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  Subjects -> CHEMISTRY (Total: 852 journals)
    - ANALYTICAL CHEMISTRY (52 journals)
    - CHEMISTRY (598 journals)
    - CRYSTALLOGRAPHY (21 journals)
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    - INORGANIC CHEMISTRY (41 journals)
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CHEMISTRY (598 journals)                  1 2 3 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 10)
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: 38)
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: 252)
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: 57)
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: 18)
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: 66)
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: 179)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 229)
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   (Followers: 1)
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: 326)
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: 85)
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: 68)
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: 5)
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: 70)
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: 21)
Chemical Reviews     Full-text available via subscription   (Followers: 184)
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: 146)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 15)
Chemistry and Materials Research     Open Access   (Followers: 20)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 5)
Chemistry in Education     Open Access   (Followers: 9)
Chemistry International     Hybrid Journal   (Followers: 2)
Chemistry Letters     Full-text available via subscription   (Followers: 42)
Chemistry of Materials     Full-text available via subscription   (Followers: 246)
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: 10)
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: 6)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
Combustion Science and Technology     Hybrid Journal   (Followers: 19)
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: 18)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 64)
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
  [SJR: 1.064]   [H-I: 119]   [120 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0968-0896
   Published by Elsevier Homepage  [3118 journals]
  • Evaluation of alkylating pyrrole-imidazole polyamide conjugates by a novel
           method for high-throughput sequencer
    • Authors: Gengo Kashiwazaki; Rina Maeda; Takashi Kawase; Kaori Hashiya; Toshikazu Bando; Hiroshi Sugiyama
      Pages: 1 - 7
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Gengo Kashiwazaki, Rina Maeda, Takashi Kawase, Kaori Hashiya, Toshikazu Bando, Hiroshi Sugiyama
      N-Methylpyrrole-N-methylimidazole (PI) polyamides are a class of DNA minor groove binders with DNA sequence-specificity. DNA-alkylating PI polyamide conjugates are attractive candidates as anticancer drugs acting through DNA damage and its subsequent inhibition of cell proliferation. One example is a chlorambucil-PI polyamide conjugate targeting the runt-related transcription factor (RUNX) family. RUNX1 has pro-oncogenic properties in acute myeloid leukemia, and recently the chlorambucil-PI polyamide conjugate was demonstrated to have anticancer effects. Herein, we apply another DNA-alkylating agent, seco-CBI, to target the consensus sequence of the RUNX family. Two types of CBI conjugates were prepared and their binding properties were characterized by Bind-n-Seq analysis using a high-throughput sequencer. The sequencing data were analyzed by two methods, MERMADE and our new MR (motif identification with a reference sequence), and the resultant binding motif logos were as predicted from the pairing rules proposed by Dervan et al. This is the first report to employ the MR method on alkylating PI polyamide conjugates. Moreover, cytotoxicity of conjugates 3 and 4 against a human non-small cell lung cancer, A549, were examined to show promising IC50s of 120 nm and 63 nm, respectively. These findings suggest seco-CBI-PI polyamide conjugates are candidates for oncological therapy.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.08.057
       
  • Synthesis and biological evaluation of novel synthetic chalcone
           derivatives as anti-tumor agents targeting Cat L and Cat K
    • Authors: Yali Wang; Situ Xue; Ruolan Li; Zhihui Zheng; Hong Yi; Zhuorong Li
      Pages: 8 - 16
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Yali Wang, Situ Xue, Ruolan Li, Zhihui Zheng, Hong Yi, Zhuorong Li
      A series of chalcone derivatives bearing benzamide or benzenesulfonamide moieties were synthesized and evaluated for their anti-tumor effect on HCT116, MCF7 and 143B cell lines in vitro. SAR analysis showed that compounds bearing a benzenesulfonamide group had greater potency than those bearing a benzamide group. It was also shown that compounds with a mono-methyl or mono-halogen group at the 3-position on the terminal phenyl ring were more effective than those with trifluoromethyl or methoxy groups. Compound 8e exhibited the most potent anti-tumor activities against HCT116, MCF7 and 143B cell lines, with IC50 values of 0.597, 0.886 and 0.791μM, respectively. Molecular docking studies and enzymatic assays demonstrated that the anti-tumor activity of compound 8e might be regulated by Cat L and Cat K.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.09.019
       
  • Synthesis and anti-influenza virus evaluation of triterpene-sialic acid
           conjugates
    • Authors: Mitsuru Tsuji; Nongluk Sriwilaijaroen; Hideo Inoue; Kazuhiko Miki; Kaoru Kinoshita; Kiyotaka Koyama; Kimio Furuhata; Yasuo Suzuki; Kunio Takahashi
      Pages: 17 - 24
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Mitsuru Tsuji, Nongluk Sriwilaijaroen, Hideo Inoue, Kazuhiko Miki, Kaoru Kinoshita, Kiyotaka Koyama, Kimio Furuhata, Yasuo Suzuki, Kunio Takahashi
      We are interested in new non-natural glycosides with sialic acid conjugates and their biological activities. We report the synthesis of eleven non-natural occurring glycosides, which are triterpene (glycyrrhetinic acid and its derivatives)-sialic acid conjugates, and their inhibitory activities against influenza virus sialidases and influenza virus multiplication in MDCK host cells. Deoxoglycyrrhetol-sialic acid conjugates (6d and 6e) and oleanolic acid-sialic acid conjugates (7d and 7e) showed strong inhibitory activities against three subtypes of influenza virus sialidases. These four compounds (6d, 6e, 7d and 7e) showed clear inhibition to influenza virus multiplication but not to MDCK host cell survival.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.09.038
       
  • Exploiting a water network to achieve enthalpy-driven,
           bromodomain-selective BET inhibitors
    • Authors: William R. Shadrick; Peter J. Slavish; Sergio C. Chai; Brett Waddell; Michele Connelly; Jonathan A. Low; Cynthia Tallant; Brandon M. Young; Nagakumar Bharatham; Stefan Knapp; Vincent A. Boyd; Marie Morfouace; Martine F. Roussel; Taosheng Chen; Richard E. Lee; R. Kiplin Guy; Anang A. Shelat; Philip M. Potter
      Pages: 25 - 36
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): William R. Shadrick, Peter J. Slavish, Sergio C. Chai, Brett Waddell, Michele Connelly, Jonathan A. Low, Cynthia Tallant, Brandon M. Young, Nagakumar Bharatham, Stefan Knapp, Vincent A. Boyd, Marie Morfouace, Martine F. Roussel, Taosheng Chen, Richard E. Lee, R. Kiplin Guy, Anang A. Shelat, Philip M. Potter
      Within the last decade, the Bromodomain and Extra-Terminal domain family (BET) of proteins have emerged as promising drug targets in diverse clinical indications including oncology, auto-immune disease, heart failure, and male contraception. The BET family consists of four isoforms (BRD2, BRD3, BRD4, and BRDT/BRDT6) which are distinguished by the presence of two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine (KAc) residues and appear to have distinct biological roles. BET BD1 and BD2 bromodomains differ at five positions near the substrate binding pocket: the variation in the ZA channel induces different water networks nearby. We designed a set of congeneric 2- and 3-heteroaryl substituted tetrahydroquinolines (THQ) to differentially engage bound waters in the ZA channel with the goal of achieving bromodomain selectivity. SJ830599 (9) showed modest, but consistent, selectivity for BRD2-BD2. Using isothermal titration calorimetry, we showed that the binding of all THQ analogs in our study to either of the two bromodomains was enthalpy driven. Remarkably, the binding of 9 to BRD2-BD2 was marked by negative entropy and was entirely driven by enthalpy, consistent with significant restriction of conformational flexibility and/or engagement with bound waters. Co-crystallography studies confirmed that 9 did indeed stabilize a water-mediated hydrogen bond network. Finally, we report that 9 retained cytotoxicity against several pediatric cancer cell lines with EC50 values comparable to BET inhibitor (BETi) clinical candidates.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.10.042
       
  • UVA irradiation of BrU-substituted DNA in the presence of Hoechst 33258
    • Authors: Abhijit Saha; Seiichiro Kizaki; Ji Hoon Han; Zutao Yu; Hiroshi Sugiyama
      Pages: 37 - 40
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Abhijit Saha, Seiichiro Kizaki, Ji Hoon Han, Zutao Yu, Hiroshi Sugiyama
      Given that our knowledge of DNA repair is limited because of the complexity of the DNA system, a technique called UVA micro-irradiation has been developed that can be used to visualize the recruitment of DNA repair proteins at double-strand break (DSB) sites. Interestingly, Hoechst 33258 was used under micro-irradiation to sensitize 5-bromouracil (BrU)-labelled DNA, causing efficient DSBs. However, the molecular basis of DSB formation under UVA micro-irradiation remains unknown. Herein, we investigated the mechanism of DSB formation under UVA micro-irradiation conditions. Our results suggest that the generation of a uracil-5-yl radical through electron transfer from Hoechst 33258 to BrU caused DNA cleavage preferentially at self-complementary 5′-AABrUBrU-3′ sequences to induce DSB. We also investigated the DNA cleavage in the context of the nucleosome to gain a better understanding of UVA micro-irradiation in a cell-like model. We found that DNA cleavage occurred in both core and linker DNA regions although its efficiency reduced in core DNA.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.011
       
