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  Subjects -> CHEMISTRY (Total: 846 journals)
    - ANALYTICAL CHEMISTRY (50 journals)
    - CHEMISTRY (597 journals)
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CHEMISTRY (597 journals)                  1 2 3 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 7)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 26)
ACS Catalysis     Full-text available via subscription   (Followers: 31)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 17)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 23)
ACS Macro Letters     Full-text available via subscription   (Followers: 22)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 39)
ACS Nano     Full-text available via subscription   (Followers: 217)
ACS Photonics     Full-text available via subscription   (Followers: 10)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 20)
Acta Chemica Iasi     Open Access   (Followers: 2)
Acta Chimica Sinica     Full-text available via subscription  
Acta Chimica Slovaca     Open Access   (Followers: 1)
Acta Chromatographica     Full-text available via subscription   (Followers: 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: 48)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 53)
Advances in Chemical Science     Open Access   (Followers: 12)
Advances in Chemistry     Open Access   (Followers: 12)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Enzyme Research     Open Access   (Followers: 10)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 14)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 18)
Advances in Nanoparticles     Open Access   (Followers: 12)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15)
Advances in Polymer Science     Hybrid Journal   (Followers: 40)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 18)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Science and Technology     Full-text available via subscription   (Followers: 10)
African Journal of Bacteriology Research     Open Access  
African Journal of Chemical Education     Open Access   (Followers: 2)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 7)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 65)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 14)
American Journal of Chemistry     Open Access   (Followers: 25)
American Journal of Plant Physiology     Open Access   (Followers: 13)
American Mineralogist     Full-text available via subscription   (Followers: 12)
Analyst     Full-text available via subscription   (Followers: 38)
Angewandte Chemie     Hybrid Journal   (Followers: 153)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 203)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 1)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 3)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 7)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 12)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 14)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Hybrid Journal  
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 6)
Applied Spectroscopy     Full-text available via subscription   (Followers: 22)
Applied Surface Science     Hybrid Journal   (Followers: 26)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 2)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Atomization and Sprays     Full-text available via subscription   (Followers: 3)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 9)
Biochemistry     Full-text available via subscription   (Followers: 277)
Biochemistry Insights     Open Access   (Followers: 5)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 9)
Bioinspired Materials     Open Access   (Followers: 3)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access  
Biomacromolecules     Full-text available via subscription   (Followers: 18)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 6)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 4)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 107)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 99)
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: 2)
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 2)
Canadian Journal of Chemistry     Full-text available via subscription   (Followers: 10)
Canadian Mineralogist     Full-text available via subscription   (Followers: 3)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 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: 69)
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: 165)
Chemical Science     Open Access   (Followers: 21)
Chemical Technology     Open Access   (Followers: 15)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 4)
Chemical Week     Full-text available via subscription   (Followers: 7)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 55)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 25)
ChemInform     Hybrid Journal   (Followers: 7)
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: 136)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 15)
Chemistry and Materials Research     Open Access   (Followers: 17)
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: 43)
Chemistry of Materials     Full-text available via subscription   (Followers: 189)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry-Didactics-Ecology-Metrology     Open Access  
ChemistryOpen     Open Access   (Followers: 2)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 2)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 15)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 8)
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: 23)
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: 10)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Metabolomics     Hybrid Journal   (Followers: 4)
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 48)
Dalton Transactions     Full-text available via subscription   (Followers: 18)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)
Diamond and Related Materials     Hybrid Journal   (Followers: 11)
Dislocations in Solids     Full-text available via subscription  
Doklady Chemistry     Hybrid Journal  
Drying Technology: An International Journal     Hybrid Journal   (Followers: 3)
Eclética Química     Open Access   (Followers: 1)
Ecological Chemistry and Engineering S     Open Access   (Followers: 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: 8)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 4)
Environmental Science & Technology Letters     Full-text available via subscription   (Followers: 5)
Environmental Science : Nano     Partially Free   (Followers: 1)
Environmental Toxicology & Chemistry     Hybrid Journal   (Followers: 19)

        1 2 3 | Last

Journal Cover Bioorganic & Medicinal Chemistry Letters
  [SJR: 0.952]   [H-I: 112]   [99 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0960-894X
   Published by Elsevier Homepage  [3031 journals]
  • Pharmacological property optimization for allosteric ligands: A medicinal
           chemistry perspective
    • Authors: Shawn Johnstone; Jeffrey S. Albert
      Pages: 2239 - 2258
      Abstract: Publication date: 1 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 11
      Author(s): Shawn Johnstone, Jeffrey S. Albert
      New strategies to potentially improve drug safety and efficacy emerge with allosteric programs. Biased allosteric modulators can be designed with high subtype selectivity and defined receptor signaling endpoints, however, selecting the most meaningful parameters for optimization can be perplexing. Historically, “potency hunting” at the expense of physicochemical and pharmacokinetic optimization has led to numerous tool compounds with excellent pharmacological properties but no path to drug development. Conversely, extensive physicochemical and pharmacokinetic screening with only post hoc bias and allosteric characterization has led to inefficacious compounds or compounds with on-target toxicities. This field is rapidly evolving with new mechanistic understanding, changes in terminology, and novel opportunities. The intent of this digest is to summarize current understanding and debates within the field. We aim to discuss, from a medicinal chemistry perspective, the parameter choices available to drive SAR.
      Graphical abstract image

      PubDate: 2017-05-11T01:58:09Z
      DOI: 10.1016/j.bmcl.2017.03.084
       
  • Recent advances in the chemistry and biology of anti-inflammatory and
           specialized pro-resolving mediators biosynthesized from n-3
           docosapentaenoic acid
    • Authors: Anders Vik; Jesmond Dalli; Trond Vidar Hansen
      Pages: 2259 - 2266
      Abstract: Publication date: 1 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 11
      Author(s): Anders Vik, Jesmond Dalli, Trond Vidar Hansen
      Several novel oxygenated polyunsaturated lipid mediators biosynthesized from n-3 docosapentaenoic acid were recently isolated from murine inflammatory exudates and human primary cells. These compounds belong to a distinct family of specialized pro-resolving mediators, and display potent in vivo anti-inflammatory and pro-resolution effects. The endogenously formed specialized pro-resolving mediators have attracted a great interest as lead compounds in drug discovery programs towards the development of new classes of drugs that dampen inflammation without interfering with the immune response. Detailed information on the chemical structures, cellular functions and distinct biosynthetic pathways of specialized pro-resolving lipid mediators is a central aspect of these biological actions. Herein, the isolation, structural elucidation, biosynthetic pathways, total synthesis and bioactions of the n-3 docosapentaenoic acid derived mediators PD1n-3 DPA and MaR1n-3 DPA are discussed. In addition, a brief discussion of a novel family of mediators derived from n-3 docosapentaenoic acid, termed 13-series resolvins is included.
      Graphical abstract image

      PubDate: 2017-05-11T01:58:09Z
      DOI: 10.1016/j.bmcl.2017.03.079
       
  • Cytotoxic steroidal saponins from Trillium kamtschaticum
    • Authors: Xu-Jie Qin; Yong-Ai Si; Yu Chen; Hui Liu; Wei Ni; Huan Yan; Tong Shu; Yun-Heng Ji; Hai-Yang Liu
      Pages: 2267 - 2273
      Abstract: Publication date: 1 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 11
      Author(s): Xu-Jie Qin, Yong-Ai Si, Yu Chen, Hui Liu, Wei Ni, Huan Yan, Tong Shu, Yun-Heng Ji, Hai-Yang Liu
      Eight new steroidal saponins, trillikamtosides K–R (1–8), along with three known analogues, were isolated from the whole plants of Trillium kamtschaticum. Their structures were unambiguously established by interpretation of spectroscopic data (MS and NMR) and chemical methods. Compound 1 had a rare aglycone featuring a skeleton of 16-oxaandrost-5-en-3-ol-17-one, which was reported for the first time. The isolated saponins were tested for cytotoxicities against HCT116 cells, and trillikamtoside R (8) was found to show the most cytotoxic effect with an IC50 value of 4.92μM.
      Graphical abstract image

