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  Subjects -> CHEMISTRY (Total: 876 journals)
    - ANALYTICAL CHEMISTRY (54 journals)
    - CHEMISTRY (614 journals)
    - CRYSTALLOGRAPHY (21 journals)
    - ELECTROCHEMISTRY (26 journals)
    - INORGANIC CHEMISTRY (43 journals)
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    - PHYSICAL CHEMISTRY (70 journals)

CHEMISTRY (614 journals)                  1 2 3 4 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 13)
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: 42)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 20)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 20)
ACS Macro Letters     Full-text available via subscription   (Followers: 25)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 40)
ACS Nano     Full-text available via subscription   (Followers: 265)
ACS Photonics     Full-text available via subscription   (Followers: 13)
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: 8)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 6)
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: 54)
Advanced Science Focus     Free   (Followers: 5)
Advances in Chemical Engineering and Science     Open Access   (Followers: 65)
Advances in Chemical Science     Open Access   (Followers: 16)
Advances in Chemistry     Open Access   (Followers: 20)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 19)
Advances in Drug Research     Full-text available via subscription   (Followers: 21)
Advances in Enzyme Research     Open Access   (Followers: 9)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 7)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 15)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 9)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 25)
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: 43)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 17)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 18)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6)
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: 3)
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: 2)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 61)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 15)
American Journal of Chemistry     Open Access   (Followers: 29)
American Journal of Plant Physiology     Open Access   (Followers: 11)
American Mineralogist     Hybrid Journal   (Followers: 15)
Analyst     Full-text available via subscription   (Followers: 38)
Angewandte Chemie     Hybrid Journal   (Followers: 164)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 236)
Annales UMCS, Chemia     Open Access  
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 5)
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: 9)
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: 13)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Hybrid Journal   (Followers: 1)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 8)
Applied Spectroscopy     Full-text available via subscription   (Followers: 22)
Applied Surface Science     Hybrid Journal   (Followers: 31)
Arabian Journal of Chemistry     Open Access   (Followers: 5)
ARKIVOC     Open Access   (Followers: 1)
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  
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Biochemistry     Full-text available via subscription   (Followers: 337)
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: 20)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 7)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 5)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 119)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 84)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 2)
Bitácora Digital     Open Access  
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 2)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 24)
Bulletin of the Korean Chemical Society     Hybrid Journal   (Followers: 1)
C - Journal of Carbon Research     Open Access   (Followers: 3)
Cakra Kimia (Indonesian E-Journal of Applied Chemistry)     Open Access  
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 2)
Canadian Journal of Chemistry     Hybrid Journal   (Followers: 10)
Canadian Mineralogist     Full-text available via subscription   (Followers: 6)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 71)
Catalysis for Sustainable Energy     Open Access   (Followers: 7)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 7)
Catalysis Science and Technology     Free   (Followers: 8)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 9)
Cellulose     Hybrid Journal   (Followers: 7)
Cereal Chemistry     Full-text available via subscription   (Followers: 4)
ChemBioEng Reviews     Full-text available via subscription   (Followers: 1)
ChemCatChem     Hybrid Journal   (Followers: 8)
Chemical and Engineering News     Free   (Followers: 18)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 73)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 26)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 22)
Chemical Reviews     Full-text available via subscription   (Followers: 181)
Chemical Science     Open Access   (Followers: 23)
Chemical Technology     Open Access   (Followers: 22)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemical Week     Full-text available via subscription   (Followers: 7)
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: 7)
Chemistry & Biology     Full-text available via subscription   (Followers: 32)
Chemistry & Industry     Hybrid Journal   (Followers: 6)
Chemistry - A European Journal     Hybrid Journal   (Followers: 151)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 16)
Chemistry and Materials Research     Open Access   (Followers: 20)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 5)
Chemistry in Education     Open Access   (Followers: 9)
Chemistry International     Hybrid Journal   (Followers: 2)
Chemistry Letters     Full-text available via subscription   (Followers: 44)
Chemistry of Materials     Full-text available via subscription   (Followers: 245)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 19)
Chemistry-Didactics-Ecology-Metrology     Open Access   (Followers: 1)
ChemistryOpen     Open Access   (Followers: 1)
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: 11)
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: 11)
Chromatographia     Hybrid Journal   (Followers: 24)
Chromatography     Open Access   (Followers: 2)
Chromatography Research International     Open Access   (Followers: 6)
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: 11)
Colloids and Interfaces     Open Access  
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 6)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 5)
Combustion Science and Technology     Hybrid Journal   (Followers: 22)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Composite Interfaces     Hybrid Journal   (Followers: 7)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 1)
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: 10)
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 Chromatography     Hybrid Journal  
Current Green Chemistry     Hybrid Journal  
Current Metabolomics     Hybrid Journal   (Followers: 5)
Current Microwave Chemistry     Hybrid Journal  
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 14)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 70)
Current Trends in Biotechnology and Chemical Research     Open Access   (Followers: 3)
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  

        1 2 3 4 | Last

Journal Cover Bioorganic & Medicinal Chemistry
  [SJR: 1.064]   [H-I: 119]   [119 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0968-0896
   Published by Elsevier Homepage  [3177 journals]
  • Sequence-specific DNA binding Pyrrole–imidazole polyamides and their
           applications
    • Authors: Yusuke Kawamoto; Toshikazu Bando; Hiroshi Sugiyama
      Pages: 1393 - 1411
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Yusuke Kawamoto, Toshikazu Bando, Hiroshi Sugiyama
      Pyrrole–imidazole polyamides (Py–Im polyamides) are cell-permeable compounds that bind to the minor groove of double-stranded DNA in a sequence-specific manner without causing denaturation of the DNA. These compounds can be used to control gene expression and to stain specific sequences in cells. Here, we review the history, structural variations, and functional investigations of Py–Im polyamides.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.01.026
       
  • Structural basis of the broad substrate tolerance of the antibody
           7B9-catalyzed hydrolysis of p-nitrobenzyl esters
    • Authors: Naoki Miyamoto; Miho Yoshimura; Yuji Okubo; Kayo Suzuki-Nagata; Takeshi Tsumuraya; Nobutoshi Ito; Ikuo Fujii
      Pages: 1412 - 1417
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Naoki Miyamoto, Miho Yoshimura, Yuji Okubo, Kayo Suzuki-Nagata, Takeshi Tsumuraya, Nobutoshi Ito, Ikuo Fujii
      Catalytic antibody 7B9, which was elicited against p-nitrobenzyl phosphonate transition-state analogue (TSA) 1, hydrolyzes a wide range of p-nitrobenzyl monoesters and thus shows broad substrate tolerance. To reveal the molecular basis of this substrate tolerance, the 7B9 Fab fragment complexed with p-nitrobenzyl ethylphosphonate 2 was crystallized and the three-dimensional structure was determined. The crystal structure showed that the strongly antigenic p-nitrobenzyl moiety occupied a relatively shallow antigen-combining site and therefore the alkyl moiety was located outside the pocket. These results support the observed broad substrate tolerance of 7B9 and help rationalize how 7B9 can catalyze various p-nitrobenzyl ester derivatives. The crystal structure also showed that three amino acid residues (AsnH33, SerH95, and ArgL96) were placed in key positions to form hydrogen bonds with the phosphonate oxygens of the transitions-state analogue. In addition, the role of these amino acid residues was examined by site-directed mutagenesis to alanine: all mutants (AsnH33Ala, SerH95Ala, and ArgL96Ala) showed no detectable catalytic activity. Coupling the findings from our structural studies with these mutagenesis results clarified the structural basis of the observed broad substrate tolerance of antibody 7B9-catalyzed hydrolyses. Our findings provide new strategies for the generation of catalytic antibodies that accept a broad range of substrates, aiding their practical application in synthetic organic chemistry.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2017.07.050
       
  • Design, synthesis and biological evaluation of novel hydroxamic acid based
           histone deacetylase 6 selective inhibitors bearing phenylpyrazol scaffold
           as surface recognition motif
    • Authors: Jinyu Yang; Gaoliang Cheng; Qihao Xu; Shenglin Luan; Shuxiang Wang; Dan Liu; Linxiang Zhao
      Pages: 1418 - 1425
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Jinyu Yang, Gaoliang Cheng, Qihao Xu, Shenglin Luan, Shuxiang Wang, Dan Liu, Linxiang Zhao
      In recent years, inhibition of HDAC6 became a promising therapeutic strategy for the treatment of cancer and HDAC6 inhibitors were considered to be potent anti-cancer agents. In this work, celecoxib showed moderate degree of HDAC6 inhibition activity and selectivity in preliminary enzyme inhibition activity assay. A series of hydroxamic acid derivatives bearing phenylpyrazol moiety were designed and synthesized as HDAC6 inhibitors. Most compounds showed potent HDAC6 inhibition activity. 11i was the most selective compound against HDAC6 with IC50 values of 0.020µM and selective factor of 101.1. Structure-activity relationship analysis indicated that locating the linker group at 1′ of pyrazol gave the most selectivity. The most compounds 11i (GI50 =3.63μM) exhibited 6-fold more potent than vorinostat in HepG2 cells. Considering of the high selectivity against HDAC6 and anti-proliferation activity, such compounds have potential to be developed as anti-cancer agents.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2017.08.029
       