  • Microwave-assisted diastereoselective two-step three-component synthesis
           
    • Authors: Guido V. Janssen; Joyce A.C. van den Heuvel; Rik P. Megens; Jorg C.J. Benningshof; Huib Ovaa
      Pages: 41 - 49
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Guido V. Janssen, Joyce A.C. van den Heuvel, Rik P. Megens, Jorg C.J. Benningshof, Huib Ovaa
      Large, diverse compound libraries are an essential requisite in target-based drug development. In this work, a robust microwave-assisted synthesis for the diastereoselective generation of 3-saccharinyl-trans-β-lactams is reported. The method is optimised for combinatorial library synthesis in which decoration of the scaffold is varied on both the β-lactam and the saccharine moiety. Within the European Lead Factory (ELF) consortium, a library of 263 compounds was efficiently produced using the developed methodology.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.014
       
  • Design and synthesis of aminoester heterodimers containing flavone or
           chromone moieties as modulators of P-glycoprotein-based multidrug
           resistance (MDR)
    • Authors: Silvia Dei; Maria Novella Romanelli; Dina Manetti; Niccolò Chiaramonte; Marcella Coronnello; Milena Salerno; Elisabetta Teodori
      Pages: 50 - 64
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Silvia Dei, Maria Novella Romanelli, Dina Manetti, Niccolò Chiaramonte, Marcella Coronnello, Milena Salerno, Elisabetta Teodori
      In this study, a new series of heterodimers was synthesized. These derivatives are N,N -bis(alkanol)amine aryl esters or N,N -bis(ethoxyethanol)amine aryl esters carrying a methoxylated aryl residue combined with a flavone or chromone moiety. The new compounds were studied to evaluate their P-gp modulating activity on a multidrug-resistant leukemia cell line. Some of the new compounds show a good MDR reversing activity; interestingly this new series of compounds does not comply with the structure-activity relationships (SAR) outlined by previously synthesized analogs carrying different aromatic moieties. In the case of the compounds described in this paper, activity is linked to different features, in particular the characteristics of the spacer, which seem to be critical for the interaction with the pump. This fact indicates that the presence of a flavone or chromone residue influences the SAR of these series of products, and that flexible molecules can find different productive binding modes with the P-gp recognition site. These results support the synthesis of new compounds that might be useful leads for the development of drugs to control P-gp-dependent MDR.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.016
       
  • A novel series of enoyl reductase inhibitors targeting the ESKAPE
           pathogens, Staphylococcus aureus and Acinetobacter baumannii
    • Authors: Jieun Kwon; Tina Mistry; Jinhong Ren; Michael E. Johnson; Shahila Mehboob
      Pages: 65 - 76
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Jieun Kwon, Tina Mistry, Jinhong Ren, Michael E. Johnson, Shahila Mehboob
      S. aureus and A. baumannii are among the ESKAPE pathogens that are increasingly difficult to treat due to the rise in the number of drug resistant strains. Novel therapeutics targeting these pathogens are much needed. The bacterial enoyl reductase (FabI) is as potentially significant drug target for developing pathogen-specific antibiotics due to the presence of alternate FabI isoforms in many other bacterial species. We report the identification and development of a novel N-carboxy pyrrolidine scaffold targeting FabI in S. aureus and A. baumannii, two pathogens for which FabI essentiality has been established. This scaffold is unrelated to other known antibiotic families, and FabI is not targeted by any currently approved antibiotic. Our data shows that this scaffold displays promising enzyme inhibitory activity against FabI from both S. aureus and A. baumannii, as well as encouraging antibacterial activity in S. aureus. Compounds also display excellent synergy when combined with colistin and tested against A. baumannii. In this combination the MIC of colistin is reduced by 10-fold. Our first generation compound displays promising enzyme inhibition, targets FabI in S. aureus with a favorable selectivity index (ratio of cytotoxicity to MIC), and has excellent synergy with colistin against A. baumannii, including a multidrug resistant strain.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.018
       
  • TLR8 activation and inhibition by guanosine analogs in RNA: Importance of
           functional groups and chain length
    • Authors: Tiannan Hu; Scott R. Suter; Madeline M. Mumbleau; Peter A. Beal
      Pages: 77 - 83
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Tiannan Hu, Scott R. Suter, Madeline M. Mumbleau, Peter A. Beal
      Toll-like receptor 8 (TLR8) is an important component of the human innate immune system that recognizes single stranded RNA (ssRNA). Recent X-ray crystal structures of TLR8 bound to ssRNA revealed a previously unrecognized binding site for a 5′-UpG-3′ dinucleotide. Here we use an atomic mutagenesis strategy coupled with a cellular TLR8 activation assay to probe the importance of specific functional groups present on the guanine base in RNA-mediated receptor agonism and antagonism. Results from RNA analogs containing 7-deazaguanosine, 2-aminopurine and inosine confirm the importance of guanine N7, O6 and N2, respectively, in TLR8 activation. Nevertheless, these RNAs each retained TLR8 antagonism activity. RNA containing 7-deaza-8-azainosine (7d8aI) was prepared from a novel phosphoramidite and found to be a weaker TLR8 activator than guanosine-containing RNA. However, 7d8aI-containing RNA also retained TLR8 antagonism activity indicating that removal of multiple TLR8 H-bonding sites on guanine is insufficient for blocking TLR8 antagonism by guanine-containing RNA. We also identified an oligoribonucleotide length dependence on both TLR8 activation and antagonism. These studies extend our understanding of the effects of nucleobase modification on immune stimulation and will inform the design of novel RNA-based therapeutics.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.020
       
  • Design and synthesis of highly selective pyruvate dehydrogenase complex E1
           inhibitors as bactericides
    • Authors: Yuan Zhou; Shasha Zhang; Hongwu He; Wen Jiang; Leifeng Hou; Dan Xie; Meng Cai; Hao Peng; Lingling Feng
      Pages: 84 - 95
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Yuan Zhou, Shasha Zhang, Hongwu He, Wen Jiang, Leifeng Hou, Dan Xie, Meng Cai, Hao Peng, Lingling Feng
      In order to obtain PDHc-E1 inhibitors with high selectivity and efficacy, four series (7, 12, 15, and 19) of 35 novel 4-aminopyrimidine derivatives were rationally designed and synthesized based on the binding site of ThDP in E. coli PDHc-E1. 12, 15, and 19 were confirmed to be potent inhibitors against E. coli PDHc-E1. Selected compounds 12g, 12i, 15f, and 19a showed negligible inhibition against porcine PDHc-E1. To understand their selectivity, the interaction of inhibitor and E. coli PDHc-E1 or porcine PDHc-E1 was studied by molecular docking. The newly introduced acylhydrazone and N-phenylbenzamide moieties could form stronger interaction by hydrogen bond at the active site of E. coli PDHc-E1 compared with that of porcine PDHc-E1. A part of title compounds as potent PDHc-E1 inhibitors also exhibited notable antibacterial activity. In particular, 12e, 12f, 12g, 12o, and 19a exhibited 72–92% inhibition against Xanthomonas oryzae pv. Oryzae and Ralstonia solanacearum at 100 μg/mL, which was better than thiodiazole-copper (34 and 29%, respectively) and bismerthiazol (56 and 55%, respectively). The results proved that we could obtain effective bactericidal compounds as highly selective PDHc inhibitors by rational molecular design utilizing the binding model of active site of E. coli PDHc-E1.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.021
       
  • N-Arylsulfonylsubstituted-1H indole derivatives as small molecule dual
           inhibitors of signal transducer and activator of transcription 3 (STAT3)
           and tubulin
    • Authors: Qiang Zhou; Jinjin Zhu; Jinglei Chen; Peng Ji; Chunhua Qiao
      Pages: 96 - 106
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Qiang Zhou, Jinjin Zhu, Jinglei Chen, Peng Ji, Chunhua Qiao
      Signal transducer and activator of transcription (STAT3) is a proposed therapeutic target for the development of anti-cancer agents. In this report, a series of N-arylsulfonylsubstituted-1H indole derivatives were designed and synthesized as STAT3 inhibitors, their anti-proliferative activities were evaluated against a number of tumor cells, some potent compounds exhibited IC50 values less than 10 μM. The most potent compound 4a was further confirmed to inhibit STAT3 phosphorylation at Tyr705. It was further revealed that 4a arrested the cell cycle at the G2/M phase and inhibited tubulin polymerization. This study describes a series of N-arylsulfonylsubstituted-1H indole derivatives as potent anti-cancer agents targeting both STAT3 and tubulin.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.023
       