      PubDate: 2017-05-11T01:58:09Z
      DOI: 10.1016/j.bmcl.2017.04.057
       
  • Structure-related protein tyrosine phosphatase 1B inhibition by naringenin
           derivatives
    • Authors: Hyun Ah Jung; Pradeep Paudel; Su Hui Seong; Byung-Sun Min; Jae Sue Choi
      Pages: 2274 - 2280
      Abstract: Publication date: 1 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 11
      Author(s): Hyun Ah Jung, Pradeep Paudel, Su Hui Seong, Byung-Sun Min, Jae Sue Choi
      Naturally occurring flavonoids co-exist as glycoside conjugates, which dominate aglycones in their content. To unveil the structure-activity relationship of a naturally occurring flavonoid, we investigated the effects of the glycosylation of naringenin on the inhibition of enzyme systems related to diabetes (protein tyrosine phosphatase 1B (PTP1B) and α-glycosidase) and on glucose uptake in the insulin-resistant state. Among the tested naringenin derivatives, prunin, a single-glucose-containing flavanone glycoside, potently inhibited PTP1B with an IC50 value of 17.5±2.6µM. Naringenin, which lacks a sugar molecule, was the weakest inhibitor compared to the reference compound, ursolic acid (IC50: 5.4±0.30µM). In addition, prunin significantly enhanced glucose uptake in a dose-dependent manner in insulin-resistant HepG2 cells. Regarding the inhibition of α-glucosidase, naringenin exhibited more potent inhibitory activity (IC50: 10.6±0.49µM) than its glycosylated forms and the reference inhibitor, acarbose (IC50: 178.0±0.27µM). Among the glycosides, only prunin (IC50: 106.5±4.1µM) was more potent than the positive control. A molecular docking study revealed that prunin had lower binding energy and higher binding affinity than glycosides with higher numbers of H-bonds, suggesting that prunin is the best fit to the PTP1B active site cavity. Therefore, in addition to the number of H-bonds present, possible factors affecting the protein binding and PTP1B inhibition of flavanones include their fit to the active site, hydrogen-bonding affinity, Van der Waals interactions, H-bond distance, and H-bond stability. Furthermore, this study clearly depicted the association of the intensity of bioactivity with the arrangement and characterization of the sugar moiety on the flavonoid skeleton.
      Graphical abstract image

      PubDate: 2017-05-11T01:58:09Z
      DOI: 10.1016/j.bmcl.2017.04.054
       
  • Design, synthesis and evaluation of
           1,3,6-trisubstituted-4-oxo-1,4-dihydroquinoline-2-carboxylic acid
           derivatives as ETA receptor selective antagonists using FRET assay
    • Authors: Nikhil Khadtare; Ralph Stephani; Vijaya Korlipara
      Pages: 2281 - 2285
      Abstract: Publication date: 1 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 11
      Author(s): Nikhil Khadtare, Ralph Stephani, Vijaya Korlipara
      The endothelin axis and in particular the two receptor subtypes, ETA and ETB, are under investigation for the treatment of various diseases such as pulmonary arterial hypertension, fibrosis, renal failure and cancer. Previous work in our lab has shown that 1,3,6-trisubstituted-4-oxo-1,4-dihydroquinoline-2-carboxylic acid derivatives exhibit noteworthy endothelin receptor antagonist activity. A series of analogues with modifications centered around position 6 of the heterocyclic quinolone core and replacement of the aryl carboxylic acid group with an isosteric tetrazole ring was designed and synthesized to further optimize the structure activity relationship. The endothelin receptor antagonist activity was determined by in vitro Förster resonance energy transfer (FRET) using GeneBLAzer® assay technology. The most potent member of this series exhibited ETA receptor antagonist activity in the subnanomolar range with an IC50 value of 0.8nM, and was 1000-fold selective for the ETA receptor compared to the ETB receptor. Its activity and selectivity profile resembles that of the most recently approved drug, macitentan.
      Graphical abstract image

      PubDate: 2017-05-11T01:58:09Z
      DOI: 10.1016/j.bmcl.2017.04.049
       
  • Brefeldin A enhances docetaxel-induced growth inhibition and apoptosis in
           prostate cancer cells in monolayer and 3D cultures
    • Authors: Huarong Huang; Ting Liu; Junxi Guo; Lin Yu; Xiaofeng Wu; Yan He; Dongli Li; Junlei Liu; Kun Zhang; Xi Zheng; Susan Goodin
      Pages: 2286 - 2291
      Abstract: Publication date: 1 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 11
      Author(s): Huarong Huang, Ting Liu, Junxi Guo, Lin Yu, Xiaofeng Wu, Yan He, Dongli Li, Junlei Liu, Kun Zhang, Xi Zheng, Susan Goodin
      Docetaxel is a commonly used chemotherapeutic drug for patients with late stage prostate cancer. However, serious side effect and drug resistance limit its clinical success. Brefeldin A is a 16-membered macrolide antibiotic from mangrove-derived Fungus Aspergillus sp. (9Hu), which exhibited potent cytotoxicity against human cancer cells. In the present study, we determined the effect of brefeldin A on docetaxel-induced growth inhibition and apoptosis in human prostate cancer PC-3 cells. Brefeldin A in combination with docetaxel inhibited the growth of PC-3 cells in monolayer and in three dimensional cultures. The combination also potently stimulated apoptosis in PC-3 cells as determined by propidium iodide staining and morphological assessment. Mechanistic studies showed that growth inhibition and apoptosis in PC-3 cells treated with brefeldin A and docetaxel were associated with decrease in the level of Bcl-2. The present study indicates that combined brefeldin A with docetaxel may represent a novel approach for improving the efficacy of docetaxel, and Bcl-2 may serve as a target for brefeldin A to enhance the effects of docetaxel chemotherapy.
      Graphical abstract image

      PubDate: 2017-05-11T01:58:09Z
      DOI: 10.1016/j.bmcl.2017.04.047
       
  • Copalic acid analogs down-regulate androgen receptor and inhibit small
           chaperone protein
    • Authors: Nethrie D. Idippily; Qiaoyun Zheng; Chunfang Gan; Aicha Quamine; Morgan M. Ashcraft; Bo Zhong; Bin Su
      Pages: 2292 - 2295
      Abstract: Publication date: 1 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 11
      Author(s): Nethrie D. Idippily, Qiaoyun Zheng, Chunfang Gan, Aicha Quamine, Morgan M. Ashcraft, Bo Zhong, Bin Su
      Copalic acid, one of the diterpenoid acids in copaiba oil, inhibited the chaperone function of α-crystallin and heat shock protein 27kD (HSP27). It also showed potent activity in decreasing an HSP27 client protein, androgen receptor (AR), which makes it useful in prostate cancer treatment or prevention. To develop potent drug candidates to decrease the AR level in prostate cancer cells, more copalic acid analogs were synthesized. Using the level of AR as the readout, 15 of the copalic acid analogs were screened and two compounds were much more potent than copalic acid. The compounds also dose-dependently inhibited AR positive prostate cancer cell growth. Furthermore, they inhibited the chaperone activity of α-crystallin as well.
      Graphical abstract image

      PubDate: 2017-05-11T01:58:09Z
      DOI: 10.1016/j.bmcl.2017.04.046
       
  • Optimization of M4 positive allosteric modulators (PAMs): The discovery of
           VU0476406, a non-human primate in vivo tool compound for translational
           pharmacology
    • Authors: Bruce J. Melancon; Michael R. Wood; Meredith J. Noetzel; Kellie D. Nance; Eileen M. Engelberg; Changho Han; Atin Lamsal; Sichen Chang; Hyekyung P. Cho; Frank W. Byers; Michael Bubser; Carrie K. Jones; Colleen M. Niswender; Michael W. Wood; Darren W. Engers; Dedong Wu; Nicholas J. Brandon; Mark E. Duggan; P. Jeffrey Conn; Thomas M. Bridges; Craig W. Lindsley
      Pages: 2296 - 2301
      Abstract: Publication date: 1 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 11
      Author(s): Bruce J. Melancon, Michael R. Wood, Meredith J. Noetzel, Kellie D. Nance, Eileen M. Engelberg, Changho Han, Atin Lamsal, Sichen Chang, Hyekyung P. Cho, Frank W. Byers, Michael Bubser, Carrie K. Jones, Colleen M. Niswender, Michael W. Wood, Darren W. Engers, Dedong Wu, Nicholas J. Brandon, Mark E. Duggan, P. Jeffrey Conn, Thomas M. Bridges, Craig W. Lindsley
      This letter describes the further chemical optimization of the 5-amino-thieno[2,3-c]pyridazine series (VU0467154/VU0467485) of M4 positive allosteric modulators (PAMs), developed via iterative parallel synthesis, culminating in the discovery of the non-human primate (NHP) in vivo tool compound, VU0476406 (8p). VU0476406 is an important in vivo tool compound to enable translation of pharmacodynamics from rodent to NHP, and while data related to a Parkinson’s disease model has been reported with 8p, this is the first disclosure of the optimization and discovery of VU0476406, as well as detailed pharmacology and DMPK properties.
      Graphical abstract image

