Jae Kim; Jin Tae Hong; Heesoon Lee; Jae-Kyung Jung
      Pages: 3374 - 3377
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Hyeju Jo, Minho Choi, Jaeuk Sim, Mayavan Viji, Siyuan Li, Young Hee Lee, Youngsoo Kim, Seung-Yong Seo, Yuanyuan Zhou, Kiho Lee, Wun-Jae Kim, Jin Tae Hong, Heesoon Lee, Jae-Kyung Jung
      We have disclosed our effort to develop caffeic acid derivatives as potent and non-toxic inhibitors of α-MSH-stimulated melanogenesis to treat pigmentation disorders and skin medication including a cosmetic skin-whitening agent. The SAR studies revealed that cyclohexyl ester and secondary amide derivatives of caffeic acid showed significant inhibitory activities.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.011
       
  • Synthesis, potential anti-inflammatory and analgesic activities study of
           (S)-N-substituted-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamides
    • Authors: Li-Ping Guan; Ya-Nan Xia; Qing-Hao Jin; Bing-Yu Liu; Si-Hong Wang
      Pages: 3378 - 3381
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Li-Ping Guan, Ya-Nan Xia, Qing-Hao Jin, Bing-Yu Liu, Si-Hong Wang
      A series of (S)-N-substitued-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide derivatives were designed, synthesized and evaluated for their anti-inflammatory and analgesic effects in vivo. Among the synthesized compounds 2a and 2n showed the best anti-inflammatory activity (inhibition rate: 95% and 92.7%, respectively) and analgesic effect (inhibition rate: 100% and 100%, respectively), which was greater than that or nearly equivalent to that of indomethacin. Compounds 2a and 2n were selected to test their inhibitory effects against ovine COX-1 and COX-2 using the cyclooxygenase inhibition assay in vitro. Compounds 2a and 2n are weak inhibitors of COX-1 isozyme but displayed moderate COX-2 isozyme inhibitory effects (IC50 =0.47μM and 1.63μM, respectively) and COX-2 selectivity indexes (SI=11.5 and 4.8). Furthermore, compound 2a was more inhibitors of COX-2 isozyme active than the reference drug celecoxib.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.002
       
  • Varic acid analogues from fungus as PTP1B inhibitors: Biological
           evaluation and structure–activity relationships
    • Authors: Wenlong Sun; Chunlin Zhuang; Xia Li; Bowei Zhang; Xinhua Lu; Zhihui Zheng; Yuesheng Dong
      Pages: 3382 - 3385
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Wenlong Sun, Chunlin Zhuang, Xia Li, Bowei Zhang, Xinhua Lu, Zhihui Zheng, Yuesheng Dong
      Protein tyrosine phosphatase 1B (PTP1B) inhibitors as potential therapies for diabetes and obesity have attracted much attention in recent years. Six varic acid analogues were isolated from two strains of fungi and evaluated for PTP1B inhibition activities. The structure-activity relationships were also characterized and predicted by molecular modeling. Further kinetic studies indicated the reversible and competitive inhibition manner of varic acid analogues. Trivaric acid showed insulin-sensitizing effect not only in vitro but also in vivo, representing a promising lead compound for further optimization.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.001
       
  • A novel intestinal-restricted FXR agonist
    • Authors: Hong Wang; Zhou Zhao; Jiyu Zhou; Yitong Guo; Guangji Wang; Haiping Hao; Xiaowei Xu
      Pages: 3386 - 3390
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Hong Wang, Zhou Zhao, Jiyu Zhou, Yitong Guo, Guangji Wang, Haiping Hao, Xiaowei Xu
      In this study, a new intestinal-restricted FXR agonist named fexaramine-3 (Fex-3) was developed and investigated both in vitro and in vivo. Fex-3 could selectively activate intestinal FXR and promote the expression of BSEP and SHP while suppressing CYP7A1 which is involved in bile acids syntheses better than the reported intestinal-restricted FXR agonist fexaramine (Fex). We demonstrated that Fex-3 targeted on FXR in ileum and has better selectivity than Fex. And the study of utilizing Fex-3 to reduce obesity was undergoing.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.003
       