  • Identification of novel PDEδ interacting proteins
    • Authors: Philipp Küchler; Gunther Zimmermann; Michael Winzker; Petra Janning; Herbert Waldmann; Slava Ziegler
      Pages: 1426 - 1434
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Philipp Küchler, Gunther Zimmermann, Michael Winzker, Petra Janning, Herbert Waldmann, Slava Ziegler
      Prenylation is a post-translational modification that increases the affinity of proteins for membranes and mediates protein-protein interactions. The retinal rod rhodopsin-sensitive cGMP 3′,5′-cyclic phosphodiesterase subunit delta (PDEδ) is a prenyl binding protein that is essential for the shuttling of small GTPases between different membrane compartments and, thus, for their proper functioning. Although the prenylome comprises up to 2% of the mammalian proteome, only few prenylated proteins are known to interact with PDEδ. A proteome-wide approach was employed to map the PDEδ interactome among the prenylome and revealed RAB23, CDC42 and CNP as novel PDEδ interacting proteins. Moreover, PDEδ associates with the lamin A mutant progerin in a prenyl-dependent manner. These findings shed new light on the role of PDEδ in binding (and regulating) prenylated proteins in cells.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2017.08.033
       
  • Synthesis and evaluation of 1H-pyrrole-2,5-dione derivatives as
           cholesterol absorption inhibitors for suppressing the formation of foam
           cells and inflammatory response
    • Authors: Xinrui Yuan; Yineng Xia; Peng Lu; Lijuan Zhu; Yuejiao Zhong; Yubin Wang
      Pages: 1435 - 1447
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Xinrui Yuan, Yineng Xia, Peng Lu, Lijuan Zhu, Yuejiao Zhong, Yubin Wang
      Excess lipid accumulation in the arterial intima and formation of macrophage-derived foam cells in the plaque could cause atherosclerotic lesion. Cholesterol absorption inhibitors could suppress the lipid accumulation of human macrophage, inflammatory response and the development of atherosclerosis. In this research, a series of 1H-pyrrole-2,5-dione derivatives were synthesized as cholesterol absorption inhibitor and tested in in vitro experiments. One of the most active inhibitors, compound 20 exhibited stronger in vitro cholesterol absorption activity than ezetimibe, no cytotoxicity in HEK293 and RAW264.7 cell lines and satisfied lipophilicity. The further study indicated that 20 could inhibit lipid accumulation of macrophage and reduce the secretion of LDH, MDA, TNF-α and ROS in a concentration-dependent manner. In conclusion, as a novel and potent cholesterol absorption inhibitor, compound 20 could suppress the formation of foam cells and inflammatory response.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2017.08.046
       
  • A Rhodamine B-based fluorescent probe for imaging Cu2+ in maize roots
    • Authors: Ting Lv; Yongqian Xu; Hongjuan Li; Fengyu Liu; Shiguo Sun
      Pages: 1448 - 1452
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Ting Lv, Yongqian Xu, Hongjuan Li, Fengyu Liu, Shiguo Sun
      A new Rhodamine B-based fluorescent probe (RBO) is successfully designed and synthesized, which is a higher selective and sensitive chemosensor for Cu2+ than other ions. Under physiological conditions (pH = 7.0), the non emission RBO displays a rapid fluorescence increase together with a color change after addition of Cu2+ and the detection limit is down to 28nM, which can clearly illustrate the distribution of Cu2+ with the help of laser scanning confocal microscope in plant tissues. Eventually, it confirmed that the Cu2+ accumulates mostly in the vascular cylinder and very less in the epidermal cells of maize roots, which is important to understand how the plants take up, transport and store in the Cu2+.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2017.09.026
       
  • Identification of cytotoxic, glutathione-reactive moieties inducing
           accumulation of reactive oxygen species via glutathione depletion
    • Authors: Julian Wilke; Tatsuro Kawamura; Nobumoto Watanabe; Hiroyuki Osada; Slava Ziegler; Herbert Waldmann
      Pages: 1453 - 1461
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Julian Wilke, Tatsuro Kawamura, Nobumoto Watanabe, Hiroyuki Osada, Slava Ziegler, Herbert Waldmann
      Reactive oxygen species (ROS) play an essential role in the survival and progression of cancer. Moderate oxidative stress drives proliferation, whereas high levels of ROS induce cytotoxicity. Compared to cancer cells, healthy cells often exhibit lower levels of oxidative stress. Elevation of cellular ROS levels by small molecules could therefore induce cancer-specific cytotoxicity. We have employed high-throughput phenotypic screening to identify inducers of ROS accumulation. We found 4,5-dihalo-2-methylpyridazin-3-one (DHMP) and 2,3,4,5(6)-tetrachloro-6(5)-methylpyridine (TCMP) moieties to strongly deplete GSH, to cause ROS accumulation and to induce cell death. Small molecules containing these fragments will most likely share the same properties and should therefore be carefully considered in the development of bioactive molecules.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2017.11.009
       
  • Synthesis and evaluation of
           4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran] analogues
           against both active and dormant Mycobacterium tuberculosis
    • Authors: Kiran Kumar Alluri; Rudraraju Srilakshmi Reshma; Raghuram Suraparaju; Suryanarayana Gottapu; Dharmarajan Sriram
      Pages: 1462 - 1469
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Kiran Kumar Alluri, Rudraraju Srilakshmi Reshma, Raghuram Suraparaju, Suryanarayana Gottapu, Dharmarajan Sriram
      Need for new drugs to fight against tuberculosis (TB) is increasing day by day. In the present work we have taken a spiro compound (GSK 2200150A) reported by GSK as a lead and we modified the structure of the lead to study the antitubercular activity. For structure activity profiling twenty-one molecules have been synthesized, characterized and evaluated for their antimycobacterial potency against both active and dormant TB. Compound 06, 1-((4-methoxyphenyl)sulfonyl)-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran] was found to be the most potent compound (MIC: 8.23 µM) in active TB and was less effective than the lead but more potent than standard first line drug ethambutol. It was also found to be more efficacious than Isoniazid and Rifampicin and equipotent as Moxifloxacin against dormant Mycobacterium tuberculosis (MTB). Compound 06 also showed good inhibitory potential against over expressed latent MTB enzyme lysine ε-amino transferase with an IC50 of 1.04 ± 0.32 µM. This compound is a good candidate for drug development owing to potential against both active and dormant stages of MTB.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2017.12.044
       
  • Enhancing the anti-biofilm activity of 5-aryl-2-aminoimidazoles through
           nature inspired dimerisation
    • Authors: Tran Thi Thu Trang; Lise Dieltjens; Geert Hooyberghs; Kai Waldrant; Denis S. Ermolat'ev; Erik V. Van der Eycken; Hans P.L. Steenackers
      Pages: 1470 - 1480
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Tran Thi Thu Trang, Lise Dieltjens, Geert Hooyberghs, Kai Waldrant, Denis S. Ermolat'ev, Erik V. Van der Eycken, Hans P.L. Steenackers
      The increased tolerance of biofilms against disinfectants and antibiotics has stimulated research into new methods of biofilm prevention and eradication. In our previous work, we have identified the 5-aryl-2-aminoimidazole core as a scaffold that demonstrates preventive activity against biofilm formation of a broad range of bacterial and fungal species. Inspired by the dimeric nature of natural 2-aminoimidazoles of the oroidin family, we investigated the potential of dimers of our decorated 5-aryl-2-aminoimidazoles as biofilm inhibitors. A synthetic approach towards 2-aminoimidazole dimers linked by an alkyl chain was developed and a total of 48 dimers were synthesized. The linkers were introduced at two different positions, the N1-position or the N2-position, and the linker length and the substitution of the 5-phenyl ring (H, F, Cl, Br) were varied. Although, no clear correlation between linker length and biofilm inhibition was observed, a strong increase in anti-biofilm activity for almost all N1,N1′-linked dimers was obtained, compared to the respective monomers against Salmonella Typhimurium, Escherichia coli and Staphylococcus aureus. The N2,N2′-linked dimers, having a H- or F-substitution, were also found to show a strong increase in anti-biofilm activity compared to the respective monomers against these three bacterial species and against Pseudomonas aeruginosa. In addition, the obtained growth measurements suggest a broad concentration range with specific biofilm inhibition and no effect on the planktonic growth against Salmonella Typhimurium and Pseudomonas aeruginosa.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.01.005
       
  • Borrelidins F–I, cytotoxic and cell migration inhibiting agents from
           mangrove-derived Streptomyces rochei SCSIO ZJ89
    • Authors: Jianbin Sun; Junli Shao; Changli Sun; Yongxiang Song; Qinglian Li; Laichun Lu; Yunfeng Hu; Chun Gui; Hua Zhang; Jianhua Ju
      Pages: 1488 - 1494
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Jianbin Sun, Junli Shao, Changli Sun, Yongxiang Song, Qinglian Li, Laichun Lu, Yunfeng Hu, Chun Gui, Hua Zhang, Jianhua Ju
      Borrelidin A (1) is produced by several species of Streptomyces and within its bioactive scaffold, the vinylic nitrile moiety is essential for activity. We report herein newly discovered members of the borrelidin family, borrelidin F (2), borrelidin G (3), borrelidin H (4) and borrelidin I (5); all were isolated from Streptomyces rochei SCSIO ZJ89 originating from a mangrove-derived sediment sample. These structurally diverse metabolites enabled a number of new structure-activity relationships (SARs) to be identified, especially with respect to the different configurations at the C11-OH and C12–C15 double bonds for which the absolute configurations were determined using spectroscopic methods. Importantly, borrelidin H (4) was found to have a therapeutic window superior to that of borrelidin A (1) in vitro and could inhibit migration of cancer cells.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.01.010
       