      PubDate: 2017-05-11T01:58:09Z
      DOI: 10.1016/j.bmcl.2017.04.043
       
  • Stereoselective synthesis of enantiopure N-substituted
           pyrrolidin-2,5-dione derivatives by 1,3-dipolar cycloaddition and
           assessment of their in vitro antioxidant and antibacterial activities
    • Authors: Siwar Ghannay; Sana Bakari; Ameni Ghabi; Adel Kadri; Moncef Msaddek; Kaïss Aouadi
      Pages: 2302 - 2307
      Abstract: Publication date: 1 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 11
      Author(s): Siwar Ghannay, Sana Bakari, Ameni Ghabi, Adel Kadri, Moncef Msaddek, Kaïss Aouadi
      1,3-Dipolar cycloaddition between a chiral nitrone and N-substituted maleimides afforded unprecedented enantiopure spiro-fused heterocycles in good yields with a high enantio- and diastereoselectivity. The reaction was taking place on the less hindered face of the nitrone. The obtaining heterocycles were screened for their in vitro antioxidant properties and the results revealed that the potent antioxidant activity was generally recorded to compounds (3g) and (3e). The in vitro antibacterial activities of these two compounds were also investigated and the results demonstrated the strongest potential of compound (3g) against all the tested bacteria. Molecular properties were analyzed and showed good oral drug candidate like properties and that could be exploited as a potential antioxidant and antimicrobial agent. Finally, the preliminary results obtained from this investigation attempted to clarify if the structurally different side chains of active compounds interfere with their biological properties.
      Graphical abstract image

      PubDate: 2017-05-11T01:58:09Z
      DOI: 10.1016/j.bmcl.2017.04.044
       
  • Novel non-trimethoxylphenyl piperlongumine derivatives selectively kill
           cancer cells
    • Authors: Youjun Zhang; Hao Ma; Yuelin Wu; Zhongli Wu; Zhengguang Yao; Wannian Zhang; Chunlin Zhuang; Zhenyuan Miao
      Pages: 2308 - 2312
      Abstract: Publication date: 1 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 11
      Author(s): Youjun Zhang, Hao Ma, Yuelin Wu, Zhongli Wu, Zhengguang Yao, Wannian Zhang, Chunlin Zhuang, Zhenyuan Miao
      Piperlongumine (PL) is a natural alkaloid with broad biological activities. Twelve analogues have been designed and synthesized with non-substituted benzyl rings or heterocycles in this work. Most of the compounds showed better anticancer activities than the parent PL without apparent toxicity in normal cells. Elevation of cellular ROS levels was one of the main anticancer mechanisms of these compounds. Cell apoptosis and cell cycle arrest for the best compound ZM90 were evaluated and similar mechanism of action with PL was demonstrated. The SAR was also characterized, providing worthy directions for further optimization of PL compounds.
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      PubDate: 2017-05-11T01:58:09Z
      DOI: 10.1016/j.bmcl.2017.04.035
       
  • Approaches towards the development of chimeric DPP4/ACE inhibitors for
           treating metabolic syndrome
    • Authors: Jitendra A. Sattigeri; Sachin Sethi; Joseph A. Davis; Shahadat Ahmed; Geeta V. Rayasam; Balasaheb G. Jadhav; Satya M. Chilla; Dhrubajyoti Datta; A. Gadhave; Vamshi K. Tulasi; Tarun Jain; Sreedhara Voleti; Biju Benjamin; Sunitha Udupa; Garima Jain; Yogender Singh; Kona Srinivas; Vinay S. Bansal; Abhijit Ray; Pradip K. Bhatnagar; Ian A. Cliffe
      Pages: 2313 - 2318
      Abstract: Publication date: 1 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 11
      Author(s): Jitendra A. Sattigeri, Sachin Sethi, Joseph A. Davis, Shahadat Ahmed, Geeta V. Rayasam, Balasaheb G. Jadhav, Satya M. Chilla, Dhrubajyoti Datta, A. Gadhave, Vamshi K. Tulasi, Tarun Jain, Sreedhara Voleti, Biju Benjamin, Sunitha Udupa, Garima Jain, Yogender Singh, Kona Srinivas, Vinay S. Bansal, Abhijit Ray, Pradip K. Bhatnagar, Ian A. Cliffe
      Designing drug candidates exhibiting polypharmacology is one of the strategies adopted by medicinal chemists to address multifactorial diseases. Metabolic disease is one such multifactorial disorder characterized by hyperglycaemia, hypertension and dyslipidaemia among others. In this paper we report a new class of molecular framework combining the pharmacophoric features of DPP4 inhibitors with those of ACE inhibitors to afford potent dual inhibitors of DPP4 and ACE.
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      PubDate: 2017-05-11T01:58:09Z
      DOI: 10.1016/j.bmcl.2017.04.036
       
  • Acetanilide and bromoacetyl-lysine derivatives as activators for human
           histone deacetylase 8
    • Authors: Yusif M. Mukhtar; Yajun Huang; Jiajia Liu; Di Chen; Weiping Zheng
      Pages: 2319 - 2323
      Abstract: Publication date: 1 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 11
      Author(s): Yusif M. Mukhtar, Yajun Huang, Jiajia Liu, Di Chen, Weiping Zheng
      In the current study, seven compounds (i.e. 1–7) were found to be novel activators for the Nε-acetyl-lysine deacetylation reaction catalyzed by human histone deacetylase 8 (HDAC8). When assessed with the commercially available HDAC8 peptide substrate Fluor-de-Lys®-HDAC8 that harbors the unnatural 7-amino-4-methylcoumarin (AMC) residue immediately C-terminal to the Nε-acetyl-lysine residue to be deacetylated, our compounds exhibited comparable activation potency to that of TM-2-51, the strongest HDAC8 activator reported in the current literature. However, when assessed with an AMC-less peptide substrate derived from the native HDAC8 non-histone substrate protein Zinc finger protein ZNF318, while our compounds were all found to be able to activate HDAC8 deacetylation reaction, TM-2-51 was found not to be able to. Our compounds also seemed to be largely selective for HDAC8 over other classical HDACs. Moreover, treatment with the strongest activator among our compounds (i.e. 7) was found to decrease the K M of the above AMC-less HDAC8 substrate, while nearly maintaining the k cat of the HDAC8-catalyzed deacetylation on this substrate.
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      PubDate: 2017-05-11T01:58:09Z
      DOI: 10.1016/j.bmcl.2017.04.037
       
  • Identification of low micromolar dual inhibitors for aldose reductase
           (ALR2) and poly (ADP-ribose) polymerase (PARP-1) using structure based
           design approach
    • Authors: Navriti Chadha; Om Silakari
      Pages: 2324 - 2330
      Abstract: Publication date: 1 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 11
      Author(s): Navriti Chadha, Om Silakari
      Clinical studies have revealed that diabetic retinopathy is a multifactorial disorder. Moreover, studies also suggest that ALR2 and PARP-1 co-occur in retinal cells, making them appropriate targets for the treatment of diabetic retinopathy. To find the dual inhibitors of ALR2 and PARP-1, the structure based design was carried out in parallel for both the target proteins. A series of novel thiazolidine-2,4-dione (TZD) derivatives were therefore rationally designed, synthesized and their in vitro inhibitory activities against ALR2 and PARP-1 were evaluated. The experimental results showed that compounds 5b and 5f, with 2-chloro and 4-fluoro substitutions, showed biochemical activities in micromolar and submicromolar range (IC50 1.34–5.03μM) against both the targeted enzymes. The structure-activity relationship elucidated for these novel inhibitors against both the enzymes provide new insight into the binding mode of the inhibitors to the active sites of enzymes. The positive results of the biochemical assay suggest that these compounds may be further optimized and utilized for the treatment of diabetic retinopathy.
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      PubDate: 2017-05-11T01:58:09Z
      DOI: 10.1016/j.bmcl.2017.04.038
       