  • Synthetic ligand promotes gene expression by affecting GC sequence in
           promoter
    • Authors: Saki Matsumoto; Kei Iida; Asako Murata; Masatsugu Denawa; Masatoshi Hagiwara; Kazuhiko Nakatani
      Pages: 3391 - 3394
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Saki Matsumoto, Kei Iida, Asako Murata, Masatsugu Denawa, Masatoshi Hagiwara, Kazuhiko Nakatani
      A naphthyridine carbamate tetramer (NCT8) is a synthetic compound, which selectively binds to nucleic acids containing CGG/CGG sequence. Although NCT8 is a promising compound for a wide range of DNA and RNA based biotechnology such as modulation of specific gene expression, little is known about its behavior in human cells. In the present study, we investigated the changes induced in gene expression by NCT8. Genes differentially expressed in the presence of NCT8 in HeLa cells were identified by whole-transcriptome analysis. The whole-transcriptome analysis showed that NCT8 significantly induced up-regulation of specific genes, whose promoter region has GC-rich sequence.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.006
       
  • Design, synthesis and biological evaluation of novel 3H-imidazole [4,5-b]
           pyridine derivatives as selective mTOR inhibitors
    • Authors: Lingzhi Zhang; Tantan Bu; Xiaobo Bao; Tingting Liang; Yiran Ge; Yungen Xu; Qihua Zhu
      Pages: 3395 - 3398
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Lingzhi Zhang, Tantan Bu, Xiaobo Bao, Tingting Liang, Yiran Ge, Yungen Xu, Qihua Zhu
      A series of 3H-imidazo [4,5-b] pyridines derivatives were designed and synthesized as selective mTOR inhibitors. The systematic optimization of the molecules resulted in the identification of two compounds 10d and 10n with nanomolar mTOR inhibitory activity and selectivity over PI3Kα. Besides, compounds 10d and 10n demonstrated attractive potency against human breast cancer cells (MCF-7) and human ovarian cancer cell (A2780).
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.010
       
  • Synthesis and antibacterial activity of 5-methylphenanthridium derivatives
           as FtsZ inhibitors
    • Authors: Fang Liu; Henrietta Venter; Fangchao Bi; Susan J. Semple; Jingru Liu; Chaobin Jin; Shutao Ma
      Pages: 3399 - 3402
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Fang Liu, Henrietta Venter, Fangchao Bi, Susan J. Semple, Jingru Liu, Chaobin Jin, Shutao Ma
      5-Methylphenanthridium derivatives were designed, synthesized and evaluated for their in vitro antibacterial activity and cell division inhibitory activity against various Gram-positive and -negative bacteria. Among them, compounds 5A2, 5B1, 5B2, 5B3, 5C1 and 5C2 displayed the best on-target antibacterial activity with an MIC value of 4µg/mL against B. subtilis ATCC9372 and S. pyogenes PS, showing over 2-fold better activity than sanguinarine. The SARs showed that the 5-methylphenanthridium derivatives with the alkyl side chains at the 2-postion, especially the straight alkyl side chains exerted better on-target antibacterial activity.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.005
       
  • Synthesis and biological evaluation of
           2-methyl-1H-benzimidazole-5-carbohydrazides derivatives as modifiers of
           redox homeostasis of Trypanosoma cruzi
    • Authors: Silvia Melchor-Doncel de la Torre; Citlali Vázquez; Zabdi González-Chávez; Lilián Yépez-Mulia; Rocío Nieto-Meneses; Ricardo Jasso-Chávez; Emma Saavedra; Francisco Hernández-Luis
      Pages: 3403 - 3407
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Silvia Melchor-Doncel de la Torre, Citlali Vázquez, Zabdi González-Chávez, Lilián Yépez-Mulia, Rocío Nieto-Meneses, Ricardo Jasso-Chávez, Emma Saavedra, Francisco Hernández-Luis
      Twelve novel benzimidazole derivatives were synthesized and their in vitro activities against epimastigotes of Trypanosoma cruzi were evaluated. Two derivatives (6 and 7), which have 4-hydroxy-3-methoxyphenyl moiety in their structures, proved to be the most active in inhibiting the parasite growth. Compound 6 showed a trypanocidal activity higher than benznidazole (IC50 =5µM and 7.5µM, respectively) and less than nifurtimox (IC50 =3.6µM). In addition, the ability of 6 and 7 to modify the redox homeostasis in T cruzi epimastigote was studied; cysteine and glutathione increased in parasites exposed to both compounds, whereas trypanothione only increased with 7 treatment. These results suggest that the decrease in viability of T. cruzi may be attributed to the change in cellular redox balance caused by compound 6 or 7. Furthermore, compounds 6 and 7 showed CC50 values of 160.64 and 160.66µM when tested in mouse macrophage cell line J774 and selectivity indexes (macrophage/parasite) of 32 and 20.1, respectively.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.06.013
       