  • Mitochondria-targeted cationic porphyrin-triphenylamine hybrids for
           enhanced two-photon photodynamic therapy
    • Authors: Fabien Hammerer; Florent Poyer; Laura Fourmois; Su Chen; Guillaume Garcia; Marie-Paule Teulade-Fichou; Philippe Maillard; Florence Mahuteau-Betzer
      Pages: 107 - 118
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Fabien Hammerer, Florent Poyer, Laura Fourmois, Su Chen, Guillaume Garcia, Marie-Paule Teulade-Fichou, Philippe Maillard, Florence Mahuteau-Betzer
      The proof of concept for two-photon activated photodynamic therapy has already been achieved for cancer treatment but the efficiency of this approach still heavily relies on the availability of photosensitizers combining high two-photon absorption and biocompatibility. In this line we recently reported on a series of porphyrin-triphenylamine hybrids which exhibit high singlet oxygen production quantum yield as well as high two-photon absorption cross-sections but with a very poor cellular internalization. We present herein new photosensitizers of the same porphyrin-triphenylamine hybrid series but bearing cationic charges which led to strongly enhanced water solubility and thus cellular penetration. In addition the new compounds have been found localized in mitochondria that are preferential target organelles for photodynamic therapy. Altogether the strongly improved properties of the new series combined with their specific mitochondrial localization lead to a significantly enhanced two-photon activated photodynamic therapy efficiency.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.024
       
  • Discovery of novel purine nucleoside derivatives as phosphodiesterase 2
           (PDE2) inhibitors: Structure-based virtual screening, optimization and
           biological evaluation
    • Authors: Xiaoxia Qiu; Yiyou Huang; Deyan Wu; Fei Mao; Jin Zhu; Wenzhong Yan; Hai-Bin Luo; Jian Li
      Pages: 119 - 133
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Xiaoxia Qiu, Yiyou Huang, Deyan Wu, Fei Mao, Jin Zhu, Wenzhong Yan, Hai-Bin Luo, Jian Li
      Phosphodiesterase 2 (PDE2) has received much attention for the potential treatment of the central nervous system (CNS) disorders and pulmonary hypertension. Herein, we identified that clofarabine (4), an FDA-approved drug, displayed potential PDE2 inhibitory activity (IC50 = 3.12 ± 0.67 μM) by structure-based virtual screening and bioassay. Considering the potential therapeutic benefit of PDE2, a series of purine nucleoside derivatives based on the structure and binding mode of 4 were designed, synthesized and evaluated, which led to the discovery of the best compound 14e with a significant improvement of inhibitory potency (IC50 = 0.32 ± 0.04 μM). Further molecular docking and molecular dynamic (MD) simulations studies revealed that 5′-benzyl group of 14e could interact with the unique hydrophobic pocket of PDE2 by forming extra van der Waals interactions with hydrophobic residues such as Leu770, Thr768, Thr805 and Leu809, which might contribute to its enhancement of PDE2 inhibition. These potential compounds reported in this article and the valuable structure-activity relationships (SARs) might bring significant instruction for further development of potent PDE2 inhibitors.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.022
       
  • Bioluminescence probe for γ-glutamyl transpeptidase detection in vivo
    • Authors: Yuxing Lin; Yuqi Gao; Zhao Ma; Tianyu Jiang; Xin Zhou; Zhenzhen Li; Xiaojun Qin; Yun Huang; Lupei Du; Minyong Li
      Pages: 134 - 140
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Yuxing Lin, Yuqi Gao, Zhao Ma, Tianyu Jiang, Xin Zhou, Zhenzhen Li, Xiaojun Qin, Yun Huang, Lupei Du, Minyong Li
      To detect γ-Glutamyl Transpeptidase (GGT) activity in vitro and in vivo, a bioluminescence probe with high sensitivity and specificity was well designed and synthesized. This probe can be recognized by GGT and release strong bioluminescence with its further reaction with luciferase. The performance of this probe was demonstrated in vitro and in cells. Finally, we applied the probe for detection of GGT activity in xenograft model.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.025
       
  • Synthesis, in vitro and in silico evaluation of novel trans-stilbene
           analogues as potential COX-2 inhibitors
    • Authors: Miłosz Regulski; Hanna Piotrowska-Kempisty; Wiesław Prukała; Zbigniew Dutkiewicz; Katarzyna Regulska; Beata Stanisz; Marek Murias
      Pages: 141 - 151
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Miłosz Regulski, Hanna Piotrowska-Kempisty, Wiesław Prukała, Zbigniew Dutkiewicz, Katarzyna Regulska, Beata Stanisz, Marek Murias
      25 new trans-stilbene and trans-stilbazole derivatives were investigated using in vitro and in silico techniques. The selectivity and potency of the compounds were assessed using commercial ELISA test. The obtained results were incorporated into 2D QSAR assay. The most promising compound 4-nitro-3′,4′,5′-trihydroxy-trans-stilbene (N1) was synthetized and its potency and selectivity were confirmed. N1 was classified as preferential COX-2 inhibitor. Its ability to inhibit COX-2 in MCF-7 cell line was established and its cytotoxicity by MTT test was assessed. The compound was more cytotoxic than celecoxib within studied concentration range. Finally, the investigated trans-stilbene was docked into COX-1 and COX-2 active sites using “CDOCKER” protocol.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.027
       
  • Bisindolylmethane thiosemicarbazides as potential inhibitors of urease:
           Synthesis and molecular modeling studies
    • Authors: Muhammad Taha; Hayat Ullah; Laode Muhammad Ramadhan Al Muqarrabun; Muhammad Naseem Khan; Fazal Rahim; Norizan Ahmat; Muhammad Tariq Javid; Muhammad Ali; Khalid Mohammed Khan
      Pages: 152 - 160
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Muhammad Taha, Hayat Ullah, Laode Muhammad Ramadhan Al Muqarrabun, Muhammad Naseem Khan, Fazal Rahim, Norizan Ahmat, Muhammad Tariq Javid, Muhammad Ali, Khalid Mohammed Khan
      Bisindolylmethane thiosemicarbazides 1-18 were synthesized, characterized by 1H NMR and ESI MS and evaluated for urease inhibitory potential. All analogs showed outstanding urease inhibitory potentials with IC50 values ranging between 0.14 ± 0.01 to 18.50 ± 0.90 μM when compared with the standard inhibitor thiourea having IC50 value 21.25 ± 0.90 μM. Among the series, analog 9 (0.14 ± 0.01 μM) with di-chloro substitution on phenyl ring was identified as the most potent inhibitor of urease. The structure activity relationship has been also established on the basis of binding interactions of the active analogs. These binding interactions were identified by molecular docking studies.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.028
       
  • Design, synthesis and evaluation against Mycobacterium tuberculosis of
           azole piperazine derivatives as dicyclotyrosine (cYY) mimics
    • Authors: Hend A.A. Abd El-wahab; Mauro Accietto; Leonardo B. Marino; Kirsty J. McLean; Colin W. Levy; Hamdy M. Abdel-Rahman; Mahmoud A. El-Gendy; Andrew W. Munro; Ahmed S. Aboraia; Claire Simons
      Pages: 161 - 176
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Hend A.A. Abd El-wahab, Mauro Accietto, Leonardo B. Marino, Kirsty J. McLean, Colin W. Levy, Hamdy M. Abdel-Rahman, Mahmoud A. El-Gendy, Andrew W. Munro, Ahmed S. Aboraia, Claire Simons
      Three series of azole piperazine derivatives that mimic dicyclotyrosine (cYY), the natural substrate of the essential Mycobacterium tuberculosis cytochrome P450 CYP121A1, were prepared and evaluated for binding affinity and inhibitory activity (MIC) against M. tuberculosis. Series A replaces one phenol group of cYY with a C3-imidazole moiety, series B includes a keto group on the hydrocarbon chain preceding the series A imidazole, whilst series C explores replacing the keto group of the piperidone ring of cYY with a CH2-imidazole or CH2-triazole moiety to enhance binding interaction with the heme of CYP121A1. The series displayed moderate to weak type II binding affinity for CYP121A1, with the exception of series B 10a, which displayed mixed type I binding. Of the three series, series C imidazole derivatives showed the best, although modest, inhibitory activity against M. tuberculosis (17d MIC = 12.5 μg/mL, 17a 50 μg/mL). Crystal structures were determined for CYP121A1 bound to series A compounds 6a and 6b that show the imidazole groups positioned directly above the haem iron with binding between the haem iron and imidazole nitrogen of both compounds at a distance of 2.2 Å. A model generated from a 1.5 Å crystal structure of CYP121A1 in complex with compound 10a showed different binding modes in agreement with the heterogeneous binding observed. Although the crystal structures of 6a and 6b would indicate binding with CYP121A1, the binding assays themselves did not allow confirmation of CYP121A1 as the target.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.030
       
  • Lead identification and optimization of bacterial glutamate racemase
           inhibitors
    • Authors: Prasanthi Malapati; Vagolu Siva Krishna; Radhika Nallangi; Nikhila Meda; Rudraraju Reshma Srilakshmi; Dharmarajan Sriram
      Pages: 177 - 190
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Prasanthi Malapati, Vagolu Siva Krishna, Radhika Nallangi, Nikhila Meda, Rudraraju Reshma Srilakshmi, Dharmarajan Sriram
      Mycobacterium tuberculosis glutamate racemase is an essential enzyme involved in peptidoglycan synthesis and conserved in most bacteria. Small molecule inhibitors were reported on other bacterial species whereas in M. tuberculosis it wasn’t explored much. In this study we have screened in house compound library using fluorescence thermal shift assay and enzyme inhibition assay, form this (1-(3-(benzo[d]thiazol-2-yl)phenyl)-3-(p-tolyl)thiourea) was identified as lead compound with IC50 19.47 ± 0.81 μM. Further lead optimization by synthesis resulted in twenty-three compounds, of which Compound 25 has shown more efficacy compared to lead 1 showing non-competitive mode of inhibition with IC50 1.32 ± 0.43 μM. It also showed significant activity (represented in log reduction) in nutrient starved dormant M. tuberculosis model (2.1), M. tuberculosis biofilm assay (2.0) and in vivo M. marinum infected zebrafish model (3.5).
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.031
       