  • Potent and selective oxytocin receptor agonists without disulfide bridges
    • Authors: Yusuke Adachi; Katsuya Sakimura; Yuji Shimizu; Masaharu Nakayama; Yasuko Terao; Takahiko Yano; Taiji Asami
      Pages: 2331 - 2335
      Abstract: Publication date: 1 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 11
      Author(s): Yusuke Adachi, Katsuya Sakimura, Yuji Shimizu, Masaharu Nakayama, Yasuko Terao, Takahiko Yano, Taiji Asami
      Oxytocin (OT) is a neuropeptide involved in a wide variety of physiological actions, both peripherally and centrally. Many human studies have revealed the potential of OT to treat autism spectrum disorders and schizophrenia. OT interacts with the OT receptor (OTR) as well as vasopressin 1a and 1b receptors (V1aR, V1bR) as an agonist, and agonistic activity for V1aR and V1bR may have a negative impact on the therapeutic effects of OTR agonism in the CNS. An OTR-selective agonistic peptide, FE 202767, in which the structural differences from OT are a sulfide bond instead of a disulfide bond, and N-alkylglycine replacement for Pro at position 7, was reported. However, the effects of amino acid substitutions in OT have not been comprehensively investigated to compare OTR, V1aR, and V1bR activities. This led us to obtain a new OTR-selective analog by comprehensive amino acid substitutions of OT and replacement of the disulfide bond. A systematic amino acid scanning (Ala, Leu, Phe, Ser, Glu, or Arg) of desamino OT (dOT) at positions 2, 3, 4, 5, 7, and 8 revealed the tolerability for the substitution at positions 7 and 8. Further detailed study showed that trans-4-hydroxyproline (trans-Hyp) at position 7 and γ-methylleucine [Leu(Me)] at position 8 were markedly effective for improving receptor selectivity without decreasing the potency at the OTR. Subsequently, a combination of these amino acid substitutions with the replacement of the disulfide bond of dOT analogs with a sulfide bond (carba analog) or an amide bond (lactam analog) yielded several promising analogs, including carba-1-[trans-Hyp7,Leu(Me)8]dOT (14) with a higher potency (7.2pM) at OTR than that of OT and marked selectivity (>10,000-fold) over V1aR and V1bR. Hence, we investigated comprehensive modification of OT and obtained new OT analogs that exhibited high potency at OTR with marked selectivity. These OTR-selective agonists could be useful to investigate OTR-mediated effects on psychiatric disorders.
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      PubDate: 2017-05-11T01:58:09Z
      DOI: 10.1016/j.bmcl.2017.04.030
       
  • Evaluation of synthesized coumarin derivatives on aromatase inhibitory
           activity
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Yuki Yamaguchi, Naozumi Nishizono, Daisuke Kobayashi, Teruki Yoshimura, Keiji Wada, Kazuaki Oda
      In women across the world, the most common type of cancer is breast cancer. Among medical treatments, endocrine therapy based on aromatase inhibitors (AI) is expected to be effective against not only post-menopausal but also pre-menopausal breast cancer. In this study, we examined the structure–activity relationship between the aromatase inhibitory effects of 7-diethylaminocoumarin derivatives with a substituent at position 3 and coumarin derivatives with a substituent at position 7. Consequently, we found that 7-(pyridin-3-yl)coumarin (IC50 values 30.3nM) and 7,7′-diethylamino-3,3′-biscoumarin (28.7nM) are the most potent inhibitors of aromatase. These inhibitors were found to be comparable to the existing CYP19 inhibitor exemestane (42.5nM).
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      PubDate: 2017-05-25T15:10:58Z
       
  • Neutral macrocyclic factor VIIa inhibitors
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Nicholas R. Wurtz, Brandon L. Parkhurst, Indawati DeLucca, Peter W. Glunz, Wen Jiang, Xiaojun Zhang, Daniel L. Cheney, Jeffrey M. Bozarth, Alan R. Rendina, Anzhi Wei, Tim Harper, Joseph M. Luettgen, Yiming Wu, Pancras C. Wong, Dietmar A. Seiffert, Ruth R. Wexler, E. Scott Priestley
      Factor VIIa (FVIIa) inhibitors have shown strong antithrombotic efficacy in preclinical thrombosis models with limited bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful due to the requirement of a basic P1 group to interact with Asp189 in the S1 binding pocket, limiting their membrane permeability. We have combined recently reported neutral P1 binding substituents with a highly optimized macrocyclic chemotype to produce FVIIa inhibitors with low nanomolar potency and enhanced permeability.
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      PubDate: 2017-05-25T15:10:58Z
       
  • Nucleobase azide–ethynylribose click chemistry contributes to
           stabilizing oligonucleotide duplexes and stem-loop structures
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Yoshiaki Kitamura, Ryo Asakura, Koki Terazawa, Aya Shibata, Masato Ikeda, Yukio Kitade
      The formation of 1,4-disubstituted 1,2,3-triazoles through copper-catalyzed azide–alkyne cycloaddition (CuAAC) in oligonucleotides bearing 1-deoxy-1-ethynyl-β-d-ribofuranose (RE) can have a positive impact on the stability of oligonucleotide duplexes and stem-loop structures.
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      PubDate: 2017-05-25T15:10:58Z
       
  • Sulfoximines as ATR inhibitors: Analogs of VE-821
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Christine M.M. Hendriks, Jörg Hartkamp, Stefan Wiezorek, Anne-Dorothee Steinkamp, Giulia Rossetti, Bernhard Lüscher, Carsten Bolm
      The ATM- and Rad3-related (ATR) kinases play a key role in DNA repair processes and thus ATR is an attractive target for cancer therapy. Here we designed and synthesized sulfilimidoyl- and sulfoximidoyl-substituted analogs of the sulfone VE-821, a reported ATR inhibitor. The properties of these analogs have been investigated by calculating physicochemical parameters and studying their potential to specifically inhibit ATR in cells. Prolonged inhibition of ATR by the analogs in a Burkitt lymphoma cell line resulted in enhanced DNA damage and a substantial amount of apoptosis. Together our findings suggest that the sulfilimidoyl- and sulfoximidoyl-substituted analogs are efficient ATR inhibitors.
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      PubDate: 2017-05-25T15:10:58Z
       
  • N-(1H-Pyrazol-3-yl)quinazolin-4-amines as a novel class of casein kinase
           1δ/ε inhibitors: Synthesis, biological evaluation and molecular modeling
           studies
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Chandrabose Karthikeyan, Pramod Jharia, Digambar Kumar Waiker, Amy Catherine Nusbaum, Haneen Amawi, Erin Marie Kirwen, Ryann Christman, Sri Krishna Chaitanya Arudra, Laurent Meijer, Amit K. Tiwari, Piyush Trivedi
      Described herein is the design, synthesis and biological evaluation of a series of N-(1H-pyrazol-3-yl)quinazolin-4-amines against a panel of eight disease relevant protein kinases. The kinase inhibition results indicated that two compounds inhibited casein kinase 1δ/ε (CK1δ/ε) with some selectivity over related kinases, namely CDK5/p25, GSK-3α/β, and DYRK1A. Docking studies with 3c and 3d revealed the key interactions with desired amino acids in the ATP binding site of CK1δ. Furthermore, compound 3c also elicited selective cytotoxic activity against the pancreas ductal adenocarcinoma (PANC-1) cell line. Taken together, the results of this study establish N-(1H-pyrazol-3-yl)quinazolin-4-amines especially 3c and 3d as valuable lead molecules with great potential for CK1δ/ε inhibitor development targeting neurodegenerative disorders and cancer.
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      PubDate: 2017-05-25T15:10:58Z
       
