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  Subjects -> CHEMISTRY (Total: 846 journals)
    - ANALYTICAL CHEMISTRY (51 journals)
    - CHEMISTRY (596 journals)
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    - INORGANIC CHEMISTRY (41 journals)
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    - PHYSICAL CHEMISTRY (67 journals)

CHEMISTRY (596 journals)                  1 2 3 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 8)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 26)
ACS Catalysis     Full-text available via subscription   (Followers: 34)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 18)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 23)
ACS Macro Letters     Full-text available via subscription   (Followers: 24)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 39)
ACS Nano     Full-text available via subscription   (Followers: 246)
ACS Photonics     Full-text available via subscription   (Followers: 12)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 23)
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 Chimica Slovenica     Open Access  
Acta Chromatographica     Full-text available via subscription   (Followers: 9)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 5)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 8)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 5)
Advanced Functional Materials     Hybrid Journal   (Followers: 51)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 56)
Advances in Chemical Science     Open Access   (Followers: 13)
Advances in Chemistry     Open Access   (Followers: 15)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Enzyme Research     Open Access   (Followers: 9)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 16)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 9)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 21)
Advances in Nanoparticles     Open Access   (Followers: 15)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15)
Advances in Polymer Science     Hybrid Journal   (Followers: 41)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 17)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Science and Technology     Full-text available via subscription   (Followers: 12)
African Journal of Bacteriology Research     Open Access  
African Journal of Chemical Education     Open Access   (Followers: 2)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 7)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Al-Kimia : Jurnal Penelitian Sains Kimia     Open Access  
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: 15)
American Journal of Chemistry     Open Access   (Followers: 27)
American Journal of Plant Physiology     Open Access   (Followers: 14)
American Mineralogist     Hybrid Journal   (Followers: 14)
Analyst     Full-text available via subscription   (Followers: 39)
Angewandte Chemie     Hybrid Journal   (Followers: 220)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 223)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 4)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 4)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 8)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 12)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 16)
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: 22)
Applied Surface Science     Hybrid Journal   (Followers: 28)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 2)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Atomization and Sprays     Full-text available via subscription   (Followers: 4)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Biochemistry     Full-text available via subscription   (Followers: 318)
Biochemistry Insights     Open Access   (Followers: 6)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 9)
Bioinspired Materials     Open Access   (Followers: 5)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access   (Followers: 1)
Biomacromolecules     Full-text available via subscription   (Followers: 19)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 6)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 5)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 120)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 84)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 1)
Bitácora Digital     Open Access  
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 2)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 24)
Bulletin of the Korean Chemical Society     Hybrid Journal   (Followers: 1)
C - Journal of Carbon Research     Open Access   (Followers: 3)
Cakra Kimia (Indonesian E-Journal of Applied Chemistry)     Open Access  
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 3)
Canadian Journal of Chemistry     Hybrid Journal   (Followers: 10)
Canadian Mineralogist     Full-text available via subscription   (Followers: 5)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 66)
Catalysis for Sustainable Energy     Open Access   (Followers: 7)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 8)
Catalysis Science and Technology     Free   (Followers: 7)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 8)
Cellulose     Hybrid Journal   (Followers: 7)
Cereal Chemistry     Full-text available via subscription   (Followers: 4)
ChemBioEng Reviews     Full-text available via subscription   (Followers: 1)
ChemCatChem     Hybrid Journal   (Followers: 8)
Chemical and Engineering News     Free   (Followers: 15)
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: 25)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 20)
Chemical Reviews     Full-text available via subscription   (Followers: 182)
Chemical Science     Open Access   (Followers: 22)
Chemical Technology     Open Access   (Followers: 16)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemical Week     Full-text available via subscription   (Followers: 8)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 56)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 24)
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: 153)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 15)
Chemistry and Materials Research     Open Access   (Followers: 20)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 5)
Chemistry in Education     Open Access   (Followers: 9)
Chemistry International     Hybrid Journal   (Followers: 2)
Chemistry Letters     Full-text available via subscription   (Followers: 42)
Chemistry of Materials     Full-text available via subscription   (Followers: 228)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 22)
Chemistry-Didactics-Ecology-Metrology     Open Access   (Followers: 1)
ChemistryOpen     Open Access   (Followers: 2)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 4)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 14)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 9)
ChemPlusChem     Hybrid Journal   (Followers: 2)
ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 2)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 10)
Chromatographia     Hybrid Journal   (Followers: 24)
Clay Minerals     Full-text available via subscription   (Followers: 10)
Cogent Chemistry     Open Access  
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 10)
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 7)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
Combustion Science and Technology     Hybrid Journal   (Followers: 18)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Composite Interfaces     Hybrid Journal   (Followers: 6)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 2)
Comptes Rendus Chimie     Full-text available via subscription  
Comptes Rendus Physique     Full-text available via subscription   (Followers: 1)
Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 9)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 11)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 9)
Coordination Chemistry Reviews     Full-text available via subscription   (Followers: 3)
Copernican Letters     Open Access   (Followers: 1)
Corrosion Series     Full-text available via subscription   (Followers: 6)
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 5)
Croatica Chemica Acta     Open Access  
Crystal Structure Theory and Applications     Open Access   (Followers: 4)
CrystEngComm     Full-text available via subscription   (Followers: 13)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Metabolomics     Hybrid Journal   (Followers: 5)
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 17)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 62)
Dalton Transactions     Full-text available via subscription   (Followers: 23)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)
Diamond and Related Materials     Hybrid Journal   (Followers: 12)
Dislocations in Solids     Full-text available via subscription  
Doklady Chemistry     Hybrid Journal  
Drying Technology: An International Journal     Hybrid Journal   (Followers: 4)
Eclética Química     Open Access   (Followers: 1)
Ecological Chemistry and Engineering S     Open Access   (Followers: 3)
Ecotoxicology and Environmental Contamination     Open Access  
Educación Química     Open Access   (Followers: 1)
Education for Chemical Engineers     Hybrid Journal   (Followers: 5)
EJNMMI Radiopharmacy and Chemistry     Open Access  

        1 2 3 | Last

Journal Cover Bioorganic & Medicinal Chemistry Letters
  [SJR: 0.952]   [H-I: 112]   [84 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0960-894X
   Published by Elsevier Homepage  [3089 journals]
  • Factors affecting the uncaging efficiency of 500 nm
           light-activatable BODIPY caging group
    • Authors: Minoru Kawatani; Mako Kamiya; Hironori Takahashi; Yasuteru Urano
      Pages: 1 - 5
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1
      Author(s): Minoru Kawatani, Mako Kamiya, Hironori Takahashi, Yasuteru Urano
      Photoremovable protective groups, or caging groups, enable us to regulate the activities of bioactive molecules in living cells upon photoirradiation. Nevertheless, requirement of UV light for activating caging group is a significant limitation due to its cell toxicity and its poor tissue penetration. Our group previously reported a 500 nm light-activatable caging group based on BODIPY scaffold, however, its uncaging efficiency was lower than those of conventional caging groups. Here we show that the uncaging quantum yield (QY) of BODIPY caging group depends upon the driving force of photo-induced electron transfer (PeT). We also found that the uncaging QY increased in less polar solvents. We applied these findings to develop BODIPY-caged capsaicin, which is well localized to low-polarity intracellular compartments, as a tool to stimulate TRPV1 in live cells in response to blue-green light.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.030
       
  • Identification of a 4-fluorobenzyl l-valinate amide benzoxaborole
           (AN11736) as a potential development candidate for the treatment of Animal
           African Trypanosomiasis (AAT)
    • Authors: Tsutomu Akama; Yong-Kang Zhang; Yvonne R. Freund; Pamela Berry; Joanne Lee; Eric E. Easom; Robert T. Jacobs; Jacob J. Plattner; Michael J. Witty; Rosemary Peter; Tim G. Rowan; Kirsten Gillingwater; Reto Brun; Bakela Nare; Luke Mercer; Musheng Xu; Jiangong Wang; Hao Liang
      Pages: 6 - 10
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1
      Author(s): Tsutomu Akama, Yong-Kang Zhang, Yvonne R. Freund, Pamela Berry, Joanne Lee, Eric E. Easom, Robert T. Jacobs, Jacob J. Plattner, Michael J. Witty, Rosemary Peter, Tim G. Rowan, Kirsten Gillingwater, Reto Brun, Bakela Nare, Luke Mercer, Musheng Xu, Jiangong Wang, Hao Liang
      Novel l-valinate amide benzoxaboroles and analogues were designed and synthesized for a structure-activity-relationship (SAR) investigation to optimize the growth inhibitory activity against Trypanosoma congolense (T. congolense) and Trypanosoma vivax (T. vivax) parasites. The study identified 4-fluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-l-valinate (5, AN11736), which showed IC50 values of 0.15 nM against T. congolense and 1.3 nM against T. vivax, and demonstrated 100% efficacy with a single dose of 10 mg/kg against both T. congolense and T. vivax in mouse models of infection (IP dosing) and in the target animal, cattle, dosed intramuscularly. AN11736 has been advanced to early development studies.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.028
       