  • 7-Methylguanosine monophosphate analogues with 5′-(1,2,3-triazoyl)
           
    • Authors: Mateusz Kozarski; Dorota Kubacka; Blazej A. Wojtczak; Renata Kasprzyk; Marek R. Baranowski; Joanna Kowalska
      Pages: 191 - 199
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Mateusz Kozarski, Dorota Kubacka, Blazej A. Wojtczak, Renata Kasprzyk, Marek R. Baranowski, Joanna Kowalska
      The hydrolysis of nucleoside 5′-monophosphates to the corresponding nucleosides and inorganic phosphate is catalysed by 5′-nucleotidases, thereby contributing to the control of endogenous nucleotide turnover and affecting the fate of exogenously delivered nucleotide- and nucleoside-derived therapeutics in cells. A recently identified nucleotidase cNIIIB shows preference towards 7-methylguanosine monophosphate (m7GMP) as a substrate, which suggests its potential involvement in mRNA degradation. However, the extent of biological functions and the significance of cNIIIB remains to be elucidated. Here, we synthesised a series of m7GMP analogues carrying a 1,2,3-triazole moiety at the 5′ position as the potential inhibitors of human cNIIIB. The compounds were synthesised by using the copper-catalysed azide-alkyne cycloaddition (CuAAC) between 5′-azido-5′-deoxy-7-methylguanosine and different phosphate or phosphonate derivatives carrying terminal alkyne. The analogues were evaluated as cNIIIB inhibitors using HPLC and malachite green assays, demonstrating that compound 1a, carrying a 1,2,3-triazoylphosphonate moiety, inhibits cNIIIB activity at micromolar concentrations (IC50 87.8 ± 7.5 µM), while other analogues showed no activity. In addition, compound 1d was identified as an artifical substrate for HscNIIIB. Further characterization of inhibitor 1a revealed that it is poorly recognised by other m7G-binding proteins, eIF4E and DcpS, indicating its selectivity towards cNIIIB. The first inhibitor (1a) and unnatural substrate (1d) of cNIIIB, identified here, can be used as molecular probes for the elucidation of biological roles of cNIIIB, including the verification of its proposed function in mRNA metabolism.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.032
       
  • Synthesis and evaluation of a potent, well-balanced EP2/EP3 dual agonist
    • Authors: Akihiro Kinoshita; Masato Higashino; Koji Yoshida; Yoshiyuki Aratani; Akito Kakuuchi; Keisuke Hanada; Hiroyuki Takeda; Atsushi Naganawa; Hidekazu Matsuya; Kazuyuki Ohmoto
      Pages: 200 - 214
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Akihiro Kinoshita, Masato Higashino, Koji Yoshida, Yoshiyuki Aratani, Akito Kakuuchi, Keisuke Hanada, Hiroyuki Takeda, Atsushi Naganawa, Hidekazu Matsuya, Kazuyuki Ohmoto
      A highly potent and well-balanced dual agonist for the EP2 and EP3 receptors is described. Optimization of the lead compound was accomplished in consideration of the relative agonist activity against each EP subtype receptor and the pharmacokinetic profile. As the result, 2-[(2-{(1R,2R)-2-[(1E,4S)-5-cyclopentyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}eth-yl)thio]-1,3-thiazole-4-carboxylic acid (10) showed excellent potency (human EC50 EP2 = 1.1 nM, EP3 = 1.0 nM) with acceptable selectivity over the EP1 and EP4 subtypes (>2000-fold). Further fine-tuning of compound 10 led to identification of ONO-8055 as a clinical candidate. ONO-8055 was effective at an extremely low dose (0.01 mg/kg, po, bid) in rats, and dose-dependently improved voiding dysfunction in a monkey model of underactive bladder (UAB). ONO-8055 is expected to be a novel and highly promising drug for UAB.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.035
       
  • Design, synthesis and pharmacological evaluation of some novel indanone
           derivatives as acetylcholinesterase inhibitors for the management of
           cognitive dysfunction
    • Authors: Poonam Piplani; Ankit Jain; Dhiksha Devi; Anjali; Anuradha Sharma; Pragati Silakari
      Pages: 215 - 224
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Poonam Piplani, Ankit Jain, Dhiksha Devi, Anjali, Anuradha Sharma, Pragati Silakari
      The present study reports the effect of indanone derivatives on scopolamine induced deficit cholinergic neurotransmission serving as promising leads for the therapeutics of cognitive dysfunction. Eleven compounds 54–64 have been designed, synthesised and evaluated against behavioural alterations using step down passive avoidance protocol at a dose of 0.5 mg/kg with Donepezil (1) as the reference standard. All the synthesised compounds were evaluated for their in vitro acetylcholinesterase (AChE) inhibition at five different concentrations using mice brain homogenate as the source of the enzyme. Compounds 54, 56, 59 and 64 displayed appreciable activity with an IC50 value of 14.06 µM, 12.30 µM, 14.06 µM and 12.01 µM, respectively towards acetylcholinesterase inhibition. The molecular docking study performed to predict the binding mode of the compounds suggested that these compounds could bind appreciably to the amino acids present at the active site of recombinant human acetylcholinesterase (rhAChE). The behavioural, biochemical and in silico pharmacokinetic studies were in concordance with each other.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.033
       
  • Synthesis and evaluation of 18F-hexafluorophosphate as a novel PET probe
           for imaging of sodium/iodide symporter in a murine C6-glioma tumor model
    • Authors: Huailei Jiang; Aditya Bansal; Ribu Goyal; Kah-Whye Peng; Stephen J. Russell; Timothy R. DeGrado
      Pages: 225 - 231
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Huailei Jiang, Aditya Bansal, Ribu Goyal, Kah-Whye Peng, Stephen J. Russell, Timothy R. DeGrado
      Noninvasive imaging of iodide uptake via the sodium/iodide symporter (NIS) has received great interest for evaluation of thyroid cancer and reporter imaging of NIS-expressing viral therapies. In this study, we investigate 18F-labeled hexafluorophosphate (HFP or PF6 −) as a high-affinity iodide analog for NIS imaging. 18F-HFP was synthesized by radiofluorination of phosphorus pentafluoride·N-methylpyrrolidine complex and evaluated in human NIS (hNIS)-expressing C6 glioma cells and a C6 glioma xenograft mouse model. 18F-HFP was obtained in radiochemical yield of 10 ± 5%, radiochemical purity of >96% and specific radioactivity of 604 ± 18 MBq/µmol. Specific uptake of 18F-HFP and high affinity of 19F-HFP were observed in hNIS+ C6-glioma cells. PET imaging showed robust uptake of 18F-HFP in NIS-expressing tissues (thyroid, stomach, and hNIS+ C6 glioma xenografts), and the uptake of 18F-HFP was blocked by NaClO4 pretreatment. Specific accumulation in hNIS-expressing xenograft (hNIS+) was observed relative to isogenic control tumor (hNIS−). Clearance of 18F-HFP was predominantly through renal excretion. The biodistribution showed consistent results with PET imaging. Minimal bone uptake was observed over 2 h period post-injection, indicating excellent in vivo stability of 18F-HFP. Although improvement in specific radioactivity is desirable, the results indicate that 18F-HFP is a promising candidate radiotracer for further evaluation for NIS imaging.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.034
       
  • Synthesis and evaluation of biaryl derivatives for structural
           characterization of selective monoamine oxidase B inhibitors toward
           Parkinson’s disease therapy
    • Authors: Seul Ki Yeon; Ji Won Choi; Jong-Hyun Park; Ye Rim Lee; Hyeon Jeong Kim; Su Jeong Shin; Bo Ko Jang; Siwon Kim; Yong-Sun Bahn; Gyoonhee Han; Yong Sup Lee; Ae Nim Pae; Ki Duk Park
      Pages: 232 - 244
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Seul Ki Yeon, Ji Won Choi, Jong-Hyun Park, Ye Rim Lee, Hyeon Jeong Kim, Su Jeong Shin, Bo Ko Jang, Siwon Kim, Yong-Sun Bahn, Gyoonhee Han, Yong Sup Lee, Ae Nim Pae, Ki Duk Park
      Benzyloxyphenyl moiety is a common structure of highly potent, selective and reversible inhibitors of monoamine oxidase B (MAO-B), safinamide and sembragiline. We synthesized 4-(benzyloxy)phenyl and biphenyl-4-yl derivatives including halogen substituents on the terminal aryl unit. In addition, we modified the carbon linker between amine group and the biaryl linked unit. Among synthesized compounds, 12c exhibited the most potent and selective MAO-B inhibitory effect (hMAO-B IC50: 8.9 nM; >10,000-fold selectivity over MAO-A) as a competitive inhibitor. In addition, 12c showed greater MAO-B inhibitory activity and selectivity compared to well-known MAO-B inhibitors such as selegiline, safinamide and sembragiline. In the MPTP-induced mouse model of Parkinson’s disease (PD), 12c significantly protected the tyrosine hydroxylase (TH)-immunopositive DAergic neurons and attenuated the PD-associated behavioral deficits. This study suggests characteristic structures as a MAO-B inhibitor that may provide a good insight for the development of therapeutic agents for PD.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.036
       