  • Development of selective inhibitors for the treatment of rheumatoid
           arthritis:
           (R)-3-(3-(Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile
           as a JAK1-selective inhibitor
    • Authors: Chieyeon Chough; Misuk Joung; Sunmin Lee; Jaemin Lee; Jong Hoon Kim; B. Moon Kim
      Pages: 1495 - 1510
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Chieyeon Chough, Misuk Joung, Sunmin Lee, Jaemin Lee, Jong Hoon Kim, B. Moon Kim
      A series of 3(R)-aminopyrrolidine derivatives were designed and synthesized for JAK1-selective inhibitors through the modification of tofacitinib’s core structure, (3R,4R)-3-amino-4-methylpiperidine. From the new core structures, we selected (R)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a scaffold for further SAR studies. From biochemical enzyme assays and liver microsomal stability tests, (R)-3-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile (6) was chosen for further in vivo test through oral administration. Compound 6 showed improved selectivity for JAK1 compared to that of tofacitinib (IC50 11, 2.4 × 102, 2.8 × 103, and 1.1 × 102 nM for JAK1, JAK2, JAK3, and TYK2, respectively). In CIA and AIA model tests, compound 6 exhibited similar efficacy to tofacitinib citrate.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.01.021
       
  • In silico studies, synthesis and pharmacological evaluation to explore
           multi-targeted approach for imidazole analogues as potential
           cholinesterase inhibitors with neuroprotective role for Alzheimer’s
           disease
    • Authors: Archana S. Gurjar; Mrunali N. Darekar; Keng Yoon Yeong; Luyi Ooi
      Pages: 1511 - 1522
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Archana S. Gurjar, Mrunali N. Darekar, Keng Yoon Yeong, Luyi Ooi
      Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with multiple factors associated with its pathogenesis. Our strategy against AD involves design of multi-targeted 2-substituted-4,5-diphenyl-1H-imidazole analogues which can interact and inhibit AChE, thereby, increasing the synaptic availability of ACh, inhibit BuChE, relieve induced oxidative stress and confer a neuroprotective role. Molecular docking was employed to study interactions within the AChE active site. In silico ADME study was performed to estimate pharmacokinetic parameters. Based on computational studies, some analogues were synthesized and subjected to pharmacological evaluation involving antioxidant activity, toxicity and memory model studies in animals followed by detailed mechanistic in vitro cholinesterase inhibition study. Amongst the series, analogue 13 and 20 are the most promising multi-targeted candidates which can potentially increase memory, decrease free radical levels and protect neurons against cognitive deficit.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.01.029
       
  • New histone demethylase LSD1 inhibitor selectively targets teratocarcinoma
           and embryonic carcinoma cells
    • Authors: Nam Hoang; Xuan Zhang; Chunxiao Zhang; Van Vo; Feng Leng; Lovely Saxena; Feng Yin; Fei Lu; Guangrong Zheng; Pradip Bhowmik; Hui Zhang
      Pages: 1523 - 1537
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Nam Hoang, Xuan Zhang, Chunxiao Zhang, Van Vo, Feng Leng, Lovely Saxena, Feng Yin, Fei Lu, Guangrong Zheng, Pradip Bhowmik, Hui Zhang
      LSD1/KDM1 is a histone demethylase that preferentially removes methyl groups from the mono- and di-methylated lysine 4 in histone H3 (H3K4), key marks for active chromatin for transcriptional activation. LSD1 is essential for pluripotent embryonic stem cells and embryonic teratocarcinoma/carcinoma cells and its expression is often elevated in various cancers. We developed a new LSD1 inhibitor, CBB3001, which potently inhibited LSD1 activity both in vitro and in vivo. CBB3001 also selectively inhibited the growth of human ovarian teratocarcinoma PA-1 and mouse embryonic carcinoma F9 cells, caused the downregulation of pluripotent stem cell proteins SOX2 and OCT4. However, CBB3001 does not have significant inhibition on the growth of human colorectal carcinoma HCT116 cells or mouse fibroblast NIH3T3 cells that do not express these stem cell proteins. Our studies strongly indicate that CBB3001 is a specific LSD1 inhibitor that selectively inhibits teratocarcinoma and embryonic carcinoma cells that express SOX2 and OCT4.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.01.031
       
  • Mechanistic analyses of the suppression of amyloid β42 aggregation by
           apomorphine
    • Authors: Mizuho Hanaki; Kazuma Murakami; Sumie Katayama; Ken-ichi Akagi; Kazuhiro Irie
      Pages: 1538 - 1546
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Mizuho Hanaki, Kazuma Murakami, Sumie Katayama, Ken-ichi Akagi, Kazuhiro Irie
      (R)-Apomorphine (1) has the potential to reduce the accumulation of amyloid β-protein (Aβ42), a causative agent of Alzheimer’s disease (AD). Although the inhibition of Aβ42 aggregation by 1 is ascribable to the antioxidative effect of its phenol moiety, its inhibitory mechanism at the molecular level remains to be fully elucidated. LC–MS and UV analyses revealed that 1 is autoxidized during incubation to produce an unstable o-quinone form (2), which formed a Michael adduct with Lys 16 and 28 of Aβ42. A further autoxidized form of 1 (3) with o-quinone and phenanthrene moieties suppressed Aβ42 aggregation comparable to 1, whereas treating 1 with a reductant, tris(2-carboxyethyl)phosphine diminished its inhibitory activity. 1H-15N SOFAST-HMQC NMR studies suggested that 1 interacts with Arg5, His13,14, Gln15, and Lys16 of the Aβ42 monomer. These regions form intermolecular β-sheets in Aβ42 aggregates. Since 3 did not perturb the chemical shift of monomeric Aβ42, we performed aggregation experiments using 1,1,1,3,3,3-hexafluoro-2-propanol-treated Aβ42 to investigate whether 3 associates with Aβ42 oligomers. Compounds 1 and 3 delayed the onset of the oligomer-driven nucleation phase. Despite their cytotoxicity, they did not exacerbate Aβ42-mediated neurotoxicity in SH-SY5Y neuroblastoma cells. These results demonstrate that extension of the conjugated system in 1 by autoxidation can promote its planarity, which is required for intercalation into the β-sheet of Aβ42 nuclei, thereby suppressing further aggregation.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.01.028
       
  • Design, synthesis and biological assessment of N-adamantyl, substituted
           adamantyl and noradamantyl phthalimidines for nitrite, TNF-α and
           angiogenesis inhibitory activities
    • Authors: Weiming Luo; David Tweedie; Shaunna L. Beedie; Neil Vargesson; William D. Figg; Nigel H. Greig; Michael T. Scerba
      Pages: 1547 - 1559
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Weiming Luo, David Tweedie, Shaunna L. Beedie, Neil Vargesson, William D. Figg, Nigel H. Greig, Michael T. Scerba
      A library of 15 novel and heretofore uncharacterized adamantyl and noradamantyl phthalimidines was synthesized and evaluated for neuroprotective and anti-angiogenic properties. Phthalimidine treatment in LPS-challenged cells effected reductions in levels of secreted TNF-α and nitrite relative to basal amounts. The primary SAR suggests nitration of adamantyl phthalimidines has marginal effect on TNF-α activity but promotes anti-nitrite activity; thioamide congeners retain anti-nitrite activity but are less effective reducing TNF-α. Site-specific nitration and thioamidation provided phthalimidine 24, effecting an 88.5% drop in nitrite concurrent with only a 4% drop in TNF-α. Notable anti-angiogenesis activity was observed for 20, 21 and 22.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.01.032
       
  • Probing biological activity through structural modelling of
           ligand-receptor interactions of 2,4-disubstituted thiazole retinoids
    • Authors: Hesham Haffez; David R. Chisholm; Natalie J. Tatum; Roy Valentine; Christopher Redfern; Ehmke Pohl; Andrew Whiting; Stefan Przyborski
      Pages: 1560 - 1572
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Hesham Haffez, David R. Chisholm, Natalie J. Tatum, Roy Valentine, Christopher Redfern, Ehmke Pohl, Andrew Whiting, Stefan Przyborski
      Retinoids, such as all-trans-retinoic acid (ATRA), regulate cellular differentiation and signalling pathways in chordates by binding to nuclear retinoic acid receptors (RARα/β/γ). Polar interactions between receptor and ligand are important for binding and facilitating the non-polar interactions and conformational changes necessary for RAR-mediated transcriptional regulation. The constraints on activity and RAR-type specificity with respect to the structural link between the polar and non-polar functions of synthetic retinoids are poorly understood. To address this, predictions from in silico ligand-RAR docking calculations and molecular dynamics simulations for a small library of stable, synthetic retinoids (designated GZ series) containing a central thiazole linker structure and different hydrophobic region substituents, were tested using a ligand binding assay and a range of cellular biological assays. The docking analysis showed that these thiazole-containing retinoids were well suited to the binding pocket of RARα, particularly via a favorable hydrogen bonding interaction between the thiazole and Ser232 of RARα. A bulky hydrophobic region (i.e., present in compounds GZ23 and GZ25) was important for interaction with the RAR binding pockets. Ligand binding assays generally reflected the findings from in silico docking, and showed that GZ25 was a particularly strongly binding ligand for RARα/β. GZ25 also exhibited higher activity as an inducer of neuronal differentiation than ATRA and other GZ derivatives. These data demonstrate that GZ25 is a stable synthetic retinoid with improved activity which efficiently regulates neuronal differentiation and help to define the key structural requirements for retinoid activity enabling the design and development of the next generation of more active, selective synthetic retinoids as potential therapeutic regulators of neurogenesis.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.02.002
       