  • Isosteric ribavirin analogues: Synthesis and antiviral activities
    • Authors: Nikolay I. Zhurilo; Mikhail V. Chudinov; Andrey V. Matveev; Olga S. Smirnova; Irina D. Konstantinova; Anatoly I. Miroshnikov; Alexander N. Prutkov; Lyubov E. Grebenkina; Natalya V. Pulkova; Vitaly I. Shvets
      Pages: 11 - 14
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1
      Author(s): Nikolay I. Zhurilo, Mikhail V. Chudinov, Andrey V. Matveev, Olga S. Smirnova, Irina D. Konstantinova, Anatoly I. Miroshnikov, Alexander N. Prutkov, Lyubov E. Grebenkina, Natalya V. Pulkova, Vitaly I. Shvets
      The novel isosteric ribavirin analogues were synthesized by two different ways. Some of them showed significant antiviral action against hepatitis C virus (HCV), herpes simplex (HCV-1) and influenza A virus comparable to that of ribavirin itself. The data obtained confirm the proposed theory of the ribavirin possible antiviral activity mechanism related with bioisosterism.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.029
       
  • Design and synthesis of a biaryl series as inhibitors for the bromodomains
           of CBP/P300
    • Authors: Kwong Wah Lai; F. Anthony Romero; Vickie Tsui; Maureen H. Beresini; Gladys de Leon Boenig; Sarah M. Bronner; Kevin Chen; Zhongguo Chen; Edna F. Choo; Terry D. Crawford; Patrick Cyr; Susan Kaufman; Yingjie Li; Jiangpeng Liao; Wenfeng Liu; Justin Ly; Jeremy Murray; Weichao Shen; John Wai; Fei Wang; Caicai Zhu; Xiaoyu Zhu; Steven Magnuson
      Pages: 15 - 23
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1
      Author(s): Kwong Wah Lai, F. Anthony Romero, Vickie Tsui, Maureen H. Beresini, Gladys de Leon Boenig, Sarah M. Bronner, Kevin Chen, Zhongguo Chen, Edna F. Choo, Terry D. Crawford, Patrick Cyr, Susan Kaufman, Yingjie Li, Jiangpeng Liao, Wenfeng Liu, Justin Ly, Jeremy Murray, Weichao Shen, John Wai, Fei Wang, Caicai Zhu, Xiaoyu Zhu, Steven Magnuson
      A novel, potent, and orally bioavailable inhibitor of the bromodomain of CBP, compound 35 (GNE-207), has been identified through SAR investigations focused on optimizing al bicyclic heteroarene to replace the aniline present in the published GNE-272 series. Compound 35 has excellent CBP potency (CBP IC50 = 1 nM, MYC EC50 = 18 nM), a selectively index of >2500-fold against BRD4(1), and exhibits a good pharmacokinetic profile.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.025
       
  • Synthesis and in vitro evaluations of
           6-(hetero)-aryl-imidazo[1,2-b]pyridazine-3-sulfonamide’s as an inhibitor
           of TNF-α production
    • Authors: Shivaji S. Pandit; Mahesh R. Kulkarni; Yashwant B. Pandit; Nitin P. Lad; Vijay M. Khedkar
      Pages: 24 - 30
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1
      Author(s): Shivaji S. Pandit, Mahesh R. Kulkarni, Yashwant B. Pandit, Nitin P. Lad, Vijay M. Khedkar
      Tumor necrosis factor-α is an important pro-inflammatory cytokine having a key role in hosts defensive process of immune systems and its over expression led to a diverse range of inflammatory diseases such as Rheumatoid arthritis, Cronh’s disease, psoriasis, etc. This paper describes our medicinal chemistry efforts on imidazo[1,2-b]pyridazine scaffold: design, synthesis and biological evaluation. By the introducing sulfonamide functionality at 3 positions and substituting 6 positions with (hetero)-aryl groups’, a small library of compounds was prepared. All synthesized compounds were screened for lipopolysaccharide (LPS) mediated TNF-α production inhibitory activity. Biological data revealed that the majority of the compounds of this series showed moderate to potent TNF-α production inhibitory activity. Compound 5u and 5v are the most potent compounds from the series with activity of IC50 = 0.5 µM and 0.3 µM respectively. A short SAR demonstrates that 3-sulfonyl-4-arylpiperidine-4-carbonitrile moiety on imidazo[1,2-b]pyridazine showed better activity compared to the 3-(4-aryllpiperazin-1-yl) sulfonyl) in hPBMC assay. The molecular modeling studies revealed that the potent TNF-α production inhibitory activity 5v due to the extra stability of complex because of an extra pi-pi (π-π) stacking, hydrogen-bonding interactions.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.026
       
  • Discovery of 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide
           (SBI-425), a potent and orally bioavailable tissue-nonspecific alkaline
           phosphatase (TNAP) inhibitor
    • Authors: Anthony B. Pinkerton; Eduard Sergienko; Yalda Bravo; Russell Dahl; Chen-Ting Ma; Qing Sun; Michael R. Jackson; Nicholas D.P. Cosford; José Luis Millán
      Pages: 31 - 34
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1
      Author(s): Anthony B. Pinkerton, Eduard Sergienko, Yalda Bravo, Russell Dahl, Chen-Ting Ma, Qing Sun, Michael R. Jackson, Nicholas D.P. Cosford, José Luis Millán
      Tissue-nonspecific alkaline phosphatase (TNAP) is an ectoenzyme crucial for bone matrix mineralization via its ability to hydrolyze extracellular inorganic pyrophosphate (ePPi), a potent mineralization inhibitor, to phosphate (Pi). By the controlled hydrolysis of ePPi, TNAP maintains the correct ratio of Pi to ePPi and therefore enables normal skeletal and dental calcification. In other areas of the body low ePPi levels lead to the development of pathological soft-tissue calcification, which can progress to a number of disorders. TNAP inhibitors have been shown to prevent these processes via an increase of ePPi. Herein we describe the use of a whole blood assay to optimize a previously described series of TNAP inhibitors resulting in 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425), a potent, selective and oral bioavailable compound that robustly inhibits TNAP in vivo.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.024
       
  • Selective incorporation of foreign functionality into fibrin gels through
           a chemically modified DNA aptamer
    • Authors: Hiroto Fujita; Yusuke Inoue; Masayasu Kuwahara
      Pages: 35 - 39
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1
      Author(s): Hiroto Fujita, Yusuke Inoue, Masayasu Kuwahara
      We found for the first time that a thrombin-binding DNA aptamer (TBA) is selectively entrapped in fibrin gels during the gel growth reaction catalyzed by thrombin. Furthermore, using this phenomenon, we successfully demonstrated multiple incorporation of amphiphilic aliphatic groups into fibrin gels via chemically modified TBA.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.022
       
  • Antiplasmodial alkaloids from bulbs of Amaryllis belladonna Steud.
    • Authors: Namki Cho; Yongle Du; Ana Lisa Valenciano; Maria L. Fernández-Murga; Michael Goetz; Jason Clement; Maria B. Cassera; David G.I. Kingston
      Pages: 40 - 42
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1
      Author(s): Namki Cho, Yongle Du, Ana Lisa Valenciano, Maria L. Fernández-Murga, Michael Goetz, Jason Clement, Maria B. Cassera, David G.I. Kingston
      A bioassay-guided fractionation and chemical investigation of Amaryllis belladonna Steud. bulbs resulted in the isolation and identification of the new crinane alkaloid 1,4-dihydroxy-3-methoxy powellan (1), along with the 3 known crinane alkaloids 2–4 and the two lycorane alkaloids 5–6. The structures were elucidated by interpretation of combined HR-ESIMS, CD and 2D NMR spectroscopic data. Among these isolated compounds the lycorane-type alkaloid acetylcaranine (5) exhibited strong antiplasmodial activity, while compounds 3 and 4 were moderately active, and compounds 1 and 6 were inactive.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.021
       
  • The discovery and optimization of naphthalene-linked P2-P4 Macrocycles as
           inhibitors of HCV NS3 protease
    • Authors: Michael Bowsher; Sheldon Hiebert; Rongti Li; Alan X. Wang; Jacques Friborg; Fei Yu; Dennis Hernandez; Ying-Kai Wang; Herbert Klei; Ramkumar Rajamani; Kathy Mosure; Jay O. Knipe; Nicholas A. Meanwell; Fiona McPhee; Paul M. Scola
      Pages: 43 - 48
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1
      Author(s): Michael Bowsher, Sheldon Hiebert, Rongti Li, Alan X. Wang, Jacques Friborg, Fei Yu, Dennis Hernandez, Ying-Kai Wang, Herbert Klei, Ramkumar Rajamani, Kathy Mosure, Jay O. Knipe, Nicholas A. Meanwell, Fiona McPhee, Paul M. Scola
      Naphthalene-linked P2-P4 macrocycles within a tri-peptide-based acyl sulfonamide chemotype have been synthesized and found to inhibit HCV NS3 proteases representing genotypes 1a and 1b with single digit nanomolar potency. The pharmacokinetic profile of compounds in this series was optimized through structural modifications along the macrocycle tether as well as the P1 subsite. Ultimately a compound with oral bioavailability of 100% in rat, and a long half-life in plasma was obtained. However, compounds in this macrocyclic series exhibited cardiac effects in an isolated rabbit heart model and for this reason further optimization efforts were discontinued.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.005
       