  • Synthesis and bioevaluation study of novel N-methylpicolinamide and
           thienopyrimidine derivatives as selectivity c-Met kinase inhibitors
    • Authors: Linxiao Wang; Shan Xu; Xiuying Chen; Xiaobo Liu; Yongli Duan; Dejia Kong; Dandan Zhao; Pengwu Zheng; Qidong Tang; Wufu Zhu
      Pages: 245 - 256
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Linxiao Wang, Shan Xu, Xiuying Chen, Xiaobo Liu, Yongli Duan, Dejia Kong, Dandan Zhao, Pengwu Zheng, Qidong Tang, Wufu Zhu
      Four series of N-methylpicolinamide moiety and thienopyrimidine moiety bearing pyridazinone were designed and synthesized and evaluated for the IC50 values against three cancer cell lines (A549, HepG2 and MCF-7) and some selected compounds were further evaluated for the activity against c-Met, Flt-3, VEGFR-2, c-Kit and EGFR kinases. Three compounds (35, 39 and 43) showed more active than positive control Foretinib against A549, HepG2 and MCF-7 cell lines. The most promising compound 43 showed superior activity against A549, HepG2 and MCF-7, with the IC50 values of 0.58 ± 0.15 µM, 0.47 ± 0.06 µM and 0.74 ± 0.12 µM, which were 3.73–5.39-fold more activity than Foretinib, respectively. The experiments of enzyme-based showed that 43 restrain the c-Met selectively, with the IC50 values of 16 nM, which showed equal activity to Foretinib (14 nM) and better than the compound 5 (90 nM). Moreover, AO and Annexin V/PI staining and docking studies were carried out.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.039
       
  • Identification of potent lysophosphatidic acid receptor 5 (LPA5)
           antagonists as potential analgesic agents
    • Authors: Yuichiro Kawamoto; Ryushi Seo; Nobuhito Murai; Hideki Hiyama; Hiromasa Oka
      Pages: 257 - 265
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Yuichiro Kawamoto, Ryushi Seo, Nobuhito Murai, Hideki Hiyama, Hiromasa Oka
      Lysophosphatidic acid (LPA) plays an important role in a variety of cellular functions. In particular, LPA5 receptor is highly expressed in spinal cord and dorsal root ganglion, which are associated with pain. This fact prompted us to hypothesize that LPA5 antagonists show analgesic effects. To search for potent LPA5 antagonists with blood brain barrier (BBB) permeability, we conducted high throughput screening (HTS). In HTS campaign, we found a 2H-isoquinoline-1-one scaffold showing antagonistic activity against LPA5 and synthesized a series of 2H-isoquinoline-1-one derivatives and evaluated their LPA5 activities. Among these compounds, compound 7e showed potent LPA5 activity with an IC50 value of 0.12 μM, and acceptable BBB permeability. Furthermore, it showed effective analgesic effect in a chronic constriction injury rat model. Therefore, 7e may have a potential as novel pain therapeutic approach.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.038
       
  • Design, synthesis and biological evaluation of novel indole-xanthendione
           hybrids as selective estrogen receptor modulators
    • Authors: Ramit Singla; Kunj Bihari Gupta; Shishir Upadhyay; Monisha Dhiman; Vikas Jaitak
      Pages: 266 - 277
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Ramit Singla, Kunj Bihari Gupta, Shishir Upadhyay, Monisha Dhiman, Vikas Jaitak
      Ground breaking clinical therapeutic advances in the treatment of breast cancer (BC) is the introduction of selective estrogen receptor modulators (SERMs). We have expeditiously designed and synthesized indole-xanthendione hybrids by coalescing the indole nucleus with xanthendione. All the compounds were first screened for anti-proliferative activity, cytotoxicity and ER-α binding affinity by utilizing ER-α dominant T47D BC cell lines, PBMCs and ER-α competitor assay kit. From this study, two representative compounds 6e and 6f showing most promising activity were advanced for gene expression studies for targeting ER-α. Cell imaging experiment undoubtedly indicate that both the compounds were able to cross cellular bio membrane and accumulate thus instigating cytotoxicity. RT-PCR and Western blotting experiments further strengthened that both compounds altered the expression of mRNA and receptor protein of ER-α, thereby forestalling downstream transactivation and signalling pathway in T47D cells line. Structural investigation from induced fit simulation study suggest that indole moiety of the compounds 6e and 6f helps in the anchoring of the xanthendione moiety in the hydrophobic region of the cavity thus enabling the compound to bind in antagonistic conformation similar to bazedoxifene by extensive hydrogen bonding and Van der Waals forces. All these finding collectively imply that compound 6e and 6f represents a novel potent ER-α antagonist and in the development of SERMs for the management of BC.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.040
       
  • Antitussive and expectorant activities of licorice and its major compounds
    • Authors: Yi Kuang; Bin Li; Jingran Fan; Xue Qiao; Min Ye
      Pages: 278 - 284
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Yi Kuang, Bin Li, Jingran Fan, Xue Qiao, Min Ye
      Licorice has been used as an antitussive and expectorant herbal medicine for a long history. This work evaluated the activities of 14 major compounds and crude extracts of licorice, using the classical ammonia-induced cough model and phenol red secretion model in mice. Liquiritin apioside (1), liquiritin (2), and liquiritigenin (3) at 50 mg/kg (i.g.) could significantly decrease cough frequency by 30–78% (p < .01). The antitussive effects could be partially antagonized by the pretreatment of methysergide or glibenclamide, but not naloxone. Moreover, compounds 1–3 showed potent expectorant activities after 3 days treatment (p < .05). The water and ethanol extracts of licorice, which contain abundant 1 and 2, could decrease cough frequency at 200 mg/kg by 25–59% (p < .05), and enhance the phenol red secretion (p < .05), while the ethyl acetate extract showed little effect. These results indicate liquiritin apioside and liquiritin are the major antitussive and expectorant compounds of licorice. Their antitussive effects depend on both peripheral and central mechanisms.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.046
       
  • Studies on interactions of carbazole derivatives with DNA, cell image, and
           cytotoxicity
    • Authors: Guoyan Hao; Jinyu Sun; Chunying Wei
      Pages: 285 - 294
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Guoyan Hao, Jinyu Sun, Chunying Wei
      DNA-binding agents have been considered as an established opportunity for the development of anticancer drugs and DNA fluorescence probes. This work reported the synthesis of two novel carbazole derivatives (1 and 2) and investigated their DNA binding properties, living cell image, and cytotoxicity. The results demonstrated that both compounds presented the higher binding affinity to G-quadruplex than to duplex DNA by means of UV–Vis absorption titration and fluorescent intercalator displacement. Continuous variation analysis indicated that their binding stoichiometries of the compound/G-quadruplex were near 2 except the compound/bcl-2. Circular dichroism spectra showed that both compounds had no influence on the conformation of G-quadruplexes. Fluorescence titrations indicated that 2 had the potential to be a G-quadruplex selective fluorescent probe, while 1 could be used as a fluorescent probe for duplex DNA. Confocal fluorescence images indicated that both compounds could enter the living HepG2 cells, and 1 mainly located in nucleus whereas 2 mainly distributed in cytoplasm. DNase and RNase digest tests indicated that both compounds could enter into the nucleus and interact with duplex DNA, especially, 2 could interact with RNA and/or G-quadruplex DNA. They also exhibited an obvious antiproliferative activity to HepG2 by using MTT assays, with IC50 values of 2.7 and 9.5 μM for 1 and 2, respectively.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.044
       
  • Novel sulfenamides and sulfonamides based on pyridazinone and pyridazine
           scaffolds as CB1 receptor ligand antagonists
    • Authors: Gabriele Murineddu; Francesco Deligia; Giulio Ragusa; Laura García-Toscano; María Gómez-Cañas; Battistina Asproni; Valentina Satta; Elena Cichero; Ruth Pazos; Paola Fossa; Giovanni Loriga; Javier Fernández-Ruiz; Gerard A. Pinna
      Pages: 295 - 307
      Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1
      Author(s): Gabriele Murineddu, Francesco Deligia, Giulio Ragusa, Laura García-Toscano, María Gómez-Cañas, Battistina Asproni, Valentina Satta, Elena Cichero, Ruth Pazos, Paola Fossa, Giovanni Loriga, Javier Fernández-Ruiz, Gerard A. Pinna
      A series of sulfenamide and sulfonamide derivatives was synthesized and evaluated for the affinity at CB1 and CB2 receptors. The N-bornyl-S-(5,6-di-p-tolylpyridazin-3-yl)-sulfenamide, compound 11, displayed good affinity and high selectivity for CB1 receptors (K i values of 44.6 nM for CB1 receptors and >40 μM for CB2 receptors, respectively). The N-isopinocampheyl-sulfenamide 12 and its sulfonamide analogue 22 showed similar selectivity for CB1 receptors with K i values of 75.5 and 73.2 nM, respectively. These novel compounds behave as antagonists/inverse agonists at CB1 receptor in the [35S]-GTPγS binding assays, and none showed adequate predictive blood–brain barrier permeation, exhibiting low estimated LD50. However, testing compound 12 in a supraspinal analgesic test (hot-plate) revealed that it was as effective as the classic CB1 receptor antagonist rimonabant, in reversing the analgesic effect of a cannabinoid agonist.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.11.051
       