  • Synthesis and biological evaluation of steroidal derivatives bearing a
           small ring as vitamin D receptor agonists
    • Authors: Norihito Arichi; Shinichi Fujiwara; Michiyasu Ishizawa; Makoto Makishima; Duy H. Hua; Ken-ichi Yamada; Yousuke Yamaoka; Kiyosei Takasu
      Pages: 3408 - 3411
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Norihito Arichi, Shinichi Fujiwara, Michiyasu Ishizawa, Makoto Makishima, Duy H. Hua, Ken-ichi Yamada, Yousuke Yamaoka, Kiyosei Takasu
      A novel series of 3-ketolithocholic acid derivatives as well as estrone derivatives bearing a small ring for the conformational fixation of the side chain were synthesized by using a catalytic [2+2] cycloaddition and a ring-contraction rearrangement. The steroidal derivatives were evaluated for transcriptional activation of vitamin D receptor by luciferase reporter assays. Among them, two estrone derivatives showed a higher efficacy of the transactivation of vitamin D receptor than 3-ketolithocholic acid, and the small ring moieties were found to be important for the efficacy.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.05.089
       
  • Urotensin core mimics that modulate the biological activity of
           urotensin-II related peptide but not urotensin-II
    • Authors: Martin Strack; Étienne Billard; David Chatenet; William D. Lubell
      Pages: 3412 - 3416
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Martin Strack, Étienne Billard, David Chatenet, William D. Lubell
      A novel approach for the synthesis of head-to-tail cyclic peptides has been developed and used to prepare two mimics of the urotensin II-related peptide (URP) cyclic core. Mimics 1 and 2 (c[Trp-Lys-Tyr-Gly-ψ(triazole)-Gly] and c[Phe-Trp-Lys-Tyr-Gly-ψ(triazole)-Gly]) were respectively prepared using a combination of solid- and solution-phase synthesis. The silyl-based alkyne-modifying (SAM) linker enabled installation of C-terminal alkyne and N-terminal azide moieties onto linear peptide precursors, which underwent head-to-tail copper-catalyzed azide-alkyne cycloaddition (CuAAC) in solution. In an aortic ring contraction assay, neither 1 nor 2 exhibited agonist activity; however, both inhibited selectively URP- but not UII-mediated vasoconstriction. The core phenylalanine residue was shown to be important for enhancing modulatory activity of the urotensinergic system.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.05.088
       
  • Development of an ON/OFF switchable fluorescent probe targeting His tag
           fused proteins in living cells
    • Authors: Koyo Okitsu; Takashi Misawa; Takuji Shoda; Masaaki Kurihara; Yosuke Demizu
      Pages: 3417 - 3422
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Koyo Okitsu, Takashi Misawa, Takuji Shoda, Masaaki Kurihara, Yosuke Demizu
      The fluorescent labeling of target proteins is useful for analyzing their functions and localization in cells, and several fluorescent probes have been developed. However, the fusion of tags such as green fluorescent protein (GFP) to target proteins occasionally affects their functions and/or localization in living cells. Therefore, an imaging method that uses short peptide tags such as hexa-histidine (the His tag) has been attracting increasing attention. Few studies have investigated ON/OFF switchable fluorescent probes for intracellular His-tagged proteins. We herein developed a novel ON/OFF switchable probe for imaging targeted intracellular proteins fused with a CH6 tag, which is composed of one cysteine residue and six histidine residues.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.05.087
       