  • Synthesis and biological evaluation of water-soluble derivatives of chiral
           gossypol as HIV fusion inhibitors targeting gp41
    • Authors: Jian Yang; Long-Long Li; Ju-Rong Li; Jing-Xiang Yang; Fang Zhang; Gang Chen; Rui Yu; Wen-Jie Ouyang; Shu-Wen Wu
      Pages: 49 - 52
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1
      Author(s): Jian Yang, Long-Long Li, Ju-Rong Li, Jing-Xiang Yang, Fang Zhang, Gang Chen, Rui Yu, Wen-Jie Ouyang, Shu-Wen Wu
      A series of novel or known water-soluble derivatives of chiral gossypol were synthesized and screened in vitro for their anti-HIV-1 activity. (−)-gossypol derivative was more active against HIV-1 than the corresponding (+)-gossypol derivative, respectively. Among these derivatives, d-glucosamine derivative of (−)-gossypol, oligopeptide derivative of (−)-gossypol and taurine derivative of (−)-gossypol, such as compounds 1a, 3a and 14a, showed significant inhibitory activities against HIV-1 replication, HIV-1 mediated cell-cell fusion and HIV gp41 6-helix bundle formation as some amino acid derivatives of (−)-gossypol.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.08.049
       
  • Drug-target interactions that involve the replacement or displacement of
           magnesium ions
    • Authors: Nicholas A. Meanwell
      Pages: 5355 - 5372
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Nicholas A. Meanwell
      Metal ions play important roles in protein and RNA structure and function and the construction of ligands frequently focuses on the exploitation of functionality designed to engage a metal. However, there are circumstances where functionality can be incorporated into a ligand to emulate the metal ion, allowing target engagement by displacing or replacing the metal and directly interacting with the metal-binding elements in the target. In this Digest, we illustrate protein and RNA modulators that exploit this design principle, with all of the examples based on the displacement or replacement of a magnesium ion, and which can confer a potency advantage. Moreover, this approach relies upon an inversion of the physical chemical properties of a more conventional metal-binding ligand.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.002
       
  • New Caspase-1 inhibitor by scaffold hopping into bio-inspired 3D-fragment
           space
    • Authors: Anne Brethon; Laurent Chantalat; Olivier Christin; Laurence Clary; Jean-François Fournier; Marcus Gastreich; Craig S. Harris; Tatiana Isabet; Jonathan Pascau; Etienne Thoreau; Didier Roche; Vincent Rodeschini
      Pages: 5373 - 5377
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Anne Brethon, Laurent Chantalat, Olivier Christin, Laurence Clary, Jean-François Fournier, Marcus Gastreich, Craig S. Harris, Tatiana Isabet, Jonathan Pascau, Etienne Thoreau, Didier Roche, Vincent Rodeschini
      Virtual fragmentation of a library of 12,000 compounds inspired by natural products led to a dataset of 153,000 fragments that was used as a source to identify effective P2-P3 scaffold replacement solutions for peptidic Caspase-1 inhibitors. Our strategy led to the identification of an original 2-azabicyclo-octane scaffold (2-ABO) that was further elaborated into the potent Caspase-1 inhibitor CD10847 (IC50 = 17 nM). The crystal structure of Caspase-1 in complex with CD10847 was obtained, and its binding mode was shown to be similar to the one predicted by docking and in good agreement with other known inhibitors.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.015
       
  • Structure-activity relationship study of Aib-containing amphipathic
           helical peptide-cyclic RGD conjugates as carriers for siRNA delivery
    • Authors: Shun-ichi Wada; Anna Takesada; Yurie Nagamura; Eri Sogabe; Rieko Ohki; Junsuke Hayashi; Hidehito Urata
      Pages: 5378 - 5381
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Shun-ichi Wada, Anna Takesada, Yurie Nagamura, Eri Sogabe, Rieko Ohki, Junsuke Hayashi, Hidehito Urata
      The conjugation of Aib-containing amphipathic helical peptide with cyclo(-Arg-Gly-Asp-d-Phe-Cys-) (cRGDfC) at the C-terminus of the helix peptide (PI) has been reported to be useful for constructing a carrier for targeted siRNA delivery into cells. In order to explore structure–activity relationships for the development of potential carriers for siRNA delivery, we synthesized conjugates of Aib-containing amphipathic helical peptide with cRGDfC at the N-terminus (PII) and both the N- and C-termini (PIII) of the helical peptide. Furthermore, to examine the influence of PI helical chain length on siRNA delivery, truncated peptides containing 16 (PIV), 12 (PV), and 8 (PVI) amino acid residues at the N-terminus of the helical chain were synthesized. PII and PIII, as well as PI, could deliver anti-luciferase siRNA into cells to induce the knockdown of luciferase stably expressed in cells. In contrast, all of the truncated peptides were unlikely to transport siRNA into cells.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.018
       
  • Identification of a diverse synthetic abietane diterpenoid library and
           insight into the structure-activity relationships for antibacterial
           activity
    • Authors: Wei Hou; Guanjun Zhang; Zhi Luo; Di Li; Haoqiang Ruan; Benfang Helen Ruan; Lin Su; Hongtao Xu
      Pages: 5382 - 5386
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Wei Hou, Guanjun Zhang, Zhi Luo, Di Li, Haoqiang Ruan, Benfang Helen Ruan, Lin Su, Hongtao Xu
      A diverse natural product-like (NPL) synthetic abietane diterpenoid library containing 86 compounds were obtained and the SARs were studied based on their antibacterial potential. Further in vitro cytotoxic and in silico drug-like properties evaluation showed that the potent antibacterial compound 84 had good drug-like properties and displayed low cytotoxicity toward noncancerous mammalian cells, indicating the study of AA and DHAA might be a good starting point for the search of novel antimicrobial molecules. Future work should be focused on the optimization of their potency and selectivity.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.014
       
  • Uracil-amino acid as a scaffold for β-sheet peptidomimetics: Study of
           photophysics and interaction with BSA protein
    • Authors: Subhendu Sekhar Bag; Afsana Yashmeen
      Pages: 5387 - 5392
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Subhendu Sekhar Bag, Afsana Yashmeen
      We report herein the uracil-di-aza-amino acid (UrAA) as a new family of molecular scaffold to induce β-hairpin structure with H-bonded β-sheet conformation in a short peptide. This has been demonstrated in two conceptual fluorescent pentapeptides wherein triazolylpyrenyl alanine and/or triazolylmethoxynapthyl alanine ( TPyAlaDo and/or TMNapAlaDo ) are embedded into two arms of the uracil-amino acid via an intervening leucine. Conformational analysis by CD, IR, variable temperature and 2D NMR spectroscopy reveals the β-hairpin structures for both the peptides. Study of photophysical property reveals that the pentapeptide containing fluorescent triazolyl unnatural amino acids TMNapAlaDo and TPyAlaDo at the two termini exhibits dual path entry to exciplex emission-either via FRET from TMNapAlaDo to TPyAlaDo or via direct excitation of a FRET acceptor, TPyAlaDo . The other pentapeptide with TPyAlaDo/TPyAlaDo pair shows excimer emission. Furthermore, both the peptides maintaining their fundamental photophysics are found to interact with BSA as only a test biomolecule.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.017
       
  • Structure-activity relationships and docking studies of synthetic
           2-arylindole derivatives determined with aromatase and quinone reductase 1
           
    • Authors: Allan M. Prior; Xufen Yu; Eun-Jung Park; Tamara P. Kondratyuk; Yan Lin; John M. Pezzuto; Dianqing Sun
      Pages: 5393 - 5399
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Allan M. Prior, Xufen Yu, Eun-Jung Park, Tamara P. Kondratyuk, Yan Lin, John M. Pezzuto, Dianqing Sun
      In our ongoing effort of discovering anticancer and chemopreventive agents, a series of 2-arylindole derivatives were synthesized and evaluated toward aromatase and quinone reductase 1 (QR1). Biological evaluation revealed that several compounds (e.g., 2d, IC50 = 1.61 μM; 21, IC50 = 3.05 μM; and 27, IC50 = 3.34 μM) showed aromatase inhibitory activity with half maximal inhibitory concentration (IC50) values in the low micromolar concentrations. With regard to the QR1 induction activity, 11 exhibited the highest QR1 induction ratio (IR) with a low concentration to double activity (CD) value (IR = 8.34, CD = 2.75 μM), while 7 showed the most potent CD value of 1.12 μM. A dual acting compound 24 showed aromatase inhibition (IC50 = 9.00 μM) as well as QR1 induction (CD = 5.76 μM) activities. Computational docking studies using CDOCKER (Discovery Studio 3.5) provided insight in regard to the potential binding modes of 2-arylindoles within the aromatase active site. Predominantly, the 2-arylindoles preferred binding with the 2-aryl group toward a small hydrophobic pocket within the active site. The C-5 electron withdrawing group on indole was predicted to have an important role and formed a hydrogen bond with Ser478 (OH). Alternatively, meta-pyridyl analogs may orient with the pyridyl 3′-nitrogen coordinating with the heme group.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.010
       