  • Discovery of isatin and 1H-indazol-3-ol derivatives as d-amino acid
           oxidase (DAAO) inhibitors
    • Authors: Bence Szilágyi; Péter Kovács; György G. Ferenczy; Anita Rácz; Krisztina Németh; Júlia Visy; Pál Szabó; Janez Ilas; György T. Balogh; Katalin Monostory; István Vincze; Tamás Tábi; Éva Szökő; György M. Keserű
      Pages: 1579 - 1587
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Bence Szilágyi, Péter Kovács, György G. Ferenczy, Anita Rácz, Krisztina Németh, Júlia Visy, Pál Szabó, Janez Ilas, György T. Balogh, Katalin Monostory, István Vincze, Tamás Tábi, Éva Szökő, György M. Keserű
      d-Amino acid oxidase (DAAO) is a potential target in the treatment of schizophrenia as its inhibition increases brain d-serine level and thus contributes to NMDA receptor activation. Inhibitors of DAAO were sought testing [6+5] type heterocycles and identified isatin derivatives as micromolar DAAO inhibitors. A pharmacophore and structure-activity relationship analysis of isatins and reported DAAO inhibitors led us to investigate 1H-indazol-3-ol derivatives and nanomolar inhibitors were identified. The series was further characterized by pKa and isothermal titration calorimetry measurements. Representative compounds exhibited beneficial properties in in vitro metabolic stability and PAMPA assays. 6-fluoro-1H-indazol-3-ol (37) significantly increased plasma d-serine level in an in vivo study on mice. These results show that the 1H-indazol-3-ol series represents a novel class of DAAO inhibitors with the potential to develop drug candidates.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.02.004
       
  • Adenosine analogs bearing phosphate isosteres as human MDO1 ligands
    • Authors: Yuezhou Zhang; Mikael Jumppanen; Mirko M. Maksimainen; Samuli Auno; Zulfa Awol; Léo Ghemtio; Harikanth Venkannagari; Lari Lehtiö; Jari Yli-Kauhaluoma; Henri Xhaard; Gustav Boije af Gennäs
      Pages: 1588 - 1597
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Yuezhou Zhang, Mikael Jumppanen, Mirko M. Maksimainen, Samuli Auno, Zulfa Awol, Léo Ghemtio, Harikanth Venkannagari, Lari Lehtiö, Jari Yli-Kauhaluoma, Henri Xhaard, Gustav Boije af Gennäs
      The human O-acetyl-ADP-ribose deacetylase MDO1 is a mono-ADP-ribosylhydrolase involved in the reversal of post-translational modifications. Until now MDO1 has been poorly characterized, partly since no ligand is known besides adenosine nucleotides. Here, we synthesized thirteen compounds retaining the adenosine moiety and bearing bioisosteric replacements of the phosphate at the ribose 5′-oxygen. These compounds are composed of either a squaryldiamide or an amide group as the bioisosteric replacement and/or as a linker. To these groups a variety of substituents were attached such as phenyl, benzyl, pyridyl, carboxyl, hydroxy and tetrazolyl. Biochemical evaluation showed that two compounds, one from both series, inhibited ADP-ribosyl hydrolysis mediated by MDO1 in high concentrations.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.02.006
       
  • Design and synthesis of 1-(1-benzothiophen-7-yl)-1H-pyrazole, a novel
           series of G protein-coupled receptor 52 (GPR52) agonists
    • Authors: Takashi Nakahata; Kazuyuki Tokumaru; Yoshiteru Ito; Naoki Ishii; Masaki Setoh; Yuji Shimizu; Toshiya Harasawa; Kazunobu Aoyama; Teruki Hamada; Masakuni Kori; Kazuyoshi Aso
      Pages: 1598 - 1608
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Takashi Nakahata, Kazuyuki Tokumaru, Yoshiteru Ito, Naoki Ishii, Masaki Setoh, Yuji Shimizu, Toshiya Harasawa, Kazunobu Aoyama, Teruki Hamada, Masakuni Kori, Kazuyoshi Aso
      G-protein-coupled receptor 52 (GPR52) is classified as an orphan Gs-coupled G-protein-coupled receptor. GPR52 cancels dopamine D2 receptor signaling and activates dopamine D1/N-methyl-d-aspartate receptors via intracellular cAMP accumulation. Therefore, GPR52 agonists are expected to alleviate symptoms of psychotic disorders. A novel series of 1-(benzothiophen-7-yl)-1H-pyrazole as GPR52 agonists was designed and synthesized based on compound 1b. Compound 1b has been reported by our group as the first orally active GPR52 agonist, but high lipophilicity and poor aqueous solubility still remained as issues for candidate selection. To resolve these issues, replacement of the benzene ring at the 7-positon of compound 1b with heterocylic rings, such as pyrazole and pyridine, was greatly expected to reduce lipophilicity to levels for which calculated logD values were lower than that of compound 1b. While evaluating the pyrazole derivatives, introduction of a methyl substituent at the 3-position of the pyrazole ring led to increased GPR52 agonistic activity. Moreover, additional methyl substituent at the 5-position of the pyrazole and further introduction of hydroxy group to lower logD led to significant improvement of solubility while maintaining the activity. As a result, we identified 3-methyl-5-hydroxymethyl-1H-pyrazole derivative 17 (GPR52 EC50 = 21 nM, Emax = 103%, logD = 2.21, Solubility at pH 6.8 = 21 μg/mL) with potent GPR52 agonistic activity and good solubility compared to compound 1b. Furthermore, this compound 17 dose-dependently suppressed methamphetamine-induced hyperlocomotion in mice.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.02.005
       
  • PET probe detecting non-small cell lung cancer susceptible to epidermal
           growth factor receptor tyrosine kinase inhibitor therapy
    • Authors: Akira Makino; Anna Miyazaki; Ayaka Tomoike; Hiroyuki Kimura; Kenji Arimitsu; Masahiko Hirata; Yoshiro Ohmomo; Ryuichi Nishii; Hidehiko Okazawa; Yasushi Kiyono; Masahiro Ono; Hideo Saji
      Pages: 1609 - 1613
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Akira Makino, Anna Miyazaki, Ayaka Tomoike, Hiroyuki Kimura, Kenji Arimitsu, Masahiko Hirata, Yoshiro Ohmomo, Ryuichi Nishii, Hidehiko Okazawa, Yasushi Kiyono, Masahiro Ono, Hideo Saji
      Tyrosine kinase inhibitors for epidermal growth factor receptor (EGFR-TKIs) are used as molecular targeted therapy for non-small cell lung cancer (NSCLC) patients. The therapy is applied to the patients having EGFR-primary L858R mutation, but drug tolerance caused by EGFR-secondary mutation is occurred within one and half years. For the non-invasive detection of the EGFR-TKIs treatment positive patients by positron emission tomograpy (PET) imagaing, fluorine-18 labeled thienopyrimidine derivative, [18F]FTP2 was newly synthesized. EGFR inhibition assay, cell uptake study, and blocking study indicated [18F]FTP2 binds with high and selective affinity for EGFR with L858R mutation, and not with L858R/T790M dual mutations. On animal PET study using tumor bearing mice, H3255 cells expressing L858R mutated EGFR was more clearly visualized than H1975 cells expressing L858R/T790M dual mutated EGFR. [18F]FTP2 has potential for detecting NSCLC which is susceptible to EGFR-TKI treatment.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.02.007
       
  • Discovery of DSP-1053, a novel benzylpiperidine derivative with potent
           serotonin transporter inhibitory activity and partial 5-HT1A receptor
           agonistic activity
    • Authors: Hidefumi Yoshinaga; Tomoaki Nishida; Izumi Sasaki; Taro Kato; Hitomi Oki; Kazuki Yabuuchi; Tomohiro Toyoda
      Pages: 1614 - 1627
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Hidefumi Yoshinaga, Tomoaki Nishida, Izumi Sasaki, Taro Kato, Hitomi Oki, Kazuki Yabuuchi, Tomohiro Toyoda
      We have previously shown that SMP-304, a serotonin uptake inhibitor with weak 5-HT1A partial agonistic activity, may act under high serotonin levels as a 5-HT1A antagonist that improves the onset of paroxetine in the rat swimming test. However, SMP-304 is mostly metabolized by CYP2D6, indicating limited efficacy among individuals and increased side effects. To reduce CYP2D6 metabolic contribution and enhance SERT/5-HT1A binding affinity, we carried out a series of substitutions at the bromine atom in the left part of the benzene ring of SMP-304 and replaced the right part of SMP-304 with a chroman-4-one. This optimization work led to the identification of the antidepressant candidate DSP-1053 as a potent SERT inhibitor with partial 5-HT1A receptor agonistic activity. DSP-1053 showed low CYP2D6 metabolic contribution and a robust increase in serotonin levels in the rat frontal cortex.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.02.008
       
  • Discovery of novel 4-aryl-thieno[1,4]diazepin-2-one derivatives targeting
           multiple protein kinases as anticancer agents
    • Authors: Junghun Lee; Hoyong Jung; Minjung Kim; Eunkyu Lee; Daseul Im; Waqar Aman; Jung-Mi Hah
      Pages: 1628 - 1637
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Junghun Lee, Hoyong Jung, Minjung Kim, Eunkyu Lee, Daseul Im, Waqar Aman, Jung-Mi Hah
      A series of 4-aryl-thieno[1,4]diazepin-2-one were synthesized and evaluated for their antiproliferative activities against the A375P melanoma and U937 hematopoietic cell lines. Several compounds showed very potent antiproliferative activities toward both cell lines and the activities were better than that of sorafenib, the reference standard. Derivatives were made as amide (8a–8i, 9a–9m) and urea (10a–10d, 11a–11d) with diverse hydrophobic moieties. One of the most potent inhibitor 10d, 1-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno [3,4-b][1,4]diazepin-4-yl)phenyl)urea was found to be very potent inhibitor of multi-protein kinases including FMS kinase (IC50 = 3.73 nM) and is a promising candidate for further development in therapeutics for cancer.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.02.009
       