  • Graphical abstract TOC
    • Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1


      PubDate: 2017-12-26T19:38:26Z
       
  • Graphical abstract TOC
    • Abstract: Publication date: 1 January 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 1


      PubDate: 2017-12-26T19:38:26Z
       
  • Theoretical Research in Structure Characteristics of Different Inhibitors
           and Differences of Binding Modes with CBP Bromodomain
    • Authors: Xue-Song Wang; Qing-Chuan Zheng
      Abstract: Publication date: Available online 26 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Xue-Song Wang, Qing-Chuan Zheng
      The CBP (CREB (cAMP responsive element binding protein) binding protein) bromodomain (BRD) could recognize and bind with acetyl K382 of human tumor suppressor protein p53 which the mutation of encoding gene might cause human cancers. CBP-BRD serves as a promising drug target for several disease pathways and a series of effective drug have been discovered. In this study, molecular dynamics (MD) simulations and molecular mechanics generalized born surface area (MM-GB/SA) approaches were performed to investigate the different binding modes between five inhibitors with CBP-BRD. Based on the energy and conformation analyses, a potent core fragment is chosen to act as the starting point for new inhibitor design by means of LUDI and rational drug design approaches. Then, T.E.S.T and molinspirition were applied to evaluate oral bioavailability and drug promiscuity of the new molecules. These results shed light on the idea for further inhibitor design.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.040
       
  • One-step Synthesis of Carbohydrate Esters as Antibacterial and Antifungal
           Agents
    • Authors: Madher N. AlFindee; Qian Zhang; Yagya Prasad Subedi; Jaya P. Shrestha; Yukie Kawasaki; Michelle Grilley; Jon Y. Takemoto; Cheng-Wei Tom Chang
      Abstract: Publication date: Available online 26 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Madher N. AlFindee, Qian Zhang, Yagya Prasad Subedi, Jaya P. Shrestha, Yukie Kawasaki, Michelle Grilley, Jon Y. Takemoto, Cheng-Wei Tom Chang
      Carbohydrate esters are biodegradable, and the degraded adducts are naturally occurring carbohydrates and fatty acids which are environmentally friendly and non-toxic to human. A simple one-step regioselective acylation of mono-carbohydrates has been developed that leads to the synthesis of a wide range of carbohydrate esters. Screening of these acylated carbohydrates revealed that several compounds were active against a panel of bacteria and fungi, including Staphylococcus aureus. methicillin-resistant S. aureus (MRSA), Candida albicans, Cryptococcus neoformans, Aspergillus flavus and Fusarium graminearum. Unlike prior studies on carbohydrate esters that focus only on antibacterial applications, our compounds are found to be active against both bacteria and fungi. Furthermore, the synthetic methodology is suitable to scale-up production for a variety of acylated carbohydrates. The identified lead compound, MAN014, can be used as an antimicrobial in applications such as food processing and preservation and for treatment of bacterial and fungal diseases in animals and plants.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.038
       
  • Inhibition of protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase
           by xanthones from Cratoxylum cochinchinense, and their kinetic
           characterization
    • Authors: Zuopeng Li; Yeong Hun Song; Zia Uddin; Yan Wang; Ki Hun Park
      Abstract: Publication date: Available online 26 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Zuopeng Li, Yeong Hun Song, Zia Uddin, Yan Wang, Ki Hun Park
      Cratoxylum cochinchinense displayed significant inhibition against protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase, both of which are key target enzymes to attenuate diabetes and obesity. The compounds responsible for both enzymes inhibition were identified as twelve xanthones (1-12) among which compounds 1 and 2 were found to be new ones. All of them simultaneously inhibited PTP1B with IC50s of (2.4-52.5 µM), and α-glucosidase with IC50 values of (1.7-72.7 µM), respectively. Cratoxanthone A (3) and γ-mangostin (7) were estimated to be most active inhibitors against both PTP1B (IC50 = 2.4 µM for 3, 2.8 µM for 7) and α-glucosidase (IC50 = 4.8 µM for 3, 1.7 µM for 7). In kinetic studies, all isolated xanthones emerged to be mixed inhibitors of α-glucosidase, whereas they behaved as competitive inhibitors of PTP1B. In time dependent experiments, compound 3 showed isomerization inhibitory behavior with following kinetic parameters: K i app = 2.4 µM; k 5 = 0.05001 µM-1S-1 and k 6 = 0.02076µM-1S-1.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.043
       
  • New branched amino acids for high affinity dendrimeric DC-SIGN ligands
    • Authors: Laurent Cattiaux; Vanessa Porkolab; Franck Fieschi; Jean-Maurice Mallet
      Abstract: Publication date: Available online 26 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Laurent Cattiaux, Vanessa Porkolab, Franck Fieschi, Jean-Maurice Mallet
      A branched amino acid was synthesized from methyl glucopyranoside; this amino acid presents three amino groups protected by Fmoc and one acid group and can be used in classic peptide synthesis. In parallel, similar azido terminated blocks were synthesized. Successive coupling reaction and deprotection afforded dendrimers with up to 27 azido functional groups. As an example of application, D-mannose and L-fucose residues were linked through CuAAC coupling and resulting glycodendrimers were evaluated in their interaction with DC-SIGN using SPR competition assay.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.036
       
  • A cell surface clicked navigation system to direct specific bone targeting
    • Authors: Young Kim; Zhe Zhang; Jae-Hyuck Shim; Tae Sup Lee; Ching-Hsuan Tung
      Abstract: Publication date: Available online 26 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Young Kim, Zhe Zhang, Jae-Hyuck Shim, Tae Sup Lee, Ching-Hsuan Tung
      Cell therapies are promising up-and-coming therapeutic strategies for many diseases. For maximal therapeutic benefits, injected cells have to navigate their way to a designated area, including organ and tissue; unfortunately, the majority of therapeutic cells are currently administered without a guide or homing device. To improve this serious shortcoming, a functionalization method was developed to equip cells with a homing signal. Its application was demonstrated by applying an Azadibenzocyclooctyne-bisphosphonate (ADIBO-BP) and azide paired bioorthogonal chemistry on cells for bone specific homing. Jurkat T cells and bone marrow derived stromal cells (BMSCs) were cultured with tetraacetylated N-azidoacetyl-D-mannosamine (Ac4ManNAz) to place unnatural azido groups onto the cell’s surface; these azido groups were then reacted with ADIBO-BP. The tethered bisphosphonates were able to bring Jurkat cells to hydroxyapatite, the major component of bone, and mineralized SAOS-2 cells. The incorporated BP groups also enhanced the specific affinity of BMSCs to mouse femur bone fragments in vitro. The introduced navigation strategy is expected to have a broad application in cell therapy, because through the biocompatible ADIBO and azide reactive pair, various homing signals could be efficiently anchored onto therapeutic cells.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.037
       
  • A review on the hybrids of hydroxycinnamic acidas multi-target-directed
           ligands against Alzheimer's disease
    • Authors: Xiao Zhang; Xixin He; Qiuhe Chen; Junfeng Lu; Simona Rapposelli; Rongbiao Pi
      Abstract: Publication date: Available online 26 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Xiao Zhang, Xixin He, Qiuhe Chen, Junfeng Lu, Simona Rapposelli, Rongbiao Pi
      Alzheimer's disease (AD), a complex chronic progressive central nervous system degenerative disease and a public health problem of the world, often characters cognitive dysfunction accompaning aggression and depression, and may lead to death. More attentions should be paid on it because there is no modified strategy against AD till now. AD is featured with the loss of cholinergic neurons, the amyloid-beta peptide (Aβ) plaques and the neurofibrillary tangles and several hypotheses were established to explain the pathogenesis of AD. Hydroxycinnamic acids,including caffeic acid (CA) and ferulic acid (FA) are widely distributed in natural plants and fruits. CA and FA exert various pharmacological activities, including anti-inflammatory, antioxidant, neuroprotection, anti-amyloid aggregation and so on. All these pharmacological activities are associated with the treatment of AD. Here we summarized the pharmacological activities of CA and FA, and their hybrids as multi-target-directed ligands (MTDLs) against AD. The future application of CA and FA was also discussed, hoping to provide beneficial information for the development of CA- and FA-based MTDLs against AD.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.042
       