  • Glycyrrhiza glabra extract and quercetin reverses cisplatin resistance in
           triple-negative MDA-MB-468 breast cancer cells via inhibition of
           cytochrome P450 1B1 enzyme
    • Authors: Rajni Sharma; Linda Gatchie; Ibidapo S. Williams; Shreyans K. Jain; Ram A. Vishwakarma; Bhabatosh Chaudhuri; Sandip B. Bharate
      Pages: 5400 - 5403
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Rajni Sharma, Linda Gatchie, Ibidapo S. Williams, Shreyans K. Jain, Ram A. Vishwakarma, Bhabatosh Chaudhuri, Sandip B. Bharate
      The development of multi-drug resistance to existing anticancer drugs is one of the major challenges in cancer treatment. The over-expression of cytochrome P450 1B1 enzyme has been reported to cause resistance to cisplatin. With an objective to discover cisplatin-resistance reversal agents, herein, we report the evaluation of Glycyrrhiza glabra (licorice) extracts and its twelve chemical constituents for inhibition of CYP1B1 (and CYP1A1) enzyme in Sacchrosomes and live human cells. The hydroalcoholic extract showed potent inhibition of CYP1B1 in both Sacchrosomes as well as in live cells with IC50 values of 21 and 16 µg/mL, respectively. Amongst the total of 12 constituents tested, quercetin and glabrol showed inhibition of CYP1B1 in live cell assay with IC50 values of 2.2 and 15 µM, respectively. Both these natural products were found to be selective inhibitors of CYP1B1, and does not inhibit CYP2 and CYP3 family of enzymes (IC50 > 20 µM). The hydroalcoholic extract of G. glabra and quercetin (4) showed complete reversal of cisplatin resistance in CYP1B1 overexpressing triple negative MDA-MB-468 breast cancer cells. The selective inhibition of CYP1B1 by quercetin and glabrol over CYP2 and CYP3 family of enzymes was studied by molecular modeling studies.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.013
       
  • Scutellarin inhibits Hela cell growth and glycolysis by inhibiting the
           activity of pyruvate kinase M2
    • Authors: Lin You; Hong Zhu; Chun Wang; Fang Wang; Yongjun Li; Yan Li; Yonglin Wang; Bin He
      Pages: 5404 - 5408
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Lin You, Hong Zhu, Chun Wang, Fang Wang, Yongjun Li, Yan Li, Yonglin Wang, Bin He
      Scutellarin, one of natural flavonoids, is widely and clinically used for treating many diseases in China. Recently, scutellarin has demonstrated a broad spectrum of anti-proliferative activities against multiple cancer cell lines. However, the molecular mechanism of action remains to be investigated. We herein report the design and synthesis of biotinylated scutellareins as probes, which can be applied to discover scutellarein interacting proteins. Finally, we show that scutellarin directly targets pyruvate kinase M2 (PKM2) and inhibits its cytosolic activity to decrease glycolytic metabolism; on the other hand, scutellarin may also participate in regulating cell cycle and apoptotic proteins by activating MEK/ERK/PIN1 signaling pathway to promote the nuclear translocation of PKM2.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.011
       
  • (E)-3-(3,4,5-Trimethoxyphenyl)-1-(pyridin-4-yl)prop-2-en-1-one, a
           heterocyclic chalcone is a potent and selective CYP1A1 inhibitor and
           cancer chemopreventive agent
    • Authors: Neill J. Horley; Kenneth J.M. Beresford; Supriya Kaduskar; Prashant Joshi; Glen J.P. McCann; Ketan C. Ruparelia; Ibidapo S. Williams; Linda Gatchie; Vinay R. Sonawane; Sandip B. Bharate; Bhabatosh Chaudhuri
      Pages: 5409 - 5414
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Neill J. Horley, Kenneth J.M. Beresford, Supriya Kaduskar, Prashant Joshi, Glen J.P. McCann, Ketan C. Ruparelia, Ibidapo S. Williams, Linda Gatchie, Vinay R. Sonawane, Sandip B. Bharate, Bhabatosh Chaudhuri
      The overexpression of CYP1 family of enzymes is reported to be associated with development of human carcinomas. It has been well reported that CYP1A1 specific inhibitors prevents carcinogenesis. Herein, thirteen pyridine-4-yl series of chalcones were synthesized and screened for inhibition of CYP1 isoforms 1A1, 1B1 and 1A2 in Sacchrosomes™ and live human HEK293 cells. The structure-activity relationship analysis indicated that chalcones bearing tri-alkoxy groups (8a and 8k) on non-heterocyclic ring displayed selective inhibition of CYP1A1 enzyme, with IC50 values of 58 and 65 nM, respectively. The 3,4,5-trimethoxy substituted derivative 8a have shown >10-fold selectivity towards CYP1A1 with respect to other enzymes of the CYP1 sub-family and >100-fold selectivity with respect to CYP2 and CYP3 family of enzymes. The potent and selective CYP1A1 inhibitor 8a displayed antagonism of B[a]P mediated activation of aromatic hydrocarbon receptor (AhR) in yeast cells, and also protected human cells from CYP1A1-mediated B[a]P toxicity in human cells. This potent and selective inhibitor of CYP1A1 enzyme have a potential for development as cancer chemopreventive agent.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.009
       
  • Discovery of the first low-shift positive allosteric modulators for the
           muscarinic M1 receptor
    • Authors: Alexander Flohr; Roman Hutter; Barbara Mueller; Claudia Bohnert; Mélanie Pellisson; Hervé Schaffhauser
      Pages: 5415 - 5419
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Alexander Flohr, Roman Hutter, Barbara Mueller, Claudia Bohnert, Mélanie Pellisson, Hervé Schaffhauser
      Positive modulation of the muscarinic M1-receptor has for a long time attracted scientists and drug developers for the potential treatment of Alzheimer’s disease or Schizophrenia. The precognitive potential of M1 activation has however not been clinically demonstrated as a result of side effects associated both with agonists and positive allosteric modulators (PAM’s) of the M1-receptor. To avoid excessive activation of the M1-receptor we have designed a new screening format and developed the first low-shift positive allosteric modulators for the M1 receptor. Low-shift PAM’s offer the potential of “use-dependent” attenuation of transmitter-signaling while avoiding pseudo-agonistic behavior in vivo as a common limitation of the so far described high-shift PAM’s. With these novel M1-PAM’s, the M1 receptor is potentially the first GPCR for which both, high- and low shift PAM’s have become available.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.008
       
  • Synthesis and antidepressant activity of a series of arylalkanol and
           aralkyl piperazine derivatives targeting SSRI/5-HT1A/5-HT7
    • Authors: Zheng-Song Gu; Ying Xiao; Qing-Wei Zhang; Jian-Qi Li
      Pages: 5420 - 5423
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Zheng-Song Gu, Ying Xiao, Qing-Wei Zhang, Jian-Qi Li
      A series of arylalkanol and aralkyl piperazine derivatives have been synthesized and evaluated for 5-HT reuptake inhibitory abilities and binding affinities at the 5-HT1A/5-HT7 receptors. Antidepressant activities of the compounds in vivo were screened using the forced swimming test (FST). The results indicated that the compound 8j exhibited high affinities for the 5-HT1A/5-HT7 receptors (5-HT1A, ki = 0.84 nM; 5-HT7, ki = 12 nM) coupling with moderate 5-HT reuptake inhibitory activity (RUI, IC50 = 100 nM) and showed a marked antidepressant-like activity in the FST model.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.007
       
  • Hybrid DNA i-motif: Aminoethylprolyl-PNA (pC5) enhance the stability of
           DNA (dC5) i-motif structure
    • Authors: Chandrasekhar Reddy Gade; Nagendra K. Sharma
      Pages: 5424 - 5428
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Chandrasekhar Reddy Gade, Nagendra K. Sharma
      This report describes the synthesis of C-rich sequence, cytosine pentamer, of aep-PNA and its biophysical studies for the formation of hybrid DNA:aep-PNAi-motif structure with DNA cytosine pentamer (dC5) under acidic pH conditions. Herein, the CD/UV/NMR/ESI-Mass studies strongly support the formation of stable hybrid DNA i-motif structure with aep-PNA even near acidic conditions. Hence aep-PNA C-rich sequence cytosine could be considered as potential DNA i-motif stabilizing agents in vivo conditions.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.004
       