  • Design, synthesis, biological evaluation and molecular docking studies of
           novel 3-aryl-4-anilino-2H-chromen-2-one derivatives targeting ERα as
           anti-breast cancer agents
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Guoshun Luo, Mingqi Chen, Weiting Lyu, Ruheng Zhao, Qian Xu, Qidong You, Hua Xiang
      The estrogen receptor (ER) has played an important role in breast cancer development and progression and is a central target for anticancer drug discovery. In order to develop novel selective ERα modulators (SERMs), we designed and synthesized 18 novel 3-aryl-4-anilino-2H-chromen-2-one derivatives based on previously reported lead compounds. The biological results indicated that most of the compounds presented potent ERα binding affinity and possessed better anti-proliferative activities against MCF-7 and Ishikawa cell lines than the positive control tamoxifen. The piperidyl substituted compounds such as 16d and 18d demonstrated strong ERα binding affinities and excellent anti-proliferative activities respectively. Compound 18d displayed the most potent ERα binding affinity with RBA value of 2.83%, while 16d exhibited the best anti-proliferative activity against MCF-7 cells with IC50 value of 4.52±2.47μM. Further molecular docking studies were also carried out to investigate binding pattern of the newly synthesized compounds with ERα. All these results together with the structure–activity relationships (SARs) indicated that these 3-aryl-4-anilino-2H-chromen-2-one derivatives with basic side chain could serve as promising leads for further optimization as novel SERMs.
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      PubDate: 2017-05-25T15:10:58Z
       
  • Synthesis and in vitro biological evaluation of novel coumarin derivatives
           containing isoxazole moieties on melanin synthesis in B16 cells and
           inhibition on bacteria
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Guang Xian Pang, Chao Niu, Nuramina Mamat, Haji Akber Aisa
      A novel series of coumarin derivatives 6a–o, bearing isoxazole moieties were designed and synthesized. After that, they were evaluated for melanin synthesis in murine B16 cells and inhibitory effect on the growth of CA (Candida albicans), EC (Escherichia coli), SA (Staphylococcus aureus). It was found that eleven compounds (6b–f, 6j–o) showed a better activity on melanin synthesis than positive control (8-MOP). Among them, compounds 6d (242%) and 6f (390%), with nearly 1.6 and 2.6-fold potency compared with 8-MOP (149%) respectively, were recognized as the most promising candidate hits for further pharmacological study of anti-vitiligo. Seven halogen substituted compounds exhibited moderate antimicrobial activity against CA. It is interesting that 6e–f and 6l–m, which had two halogens on the benzene showed a comparable activity with Amphotericin B against CA. The evaluation of melanin synthesis in B16 cells and inhibitory effect on bacteria of above structurally diverse derivatives had also led to an outline of structure-activity relationship.
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      PubDate: 2017-05-25T15:10:58Z
       
  • Discovery of potent and orally active 1,4-disubstituted indazoles as novel
           allosteric glucokinase activators
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Zacharia S. Cheruvallath, Stephen L. Gwaltney, Mark Sabat, Mingnam Tang, Haixia Wang, Andy Jennings, David Hosfield, Bumsup Lee, Yiqin Wu, Petro Halkowycz, Charles E. Grimshaw
      Guided by co-crystal structural information obtained from a different series we were exploring, a scaffold morphing and SBDD approach led to the discovery of the 1,4-disubstituted indazole series as a novel class of GKAs that potently activate GK in enzyme and cell assays. anti-diabetic OGTT efficacy was demonstrated with 29 in a rodent models of type 2 diabetes.
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      PubDate: 2017-05-25T15:10:58Z
       
  • Benzoxazolinone aryl sulfonamides as potent, selective Nav1.7 inhibitors
           with in vivo efficacy in a preclinical pain model
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Joseph E. Pero, Michael A. Rossi, Hannah D.G.F. Lehman, Michael J. Kelly, James J. Mulhearn, Scott E. Wolkenberg, Matthew J. Cato, Michelle K. Clements, Christopher J. Daley, Tracey Filzen, Eleftheria N. Finger, Yun Gregan, Darrell A. Henze, Aneta Jovanovska, Rebecca Klein, Richard L. Kraus, Yuxing Li, Annie Liang, John M. Majercak, Jacqueline Panigel, Mark O. Urban, Jixin Wang, Ying-Hong Wang, Andrea K. Houghton, Mark E. Layton
      Studies on human genetics have suggested that inhibitors of the Nav1.7 voltage-gated sodium channel hold considerable promise as therapies for the treatment of chronic pain syndromes. Herein, we report novel, peripherally-restricted benzoxazolinone aryl sulfonamides as potent Nav1.7 inhibitors with excellent selectivity against the Nav1.5 isoform, which is expressed in the heart muscle. Elaboration of initial lead compound 3d afforded exemplar 13, which featured attractive physicochemical properties, outstanding lipophilic ligand efficiency and pharmacological selectivity against Nav1.5 exceeding 1000-fold. Key structure-activity relationships associated with oral bioavailability were leveraged to discover compound 17, which exhibited a comparable potency/selectivity profile as well as full efficacy following oral administration in a preclinical model indicative of antinociceptive behavior.
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      PubDate: 2017-05-25T15:10:58Z
       
  • Discovery of a novel and potent class of anti-HIV-1 maturation inhibitors
           with improved virology profile against gag polymorphisms
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Jun Tang, Stacey A. Jones, Jerry L. Jeffrey, Sonia R. Miranda, Cristin M. Galardi, David M. Irlbeck, Kevin W. Brown, Charlene B. McDanal, Brian A. Johns
      A new class of betulin-derived α-keto amides was identified as HIV-1 maturation inhibitors. Through lead optimization, GSK8999 was identified with IC50 values of 17nM, 23nM, 25nM, and 8nM for wild type, Q369H, V370A, and T371A respectively. When tested in a panel of 62 HIV-1 isolates covering a diversity of CA-SP1 genotypes including A, AE, B, C, and G using a PBMC based assay, GSK8999 was potent against 57 of 62 isolates demonstrating an improvement over the first generation maturation inhibitor BVM. The data disclosed here also demonstrated that the new α-keto amide GSK8999 has a mechanism of action consistent with inhibition of the proteolytic cleavage of CA-SP1.
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      PubDate: 2017-05-25T15:10:58Z
       
  • Design, synthesis and SAR of substituted indoles as selective TrkA
           inhibitors
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Danielle M. Hurzy, Darrell A. Henze, Tamara D. Cabalu, Kartik Narayan, Amanda Heller, Andrew J. Cooke
      A series of substituted indoles were examined as selective inhibitors of tropomyosin-related kinase receptor A (TrkA), a therapeutic target for the treatment of pain. An SAR optimization campaign based on ALIS screening lead compound 1 is reported.
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      PubDate: 2017-05-25T15:10:58Z
       
  • Optimization of a binding fragment targeting the “enlarged methionine
           pocket” leads to potent Trypanosoma brucei methionyl-tRNA synthetase
           inhibitors
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Wenlin Huang, Zhongsheng Zhang, Ranae M. Ranade, J. Robert Gillespie, Ximena Barros-Álvarez, Sharon A. Creason, Sayaka Shibata, Christophe L.M.J. Verlinde, Wim G.J. Hol, Frederick S. Buckner, Erkang Fan
      Potent inhibitors of Trypanosoma brucei methionyl-tRNA synthetase were previously designed using a structure-guided approach. Compounds 1 and 2 were the most active compounds in the cyclic and linear linker series, respectively. To further improve cellular potency, SAR investigation of a binding fragment targeting the “enlarged methionine pocket” (EMP) was performed. The optimization led to the identification of a 6,8-dichloro-tetrahydroquinoline ring as a favorable fragment to bind the EMP. Replacement of 3,5-dichloro-benzyl group (the EMP binding fragment) of inhibitor 2 using this tetrahydroquinoline fragment resulted in compound 13, that exhibited an EC50 of 4nM.
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      PubDate: 2017-05-25T15:10:58Z
       
  • Discovery of novel substituted benzo-anellated 4-benzylamino
           pyrrolopyrimidines as dual EGFR and VEGFR2 inhibitors
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Tim Fischer, Thomas Krüger, Abdulkarim Najjar, Frank Totzke, Christoph Schächtele, Wolfgang Sippl, Christoph Ritter, Andreas Hilgeroth
      The quinazoline scaffold is the main part of many marketed EGFR inhibitors. Resistance developments against those inhibitors enforced the search for novel structural lead compounds. We developed novel benzo-anellated 4-benzylamine pyrrolopyrimidines with varied substitution patterns at both the molecular scaffold and the attached residue in the 4-position. The structure-dependent affinities towards EGFR are discussed and first nanomolar derivatives have been identified. Docking studies were carried out for EGFR in order to explore the potential binding mode of the novel inhibitors. As the receptor tyrosine kinase VEGFR2 recently gained an increasing interest as an upregulated signaling kinase in many solid tumors and in tumor metastasis we determined the affinity of our compounds to inhibit VEGFR2. So we identified novel dually acting EGFR and VEGFR2 inhibitors for which first anticancer screening data are reported. Those data indicate a stronger antiproliferative effect of a VEGFR2 inhibition compared to the EGFR inhibition.
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      PubDate: 2017-05-25T15:10:58Z
       