  • Design, synthesis, and structure–activity relationships of
           pyrimido[4,5-b]indole-4-amines as microtubule depolymerizing agents that
           are effective against multidrug resistant cells
    • Authors: Ravi Kumar Vyas Devambatla; Wei Li; Nilesh Zaware; Shruti Choudhary; Ernest Hamel; Susan L. Mooberry; Aleem Gangjee
      Pages: 3423 - 3430
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Ravi Kumar Vyas Devambatla, Wei Li, Nilesh Zaware, Shruti Choudhary, Ernest Hamel, Susan L. Mooberry, Aleem Gangjee
      To identify the structural features of 9H-pyrimido[4,5-b]indoles as microtubule depolymerizers, pyrimido[4,5-b]indoles 2–8 with varied substituents at the 2-, 4- and 5-positions were designed and synthesized. Nucleophilic displacement of 2,5-substituted-4-chloro-pyrimido[4,5-b]indoles with appropriate arylamines was the final step employed in the synthesis of target compounds 2–8. Compounds 2 and 6 had two-digit nanomolar potency (IC50) against MDA-MB-435, SK-OV-3 and HeLa cancer cells in vitro. Compounds 2 and 6 also depolymerized microtubules comparable to the lead compound 1. Compounds 2, 3, 6 and 8 were effective in cells expressing P-glycoprotein or the βIII isotype of tubulin, mechanisms that are associated with clinical drug resistance to microtubule targeting drugs. Proton NMR and molecular modeling studies were employed to identify the structural basis for the microtubule depolymerizing activity of pyrimido[4,5-b]indoles.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.05.085
       
  • A new type of pharmacological chaperone for GM1-gangliosidosis related
           human lysosomal β-galactosidase: N-Substituted
           5-amino-1-hydroxymethyl-cyclopentanetriols
    • Authors: Michael Schalli; Patrick Weber; Christina Tysoe; Bettina M. Pabst; Martin Thonhofer; Eduard Paschke; Arnold E. Stütz; Marion Tschernutter; Werner Windischhofer; Stephen G. Withers
      Pages: 3431 - 3435
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Michael Schalli, Patrick Weber, Christina Tysoe, Bettina M. Pabst, Martin Thonhofer, Eduard Paschke, Arnold E. Stütz, Marion Tschernutter, Werner Windischhofer, Stephen G. Withers
      N-Functionalized amino(hydroxymethyl)cyclopentanetriols are potent inhibitors of β-d-galactosidases and, for the first time, could be shown to act as pharmacological chaperones for GM1-gangliosidosis-associated lysosomal acid β-galactosidase thus representing a new structural type of pharmacological chaperones for this lysosomal storage disease.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.05.086
       
  • Validation of onchocerciasis biomarker N-acetyltyramine-O-glucuronide
           (NATOG)
    • Authors: Daniel Globisch; Lisa M. Eubanks; Ryan J. Shirey; Kenneth M. Pfarr; Samuel Wanji; Alexander Y. Debrah; Achim Hoerauf; Kim D. Janda
      Pages: 3436 - 3440
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Daniel Globisch, Lisa M. Eubanks, Ryan J. Shirey, Kenneth M. Pfarr, Samuel Wanji, Alexander Y. Debrah, Achim Hoerauf, Kim D. Janda
      The Neglected Tropical Disease onchocerciasis is a parasitic disease. Despite many control programmes by the World Health Organization (WHO), large communities in West and Central Africa are still affected. Besides logistic challenges during biannual mass drug administration, the lack of a robust, point-of-care diagnostic is limiting successful eradication of onchocerciasis. Towards the implementation of a non-invasive and point-of-care diagnostic, we have recently reported the discovery of the biomarker N-acetyltyramine-O-glucuronide (NATOG) in human urine samples using a metabolomics-mining approach. NATOG’s biomarker value was enhanced during an investigation in a rodent model. Herein, we further detail the specificity of NATOG in active onchocerciasis infections as well as the co-infecting parasites Loa loa and Mansonella perstans. Our results measured by liquid chromatography coupled with mass spectrometry (LC-MS) reveal elevated NATOG values in mono- and co-infection samples only in the presence of the nematode Onchocerca volvulus. Metabolic pathway investigation of l-tyrosine/tyramine in all investigated nematodes uncovered an important link between the endosymbiotic bacterium Wolbachia and O. volvulus for the biosynthesis of NATOG. Based on these extended studies, we suggest NATOG as a biomarker for tracking active onchocerciasis infections and provide a threshold concentration value of NATOG for future diagnostic tool development.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.05.082
       