  • Design, synthesis and biological evaluation of novel oseltamivir
           derivatives as potent neuraminidase inhibitors
    • Authors: Zhen Wang; Li Ping Cheng; Xing Hua Zhang; Wan Pang; Liang Li; Jin Long Zhao
      Pages: 5429 - 5435
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Zhen Wang, Li Ping Cheng, Xing Hua Zhang, Wan Pang, Liang Li, Jin Long Zhao
      Neuraminidase (NA) is one of the particular potential targets for novel antiviral therapy. In this work, a series of neuraminidase inhibitors with the cyclohexene scaffold were studied based upon the combination of 3D-QSAR, molecular docking, and molecular dynamics techniques. The results indicate that the built 3D-QSAR models yield reliable statistical information: the correlation coefficient (r2) and cross-validation coefficient (q2) of CoMFA (comparative molecular field analysis) are 0.992 and 0.819; the r2 and q2 of CoMSIA (comparative molecular similarity analysis) are 0.992 and 0.863, respectively. Molecular docking and MD simulations were conducted to confirm the detailed binding mode of enzyme-inhibitor system. The new NA inhibitors had been designed, synthesized, and their inhibitory activities against group-1 neuraminidase were determined. One agent displayed excellent neuraminidase inhibition, with IC50 value of 39.6 μM against NA, while IC50 value for oseltamivir is 61.1 μM. This compound may be further investigated for the treatment of infection by the new type influenza virus.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.003
       
  • Aspergillus candidus is a newly recognized source of sphaeropsidin A:
           Isolation, semi-synthetic derivatization and anticancer evaluation
    • Authors: Yan Li; Robert Scott; Annie R. Hooper; Geoffrey A. Bartholomeusz; Alexander Kornienko; Gerald F. Bills
      Pages: 5436 - 5440
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Yan Li, Robert Scott, Annie R. Hooper, Geoffrey A. Bartholomeusz, Alexander Kornienko, Gerald F. Bills
      This report details a search for alternative strains that produce the diterpenoid sphaeropsidin A (SphA) among A. candidus strains from the USDA Northern Regional Research Laboratories Culture Collection. We identified two strains that produced SphA using a limited set of test media. An initial scaled-up fermentation of NRRL 313 and isolation effort led to the procurement of sufficient quantities of SphA to prepare five semi-synthetic analogues (1–5) and evaluate their anticancer effects against glioblastoma cells D423 and Gli56 grown in 2D and 3D cultures. Although, the effectiveness of the synthetic analogues varied depending on the cell line and the type of cell culture, compound 5, bearing an aromatic ring at C16, displayed a stronger toxicity towards both D423 and Gli56 cell lines in 2D cultures and D423 spheroids in 3D culture than either SphA or compounds 1–4.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.11.001
       
  • New terpenoids and thiophene derivatives from the aerial parts of
           Artemisia sieversiana
    • Authors: Xu-Dong Zhou; Chen Zhang; Shan He; Bin Zheng; Ke-Wu Zeng; Ming-Bo Zhao; Yong Jiang; Peng-Fei Tu
      Pages: 5441 - 5445
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Xu-Dong Zhou, Chen Zhang, Shan He, Bin Zheng, Ke-Wu Zeng, Ming-Bo Zhao, Yong Jiang, Peng-Fei Tu
      One new highly oxygenated nortriterpene, named sieverlactone (1), one new sesquiterpene, 1β,10β-epoxy-8α-acetoxyachillin (2), one new natural product, 5-propinyl-thiophene-2-carboxylic acid (3), and one new thiophene, 3-hydroxy-5-propinyl-2-acetyl-thiophene (4), together with 10 other known compounds (5−14), were isolated from the dried aerial parts of Artemisia sieversiana. Their structures were elucidated by a combination of extensive spectroscopic analysis, including 1D, 2D NMR spectroscopic and mass spectrometric data. Meanwhile, the stereochemistry of 1 and 2 was confirmed by single-crystal X-ray diffraction technique using Cu radiation. All the isolates were evaluated for their anti-neuroinflammatory effects on the lipopolysaccharide-induced nitric oxide production in BV-2 murine microglial cells. Compounds 2, 5, and 6 exhibited the significant activities with IC50 values of 6.5 ± 0.5, 11.9 ± 0.7, and 10.1 ± 0.3 μM, respectively, comparable to the positive control, quercetin, with an IC50 value of 16.3 ± 0.4 μM.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.10.077
       
  • Novel all-hydrocarbon stapled p110α[E545K] peptides as blockers of the
           oncogenic p110α[E545K]-IRS1 interaction
    • Authors: Xiao Hu; Yanhua He; Liping Wu; Yujun Hao; Zhenghe Wang; Weiping Zheng
      Pages: 5446 - 5449
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Xiao Hu, Yanhua He, Liping Wu, Yujun Hao, Zhenghe Wang, Weiping Zheng
      To follow up on our recent discovery of the 18-amino acid all-hydrocarbon [i, i + 4]-stapled p110α[E545K] peptide 1 that was shown to potently block the intracellular p110α[E545K]-IRS1 interaction (a protein-protein interaction uniquely present in cancer cells expressing p110α[E545K]) and the growth of the xenograft tumors formed by cancers harboring this mutation, in the current study we prepared and examined six derivatives of 1, i.e. stapled peptides 2-A, 2-B, 3-A, 3-B, 4-A, 4-B. We found that 2-A, 2-B, 4-A, and 4-B had higher % α-helicity than 1; moreover, the enhanced % α-helicity also led to an enhanced proteolytic stability. When compared with 1, the structurally simplified 14-amino acid 4-A and 4-B were found to more potently deactivate the AKT phosphorylation at Ser473 in the p110α[E545K]-expressing colon cancer cells, whose activation was previously demonstrated by us to be specifically derived from the p110α[E545K]-IRS1 interaction. The preliminary findings from the current study have laid a foundation for future more extensive studies on the stapled p110α[E545K] peptides newly identified in the current study.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.10.076
       
  • Identification of pyruvate dehydrogenase kinase 1 inhibitors with
           anti-osteosarcoma activity
    • Authors: Aiping Fang; Huiqiang Luo; Liping Liu; Haibo Fan; Yaying Zhou; Yuqin Yao; Yue Zhang
      Pages: 5450 - 5453
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Aiping Fang, Huiqiang Luo, Liping Liu, Haibo Fan, Yaying Zhou, Yuqin Yao, Yue Zhang
      Overexpression of pyruvate dehydrogenase kinases (PDKs), especially PDK1 has been observed in a variety of cancers. Thus, targeting PDK1 offers an attractive opportunity for the development of cancer therapies. In this letter, we reported the identification of two novel PDK1 inhibitors as anti-osteosarcoma agents. We found that TM-1 and TM-2 inhibited PDK1 with the IC50 values of 2.97 and 3.41 μM, respectively. Furthermore, TM-1 and TM-2 dose-dependently reduced phosphorylation of pyruvate dehydrogenase complex in MG-63 osteosarcoma cells. Finally, TM-1 and TM-2 were found to inhibit the proliferation of MG-63 cells with the EC50 values of 14.5, and 11.0 μM, respectively, meaning TM-1 and TM-2 could be promising leads for the discovery of potent PDK1 inhibitors.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.10.073
       
  • Introduction of 2-O-benzyl abasic nucleosides to the 3′-overhang regions
           of siRNAs greatly improves nuclease resistance
    • Authors: Yuki Nagaya; Yoshiaki Kitamura; Aya Shibata; Masato Ikeda; Yukihiro Akao; Yukio Kitade
      Pages: 5454 - 5456
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Yuki Nagaya, Yoshiaki Kitamura, Aya Shibata, Masato Ikeda, Yukihiro Akao, Yukio Kitade
      Chemically modified siRNAs containing 2-O-benzyl-1-deoxy-d-ribofuranose (RH OBn) in their 3′-overhang region were significantly more resistant towards serum nucleases than siRNAs possessing the natural nucleoside in this region. The knockdown efficacies and binding affinities of these modified siRNAs to the recombinant human Argonaute protein 2 (hAgo2) PAZ domain were comparable with that of siRNA with a thymidine dimer at the 3′-end.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.10.070
       
  • Synthesis, biological activities and SAR studies of new
           3-substitutedphenyl-4-substitutedbenzylideneamino-1,2,4-triazole Mannich
           bases and bis-Mannich bases as ketol-acid reductoisomerase inhibitors
    • Authors: Bao-Lei Wang; Li-Yuan Zhang; Xing-Hai Liu; Yi Ma; Yan Zhang; Zheng-Ming Li; Xiao Zhang
      Pages: 5457 - 5462
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Bao-Lei Wang, Li-Yuan Zhang, Xing-Hai Liu, Yi Ma, Yan Zhang, Zheng-Ming Li, Xiao Zhang
      A series of new 3-substitutedphenyl-4-substitutedbenzylideneamino-1,2,4-triazole Mannich bases and bis-Mannich bases were synthesized through Mannich reaction with high yields. Their structures were confirmed by means of IR, 1H NMR, 13C NMR and elemental analysis. The preliminary bioassay indicated that compounds 7g, 7h and 7l exhibited potent in vitro inhibitory activities against ketol-acid reductoisomerase (KARI) with K i value of (0.38 ± 0.25), (6.59 ± 2.75) and (8.46 ± 3.99) μmol/L, respectively, and were comparable with IpOHA. They could be new KARI inhibitors for follow-up research. Some of the title compounds also exhibited obvious herbicidal activities against Echinochloa crusgalli and remarkable in vitro fungicidal activities against Physalospora piricola and Rhizoctonia cerealis. The SAR of the compounds were analyzed, in which the molecular docking revealed the binding mode of 7g with the KARI, and the 3D-QSAR results provided useful information for guiding further optimization of this kind of structures to discover new fungicidal agents towards Rhizoctonia cerealis.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.10.065
       