  • Design and synthesis of estrogen receptor ligands with a
           4-heterocycle-4-phenylheptane skeleton
    • Authors: Ryo Eto; Takashi Misawa; Tomomi Noguchi-Yachide; Nobumichi Ohoka; Masaaki Kurihara; Mikihiko Naito; Masakazu Tanaka; Yosuke Demizu
      Pages: 1638 - 1642
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Ryo Eto, Takashi Misawa, Tomomi Noguchi-Yachide, Nobumichi Ohoka, Masaaki Kurihara, Mikihiko Naito, Masakazu Tanaka, Yosuke Demizu
      The estrogen receptor (ER), a member of the nuclear receptor (NR) family, is involved in the regulation of physiological effects such as reproduction and bone homeostasis. Approximately 70% of human breast cancers are hormone-dependent and ERα-positive, and, thus, ER antagonists are broadly used in breast cancer therapy. We herein designed and synthesized a set of ER antagonists with a 4-heterocycle-4-phenylheptane skeleton.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.02.010
       
  • Synthesis and evaluation of novel dolastatin 10 derivatives for versatile
           conjugations
    • Authors: Shinya Yokosaka; Akiko Izawa; Chizuka Sakai; Eri Sakurada; Yasuhiro Morita; Yukihiro Nishio
      Pages: 1643 - 1652
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Shinya Yokosaka, Akiko Izawa, Chizuka Sakai, Eri Sakurada, Yasuhiro Morita, Yukihiro Nishio
      Dolastatin 10 (1) is a highly potent cytotoxic microtubule inhibitor (cytotoxicity IC50 < 5.0 nM) and several of its analogs have recently been used as payloads in antibody drug conjugates. Herein, we describe the design and synthesis of a series of novel dolastatin 10 analogs useful as payloads for conjugated drugs. We explored analogs containing functional groups at the thiazole moiety at the C-terminal of dolastatin 10. The functional groups included amines, alcohols, and thiols, which are representative structures used in known conjugated drugs. These novel analogs showed excellent potency in a tumor cell proliferation assay, and thus this series of dolastatin 10 analogs is suitable as versatile payloads in conjugated drugs. Insights into the structure–activity relationships of the analogs are also discussed.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.02.011
       
  • Development of benzoxazole deoxybenzoin oxime and acyloxylamine
           derivatives targeting innate immune sensors and xanthine oxidase for
           treatment of gout
    • Authors: Jun Huang; Zehao Zhou; Mengze Zhou; Mingxing Miao; Huanqiu Li; Qinghua Hu
      Pages: 1653 - 1664
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Jun Huang, Zehao Zhou, Mengze Zhou, Mingxing Miao, Huanqiu Li, Qinghua Hu
      Both the inhibition of inflammatory flares and the treatment of hyperuricemia itself are included in the management of gout. Extending our efforts to development of gout therapy, two series of benzoxazole deoxybenzoin oxime derivatives as inhibitors of innate immune sensors and xanthine oxidase (XOD) were discovered in improving hyperuricemia and acute gouty arthritis. In vitro studies revealed that most compounds not only suppressed XOD activity, but blocked activations of NOD-like receptor (NLRP3) inflammasome and Toll-like receptor 4 (TLR4) signaling pathway. More importantly, (E)-1-(6-methoxybenzo[d]oxazol-2-yl)-2-(4-methoxyphenyl)ethanone oxime (5d) exhibited anti-hyperuricemic and anti-acute gouty arthritis activities through regulating XOD, NLRP3 and TLR4. Compound 5d may serve as a tool compound for further design of anti-gout drugs targeting both innate immune sensors and XOD.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.02.013
       
  • Investigation of multi-target-directed ligands (MTDLs) with
           butyrylcholinesterase (BuChE) and indoleamine 2,3-dioxygenase 1 (IDO1)
           inhibition: The design, synthesis of miconazole analogues targeting
           Alzheimer’s disease
    • Authors: Xin Lu; Si-yu He; Qi Li; Hongyu Yang; Xueyang Jiang; Hongzhi Lin; Yao Chen; Wei Qu; Feng Feng; Yaoyao Bian; You Zhou; Haopeng Sun
      Pages: 1665 - 1674
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Xin Lu, Si-yu He, Qi Li, Hongyu Yang, Xueyang Jiang, Hongzhi Lin, Yao Chen, Wei Qu, Feng Feng, Yaoyao Bian, You Zhou, Haopeng Sun
      In our endeavor towards the development of potent multi-target ligands for the treatment of Alzheimer’s disease, miconazole was identified to show BuChE-IDO1 dual-target inhibitory effects. Morris water maze test indicated that miconazole obviously ameliorated the cognitive function impaired by scopolamine. Furthermore, it showed good safety in primary hepatotoxicity evaluation. Based on these results, we designed, synthesized, and evaluated a series of miconazole derivatives as BuChE-IDO1 dual-target inhibitors. Out of the 12 compounds, 5i and 5j exhibited the best potency in enzymatic evaluation, thus were selected for subsequent behavioral study, in which the two compounds exerted much improved effect than tacrine. Meanwhile, 5i and 5j displayed no apparent hepatotoxicity. The results suggest that miconazole analogue offers an attractive starting point for further development of new BuChE-IDO1 dual-target inhibitors against Alzheimer’s disease.
      Graphical abstract image

      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.02.014
       
  • Novel 4-aminoquinazoline derivatives induce growth inhibition, cell cycle
           arrest and apoptosis via PI3Kα inhibition
    • Authors: Yan-Hua Fan; Huai-Wei Ding; Dan-Dan Liu; Hong-Rui Song; Yong-Nan Xu; Jian Wang
      Pages: 1675 - 1685
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Yan-Hua Fan, Huai-Wei Ding, Dan-Dan Liu, Hong-Rui Song, Yong-Nan Xu, Jian Wang
      Phosphatidylinositol 3-kinase (PI3K) signaling pathway has diverse functions, including the regulation of cellular survival, proliferation, cell cycle, migration, angiogenesis and apoptosis. Among class I PI3Ks (PI3Kα, β, γ, δ), the PIK3CA gene encoding PI3K p110α is frequently mutated and overexpressed in a large portion of human cancers. Therefore, the inhibition of PI3Kα has been considered as a promising target for the development of a therapeutic treatment of cancer. In this study, we designed and synthesized a series of 4-aminoquinazoline derivatives and evaluated their antiproliferative activities against six cancer cell lines, including HCT-116, SK-HEP-1, MDA-MB-231, SNU638, A549 and MCF-7. Compound 6b with the most potent antiproliferative activity and without obvious cytotoxicity to human normal cells was selected for further biological evaluation. PI3K kinase assay showed that 6b has selectivity for PI3Kα distinguished from other isoforms. The western blot assay and PI3K kinase assay indicated that 6b effectively inhibited cell proliferation via suppression of PI3Kα kinase activity with an IC50 of 13.6 nM and subsequently blocked PI3K/Akt pathway activation in HCT116 cells. In addition, 6b caused G1 cell cycle arrest owing to the inhibition of PI3K signaling and induced apoptosis via mitochondrial dependent apoptotic pathway. Our findings suggested that 6b has a therapeutic value as an anticancer agent via PI3Kα inhibition.
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      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.02.015
       
  • Targeting RORs nuclear receptors by novel synthetic steroidal inverse
           agonists for autoimmune disorders
    • Authors: Matteo Dal Prà; Davide Carta; Gyorgy Szabadkai; Matteo Suman; Yahima Frión-Herrera; Nicola Paccagnella; Giulia Castellani; Sara De Martin; Maria Grazia Ferlin
      Pages: 1686 - 1704
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Matteo Dal Prà, Davide Carta, Gyorgy Szabadkai, Matteo Suman, Yahima Frión-Herrera, Nicola Paccagnella, Giulia Castellani, Sara De Martin, Maria Grazia Ferlin
      Designing novel inverse agonists of NR RORγt still represents a challenge for the pharmaceutical community to develop therapeutics for treating immune diseases. By exploring the structure of NRs natural ligands, the representative arotenoid ligands and RORs specific ligands share some chemical homologies which can be exploited to design a novel molecular structure characterized by a polycyclic core bearing a polar head and a hydrophobic tail. Compound MG 2778 (8), a cyclopenta[a]phenantrene derivative, was identified as lead compound which was chemically modified at position 2 in order to obtain a small library for preliminary SARs. Cell viability and estrogenic activity of compounds 7, 8, 19a, 30, 31 and 32 were evaluated to attest selectivity. The selected 7, 8, 19a and 31 compounds were assayed in a Gal4 UAS-Luc co-transfection system in order to determine their ability to modulate RORγt activity in a cellular environment. They were evaluated as inverse agonists taken ursolic acid as reference compound. The potency of compounds was lower than that of ursolic acid, but their efficacy was similar. Compound 19a was the most active, significantly reducing RORγt activity at low micromolar concentrations.
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      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.02.018
       
  • Synthesis of 3-aza[4.4.3]propellanes with high σ1 receptor affinity
    • Authors: Héctor Torres-Gómez; Constantin Daniliuc; Dirk Schepmann; Bernhard Wünsch
      Pages: 1705 - 1712
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Héctor Torres-Gómez, Constantin Daniliuc, Dirk Schepmann, Bernhard Wünsch
      In order to obtain rigid σ1 receptor ligands with defined orientation of pharmacophoric elements, the azapropellane scaffold was chosen. Schmidt rearrangement of propellan-8-ones 6 and 10 provided 3-azapropellan-4-ones 7 and 11. Benzylation of the secondary lactams 7 and 11 followed by LiAlH4 reduction furnished the azapropellanes 4a and 4c, respectively. A second hydrophobic element was introduced by transformation of the alcohols 4a into carbamates 4b. The σ1 affinity of the azapropellanes 4 is strongly dependent on the stereochemistry and the substitution pattern in 12-position. anti-configured azapropellanes anti-4a and anti-4b show higher σ1 affinity than their syn-configured counterparts syn-4a and syn-4b. Conversion of the alcohol anti-4a into the carbamate anti-4b led to increased σ1 affinity, but complete removal of the 12-substituent resulted in the highest σ1 affinity (K i(4c) = 17 nM). It can be concluded that the propellane scaffold alone is able to form strong lipophilic interactions and stabilize the ligand–σ1 receptor complex as does usually the primary hydrophobic region.
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      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.02.019
       