  • Semi-quantitative models for identifying potent and selective
           transthyretin amyloidogenesis inhibitors
    • Authors: Stephen Connelly; David E. Mortenson; Sungwook Choi; Ian A. Wilson; Evan T. Powers; Jeffery W. Kelly; Steven M. Johnson
      Pages: 3441 - 3449
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Stephen Connelly, David E. Mortenson, Sungwook Choi, Ian A. Wilson, Evan T. Powers, Jeffery W. Kelly, Steven M. Johnson
      Rate-limiting dissociation of the tetrameric protein transthyretin (TTR), followed by monomer misfolding and misassembly, appears to cause degenerative diseases in humans known as the transthyretin amyloidoses, based on human genetic, biochemical and pharmacologic evidence. Small molecules that bind to the generally unoccupied thyroxine binding pockets in the native TTR tetramer kinetically stabilize the tetramer, slowing subunit dissociation proportional to the extent that the molecules stabilize the native state over the dissociative transition state—thereby inhibiting amyloidogenesis. Herein, we use previously reported structure-activity relationship data to develop two semi-quantitative algorithms for identifying the structures of potent and selective transthyretin kinetic stabilizers/amyloidogenesis inhibitors. The viability of these prediction algorithms, in particular the more robust in silico docking model, is perhaps best validated by the clinical success of tafamidis, the first-in-class drug approved in Europe, Japan, South America, and elsewhere for treating transthyretin aggregation-associated familial amyloid polyneuropathy. Tafamidis is also being evaluated in a fully-enrolled placebo-controlled clinical trial for its efficacy against TTR cardiomyopathy. These prediction algorithms will be useful for identifying second generation TTR kinetic stabilizers, should these be needed to ameliorate the central nervous system or ophthalmologic pathology caused by TTR aggregation in organs not accessed by oral tafamidis administration.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.05.080
       
  • Synthesis of 3- and 29-substituted celastrol derivatives and
           structure-activity relationship studies of their cytotoxic activities
    • Authors: Wei-Guang Shan; Han-Guang Wang; Yan Chen; Rui Wu; Yan-Tao Wen; Li-Wen Zhang; You-Min Ying; Jian-Wei Wang; Zha-Jun Zhan
      Pages: 3450 - 3453
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Wei-Guang Shan, Han-Guang Wang, Yan Chen, Rui Wu, Yan-Tao Wen, Li-Wen Zhang, You-Min Ying, Jian-Wei Wang, Zha-Jun Zhan
      A series of 3-carbamate and 29-ester celastrol derivatives (compounds 1–26) were designed and synthesized. These analogues were evaluated for their cytotoxic activities against several cancer cell lines. Cytotoxicity data revealed that the properties of substituents and substitution position had important influence on cytotoxic activity. Modification of C-3 hydroxyl with size-limited groups did not reduce the activity obviously. The introduction of polarity group like piperazine could improve the solubility. Compound 23 was chosen to further evaluate anti-tumor efficacy in vivo. It showed higher inhibition rate and better safety than celastrol during in vivo experiment by intragastric administration. The preliminary antitumor studies of compound 23 in vivo showed that it might be promising for the development of new antitumor agents.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.05.083
       
  • Identification and synthesis of novel inhibitors of mycobacterium ATP
           synthase
    • Authors: Yogesh B. Surase; Kirandeep Samby; Sagar R. Amale; Ruchi Sood; Kedar P. Purnapatre; Pawan K. Pareek; Biswajit Das; Kamna Nanda; Subodh Kumar; Ashwani K. Verma
      Pages: 3454 - 3459
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Yogesh B. Surase, Kirandeep Samby, Sagar R. Amale, Ruchi Sood, Kedar P. Purnapatre, Pawan K. Pareek, Biswajit Das, Kamna Nanda, Subodh Kumar, Ashwani K. Verma
      A non-diaryl quinoline scaffold 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one was identified by screening of diverse set of compounds against M. smegmatis ATP synthase. Herein, we disclose our efforts to develop the structure activity relationship against Mycobacterium tuberculosis (Mtb.H37Rv strain) around the identified hit 1. A scaffold hopping approach was used to identify compounds 14a, 14b and 24a with improved activity against MTb.H37Rv.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.05.081
       