  • Imidazo[1,2-a]pyridines linked with thiazoles/thiophene motif through keto
           spacer as potential cytotoxic agents and NF-κB inhibitors
    • Authors: Kamala K. Vasu; Chander Singh Digwal; Amit N. Pandya; Dhaivat H. Pandya; Jayesh A. Sharma; Sneha Patel; Milee Agarwal
      Pages: 5463 - 5466
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Kamala K. Vasu, Chander Singh Digwal, Amit N. Pandya, Dhaivat H. Pandya, Jayesh A. Sharma, Sneha Patel, Milee Agarwal
      A series of new imidazo[1,2-a]pyridine linked with thiazole/thiophene motif through a keto spacer were synthesized and tested for their cytotoxic potential against three human cancer cell lines including A549, HeLa and U87-MG using MTT assay. Compounds A2, A3, A4, C1 and C2 showed cytotoxicity against all the three cell lines. The selectivity index for compound A4 for A549 and HeLa cells was comparable to that of doxorubicin. Among the synthesized compounds, B5 showed the maximum inhibition of NF-κB activity as ascertained by NF-κB reporter assay (IC50 = 6.5 ± 0.6 µM). Treatment of NCI-H23 cells (EGFR overexpressed, KRAS G12V mutant) with erlotinib and gefitinib along with compounds A4 and B5 indicated synergistic and additive potential of combination therapy.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.10.060
       
  • Fluoroethoxy-1,4-diphenethylpiperidine and piperazine derivatives: Potent
           and selective inhibitors of [3H]dopamine uptake at the vesicular monoamine
           transporter-2
    • Authors: Emily R. Hankosky; Shyam R. Joolakanti; Justin R. Nickell; Venumadhav Janganati; Linda P. Dwoskin; Peter A. Crooks
      Pages: 5467 - 5472
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Emily R. Hankosky, Shyam R. Joolakanti, Justin R. Nickell, Venumadhav Janganati, Linda P. Dwoskin, Peter A. Crooks
      A small library of fluoroethoxy-1,4-diphenethyl piperidine and fluoroethoxy-1,4-diphenethyl piperazine derivatives were designed, synthesized and evaluated for their ability to inhibit [3H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and dopamine transporter (DAT), [3H]serotonin (5-HT) uptake at the serotonin transporter (SERT), and [3H]dofetilide binding at the human-ether-a-go-go-related gene (hERG) channel. The majority of the compounds exhibited potent inhibition of [3H]DA uptake at VMAT2, Ki changes in the nanomolar range (Ki = 0.014–0.073 µM). Compound 15d exhibited the highest affinity (Ki = 0.014 µM) at VMAT2, and had 160-, 5-, and 60-fold greater selectivity for VMAT2 vs. DAT, SERT and hERG, respectively. Compound 15b exhibited the greatest selectivity (>60-fold) for VMAT2 relative to all the other targets evaluated, and 15b had high affinity for VMAT2 (Ki = 0.073 µM). Compound 15b was considered the lead compound from this analog series due to its high affinity and selectivity for VMAT2.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.10.039
       
  • Fragment-based design, synthesis, biological evaluation, and SAR of
           1H-benzo[d]imidazol-2-yl)-1H-indazol derivatives as potent PDK1 inhibitors
           
    • Authors: Ting Chen; Venkataswamy Sorna; Susie Choi; Lee Call; Jared Bearss; Kent Carpenter; Steven L. Warner; Sunil Sharma; David J. Bearss; Hariprasad Vankayalapati
      Pages: 5473 - 5480
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Ting Chen, Venkataswamy Sorna, Susie Choi, Lee Call, Jared Bearss, Kent Carpenter, Steven L. Warner, Sunil Sharma, David J. Bearss, Hariprasad Vankayalapati
      In this work, we describe the use of the rule of 3 fragment-based strategies from biochemical screening data of 1100 in-house, small, low molecular weight fragments. The sequential combination of in silico fragment hopping and fragment linking based on S160/Y161/A162 hinge residues hydrogen bonding interactions leads to the identification of novel 1H-benzo[d]imidazol-2-yl)-1H-indazol class of Phosphoinositide-Dependent Kinase-1 (PDK1) inhibitors. Consequent SAR and follow-up screening data led to the discovery of two potent PDK1 inhibitors: compound 32 and 35, with an IC50 of 80 nM and 94 nM, respectively. Further biological evaluation showed that, at the low nanomolar concentration, the drug had potent ability to inhibit phosphorylation of AKT and p70S6, and selectively kill the cancer cells with mutations in both PTEN and PI3K. The microarray data showed that DUSP6, DUSP4, and FOSL1 were down-regulated in the sensitive cell lines with the compound treatment. The in vivo test showed that 35 can significantly inhibit tumor growth without influencing body weight growth. Our results suggest that these compounds, especially 35, merit further pre-clinical evaluation.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.10.041
       
  • Potential anti-proliferative agents from
           1,4-benzoxazinone-quinazolin-4(3H)-one templates
    • Authors: Rajitha Bollu; Saleha Banu; Suresh Kasaboina; Rajashaker Bantu; Lingaiah Nagarapu; Sowjanya Polepalli; Nishant Jain
      Pages: 5481 - 5484
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Rajitha Bollu, Saleha Banu, Suresh Kasaboina, Rajashaker Bantu, Lingaiah Nagarapu, Sowjanya Polepalli, Nishant Jain
      A novel synthetic protocol has been developed for the synthesis of 1,4-benzoxazinone-acetylphenylallyl quinazolin-4(3H)-one hybrids 7a–n by employing Pd-catalyzed CH arylation in presence of 5–10% phosphine ligand in good to excellent yields and evaluated for their anti-proliferative activity against three cancer cell lines such as A549 (lung), HeLa (cervical), MDA-MB-231 (breast). Compounds 7d, 7f, 7l and 7n exhibited promising anti-proliferative activity with GI50 values ranging from 0.37 to 2.73 µM respectively against A549, HeLa, and MDA-MB-231, while compound 7f showed significant activity against MDA-MB-231 with GI50 value 0.58 µM, 7j showed significant activity against A549 with GI50 value 0.32 µM and 7l showed significant activity against HeLa with GI50 value 0.37 µM. This is the first report on the synthesis and in vitro anti-proliferative evaluation of 1,4-benzoxazinone-acetylphenylallyl quinazolin-4(3H)-one hybrids.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.10.044
       
  • Protective effect of Opuntia ficus-indica L. cladodes against UVA-induced
           oxidative stress in normal human keratinocytes
    • Authors: Ganna Petruk; Flaviana Di Lorenzo; Paola Imbimbo; Alba Silipo; Andrea Bonina; Luisa Rizza; Renata Piccoli; Daria Maria Monti; Rosa Lanzetta
      Pages: 5485 - 5489
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): Ganna Petruk, Flaviana Di Lorenzo, Paola Imbimbo, Alba Silipo, Andrea Bonina, Luisa Rizza, Renata Piccoli, Daria Maria Monti, Rosa Lanzetta
      Opuntia ficus-indica L. is known for its beneficial effects on human health, but still little is known on cladodes as a potent source of antioxidants. Here, a direct, economic and safe method was set up to obtain water extracts from Opuntia ficus-indica cladodes rich in antioxidant compounds. When human keratinocytes were pre-treated with the extract before being exposed to UVA radiations, a clear protective effect against UVA-induced stress was evidenced, as indicated by the inhibition of stress-induced processes, such as free radicals production, lipid peroxidation and GSH depletion. Moreover, a clear protective effect against apoptosis in pre-treated irradiated cells was evidenced. We found that eucomic and piscidic acids were responsible for the anti-oxidative stress action of cladode extract. In conclusion, a bioactive, safe, low-cost and high value-added extract from Opuntia cladodes was obtained to be used for skin health/protection.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.10.043
       
  • PSMA-targeted bispecific Fab conjugates that engage T cells
    • Authors: James T. Patterson; Jason Isaacson; Lisa Kerwin; Ghazi Atassi; Rohit Duggal; Damien Bresson; Tong Zhu; Heyue Zhou; Yanwen Fu; Gunnar F. Kaufmann
      Pages: 5490 - 5495
      Abstract: Publication date: 15 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
      Author(s): James T. Patterson, Jason Isaacson, Lisa Kerwin, Ghazi Atassi, Rohit Duggal, Damien Bresson, Tong Zhu, Heyue Zhou, Yanwen Fu, Gunnar F. Kaufmann
      Bioconjugate formats provide alternative strategies for antigen targeting with bispecific antibodies. Here, PSMA-targeted Fab conjugates were generated using different bispecific formats. Interchain disulfide bridging of an αCD3 Fab enabled installation of either the PSMA-targeting small molecule DUPA (SynFab) or the attachment of an αPSMA Fab (BisFab) by covalent linkage. Optimization of the reducing conditions was critical for selective interchain disulfide reduction and good bioconjugate yield. Activity of αPSMA/CD3 Fab conjugates was tested by in vitro cytotoxicity assays using prostate cancer cell lines. Both bispecific formats demonstrated excellent potency and antigen selectivity.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.09.065
       