  • Thio-functionalized carbohydrate thiosemicarbazones and evaluation of
           their anticancer activity
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Anna Czubatka-Bieńkowska, Joanna Sarnik, Anna Macieja, Grzegorz Galita, Zbigniew J. Witczak, Tomasz Poplawski
      Thiosemicarbazides and their analogs have shown potential medical applications as antiviral, antibacterial and anticancer drugs. We designed, synthesized and evaluated in vitro anticancer activity against ovarian (A2780), cervix (HeLa), colon (LoVo), breast (MCF-7) and brain (MO59J) human cancer cell lines of seven novel compounds –S-glycosylated thiosemicarbazones. We assessed the cyto- and genotoxic properties of all novel compounds using a variety of methods including comet assay, XTT assay, various fluorescent assays and toxicology PathwayFinder expression array. We tried to evaluate their possible mechanism of action with particular attention to induction of DNA damage and repair, apoptosis, oxidative stress analysis and cellular response in terms of changes in gene expression. The most sensitive cell line was human ovarian cancer. The results revealed that the major activity against A2780 cancer cell line displayed by our compounds is induction of DNA damage. This effect is not associated with apoptosis or oxidative stress induction and the resulting damage will not lead to cell cycle arrest. We also observed up-expression of heat shock related genes and NQO1 gene in response to our compounds. The second effect seems to be specific to glycosylated S-bond compounds as we observed it earlier. Upregulation of heat shock protein encoding genes suggest that our compounds induce stressful conditions. The nature of this phenomena (heat shock, pH shift or hypoxia) needs further study.
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      PubDate: 2017-05-25T15:10:58Z
       
  • Identification of quinazoline based inhibitors of IRAK4 for the treatment
           of inflammation
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Graham F. Smith, Michael D. Altman, Brian Andresen, James Baker, Jason D. Brubaker, Hongmin Chen, Yiping Chen, Matthew Childers, Anthony Donofrio, Heidi Ferguson, Christian Fischer, Thierry O. Fischmann, Craig Gibeau, Alexander Hicks, Sue Jin, Sam Kattar, Melanie A. Kleinschek, Erica Leccese, Charles Lesburg, Chaomin Li, Jongwon Lim, Duan Liu, John K.F. Maclean, Faruk Mansoor, Lilly Y. Moy, Erin F. Mulrooney, Antoaneta S. Necheva, Jeremy Presland, Larissa Rakhilina, Ruojing Yang, Luis Torres, Jie Zhang-Hoover, Alan Northrup
      Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity. These highly selective IRAK4 compounds show activity in vivo via oral dosing in a TLR7 driven model of inflammation.
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      PubDate: 2017-05-25T15:10:58Z
       
  • Synthesis and preliminary biological evaluation of [11C]methyl
           (2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucinate for the
           fractalkine receptor (CX3CR1)
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Mingzhang Gao, Min Wang, Jill A. Meyer, Jonathan S. Peters, Hamideh Zarrinmayeh, Paul R. Territo, Gary D. Hutchins, Qi-Huang Zheng
      The reference standard methyl (2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucinate (5) and its precursor 2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucine (6) were synthesized from 6-amino-2-mercaptopyrimidin-4-ol and BnBr with overall chemical yield 7% in five steps and 4% in six steps, respectively. The target tracer [11C]methyl (2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucinate ([11C]5) was prepared from the acid precursor with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 40–50% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity (SA) at EOB was 370–1110GBq/μmol with a total synthesis time of ∼40-min from EOB. The radioligand depletion experiment of [11C]5 did not display specific binding to CX3CR1, and the competitive binding assay of ligand 5 found much lower CX3CR1 binding affinity.
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      PubDate: 2017-05-25T15:10:58Z
       
  • Antitubulin effects of aminobenzothiophene-substituted triethylated
           chromones
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Yukiko Kobayashi, Yohei Saito, Masuo Goto, Kyoko Nakagawa-Goto
      In the course of our continuing studies on the 2-(benzo[b]thiophene-3′-yl)-6,8,8-triethyldesmosdumotin B (TEDB-TB) series, we designed and synthesized nine amino-TEDB-TB derivatives to improve pharmaceutical properties, identify structure activity relationships, and discover novel antitubulin agents. Among all newly synthesized amino-TEDB-TBs, the 5′- and 6′-amino derivatives, 6 and 7, exhibited significant antiproliferative activity against five human tumor cell lines, including an MDR subline overexpressing P-gp. The IC50 values of 0.50–1.01µM were 3–6 times better than those of previously reported hydroxy-TEDB-TBs. Compounds 6 and 7 inhibited tubulin polymerization, induced both depolymerization of interphase microtubules and multiple spindle formations, and caused cell arrest at prometaphase. Among all compounds, compound 7 scored best pharmaceutically with LogP 2.11 and biologically with greater antiproliferative activity and induction of cell cycle arrest at prometaphase.
      Graphical abstract image

      PubDate: 2017-05-25T15:10:58Z
       
  • An unusual spinaceamine-bearing pregnane from a soft coral Scleronephthya
           sp. inhibits the migration of tumor cells
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Wei Cheng, Zhen Liu, Yang Yu, Leen van Ofwegen, Peter Proksch, Siwang Yu, Wenhan Lin
      An unprecedented spinaceamine-bearing pregnane namely scleronine (1) was isolated from a Chinese soft coral Scleronephthya sp. Its structure was determined on the basis of 1D and 2D NMR spectroscopic analyses in association with the HRESIMS data, while the absolute configurations were deduced by the single-crystal X-ray diffraction analysis. In addition, a dehydrogenated analogue (3) was synthesized through six steps with pregna-1,20-dien-3-one (2) as a precursor. The significantly inhibitory effects of 1 and 3 against the migration of tumor cells A549 and B16 accompanying the down-regulation of key genes (TGFβ, TNFα, IL-1β, and IL-6) were observed. These findings suggested that both 1 and 3 are potential for therapeutic usage aiming at cancer metastasis inhibition.
      Graphical abstract image

      PubDate: 2017-05-25T15:10:58Z
       
  • Novel delta opioid receptor agonists with oxazatricyclodecane structure
           showing potent agonistic activities
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Kohei Hayashida, Shigeto Hirayama, Takashi Iwai, Yoshikazu Watanabe, Toshihiro Takahashi, Junichi Sakai, Eriko Nakata, Tomio Yamakawa, Hideaki Fujii, Hiroshi Nagase
      We recently reported oxazatricyclodecane derivatives 1 as δ opioid receptor (DOR) agonists having a novel chemotype, but their DOR agonistic activities were relatively low. Based on the working hypothesis that the dioxamethylene moiety in 1 may be an accessory site and that it may interfere with the sufficient conformational change of the receptor required for exerting the full agonistic responses, we designed and synthesized new oxazatricyclodecane derivatives 2–4 lacking the dioxamethylene moiety. As we expected, the designed compounds 2–4 showed pronouncedly improved agonistic activities for the DOR. Compound 2a with the 17-cyclopropylmethyl substituent was a potent agonist with the highest selectivity for the DOR and was expected to be a lead compound for novel and selective DOR agonists.
      Graphical abstract image

      PubDate: 2017-05-25T15:10:58Z
       
  • Synthesis and evaluation of phenylisoserine derivatives for the SARS-CoV
           3CL protease inhibitor
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Hiroyuki Konno, Takumi Onuma, Ikumi Nitanai, Masaki Wakabayashi, Shigekazu Yano, Kenta Teruya, Kenichi Akaji
      Synthesis and evaluation of new scaffold phenylisoserine derivatives connected with the essential functional groups against SARS CoV 3CL protease are described. The phenylisoserine backbone was found by simulation on GOLD software and the structure activity relationship study of phenylisoserine derivatives gave SK80 with an IC50 value of 43μM against SARS CoV 3CL R188I mutant protease.
      Graphical abstract image