  • Structural optimization of N1-aryl-benzimidazoles for the discovery of new
           non-nucleoside reverse transcriptase inhibitors active against wild-type
           and mutant HIV-1 strains
    • Authors: Anna Maria Monforte; Laura De Luca; Maria Rosa Buemi; Fatima E. Agharbaoui; Christophe Pannecouque; Stefania Ferro
      Abstract: Publication date: Available online 24 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Anna Maria Monforte, Laura De Luca, Maria Rosa Buemi, Fatima E. Agharbaoui, Christophe Pannecouque, Stefania Ferro
      Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are recommended components of preferred combination antiretroviral therapies used for the treatment of human immunodeficiency virus (HIV) infection. These regimens are extremely effective in suppressing virus replication. Recently, our research group identified some N1-aryl-2-arylthioacetamido-benzimidazoles as a novel class of NNRTIs. In this research work we report the design, the synthesis and the structure-activity relationship studies of new compounds (20-34) in which some structural modifications have been introduced in order to investigate their effects on reverse trascriptase (RT) inhibition and to better define the features needed to increase the antiviral activity. Most of the new compounds proved to be highly effective in inhibiting both RT enzyme at nanomolar concentrations and HIV-1 replication in MT4 cells with minimal cytotoxicity. Among them, the most promising N1-aryl-2-arylthioacetamido-benzimidazoles and N1-aryl-2-aryloxyacetamido-benzimidazoles were also tested toward a panel of single- and double-mutants strain responsible for resistance to NNRTIs, showing in vitro antiviral activity toward single mutants L100I, K103N, Y181C, Y188L and E138K. The best results were observed for derivatives 29 and 33 active also against the double mutants F227L and V106A.. Computational approaches were applied in order to rationalize the potency of the new synthesized inhibitors.
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      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.033
       
  • Discovery of chromenes as inhibitors of macrophage migration inhibitory
           factor
    • Authors: Tjie Kok; Hannah Wapenaar; Kan Wang; Constantinos G. Neochoritis; Tryfon Zarganes-Tzitzikas; Giordano Proietti; Nikolaos Eleftheriadis; Katarzyna Kurpiewska; Justyna Kalinowska-Tłuścik; Robbert Cool; Gerrit J. Poelarends; Alexander Dömling; Frank J. Dekker
      Abstract: Publication date: Available online 24 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Tjie Kok, Hannah Wapenaar, Kan Wang, Constantinos G. Neochoritis, Tryfon Zarganes-Tzitzikas, Giordano Proietti, Nikolaos Eleftheriadis, Katarzyna Kurpiewska, Justyna Kalinowska-Tłuścik, Robbert Cool, Gerrit J. Poelarends, Alexander Dömling, Frank J. Dekker
      Macrophage migration inhibitory factor (MIF) is an essential signaling cytokine with a key role in the immune system. Binding of MIF to its molecular targets such as, among others, the cluster of differentiation 74 (CD74) receptor plays a key role in inflammatory diseases and cancer. Therefore, the identification of MIF binding compounds gained importance in drug discovery. In this study, we aim to discover novel MIF binding compounds by screening of a focused compound collection for inhibition of its tautomerase enzyme activity. Inspired by the known chromen-4-one inhibitor Orita-13, a focused collection of compounds with a chromene scaffold was screened for MIF binding. The library was synthesized using versatile cyanoacetamide chemistry to provide diversely substituted chromenes. The screening provided inhibitors with IC50‘s in the low micromolar range. Kinetic evaluation suggested that the inhibitors were reversible and did not bind in the binding pocket of the substrate. Thus, we discovered novel inhibitors of the MIF tautomerase activity, which may ultimately support the development of novel therapeutic agents against diseases in which MIF is involved.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.032
       
  • New Photodynamic Molecular Beacons (PMB) as potential cancer-targeted
           agents in PDT
    • Authors: Aurélie Stallivieri; Ludovic Colombeau; Jérôme Devy; Nicolas Etique; Carine Chaintreuil; Bauyrzhan Myrzakhmetov; Mathilde Achard; Francis Baros; Philippe Arnoux; Régis Vanderesse; Céline Frochot
      Abstract: Publication date: Available online 24 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Aurélie Stallivieri, Ludovic Colombeau, Jérôme Devy, Nicolas Etique, Carine Chaintreuil, Bauyrzhan Myrzakhmetov, Mathilde Achard, Francis Baros, Philippe Arnoux, Régis Vanderesse, Céline Frochot
      Further improvements in Photodynamic therapy (PDT) necessitate that the dye targets more selectively tumour tissues or neovascularization than healthy cells. Different enzymes such as matrix metalloproteinases (MMPs) are overexpressed in tumour areas. Among these MMPs, gelatinases (MMP-2 and MMP-9) and its activator MMP-14 are known to play a key role in tumour angiogenesis and the growth of many cancers such as glioblastoma multiforme (GBM), an aggressive malignant tumour of the brain. These last years, the concept of photodynamic molecular beacons (PMB) became interesting for controlling the photosensitizer’s ability to generate singlet oxygen (1O2) close to target biomolecules as MMPs. We report herein novel PMBs triggered by MMP-2 and/or MMP-9 and/or MMP-14, comprising a photosensitizer and a singlet oxygen quencher linked by MMP cleavable peptide linker (H-GRIGFLRTAKGG-OH). First of all, we focused on the synthesis and the photophysical study of different derivatives photosensitizer-peptide. This preliminary work concluded on an influence of the nature and the distance from the peptide, but not of the position of the photosensitizer in these derivatives on the proteolytic enzymatic action. The nature of the quencher used (a blackberry quencher (BBQ-650) or a black hole quencher (BHQ3)) does not influence the enzymatic action. We also studied the influence of an additionnal PEG spacer. Finally, the synthesis, the singlet oxygen quenching efficiency and the enzymatic activation of these new MMP- cleavable-PMBs were compared.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.034
       
  • Structure-based Design, Synthesis, and Biological Evaluation of
           Imidazo[1,2-b]pyridazine-based p38 MAP Kinase Inhibitors
    • Authors: Akira Kaieda; Masashi Takahashi; Takafumi Takai; Masayuki Goto; Takahiro Miyazaki; Yuri Hori; Satoko Unno; Tomohiro Kawamoto; Toshimasa Tanaka; Sachiko Itono; Terufumi Takagi; Teruki Hamada; Mikio Shirasaki; Kengo Okada; Gyorgy Snell; Ken Bragstad; Bi-Ching Sang; Osamu Uchikawa; Seiji Miwatashi
      Abstract: Publication date: Available online 24 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Akira Kaieda, Masashi Takahashi, Takafumi Takai, Masayuki Goto, Takahiro Miyazaki, Yuri Hori, Satoko Unno, Tomohiro Kawamoto, Toshimasa Tanaka, Sachiko Itono, Terufumi Takagi, Teruki Hamada, Mikio Shirasaki, Kengo Okada, Gyorgy Snell, Ken Bragstad, Bi-Ching Sang, Osamu Uchikawa, Seiji Miwatashi
      We identified novel potent inhibitors of p38 MAP kinase using structure-based design strategy. X-ray crystallography showed that when p38 MAP kinase is complexed with TAK-715 (1) in a co-crystal structure, Phe169 adopts two conformations, where one interacts with 1 and the other shows no interaction with 1. Our structure-based design strategy shows that these two conformations converge into one via enhanced protein-ligand hydrophobic interactions. According to the strategy, we focused on scaffold transformation to identify imidazo[1,2-b]pyridazine derivatives as potent inhibitors of p38 MAP kinase. Among the herein described and evaluated compounds, N-oxide 16 exhibited potent inhibition of p38 MAP kinase and LPS-induced TNF-α production in human monocytic THP-1 cells, and significant in vivo efficacy in rat collagen-induced arthritis models. In this article, we report the discovery of potent, selective and orally bioavailable imidazo[1,2-b]pyridazine-based p38 MAP kinase inhibitors with pyridine N-oxide group.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.031
       
  • Benzimidazole design, synthesis, and docking to build selective carbonic
           anhydrase VA inhibitors
    • Authors: Edita Čapkauskaitė; Audrius Zakšauskas; Virginijus Ruibys; Vaida Linkuvienė; Vaida Paketurytė; Marius Gedgaudas; Visvaldas Kairys; Daumantas Matulis
      Abstract: Publication date: Available online 24 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Edita Čapkauskaitė, Audrius Zakšauskas, Virginijus Ruibys, Vaida Linkuvienė, Vaida Paketurytė, Marius Gedgaudas, Visvaldas Kairys, Daumantas Matulis
      The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.035
       
  • Identification of highly potent and orally available free fatty acid
           receptor 1 agonists bearing isoxazole scaffold
    • Authors: Zheng Li; Chunxia Liu; Wei Shi; Xingguang Cai; Yuxuan Dai; Chen Liao; Wenlong Huang; Hai Qian
      Abstract: Publication date: Available online 24 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Zheng Li, Chunxia Liu, Wei Shi, Xingguang Cai, Yuxuan Dai, Chen Liao, Wenlong Huang, Hai Qian
      The free fatty acid receptor 1 (FFA1) is being considered to be a novel anti-diabetic target based on its role in amplifying insulin secretion. We have previously identified several series of FFA1 agonists with different heterocyclic scaffolds. Herein, we describe the structural exploration of other heterocyclic scaffolds directed by drug-like physicochemical properties. Further structure-based design and chiral resolution provided the most potent compound 11 (EC50 = 7.9 nM), which exhibited improved lipophilicity (LogD7.4: 1.93), ligand efficiency (LE = 0.32) and ligand lipophilicity efficiency (LLE = 6.2). Moreover, compound 11 revealed an even better pharmacokinetic property than that of TAK-875 in terms of plasma clearance, maximum concentration, and plasma exposure. Although robust agonistic activity and PK profiles for compound 11, the glucose-lowering effects in vivo is not ideal, and the exact reason for in vitro/in vivo difference was worthy for further exploration.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.030
       