  • Synthesis and Biological Evaluation of Novel Doxorubicin-containing
           ASGP-R-targeted Drug-conjugates
    • Authors: Yan A. Ivanenkov; Alexander G. Majouga; Rostislav A. Petrov; Stanislav A. Petrov; Sergey V. Kovalev; Svetlana Yu. Maklakova; Emil Yu. Yamansarov; Irina V. Saltykova; Ekaterina V. Deyneka; Gleb I. Filkov; Victor E. Kotelianski; Timofey S. Zatsepin; Elena K. Beloglazkina
      Abstract: Publication date: Available online 12 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): Yan A. Ivanenkov, Alexander G. Majouga, Rostislav A. Petrov, Stanislav A. Petrov, Sergey V. Kovalev, Svetlana Yu. Maklakova, Emil Yu. Yamansarov, Irina V. Saltykova, Ekaterina V. Deyneka, Gleb I. Filkov, Victor E. Kotelianski, Timofey S. Zatsepin, Elena K. Beloglazkina
      Asialoglycoprotein receptor (ASGP-R) belongs to a wide family of C-type lectins and it is currently regarded as an attractive protein in the field of targeted drug delivery (TDD). It is abundantly expressed in hepatocytes and can be found predominantly on the sinusoidal surface especially of HepG2 cells. Therefore, ASGP-R can be used for the TDD of anticancer therapeutics against HCC and molecular diagnostic tools. To date, a variety of mono- and multivalent selective ASGP-R ligands have been discovered. Although many of these compounds have demonstrated a relatively high binding affinity towards the target, the reported synthetic schemes are not handled, complicated and include many non-trivial steps. In the current study, we describe a convenient and versatile synthetic approach to novel monovalent drug-conjugates containing N-acetyl-2-deoxy-2-aminogalactopyranose fragment as an ASGP-R-recognition “core-head” and well-known nonselective cytostatic – Doxorubicin (Dox). This is the first example of the direct conjugation of a drug molecule to the ASGP-targeted warhead by a really convenient manner via a simple linker sequence. The performed MTS-based biological evaluation in HepG2 cells revealed the novel conjugates as having anticancer activity. Confocal microscopy showed that the molecules readily penetrated HepG2 membrane and were mainly localized within the cytoplasm instead of the nucleus. Per contra, Dox under the same conditions demonstrated good anticancer activity and was predominantly concentrated in the nucleus. Therefore, we speculate that the amide “trigger” that we have used in this study for linker attachment is a sufficiently stable inside the cells to be enzymatically or spontaneously degraded. As a consequence, we did not observe the release of the drug. Ligands containing triggers that are more liable towards endogenous hydrolysis within the tissue of targeting are strongly required.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.12.004
       
  • Identification of novel small-molecule inhibitors of Zika virus infection
    • Authors: Ewa D. Micewicz; Ronik Khachatoorian; Samuel W. French; Piotr Ruchala
      Abstract: Publication date: Available online 9 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): Ewa D. Micewicz, Ronik Khachatoorian, Samuel W. French, Piotr Ruchala
      The recent re-emergence of Zika virus (ZIKV), a member of the Flaviviridae family, has become a global emergency and a serious public health threat worldwide. ZIKV infection causes severe neuroimmunopathology and is particularly harmful to the developing fetuses of infected pregnant women causing various developmental abnormalities. Currently, there are no effective methods of preventing or treating ZIKV infection, and new treatment options are urgently needed. Therefore, we have used an in vitro plaque assay to screen a limited proprietary library of small organic compounds and identified highly bioactive leads, with the most active analogs showing activity in low picomolar range. Identified “hits” possess certain common structural features that can be used in the design of the next generation(s) of ZIKV inhibitors. Collectively, our findings suggest that identified compounds represent excellent template(s) for the development of inexpensive and orally available anti-Zika drugs.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.12.019
       
  • Spiro-1-benzofuranpiperidinylalkanoic acids as a novel and selective
           sphingosine S1P5 receptor agonist chemotype
    • Authors: Axel R. Stoit; Jos H.M. Lange; Hein K.A.C. Coolen; Annemieke Rensink; Adri van den Hoogenband; Arnold P. den Hartog; Sjoerd van Schaik; Chris G. Kruse
      Abstract: Publication date: Available online 9 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): Axel R. Stoit, Jos H.M. Lange, Hein K.A.C. Coolen, Annemieke Rensink, Adri van den Hoogenband, Arnold P. den Hartog, Sjoerd van Schaik, Chris G. Kruse
      The synthesis and SAR of a novel class of spirobenzofuranpiperidinyl-derived alkanoic acids 6-34 as sphingosine S1P5 receptor agonists are described. The target compounds generally elicit high S1P5 receptor agonistic potencies and in general are selective against both S1P1 and S1P3 receptor subtypes. The key compound 32 shows a high bioavailability of 73% and a CNS/plasma ratio of 0.8 after oral administration in rats.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.12.018
       
  • Microwave-assisted synthesis of novel 5-substituted benzylidene
           amino-2-butyl benzofuran-3-yl-4-methoxyphenyl methanones as
           antileishmanial and antioxidant agents
    • Authors: Sanjeev R. Patil; Satyanarayana Bollikonda; Rajendra H. Patil; Jaiprakash N. Sangshetti; Anil S. Bobade; Ashish Asrondkar; Padi Pratap Reddy; Devanand B. Shinde
      Abstract: Publication date: Available online 8 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): Sanjeev R. Patil, Satyanarayana Bollikonda, Rajendra H. Patil, Jaiprakash N. Sangshetti, Anil S. Bobade, Ashish Asrondkar, Padi Pratap Reddy, Devanand B. Shinde
      A series of 5-substitutedbenzylideneamino-2-butylbenzofuran-3-yl-4-methoxyphenyl methanones is synthesized and evaluated for antileishmanial and antioxidant activities. Compounds 4f (IC50= 52.0± 0.09 µg/ml),4h (IC50= 56.0± 0.71µg/ml)and 4l (IC50=59.3± 0.55µg/ml)were shown significant antileishmanial when compared with standard sodium stibogluconate(IC50=490.0± 1.5µg/ml). Antioxidant study revealed that compounds4i (IC50= 2.44 ± 0.47µg/ml) and 4l (IC50= 3.69 ± 0.44µg/ml) have shown potent comparable activity when compared with standard ascorbic acid (IC50= 3.31 ± 0.34µg/ml).Molecular docking study was carried out which replicating results of biological activity in case of initial hits 4f and4h suggesting that these compounds have a potential to become lead molecules in drug discovery process. In silico ADME study was performed for predicting pharmacokinetic profile of the synthesised antileishmanial agents and expressed good oral drug like behaviour.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.12.013
       
  • Chemical constituents from Taraxacum officinale and their
           α-glucosidase inhibitory activities.
    • Authors: Janggyoo Choi; Kee Dong Yoon; Jinwoong Kim
      Abstract: Publication date: Available online 8 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): Janggyoo Choi, Kee Dong Yoon, Jinwoong Kim
      Three novel butyrolactones (1–3) and butanoates (4–6), namely taraxiroside A–F, were isolated from Taraxacum officinale along with twenty-two known compounds (7–28). Their chemical structures were elucidated by interpretation of spectroscopic data and comparison with those of literatures. All isolates were evaluated for their α-glucosidase inhibitory activities. Novel compounds 1–6 (IC50 145.3 - 181.3 μM) showed inhibitory activities similar to that of acarbose (IC50 179.9 μM). Compound 7 and 12 were the most potent inhibitor with IC50 values of 61.2 and 39.8 μM respectively. Compounds 2 and 12 showed as mixed-type inhibition, whereas compound 7 and acarbose showed competitive inhibition.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.12.014
       
  • Discovery of novel jaspine B analogues as autophagy inducer
    • Authors: En Zhang; Shang Wang; Li-Li Li; Yong-Gang Hua; Jing-Fei Yue; Jin-Feng Li; Cheng-Yun Jin
      Abstract: Publication date: Available online 8 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): En Zhang, Shang Wang, Li-Li Li, Yong-Gang Hua, Jing-Fei Yue, Jin-Feng Li, Cheng-Yun Jin
      A series of 2-alkylaminomethyl jaspine B analogues were synthesized and evaluated for their cytotoxic effects on human lung adenocarcinoma, breast cancer, and prostate cancer cell lines and a mouse melanoma cell line. Most of the compounds exhibited moderate to good activity against the cancer cell lines. Compound 7f showed the best overall cytotoxicity on PC-3 cells (IC50 = 0.85 μM). Further mechanistic studies revealed that compound 7f induced marked changes in PC-3 cell morphology, disrupted the mitochondrial membrane potential, and increased expression of the autophagy proteins beclin-1, LC3, and P62.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.12.011
       