  • Pharmacophore requirements for HIV-1 reverse transcriptase inhibitors that
           selectively “Freeze” the pre-translocated complex during the
           polymerization catalytic cycle
    • Authors: Cyrus M. Lacbay; Michael Menni; Jean A. Bernatchez; Matthias Götte; Youla S. Tsantrizos
      Pages: 1713 - 1726
      Abstract: Publication date: 1 May 2018
      Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 8
      Author(s): Cyrus M. Lacbay, Michael Menni, Jean A. Bernatchez, Matthias Götte, Youla S. Tsantrizos
      Reverse transcriptase (RT) is responsible for replicating the HIV-1 genome and is a validated therapeutic target for the treatment of HIV infections. During each cycle of the RT-catalyzed DNA polymerization process, inorganic pyrophosphate is released as the by-product of nucleotide incorporation. Small molecules were identified that act as bioisosteres of pyrophosphate and can selectively freeze the catalytic cycle of HIV-1 RT at the pre-translocated stage of the DNA- or RNA-template-primer-enzyme complex.
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      PubDate: 2018-04-11T10:42:01Z
      DOI: 10.1016/j.bmc.2018.02.017
       
  • Discovery of potent DOT1L inhibitors by AlphaLISA based high throughput
           screening assay
    • Authors: Yakai Song; Linjuan Li; Yantao Chen; Jingqiu Liu; Senhao Xiao; Fulin Lian; Naixia Zhang; Hong Ding; Yuanyuan Zhang; Kaixian Chen; Hualiang Jiang; Chenhua Zhang; Yu-Chih Liu; Shijie Chen; Cheng Luo
      Abstract: Publication date: Available online 24 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Yakai Song, Linjuan Li, Yantao Chen, Jingqiu Liu, Senhao Xiao, Fulin Lian, Naixia Zhang, Hong Ding, Yuanyuan Zhang, Kaixian Chen, Hualiang Jiang, Chenhua Zhang, Yu-Chih Liu, Shijie Chen, Cheng Luo
      DOT1L (the disruptor of telomeric silencing 1-like), through its methyltransferase activity of H3K79, plays essential roles in transcriptional regulation, cell cycle regulation, and DNA damage response. In addition, DOT1L is believed to be involved in the development of MLL-rearranged leukemia driven by the MLL (mixed-lineage leukemia) fusion proteins, which thus to be a crucial target for leukemia therapy. Hence, discovering of novel DOT1L inhibitors has been in a great demand. In this study, we initiated the discovering process from setting up the AlphaLISA based High Throughput Screening (HTS) assay of DOT1L. Combining with radioactive inhibition assay and Surface Plasmon Resonance (SPR) binding assay, we identified compound 3 and its active analogues as novel DOT1L inhibitors with IC50 values range from 7 μM to 20 μM in vitro. Together with the analysis of structure activity relationships (SAR) and binding modes of these compounds, we provided clues to assist in the future development of more potent DOT1L inhibitors. Moreover, compounds 3 and 9 effectively inhibited the proliferation of MLL-rearranged leukemia cells MV4-11, which could induce cell cycle arrest and apoptosis. In conclusion, we developed a HTS platform based on AlphaLISA method for screening and discovery of DOT1L novel inhibitor, through which we discovered compound 3 and its analogues as potent DOT1L inhibitors with promising MLL-rearranged leukemia therapeutic application.
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      PubDate: 2018-02-25T21:23:56Z
      DOI: 10.1016/j.bmc.2018.02.020
       
  • Synthesis and SAR study of new hydroxy and chloro-substituted 2,4-diphenyl
           5H-chromeno[4,3-b]pyridines as selective topoisomerase IIα-targeting
           anticancer agents
    • Authors: Til Bahadur Thapa Magar; Seung Hee Seo; Tara Man Kadayat; Hyunji Jo; Aarajana Shrestha; Ganesh Bist; Pramila Katila; Youngjoo Kwon; Eung-Seok Lee
      Abstract: Publication date: Available online 22 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Til Bahadur Thapa Magar, Seung Hee Seo, Tara Man Kadayat, Hyunji Jo, Aarajana Shrestha, Ganesh Bist, Pramila Katila, Youngjoo Kwon, Eung-Seok Lee
      As part of our effort to develop potential topoisomerase IIα (topo IIα) targeting anticancer agents, we systematically designed a new series of hydroxy and chloro-substituted 2,4-diphenyl 5H-chromeno[4,3-b]pyridines. Total eighteen compouds were synthesized and tested for their ablity to inhibit the function of topo I and IIα, and proliferation of human breast (T47D), colorectal (HCT15), and cervix (HeLa) cancer cells. Except compound 11, all of the tested compounds displayed selective topo IIα inhibitory activity. Compounds 8-18, 22, 24, and 25 showed excellent topo IIα inhibitory activity than a positive control, etoposide. Most of the compounds appeared to be superior to reference compounds in their antiproliferative activity. Structure-activity relationship (SAR) study has shown that it is better to place the hydroxyphenyl group at the 4-position of the central pyridine for superior topo IIα inhibition and antiproliferative activity. Similarly, the 3′-, or 4′-hydroxyphenyl substitution at the 2- and 4-positon of pyridine ring is important for better activity than 2′-substitution.
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      PubDate: 2018-02-25T21:23:56Z
      DOI: 10.1016/j.bmc.2018.02.035
       
  • Aralkyl selenoglycosides and related selenosugars in acetylated form
           activate protein phosphatase-1 and -2A
    • Authors: Zoltán Kónya; Bálint Bécsi; Andrea Kiss; István Tamás; Beáta Lontay; László Szilágyi; Katalin E. Kövér; Ferenc Erdődi
      Abstract: Publication date: Available online 22 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Zoltán Kónya, Bálint Bécsi, Andrea Kiss, István Tamás, Beáta Lontay, László Szilágyi, Katalin E. Kövér, Ferenc Erdődi
      Aralkyl and aryl selenoglycosides as well as glycosyl selenocarboxylate derivatives were assayed on the activity of protein phosphatase-1 (PP1) and -2A (PP2A) catalytic subunits (PP1c and PP2Ac) in search of compounds for PP1c and PP2Ac effectors. The majority of tested selenoglycosides activated both PP1c and PP2Ac by ∼2-4-fold in a phosphatase assay with phosphorylated myosin light chain substrate when the hydroxyl groups of the glycosyl moiety were acetylated, but they were without any effects in the non-acetylated forms. A peptide from the myosin phosphatase target subunit-1 (MYPT123-38) that included an RVxF PP1c-binding motif attenuated activation of PP1c by 2-Trifluoromethylbenzyl 2,3,4,6-tetra-O-acetyl-1-seleno-β-D-glucopyranoside (TFM-BASG) and 4-Bromobenzyl 2,3,4,6-tetra-O-acetyl-1-seleno-β-D-glucopyranoside (Br-BASG). MYPT123-38 stimulated PP2Ac and contributed to PP2Ac activation exerted by either Br-BASG or TFM-BASG. Br-BASG and TFM-BASG suppressed partially binding of PP1c to MYPT1 in surface plasmon resonance based binding experiments. Molecular docking predicted that the hydrophobic binding surfaces in PP1c for interaction with either the RVxF residues of PP1c-interactors or selenoglycosides are partially overlapped. Br-BASG and TFM-BASG caused a moderate increase in the phosphatase activity of HeLa cells in 1 hour, and suppressed cell viability in 24 hour incubations. In conclusion, our present study identified selenoglycosides as novel activators of PP1 and PP2A as well as provided insights into the structural background of their interactions establishing a molecular model for future design of more efficient phosphatase activator molecules.
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      PubDate: 2018-02-25T21:23:56Z
      DOI: 10.1016/j.bmc.2018.02.039
       
  • A novel series of 4-methyl substituted pyrazole derivatives as potent
           glucagon receptor antagonists: Design, synthesis and evaluation of
           biological activities
    • Authors: Shuangjie Shu; Antao Dai; Jiang Wang; Bin Wang; Yang Feng; Jia Li; Xiaoqing Cai; Dehua Yang; Dakota Ma; Ming-Wei Wang; Hong Liu
      Abstract: Publication date: Available online 22 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Shuangjie Shu, Antao Dai, Jiang Wang, Bin Wang, Yang Feng, Jia Li, Xiaoqing Cai, Dehua Yang, Dakota Ma, Ming-Wei Wang, Hong Liu
      A novel series of 4-methyl substituted pyrazole derivatives were designed, synthesized and biologically evaluated as potent glucagon receptor (GCGR) antagonists. In this study, compounds 9q, 9r, 19d and 19e showed high GCGR binding (IC50 = 0.09 μM, 0.06 μM, 0.07 μM and 0.08 μM, respectively) and cyclic-adenosine monophosphate (cAMP) activities (IC50 = 0.22 μM, 0.26 μM, 0.44 μM and 0.46 μM, respectively) in cell-based assays. Most importantly, the docking experiment demonstrated that compound 9r formed extensive hydrophobic interactions with the receptor binding pocket, making it justifiable to further investigate the potential of becoming a GCGR antagonist.
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      PubDate: 2018-02-25T21:23:56Z
      DOI: 10.1016/j.bmc.2018.02.036
       