      PubDate: 2017-05-25T15:10:58Z
       
  • Design, synthesis and biological evaluation of fucose-truncated
           monosaccharide analogues of ipomoeassin F
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Guanghui Zong, Melissa Hirsch, Collin Mondrik, Zhijian Hu, Wei Q. Shi
      Ipomoeassin F is a plant-derived macrocyclic glycolipid with single-digit nanomolar IC50 values against cancer cell growth. In previous structure–activity relationship studies, we have demonstrated that certain modifications around the fucoside moiety did not cause significant cytotoxicity loss. To further elucidate the effect of the fucoside moiety on the biological activity, we describe here the design and synthesis of several fucose-truncated monosaccharide analogues of ipomoeassin F. Subsequent biological evaluation strongly suggests that the 6-membered ring of the fucoside moiety is essential to the overall conformation of the molecule, thereby influencing bioactivity.
      Graphical abstract image

      PubDate: 2017-05-25T15:10:58Z
       
  • Investigation of the structural requirements of K-Ras(G12D) selective
           inhibitory peptide KRpep-2d using alanine scans and cysteine bridging
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Ayumu Niida, Shigekazu Sasaki, Kazuko Yonemori, Tomoya Sameshima, Masahiro Yaguchi, Taiji Asami, Kotaro Sakamoto, Masahiro Kamaura
      A structure-activity relationship study of a K-Ras(G12D) selective inhibitory cyclic peptide, KRpep-2d was performed. Alanine scanning of KRpep-2d focusing on the cyclic moiety showed that Leu7, Ile9, and Asp12 are the key elements for K-Ras(G12D) selective inhibition of KRpep-2d. The cysteine bridging was also examined to identify the stable analog of KRpep-2d under reductive conditions. As a result, the KRpep-2d analog (12) including mono-methylene bridging showed potent K-Ras(G12D) selective inhibition in both the presence and the absence of dithiothreitol. This means that mono-methylene bridging is an effective strategy to obtain a reduction-resistance analog of parent disulfide cyclic peptides. Peptide 12 inhibited proliferation of K-Ras(G12D)-driven cancer cells significantly. These results gave valuable information for further optimization of KRpep-2d to provide novel anti-cancer drug candidates targeting the K-Ras(G12D) mutant.
      Graphical abstract image

      PubDate: 2017-05-25T15:10:58Z
       
  • Isolation of the antibiotic pseudopyronine B and SAR evaluation of C3/C6
           alkyl analogs
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Leah M. Bouthillette, Catherine A. Darcey, Tess E. Handy, Sarah C. Seaton, Amanda L. Wolfe
      Natural products are an abundant source of structurally diverse compounds with antibacterial activity that can be used to develop new and potent antibiotics. One such class of natural products is the pseudopyronines. Here we present the isolation of pseudopyronine B (2) from a Pseudomonas species found in garden soil in Western North Carolina, and SAR evaluation of C3 and C6 alkyl analogs of the natural product for antibacterial activity against Gram-positive and Gram-negative bacteria. We found a direct relationship between antibacterial activity and C3/C6 alkyl chain length. For inhibition of Gram-positive bacteria, alkyl chain lengths between 6 and 7 carbons were found to be the most active (IC50 =0.04–3.8µg/mL) whereas short alkyl chain analogs showed modest activity against Gram-negative bacteria (IC50 =223–304µg/mL). This demonstrates the potential for this class of natural products to be optimized for selective activity against either Gram-positive or Gram-negative bacteria.
      Graphical abstract image

      PubDate: 2017-05-25T15:10:58Z
       
  • Activity of resveratrol triesters against primary acute lymphoblastic
           leukemia cells
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Alicja Urbaniak, Magdalena Delgado, Karol Kacprzak, Timothy C. Chambers
      Resveratrol is a common polyphenol of plant origin known for its cancer prevention and other properties. Its wider application is limited due to poor water solubility, low stability, and weak bioavailability. To overcome these limitations, a series of 13 novel resveratrol triesters were synthesized previously. In this paper, we describe the synthesis of 3 additional derivatives and the activity of all 16 against primary acute lymphoblastic leukemia cells. Of these, 3 compounds were more potent than resveratrol (IC50 =10.5µM) namely: resveratryl triacetate (IC50 =3.4µM), resveratryl triisobutyrate (IC50 =5.1µM), and resveratryl triisovalerate (IC50 =4.9µM); all other derivatives had IC50 values of >10µM. Further studies indicated that the active compounds caused G1 phase arrest, increased expression of p53, and induced characteristics of apoptotic cell death. Moreover, the compounds were only effective in cycling cells, with cells arrested in G1 phase being refractory.
      Graphical abstract image

      PubDate: 2017-05-25T15:10:58Z
       
  • Design and synthesis of a fluorinated quinazoline-based type-II Trk
           inhibitor as a scaffold for PET radiotracer development
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Vadim Bernard-Gauthier, Anne Mahringer, Matthew Vesnaver, Gert Fricker, Ralf Schirrmacher
      NTRK1/2/3 fusions have recently been characterized as low incidence oncogenic alterations across various tumor histologies. Tyrosine kinase inhibitors (TKIs) of the tropomyosin receptor kinase family TrkA/B/C (encoded by NTRK1/2/3) are showing promises in the clinic for the treatment of cancer patients whose diseases harbor NTRK tumor drivers. We describe herein the development of [18F]QMICF ([18F]-(R)-9), a quinazoline-based type-II pan-Trk radiotracer with nanomolar potencies for TrkA/B/C (IC50 =85–650nM) and relevant TrkA fusions including TrkA-TPM3 (IC50 =162nM). Starting from a racemic FLT3 (fms like tyrosine kinase 3) inhibitor lead with off-target TrkA activity ((±)-6), we developed and synthesized the fluorinated derivative (R)-9 in three steps and 40% overall chemical yield. Compound (R)-9 displays a favorable selectivity profile on a diverse set of kinases including FLT3 (>37-fold selectivity for TrkB/C). The mesylate precursor 16 required for the radiosynthesis of [18F]QMICF was obtained in six steps and 36% overall yield. The results presented herein support the further exploration of [18F]QMICF for imaging of Trk fusions in vivo.
      Graphical abstract image

      PubDate: 2017-05-25T15:10:58Z
       
  • Structure-activity relationships of rosiglitazone for peroxisome
           proliferator-activated receptor gamma transrepression
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Yosuke Toyota, Sayaka Nomura, Makoto Makishima, Yuichi Hashimoto, Minoru Ishikawa
      Anti-inflammatory effects of peroxisome proliferator-activated receptor gamma (PPRAγ) ligands are thought to be largely due to PPARγ-mediated transrepression. Thus, transrepression-selective PPARγ ligands without agonistic activity or with only partial agonistic activity should exhibit anti-inflammatory properties with reduced side effects. Here, we investigated the structure-activity relationships (SARs) of PPARγ agonist rosiglitazone, focusing on transrepression activity. Alkenic analogs showed slightly more potent transrepression with reduced efficacy of transactivating agonistic activity. Removal of the alkyl group on the nitrogen atom improved selectivity for transrepression over transactivation. Among the synthesized compounds, 3l exhibited stronger transrepressional activity (IC50: 14μM) and weaker agonistic efficacy (11%) than rosiglitazone or pioglitazone.
      Graphical abstract image

      PubDate: 2017-05-25T15:10:58Z
       
  • Phenanthridin-6-one derivatives as the first class of non-steroidal
           pharmacological chaperones for Niemann-Pick disease type C1 protein
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Hiromitsu Fukuda, Fumika Karaki, Kosuke Dodo, Tomomi Noguchi-Yachide, Minoru Ishikawa, Yuichi Hashimoto, Kenji Ohgane
      Niemann-Pick disease type C is a fatal, progressive neurodegenerative disease mostly caused by mutations in Nieamnn-Pick type C1 (NPC1), a late endosomal membrane protein that is essential for intracellular cholesterol transport. The most prevalent mutation, I1061T (Ile to Thr), interferes with the protein folding process. Consequently, mutated but intrinsically functional NPC1 proteins are prematurely degraded via proteasome, leading to loss of NPC1 function. Previously, we reported sterol derivatives as pharmacological chaperones for NPC1, and showed that these derivatives can normalize folding-defective phenotypes of I1061T NPC1 mutant by directly binding to, and stabilizing, the protein. Here, we report a series of compounds containing a phenanthridin-6-one scaffold as the first class of non-steroidal pharmacological chaperones for NPC1. We also examined their structure-activity relationships.
      Graphical abstract image