  • Discovery of New Thienopyrimidine Derivatives as Potent and Orally
           Efficacious Phosphoinositide 3-Kinase Inhibitors
    • Authors: Songwen Lin; Chunyang Wang; Ming Ji; Deyu Wu; Yuanhao Lv; Li Sheng; Fangbin Han; Yi Dong; Kehui Zhang; Yakun Yang; Yan Li; Xiaoguang Chen; Heng Xu
      Abstract: Publication date: Available online 23 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Songwen Lin, Chunyang Wang, Ming Ji, Deyu Wu, Yuanhao Lv, Li Sheng, Fangbin Han, Yi Dong, Kehui Zhang, Yakun Yang, Yan Li, Xiaoguang Chen, Heng Xu
      A series of new thienopyrimidine derivatives has been discovered as potent PI3K inhibitors. The systematic SAR studies for these analogues are described. Among them, 8a and 9a exhibit nanomolar enzymatic potencies and sub-micromolar cellular anti-proliferative activities. 8a displays favorable pharmacokinetic profiles, while 9a easily undergoes deacetylation to yield a major metabolite 8a. Furthermore, 8a and 9a potently inhibit tumor growth in a dose-dependent manner in the NCI-H460 xenograft model with an acceptable safety profile.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.025
       
  • An improved synthesis of 1-methylcyclopropanol using the Kulinkovich
           reaction
    • Authors: Christine Delsarte; Guillaume Etuin; Laurent Petit
      Abstract: Publication date: Available online 23 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Christine Delsarte, Guillaume Etuin, Laurent Petit
      An improved process for the preparation of 1-methylcyclopropanol using the Kulinkovich reaction is described. The use of titanium tetramethoxide as catalyst resulted in minimal side product formation. The reaction, isolation and purification procedures were optimized so they can be easily implemented in multi-purpose equipment.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.029
       
  • Synthesis and biological evaluation of cyclopeptide GG-8-6 and its
           analogues as anti-hepatocellular carcinoma agents
    • Authors: Jie-Tao Chen; Ru Ma; Shi-Chang Sun; Xiao-Feng Zhu; Xiao-Li Xu; Qing Mu
      Abstract: Publication date: Available online 20 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Jie-Tao Chen, Ru Ma, Shi-Chang Sun, Xiao-Feng Zhu, Xiao-Li Xu, Qing Mu
      GG-8-6, cyclo-(Val-Leu-Pro-Ile-Leu-Leu-Leu-Val-Leu, compound 1), and its twelve analogues (compound 2 - 13) were synthesized based on the lead compound Grifficyclocin B, a cyclic peptide with anti-tumor activity which was isolated from the plants of Goniothalamus species (Annonaceae). The bioassay results showed that these synthetic cyclopeptides exhibited different extent of cytotoxicity against human hepatocellular carcinoma cell lines. Among them, GG-8-6 (1) was the most active compound with IC50 values of 6.38 μM and 12.22 μM against SMMC-7721 and HepG2, respectively. Further studies on the mechanism demonstrated that GG-8-6 (1) could induce apoptosis and G2/M arrest of HCC cells, and the activation of caspase pathways was probably involved. In vivo anti-tumor experiments showed that GG-8-6 (1) could significantly inhibit the growth of tumor in the mouse xenograft tumor model. At the dose of 40 mg/kg, the inhibition ratio was 67.9% without weight loss. Our results suggested that GG-8-6 (1), a new cyclic peptide, might be a potential candidate for developing new anti-HCC drug in the coming future.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.028
       
  • Induction of apoptosis by pyrazolo[3,4-d]pyridazine derivative in lung
           cancer cells via disruption of bcl-2/bax expression balance
    • Authors: Mervat S. Mohamed; Abdou O. Abdelhamid; Fahad M. Almutairi; Ayat G. Ali; Mai K. Bishr
      Abstract: Publication date: Available online 20 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Mervat S. Mohamed, Abdou O. Abdelhamid, Fahad M. Almutairi, Ayat G. Ali, Mai K. Bishr
      In the rapidly expanding era of cancer target therapy, regulators of apoptosis are emerging as attractive therapeutic targets. X-linked inhibitor of apoptosis (XIAP) is of specific interest owing to its characteristic overexpression in a wide variety of neoplasms, with a resultant survival advantage for tumor cells and treatment resistance. In this study, we examined three pyrazolo [3,4-d] pyridazine derivatives (PPDs) through molecular modeling and studied their modes of interaction with XIAP-BIR3 domain. PPD-1, which possessed the highest binding affinity with XIAP, was tested on A549 (lung cancer cell line); HCT-116 (colorectal carcinoma cell line); HEPG2 (liver carcinomacell line), HFB4 (normal human skin melanocyte cell line) and WI-38 (human embryonic lung fibroblasts). In comparison to cisplatin as a positive control, PPD-1 yielded remarkable cytotoxicity on all cancer cell lines, with the highest anti-tumor activity on A549 and a favorable therapeutic ratio. Flow cytometry studies concluded that PPD-1 treatment induces Sub G1 and G2/M cell cycle arrest and apoptosis. The percentage of apoptotic cells in PPD-1 treated A549 cells was considerably higher than that in untreated cells (10.06% vs 0.57%, respectively). To further investigate the mechanism of induction of apoptosis by PPD-1, Real time-PCR was used to quantify the expression levels of key apoptotic regulators. Significant overexpression of the effector capsase-3, pro-apoptotic bax and tumor suppressor gene p53 were noted as compared to untreated cells (7.19 folds, 7.28 folds, and 5.08 folds, respectively). Moreover, PPD-1 inhibited the expression of the anti-apoptotic bcl-2 gene to 0.22 folds. These findings demonstrate that PPD-1 treatment disrupts the Bcl-2/BAX balance in lung cancer cell lines, leading to apoptosis induction possibly through intrinsic mitochondria-dependent pathway. These novel insights elucidate the mechanism of PPD-1 cytotoxicity in lung cancer cell lines and offer a promising therapeutic approach that needs further study.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.026
       
  • Discovery of EBI-1051: a novel and orally efficacious MEK inhibitor with
           benzofuran scaffold
    • Authors: Biao Lu; Song Huang; Jingsong Cao; Qiyue Hu; Ru Shen; Hong Wan; Dan Wang; Jijun Yuan; Lei Zhang; Jiayin Zhang; Minsheng Zhang; Weikang Tao; Lianshan Zhang
      Abstract: Publication date: Available online 20 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Biao Lu, Song Huang, Jingsong Cao, Qiyue Hu, Ru Shen, Hong Wan, Dan Wang, Jijun Yuan, Lei Zhang, Jiayin Zhang, Minsheng Zhang, Weikang Tao, Lianshan Zhang
      A novel series of benzodihydrofuran derivatives was developed as potent MEK inhibitors through scaffold hopping based on known clinical compounds. Further SAR exploration and optimization led to another benzofuran series with good oral bioavailability in rats. One of the compounds EBI-1051 (28d) demonstrated excellent in vivo efficacy in colo-205 tumor xenograft models in mouse and is suitable for pre-clinical development studies for the treatment of melanoma and MEK associated cancers. Compared to AZD6244, EBI-1051 showed superior potency in some cancer cell lines such as colon-205, A549 and MDA-MB-231
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.019
       
  • Structure-Activity Relationships of Cryptopleurine Analogs with E-ring
           Modifications as Anti-Hepatitis C Virus Agents
    • Authors: Ying Wang; Shao-Ru Chen; Xiaoming Yang; Kuo-Hsiung Lee; Yung-Chi Cheng
      Abstract: Publication date: Available online 20 December 2017
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Ying Wang, Shao-Ru Chen, Xiaoming Yang, Kuo-Hsiung Lee, Yung-Chi Cheng
      The tylophorine analog rac-cryptopleurine exhibited potent anti-hepatitis C virus (HCV) activity through allosteric regulation of ATPase activity of heat shock cognate protein 70 (Hsc70). We evaluated the impact of modifications on the E-ring of rac-cryptopleurine to the inhibitory activity against HCV replication and regulation of ATPase activity of Hsc70. Cryptopleurine analog YXM-110 with a 13α-hydroxyl group maintained activity against HCV and promoted ATP/ADP turnover of Hsc70; however, compounds with hydroxyl groups at other positions or with other orientations (YXM-109, YXM-139, and YXM-140) did not exhibit similar activities. Size modification or heteroatom incorporation of the E-ring led to loss of anti-HCV activity. Promotion of the chaperone activity of Hsc70 with carboxyl terminus Hsc70 interacting protein (CHIP) further enhanced the anti-HCV activity of rac-cryptopleurine and XYM-110. This structure-activity relationship (SAR) study refined structural design and optimization for developing rac-crytopleurine analogs as potent anti-HCV agents targeted against the host factor involved in HCV replication.
      Graphical abstract image

      PubDate: 2017-12-26T19:38:26Z
      DOI: 10.1016/j.bmc.2017.12.027
       
 
 
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