  • Multifunctional
           5,6-dimethoxybenzo[d]isothiazol-3(2H)-one-N-alkylbenzylamine derivatives
           with acetylcholinesterase, monoamine oxidases and β-amyloid aggregation
           inhibitory activities as potential agents against Alzheimer’s disease
    • Authors: Rui Xu; Ganyuan Xiao; Yan Li; Hongyan Liu; Qing Song; Xiaoyu Zhang; Ziyi Yang; Yunxiaozhu Zheng; Zhenghuai Tan; Yong Deng
      Abstract: Publication date: Available online 21 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Rui Xu, Ganyuan Xiao, Yan Li, Hongyan Liu, Qing Song, Xiaoyu Zhang, Ziyi Yang, Yunxiaozhu Zheng, Zhenghuai Tan, Yong Deng
      A series of 5,6-dimethoxybenzo[d]isothiazol-3(2H)-one-N-alkylbenzylamine derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer’s disease (AD). The in vitro assays indicated that most of these derivatives were selective AChE inhibitors with good multifunctional properties. Among them, compounds 11b and 11d displayed comprehensive advantages, with good AChE (IC50 = 0.29 ± 0.01 μM and 0.46 ± 0.02 μM, respectively), MAO-A (IC50 = 8.2 ± 0.08 μM and 7.9 ± 0.07 μM, respectively) and MAO-B (IC50 = 20.1 ± 0.16 μM and 43.8 ± 2.0% at 10 μM, respectively) inhibitory activities, moderate self-induced Aβ 1-42 aggregation inhibitory potency (35.4 ± 0.42% and 48.0 ± 1.53% at 25 μM, respectively) and potential antioxidant activity. In addition, the two representative compounds displayed high BBB permeability in vitro. Taken together, these multifunctional properties make 11b and 11d as a promising candidate for the development of efficient drugs against AD.
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      PubDate: 2018-02-25T21:23:56Z
      DOI: 10.1016/j.bmc.2018.02.037
       
  • Discovery and optimization of tetrahydropyrido[4,3-d]pyrimidine
           derivatives as novel ATX and EGFR dual inhibitors
    • Authors: Tongfei Jing; Xiuqi Miao; Feng Jiang; Ming Guo; Lingyun Xing; Junlong Zhang; Daiying Zuo; Hongrui Lei; Xin Zhai
      Abstract: Publication date: Available online 21 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Tongfei Jing, Xiuqi Miao, Feng Jiang, Ming Guo, Lingyun Xing, Junlong Zhang, Daiying Zuo, Hongrui Lei, Xin Zhai
      In order to discovery autotoxin (ATX) and EGFR dual inhibitors with potentialtherapeutic effect on IPF-LC, a series of novel tetrahydropyrido[4,3-d]pyrimidine derivatives possessing semicarbazones moiety were designed and synthesized. The preliminary investigation at the cellular level indicated six compounds (7h, 8a, 8c, 8d, 9a and 9d) displayed preferable anti-tumor activities against A549, H1975, MKN-45 and SGC cancer cells. Further enzymatic assay against EGFR kinase identified 8a and 9a as promising hits with IC50 values of 18.0 nM and 24.2 nM. Meanwhile, anti-inflammatory assessment against cardiac fibroblasts (CFs) cell and RAW264.7 macrophages led to the discovery of candidate 9a, which exhibited considerable potency both on inhibition rate of 77% towards CFs and on reducing NO production to 1.05 μM at 10 μg/mL. Simultaneously, 9a indicated preferable potency towards ATX with IC50 value of 29.1 nM. Significantly, a RT-PCR study revealed the function of 9a to down-regulate the mRNA expression of TGF-β and TNF-α in a dose-dependent manner. The molecular docking analysis together with the pharmacological studies validated 9a as a potential ATX and EGFR dual inhibitor for IPF-LC treatments.
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      PubDate: 2018-02-25T21:23:56Z
      DOI: 10.1016/j.bmc.2018.02.023
       
  • Structure-activity relationships for analogs of the tuberculosis drug
           bedaquiline with the naphthalene unit replaced by bicyclic heterocycles
    • Authors: Hamish S. Sutherland; Amy S.T. Tong; Peter J. Choi; Daniel Conole; Adrian Blaser; Scott G. Franzblau; Christopher B. Cooper; Anna M. Upton; Manisha U. Lotlikar; William A. Denny; Brian D. Palmer
      Abstract: Publication date: Available online 20 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Hamish S. Sutherland, Amy S.T. Tong, Peter J. Choi, Daniel Conole, Adrian Blaser, Scott G. Franzblau, Christopher B. Cooper, Anna M. Upton, Manisha U. Lotlikar, William A. Denny, Brian D. Palmer
      Replacing the naphthalene C-unit of the anti-tuberculosis drug bedaquiline with a range of bicyclic heterocycles of widely differing lipophilicity gave analogs with a 4.5-fold range in clogP values. The biological results for these compounds indicate on average a lower clogP limit of about 5.0 in this series for retention of potent inhibitory activity (MIC90s) against M.tb in culture. Some of the compounds also showed a significant reduction in inhibition of hERG channel potassium current compared with bedaquiline, but there was no common structural feature that distinguished these.
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      PubDate: 2018-02-25T21:23:56Z
      DOI: 10.1016/j.bmc.2018.02.026
       
  • Design, synthesis and biological evaluation of novel 7-azaspiro[3.5]nonane
           derivatives as GPR119 agonists
    • Authors: Daisuke Matsuda; Madoka Kawamura; Yohei Kobashi; Fumiyasu Shiozawa; Youichirou Suga; Keiko Fusegi; Shinichi Nishimoto; Kayo Kimura; Masako Miyoshi; Noriko Takayama; Hiroyuki Kakinuma; Norikazu Ohtake
      Abstract: Publication date: Available online 20 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Daisuke Matsuda, Madoka Kawamura, Yohei Kobashi, Fumiyasu Shiozawa, Youichirou Suga, Keiko Fusegi, Shinichi Nishimoto, Kayo Kimura, Masako Miyoshi, Noriko Takayama, Hiroyuki Kakinuma, Norikazu Ohtake
      The design and synthesis of a novel class of 7-azaspiro[3.5]nonane GPR119 agonists are described. In this series, optimization of the right piperidine N-capping group (R2) and the left aryl group (R3) led to the identification of compound 54g as a potent GPR119 agonist. Compound 54g showed a desirable PK profile in Sprague-Dawley (SD) rats and a favorable glucose lowering effect in diabetic rats.
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      PubDate: 2018-02-25T21:23:56Z
      DOI: 10.1016/j.bmc.2018.02.032
       
  • pH-dependent production of himeic acid A and its non-enzymatic conversions
           to himeic acids B and C
    • Authors: Ayako Katsuki; Hikaru Kato; Yurika Tahara; Makoto Hashimoto; Isao Fujii; Sachiko Tsukamoto
      Abstract: Publication date: Available online 20 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Ayako Katsuki, Hikaru Kato, Yurika Tahara, Makoto Hashimoto, Isao Fujii, Sachiko Tsukamoto
      The fungus Aspergillus japonicus MF275 produces himeic acid A (1), containing a 4-pyrone ring, along with its congeners, himeic acids B (2) and C (3). During culture, 1 was gradually converted to 3, the corresponding 4-pyridone derivative. A study of the relationship between the culture pH and the fungal metabolites showed that a decrease from pH 6.5 to pH 2 is essential for production of 1, while a subsequent increase to pH 5 is necessary for production of 3. In addition, we revealed that 1 was non-enzymatically converted to 3 by the incorporation of an ammonium nitrogen atom in a pH 5 buffer, and that 1 was converted to 2 at a conversion ratio of 50% during incubation in MeOH for five days.
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      PubDate: 2018-02-25T21:23:56Z
      DOI: 10.1016/j.bmc.2018.02.034
       
  • Synthesis, Photophysical Properties, and Photodynamic Activity of
           Positional Isomers of TFPP-Glucose Conjugates
    • Authors: Arif Fadlan; Hiroki Tanimoto; Tatsuya Ito; Yusuke Aritomi; Maho Ueno; Masaya Tokuda; Shiho Hirohara; Makoto Obata; Tsumoru Morimoto; Kiyomi Kakiuchi
      Abstract: Publication date: Available online 19 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Arif Fadlan, Hiroki Tanimoto, Tatsuya Ito, Yusuke Aritomi, Maho Ueno, Masaya Tokuda, Shiho Hirohara, Makoto Obata, Tsumoru Morimoto, Kiyomi Kakiuchi
      The synthesis and characterization of a ‘complete set’ of positional isomers of tetrakis(perfluorophenyl)porphyrins (TFPP)-glucose conjugates (1OH, 2OH, 3OH, 4OH, and 6OH) are reported herein. The cellular uptake and photocytotoxicity of these conjugates were examined in order to investigate the influence of location of the TFPP moiety on the d-glucose molecule on the biological activity of the conjugates. An In vitro biological evaluation revealed that the certain of these isomers have a greater effect on cellular uptake and cytotoxicity than others. The TFPP-glucose conjugates 1OH, 3OH, and 4OH were found to exert exceptional photocytotoxicity in several types of cancer cells compared to 2OH and 6OH substituted isomers.
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      PubDate: 2018-02-25T21:23:56Z
      DOI: 10.1016/j.bmc.2018.02.031
       
  • Structure optimization and preliminary bioactivity evaluation of N-
           hydroxybenzamide-based HDAC inhibitors with Y-shaped cap
    • Authors: Chenggong Yu; Feng He; Ying Qu; Qiuqiong Zhang; Jiahui Lv; Xiangna Zhang; Ana Xu; Pannan Miao; Jingde Wu
      Abstract: Publication date: Available online 18 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Chenggong Yu, Feng He, Ying Qu, Qiuqiong Zhang, Jiahui Lv, Xiangna Zhang, Ana Xu, Pannan Miao, Jingde Wu
      Histone deacetylase inhibitors (HDACIs) are effective small molecules in the treatment of human cancers. In our continuing efforts to develop novel N-hydroxyterephthalamide-based HDACIs, herein we report the design and development of a new class of N-hydroxybenzamide-based HDACIs. In this new class of analogs, we inserted an ethylene moiety in the linker and used indole as a part of the Y-shaped cap group. Biological characterization identified compounds 4o, 4p, 4q and 4t to show improved HDAC inhibition, while no isoform selectivity for HDACs was observed. These compounds also exhibited improved anti-proliferative activity against multiple cancer cell lines when compared to their parent compound and positive control SAHA.
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      PubDate: 2018-02-25T21:23:56Z
      DOI: 10.1016/j.bmc.2018.02.033
       