  • Synthesis and biological evaluation of
           2-(3,4-dimethoxyphenyl)-6-(2-[18F]fluoroethoxy)benzothiazole ([18F]FEDBT)
           for PET imaging of breast cancer
    • Authors: Geng-Ying Li; Daria D. Vaulina; Jia-Je Li; Olga S. Fedorova; Hsin-Ell Wang; Ren-Shyan Liu; Raisa N. Krasikova; Chuan-Lin Chen
      Pages: 3460 - 3463
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Geng-Ying Li, Daria D. Vaulina, Jia-Je Li, Olga S. Fedorova, Hsin-Ell Wang, Ren-Shyan Liu, Raisa N. Krasikova, Chuan-Lin Chen
      Given the ever-present demand for improved PET radiotracer in oncology imaging, we have synthesized 2-(3,4-dimethoxyphenyl)-6-(2-[18F]fluoroethoxy)benzothiazole ([18F]FEDBT), a fluorine-18-containing fluoroethylated benzothiazole to explore its utility as a PET imaging tracer. [18F]FEDBT was prepared via kryptofix-mediated nucleophilic substitution of the tosyl group precursor. Fractionated ethanol-based solid-phase (SPE cartridge-based) purification afforded [18F]FEDBT in 60% radiochemical yield (EOB), with radiochemical purity in excess of 98% and the specific activity was 35GBq/μmol. The radiotracer displayed clearly higher cellular uptake ratio in various breast cancer cell lines MCF7, MDA-MB-468 and MDA-MB-231. However, both biodistribution and microPET studies have showed an higher abdominal accumulation of [18F]FEDMBT and the tumor/muscle ratio of 1.8 was observed in the MDA-MB-231 xenograft tumors mice model. Further the lipophilic improvement is needed for the reducement of hepatobilliary accumulation and to promote the tumor uptake for PET imaging of breast cancer.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.05.079
       
  • Fluorescence detection of serum albumin with a turnover-based sensor
           utilizing Kemp elimination reaction
    • Authors: Shingo Sakamoto; Toru Komatsu; Tasuku Ueno; Kenjiro Hanaoka; Yasuteru Urano
      Pages: 3464 - 3467
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Shingo Sakamoto, Toru Komatsu, Tasuku Ueno, Kenjiro Hanaoka, Yasuteru Urano
      The Kemp elimination reaction is a well-known chemical reaction that is facilitated on a protein surface microenvironment, and in particular is highly accelerated in a unique binding pocket of serum albumin. We have designed and synthesized a fluorescently activatable coumarin derivative with a benzisoxazole scaffold to enable monitoring of the Kemp elimination reaction in terms of fluorescence change for the first time. We show that this fluorescent sensor can sensitively and selectively quantitate serum albumin in blood samples. It also works in a dry-chemistry format.
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      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.05.076
       
  • Discovery of β-d-2′-deoxy-2′-dichlorouridine nucleotide prodrugs as
           potent inhibitors of hepatitis C virus replication
    • Authors: Pedro Pinho; Genadiy Kalayanov; Hans Westerlind; Åsa Rosenquist; Horst Wähling; Christian Sund; Maria Almeida; Susana Ayesa; Jan Tejbrant; Paul Targett-Adams; Anders Eneroth; Annelie Lindqvist
      Pages: 3468 - 3471
      Abstract: Publication date: 1 August 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 15
      Author(s): Pedro Pinho, Genadiy Kalayanov, Hans Westerlind, Åsa Rosenquist, Horst Wähling, Christian Sund, Maria Almeida, Susana Ayesa, Jan Tejbrant, Paul Targett-Adams, Anders Eneroth, Annelie Lindqvist
      Discovery of sofosbuvir has radically changed hepatitis C treatment and nucleoside/tide NS5B inhibitors are now viewed as one of the key components in combination therapies with other direct-acting antiviral agents. As part of our program to identify new nucleoside inhibitors of HCV replication, we now wish to report on the discovery of β-d-2′-deoxy-2′-dichlorouridine nucleotide prodrugs as potent inhibitors of HCV replication. Although, cytidine analogues have long been recognized to be metabolized to both cytidine and uridine triphosphates through the action of cytidine deaminase, uridine analogues are generally believed to produce exclusively uridine triphosphate. Detailed investigation of the intracellular metabolism of our newly discovered uridine prodrugs, as well as of sofosbuvir, has now revealed the formation of both uridine and cytidine triphosphates. This occurs, not only in vitro in cell lines, but also in vivo upon oral dosing to dogs.
      Graphical abstract image

      PubDate: 2017-07-08T08:40:12Z
      DOI: 10.1016/j.bmcl.2017.05.075
       
 
 
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