      PubDate: 2017-05-25T15:10:58Z
       
  • Drug-like property-driven optimization of 4-substituted 1,5-diarylanilines
           as potent HIV-1 non-nucleoside reverse transcriptase inhibitors against
           rilpivirine-resistant mutant virus
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Lei Wei, Hui-Ling Wang, Li Huang, Chin-Ho Chen, Susan L. Morris-Natschke, Kuo-Hsiung Lee, Lan Xie
      On the basis of our prior structure-activity relationship (SAR) results, our current lead optimization of 1,5-diarylanilines (DAANs) focused on the 4-substituent (R1) on the central phenyl ring as a modifiable position related simultaneously to improved drug resistance profiles and drug-like properties. Newly synthesized p-cyanovinyl-DAANs (8a–8g) with different R1 side chains plus prior active p-cyanoethyl-DAANs (4a–4c) were evaluated not only for anti-HIV potency against both wild-type HIV virus and rilpivirine-resistant (E138K, E138K+M184I) viral replication, but also for multiple drug-like properties, including aqueous solubility, lipophilicity, and metabolic stability in human liver microsomes and human plasma. This study revealed that both ester and amide R1 substituents led to low nanomolar anti-HIV potency against wild-type and rilpivirine-resistant viral strains (E138K-resistance fold changes<3). The N-substituted amide-R1 side chains were superior to ester-R1 likely due to improved aqueous solubility, lipophilicity, and higher metabolic stability in vitro. Thus, three amide-DAANs 8e, 4a, and 4b were identified with high potency against wild-type and rilpivirine-resistant viral strains and multiple desirable drug-like properties.
      Graphical abstract image

      PubDate: 2017-05-25T15:10:58Z
       
  • Cell line studies and analytical measurements of three paclitaxel complex
           variations
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Thomas Manning, Sydney Plummer, Rechelle Woods, Greg Wylie, Dennis Phillips, Logan Krajewski
      The copper(II) cation, sucrose, and hydroxychloroquine were complexed with the chemotherapy agent paclitaxel and studied for medicinal activity. Data (GI50, LD50) from single dose and five dose National Cancer Institute sixty cell line panels are presented. Analytical measurements of different complexes were made using Nuclear Magnetic Resonance (1H NMR), Matrix Assisted Laser Desorption Ionization-Time of Flight-Mass Spectrometry (MALDI-TOF-MS) and Fourier Transform-Ion Cyclotron Resonance (FT-ICR). Molecular modeling is utilized to better understand the impact that species could have on physical parameters associated with Lipinski’s Rule of Five, such as logP and TPSA. On average, Cu(II) and hydroxychloroquine decreased GI50 values, while sucrose increased GI50 values of paclitaxel.
      Graphical abstract image

      PubDate: 2017-05-25T15:10:58Z
       
  • Flex-nucleoside analogues – Novel therapeutics against filoviruses
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Mary K. Yates, Mithun R. Raje, Payel Chatterjee, Christina F. Spiropoulou, Sina Bavari, Mike Flint, Veronica Soloveva, Katherine L. Seley-Radtke
      Fleximers, a novel type of flexible nucleoside that have garnered attention due to their unprecedented activity against human coronaviruses, have now exhibited highly promising levels of activity against filoviruses. The Flex-nucleoside was the most potent against recombinant Ebola virus in Huh7 cells with an EC50 =2μM, while the McGuigan prodrug was most active against Sudan virus-infected HeLa cells with an EC50 of 7μM.
      Graphical abstract image

      PubDate: 2017-05-25T15:10:58Z
       
  • Design, synthesis, and biological evaluation of deuterated apalutamide
           with improved pharmacokinetic profiles
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Xuehai Pang, Yingwei Wang, Yuanwei Chen
      A series of deuterated apalutamide were designed and prepared. Compared to its prototype compound 18, deuterated analogues 19 and 21 showed obviously higher plasma concentrations and better PK parameters after oral administration in mice. In rats, N-trideuteromethyl compound 19 displayed 1.8-fold peak concentration (Cmax), and nearly doubled its drug exposure in plasma (AUC0–∞) compared to compound 18. Unsurprisingly, compounds 18 and 19 had similar affinity for AR in vitro. In summary, the deuteration strategy could obviously improve PK parameters of apalutamide.
      Graphical abstract image

      PubDate: 2017-05-25T15:10:58Z
       
  • Alkaloids from aerial parts of Houttuynia cordata and their
           anti-inflammatory activity
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Jongmin Ahn, Hee-Sung Chae, Young-Won Chin, Jinwoong Kim
      New alkaloids, houttuynamide B and C (1, 2) and houttuycorine (14), were isolated from the aerial parts of Houttuynia cordata Thunb. in addition to eighteen known alkaloids. Their structures were elucidated through extensive spectroscopic analysis. All the isolates were tested for their inhibitory activity against NO production in RAW 264.7 cells stimulated by LPS. Of the tested compounds, compound 15 showed the most potent anti-inflammatory activity with an IC50 value of 8.7μM.
      Graphical abstract image

      PubDate: 2017-05-25T15:10:58Z
       
  • Anti-atherosclerotic activities of flavonoids from the flowers of
           Helichrysum arenarium L. MOENCH through the pathway of anti-inflammation
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Zhonghua Mao, Chunli Gan, Jiuxin Zhu, Nan Ma, Lijun Wu, Libo Wang, Xiaobo Wang
      We have successfully established AS model using thoracic aortas vascular ring which evaluated by the morphological changes of blood vessels, the proliferation of VSMC, and the expression of inflammation factors VEGF, CRP, JNK2 and p38. This AS model has the advantages of low cost, convenient and short period of established time. Moreover, we investigated the anti-AS activities of 7 flavonoids Narirutin (1), Naringin (2), Eriodictyol (3), Luteolin (4), Galuteolin (5), Astragalin (6), Kaempferol (7) from flowers of Helichrysum arenarium L. MOENCH by examining the vascular morphology, the inhibition on the expression of inflammation factors CRP, VEGF, JNK2, p38. In addition, we investigated the anti-AS activities of these 7 flavonoids by examining NO secretion of RAW264.7 cells in response to LPS. All above inflammation factors have been proved to be involved in the formation of AS. After comprehensive analysis of all results to discuss the structure–activity relationship, we summarized the conclusions at follow: compounds 1–7 could inhibit the expression of VEGF, CRP, JNK2, p38 and NO at different level, and we evaluated that flavonol aglycone have more significant anti-inflammation than it’s glycoside, and the anti-AS activity of flavonols were stronger than flavanones and flavones, which means that 3-group might be the effective group. Eventually, we supposed the main anti-inflammatory mechanism of these compounds was to reduce the expression of CRP, inhibit the kinases activity of JNK2 and p38, and then the MAPK pathway was suppressed, which resulted in the decrease of NO synthesis, VEGF expression and endothelial adhesion factor expression. And eventually, the scar tissue and vascular stenosis formations were prevented. This conclusion suggested flavonoids have the potential of preventing AS formation.
      Graphical abstract image

      PubDate: 2017-05-25T15:10:58Z
       
  • Synthesis and α-glucosidase inhibition activity of dihydroxy
           pyrrolidines
    • Abstract: Publication date: 15 June 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 12
      Author(s): Sivaprasad Kasturi, Sujatha Surarapu, Srinivas Uppalanchi, Jaya Shree Anireddy, Shubham Dwivedi, Hasitha Shilpa Anantaraju, Yogeeswari Perumal, Dilep Kumar Sigalapalli, Bathini Nagendra Babu, Krishna S. Ethiraj
      A new series of Deacetylsarmentamide A and B derivatives, amides and sulfonamides of 3,4-dihydroxypyrrolidines as α-glucosidase inhibitors were designed and synthesized. The biological screening test against α-glucosidase showed that some of these compounds have the positive inhibitory activity against α-glucosidase. Saturated aliphatic amides were more potent than the olefinic amides. Among all the compounds, 5o/6o having polar –NH2 group, 10f/11f having polar –OH group on phenyl ring displayed 3–4-fold more potent than the standard drugs. Acarbose, Voglibose and Miglitol were used as standard references. The promising compounds 6i, 5o, 6o, 10a, 11a, 10f and 11f have been identified. Molecular docking simulations were done for compounds to identify important binding modes responsible for inhibition activity of α-glucosidase.
      Graphical abstract image

      PubDate: 2017-05-25T15:10:58Z
       
 
 
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