  • Latch and trigger role for R445 in DAT transport explains molecular basis
           of DTDS
    • Authors: Maarten E.A. Reith; Kymry T. Jones; Juan Zhen; Sid Topiol
      Abstract: Publication date: Available online 8 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): Maarten E.A. Reith, Kymry T. Jones, Juan Zhen, Sid Topiol
      A recent study reports on five different mutations as sources of Dopamine transporter (DAT) deficiency syndrome (DTDS). One of these mutations, R445C, is believed to be located on the intracellular side of DAT distant to the primary (S1) or secondary (S2) sites to which substrate binding is understood to occur. Thus, the molecular mechanism by which the R445C mutation results in DAT transport deficiency has eluded explanation. However, the recently reported X-ray structures of the endogenous amine transporters for dDAT and hSERT revealed the presence of a putative salt bridge between R445 and E428 suggesting a possible mechanism. To evaluate whether the R445C effect is a result of a salt bridge interaction, the mutants R445E, E428R, and the double mutant E428R/R445E were generated. The single mutants R445E and E428R displayed loss of binding and transport properties of the substrate [3H]DA and inhibitor [3H]CFT at the cell surface while the double mutant E428R/R445E, although nonfunctional, restored [3H]DA and [3H]CFT binding affinity to that of WT. Structure based analyses of these results led to a model wherein R445 plays a dual role in normal DAT function. R445 acts as a component of a latch in its formation of a salt bridge with E428 which holds the primary substrate binding site (S1) in place and helps enforce the inward closed protein state. When this salt bridge is broken, R445 acts as a trigger which disrupts a local polar network and leads to the release of the N-terminus from its position inducing the inward closed state to one allowing the inward open state. In this manner, both the loss of binding and transport properties of the R445C variant are explained.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.12.016
       
  • Dihydrobenzisoxazole-4-one compounds are novel selective inhibitors of
           aldosterone synthase (CYP11B2) with in vivo activity
    • Authors: Kenneth Meyers; Derek A. Cogan; Jennifer Burke; Raquel Arenas; Michael Balestra; Nicholas F. Brown; Matthew A. Cerny; Holly E. Clifford; Federico Colombo; Lee Fader; Kosea S. Frederick; Xin Guo; Keith R. Hornberger; Stanley Kugler; John Lord; Daniel R. Marshall; Neil Moss; Jeremy R. Richman; Jennifer Schmenk; Steven M. Weldon; Maolin Yu; Michael Zhang; Zhidong Chen
      Abstract: Publication date: Available online 8 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): Kenneth Meyers, Derek A. Cogan, Jennifer Burke, Raquel Arenas, Michael Balestra, Nicholas F. Brown, Matthew A. Cerny, Holly E. Clifford, Federico Colombo, Lee Fader, Kosea S. Frederick, Xin Guo, Keith R. Hornberger, Stanley Kugler, John Lord, Daniel R. Marshall, Neil Moss, Jeremy R. Richman, Jennifer Schmenk, Steven M. Weldon, Maolin Yu, Michael Zhang, Zhidong Chen
      6,7-Dihydro-5H-2,1-benzisoxazol-4-one analogs are potent inhibitors of aldosterone synthase (CYP11B2) with selectivity over the highly homologous enzyme cortisol synthase (CYP11B1). These compounds are unique among inhibitors of CYP11B2 in their lack of a strong-heme binding group such as a pyridine or imidazole. Poor metabolic stability in hepatocyte incubations was found to proceed via a reduction of the isoxazole ring. While the enzyme responsible for the reductive metabolism remains unknown, the rate of metabolism could be attenuated by the addition of polar functionality. The in vitro CYP11B2 potency and selectivity were confirmed in vivo in a cynomolgus monkey model by the inhibition of ACTH stimulated aldosterone production without impacting plasma cortisol concentrations.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.12.015
       
  • Synthesis and biological evaluation of
           4β-(thiazol-2-yl)amino-4′-O-demethyl-4-deoxypodophyllotoxins as
           topoisomerase-II inhibitors
    • Authors: Chun-Yan Sang; Heng-Zhi Tian; Yue Chen; Jian-Fei Liu; Shi-Wu Chen; Ling Hui
      Abstract: Publication date: Available online 7 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): Chun-Yan Sang, Heng-Zhi Tian, Yue Chen, Jian-Fei Liu, Shi-Wu Chen, Ling Hui
      A series of 4β-(thiazol-2-yl)amino-4′-O-demethyl-4-deoxypodophyllotoxins were synthesized, and their cytotoxicities were evaluated against four human cancer cell lines (A549, HepG2, HeLa, and LOVO cells) and normal human diploid fibroblast line WI-38. Some of the compounds exhibited promising antitumor activity and less toxicity than the anticancer drug etoposide. Among them, compounds 15 and 17 were found to be the most potent synthetic derivatives as topo-II inhibitors, and induced DNA double-strand breaks via the p73/ATM pathway as well as the H2AX phosphorylation in A549 cells. These compounds also arrested A549 cells cycle in G2/M phase by regulating cyclinB1/cdc2(p34). Taken together, these results show that a series of compounds are potential anticancer agents.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.12.012
       
  • Discovery of N-aryl-N’-pyrimidin-4-yl ureas as Irreversible L858R/T790M
           Mutant Selective Epidermal Growth Factor Receptor Inhibitors
    • Authors: Fusheng Zhou; Liang Zhang; Yunzhou Jin; Wei Liu; Pengfei Cheng; Xiangyu He; Jing Xie; Sida Shen; Jing Lei; Haixia Ji; Yi Hu; Yingtao Liu; Yumin Cui; Qiang Lv; Jiong Lan
      Abstract: Publication date: Available online 6 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): Fusheng Zhou, Liang Zhang, Yunzhou Jin, Wei Liu, Pengfei Cheng, Xiangyu He, Jing Xie, Sida Shen, Jing Lei, Haixia Ji, Yi Hu, Yingtao Liu, Yumin Cui, Qiang Lv, Jiong Lan
      A novel series of N-aryl-N’-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the EGFR L858R/T790M. The most representative compound 28 showed high activity against EGFR L858R/T790M kinase (IC50 = 4 nM) and 22-fold selectivity against wild type EGFR. Moreover, compound 28 potently inhibited EGFR L858R/T790M phosphorylation (IC50 = 41 nM) and cellular proliferation (IC50 = 37 nM) in the H1975 cell line, while being significantly less toxic to A431 cells. Further, compound 28 exhibited a great selectivity in a mini-panel of kinases.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.12.009
       
  • Facile conversion of ATP-binding RNA aptamer to quencher-free molecular
           aptamer beacon
    • Authors: Yoojin Park; Duangrat Nim-anussornkul; Tirayut Vilaivan; Takashi Morii; Byeang Hyean Kim
      Abstract: Publication date: Available online 6 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): Yoojin Park, Duangrat Nim-anussornkul, Tirayut Vilaivan, Takashi Morii, Byeang Hyean Kim
      We have developed RNA-based quencher-free molecular aptamer beacons (RNA-based QF-MABs) for the detection of ATP, taking advantage of the conformational changes associated with ATP binding to the ATP-binding RNA aptamer. The RNA aptamer, with its well-defined structure, was readily converted to the fluorescence sensors by incorporating a fluorophore into the loop region of the hairpin structure. These RNA-based QF-MABs exhibited fluorescence signals in the presence of ATP relative to their low background signals in the absence of ATP. The fluorescence emission intensity increased upon formation of a RNA-based QF-MAB·ATP complex.
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      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.12.008
       
  • Investigation of copper-free alkyne/azide 1,3-dipolar cycloadditions using
           microwave irradiation
    • Authors: Lindsay E. Chatkewitz; John F. Halonski; Marshall S. Padilla; Douglas D. Young
      Abstract: Publication date: Available online 6 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): Lindsay E. Chatkewitz, John F. Halonski, Marshall S. Padilla, Douglas D. Young
      The prevalence of 1,3-dipolar cycloadditions of azides and alkynes within both biology and chemistry highlights the utility of these reactions. However, the use of a copper catalyst can be prohibitive to some applications. Consequently, we have optimized a copper-free microwave assisted reaction to alleviate the necessity for the copper catalyst. A small array of triazoles was prepared to examine the scope of this approach, and the methodology was translated to a protein context through the use of unnatural amino acids to demonstrate one of the first microwave-mediated bioconjugations involving a full length protein.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.12.007
       
  • Synthesis, Optical Properties and Cytotoxicity of Meso-Heteroatom
           Substituted IR-786 Analogs
    • Authors: Xiaozhong Ma; Matthew Laramie; Maged Henary
      Abstract: Publication date: Available online 6 December 2017
      Source:Bioorganic & Medicinal Chemistry Letters
      Author(s): Xiaozhong Ma, Matthew Laramie, Maged Henary
      Eight near-infrared heptamethine cyanines have been successfully synthesized based on IR 786 with oxygen, sulfur and amine moieties at the central position. These dyes show diverse optical properties resulting from different substitutions. Particularly, the heptamethine dyes with amine moieties have larger Stokes shifts and higher quantum yields of fluorescence. We also investigated these dyes for tumor cell cytotoxicity using cell viability and in vitro proliferation assays. Two of the compounds showed high cytotoxicity against PC-3 cancer cells.
      Graphical abstract image

      PubDate: 2017-12-12T20:06:51Z
      DOI: 10.1016/j.bmcl.2017.12.001
       
 
 
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