  • 2-Arylthio-5-iodo pyrimidine derivatives as non-nucleoside HBV polymerase
           inhibitors
    • Authors: Jie Wang; Liang Zhang; Jianxiong Zhao; Yu Zhang; Qingchuan Liu; Chao Tian; Zhili Zhang; Junyi Liu; Xiaowei Wang
      Abstract: Publication date: Available online 17 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Jie Wang, Liang Zhang, Jianxiong Zhao, Yu Zhang, Qingchuan Liu, Chao Tian, Zhili Zhang, Junyi Liu, Xiaowei Wang
      In this study, a series of 2-arylthio-5-iodo pyrimidine derivatives, as non-nucleoside hepatitis B virus inhibitors, were evaluated and firstly reported as potential anti-HBV agents. To probe the mechanism of active agents, DHBV polymerase was isolated and a non-radioisotopic assay was established for measuring HBV polymerase. The biological results demonstrated that 2-arylthio-5-iodo pyrimidine derivatives targeted HBV polymerase. In addition, pharmacophore models were constructed for future optimization of lead compounds. Further study will be performed for the development of non-nucleoside anti-HBV agents.
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      PubDate: 2018-02-25T21:23:56Z
      DOI: 10.1016/j.bmc.2018.02.003
       
  • Synthesis and evaluation of a novel ‘off-on’ chemical sensor based on
           rhodamine B and the 2,5-pyrrolidinedione moiety for selective
           discrimination of glutathione and its bioimaging in living cells
    • Authors: Zhenzhen Xue; Lu Xiao; Hailang Chen; Tong Zhou; Yangyan Qian; Jinshuai Suo; Qinhan Hua; Baojing Zhou; Renlong Ye; Xiaofeng Bao; Jing Zhu
      Abstract: Publication date: Available online 17 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Zhenzhen Xue, Lu Xiao, Hailang Chen, Tong Zhou, Yangyan Qian, Jinshuai Suo, Qinhan Hua, Baojing Zhou, Renlong Ye, Xiaofeng Bao, Jing Zhu
      A new “turn-on” fluorescent probe, RDMBM, based on the rhodamine B dye and the 2, 5-pyrrolidinedione moiety was synthesized and characterized. Its sensing behavior toward various amino acids was evaluated via UV–vis and fluorescence spectroscopic techniques. The observed spectral changes showed that RDMBM displays high selectivity and sensitivity toward GSH in MeOH/H2O (1:2, v/v, pH 7.40, Tris-HCl buffer, 1 mM) solution and that it undergoes 1:1 covalent binding with GSH. More importantly, the hydrogenation and ring-opening of the nitrogen atom in the spirane structure of rhodamine B derivatives were tightly bound to the induction effects of different groups. Furthermore, fluorescence imaging applications demonstrated that RDMBM can be successfully used for the detection of GSH in human breast cancer cells MCF-7.
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      PubDate: 2018-02-25T21:23:56Z
      DOI: 10.1016/j.bmc.2018.02.030
       
  • Discovery of selective EGFR modulator to inhibit L858R/T790M double
           mutants bearing a N-9-Diphenyl-9H-purin-2-amine scaffold
    • Authors: Jinxing Hu; Yufei Han; Jingtao Wang; Yue Liu; Yanfang Zhao; Yajing Liu; Ping Gong
      Abstract: Publication date: Available online 17 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Jinxing Hu, Yufei Han, Jingtao Wang, Yue Liu, Yanfang Zhao, Yajing Liu, Ping Gong
      Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of N-9-Diphenyl-9H-purin-2-amine derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 23a showed excellent enzyme inhibitory activities and selectivity with nanomolar IC50 values for both the single T790M and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 23a displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R. And it was less potent against A549 (WT EGFR and k-Ras mutation) and HT-29 (non-special gene type) cells, showing a high safety index.
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      PubDate: 2018-02-25T21:23:56Z
      DOI: 10.1016/j.bmc.2018.02.029
       
  • Design, synthesis, and evaluation of the antiproliferative activity of
           hydantoin-derived antiandrogen-genistein conjugates
    • Authors: Alex George; Idris Raji; Bekir Cinar; Omer Kucuk; Adegboyega K. Oyelere
      Abstract: Publication date: Available online 16 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Alex George, Idris Raji, Bekir Cinar, Omer Kucuk, Adegboyega K. Oyelere
      Androgen receptor (AR) signaling is vital to the viability of all forms of prostate cancer (PCa). With the goal of investigating the effect of simultaneous inhibition and depletion of AR on viability of PCa cells, we designed, synthesized and characterized the bioactivities of bifunctional agents which incorporate the independent cancer killing properties of an antiandrogen and genistein, and the AR downregulation effect of genistein within a single molecular template. We observed that a representative conjugate, 9b, is much more cytotoxic to both LNCaP and DU145 cells relative to the antiandrogen and genistein building blocks as single agents or their combination. Moreover, conjugate 9b more effectively down regulates cellular AR protein levels relative to genistein and induces S phase cell cycle arrest. The promising bioactivities of these conjugates warrant further investigation.
      Graphical abstract image

      PubDate: 2018-02-25T21:23:56Z
      DOI: 10.1016/j.bmc.2018.01.009
       
  • Novel quinazoline derivatives bearing various 6-benzamide moieties as
           highly selective and potent EGFR inhibitors
    • Authors: Weijie Hou; Yan Ren; Zhenhua Zhang; Huan Sun; Yongfen Ma; Bo Yan
      Abstract: Publication date: Available online 16 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Weijie Hou, Yan Ren, Zhenhua Zhang, Huan Sun, Yongfen Ma, Bo Yan
      A series of novel quinazoline derivatives bearing various C-6 benzamide substituents were synthesized and evaluated as EGFR inhibitors, and most showed significant inhibitory potency against EGFR kinase. In particular, compound 6g possessed potent inhibitory activity against EGFR wild-type (IC50 = 5 nM), and strong antiproliferative activity against HCC827 and Ba/F3 (L858R) cell lines. Kinase profiling against a panel of 365 kinases showed that 6g was highly selective for EGFR. Furthermore, 6g showed desirable properties in assays of liver microsome metabolic stability and cytochromes P450 inhibition and preliminary pharmacokinetic study. The overall attractive profile of 6g made it an interesting compound for further development.
      Graphical abstract image

      PubDate: 2018-02-25T21:23:56Z
      DOI: 10.1016/j.bmc.2018.02.022
       
  • Discovery of 18β-glycyrrhetinic acid conjugated aminobenzothiazole
           derivatives as Hsp90-Cdc37 interaction disruptors that inhibit cell
           migration and reverse drug resistance
    • Authors: Le Jin; Rizhen Huang; Xiaochao Huang; Bin Zhang; Min Ji; Hengshan Wang
      Abstract: Publication date: Available online 16 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Le Jin, Rizhen Huang, Xiaochao Huang, Bin Zhang, Min Ji, Hengshan Wang
      A series of 18β-glycyrrhetinic acid (GA) conjugated aminobenzothiazole derivatives were designed, synthesized and evaluated for disruption activity of Hsp90-Cdc37 as well as the effects of in vitro cell migration. These compounds exhibited relatively good disruption activity against Hsp90-Cdc37 with IC50 values in low micromolar range. A docking study of the most active compound 11g revealed key interactions between 11g and Hsp90-Cdc37 complex in which the benzothiazole moiety and the amine chain group were important for improving activity. It is noteworthy that further antitumor activity screening revealed that some compounds exhibited better inhibitory activity than the commercial anticancer drug 5-FU and showed potent suppression activity against drug-resistant cancer cells. In particular, compound 11 g appeared to be the most potent compound against the A549 cell line, at least partly, by inhibition of the activity of Hsp90 and apoptosis induction. The treatment of A549 cells with compound 11g resulted in inhibition of in vitro cell migration through wound healing assay and S phase of cell cycle arrested. In addition, 11g-induced apoptosis was significantly facilitated in A549 cells. Thus, we conclude that GA aminobenzothiazole derivatives may be the potential Hsp90-Cdc37 disruptors with the ability to suppress cells migration and reversed drug-resistant.
      Graphical abstract image

      PubDate: 2018-02-25T21:23:56Z
      DOI: 10.1016/j.bmc.2018.02.021
       
  • Unprecedented sugar bridged bisindoles selective inhibiting glioma stem
           cells
    • Authors: Xin Wei; Zhi Dai; Jing Yang; Afsar Khan; Hao-Fei Yu; Yun-Li Zhao; Yi-Fen Wang; Ya-Ping Liu; Zi-Feng Yang; Wan-Yi Huang; Xin-Hua Wang; Xu-Dong Zhao; Xiao-Dong Luo
      Abstract: Publication date: Available online 16 February 2018
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Xin Wei, Zhi Dai, Jing Yang, Afsar Khan, Hao-Fei Yu, Yun-Li Zhao, Yi-Fen Wang, Ya-Ping Liu, Zi-Feng Yang, Wan-Yi Huang, Xin-Hua Wang, Xu-Dong Zhao, Xiao-Dong Luo
      Unlike reported bisindoles linked by single bond directly, alstoniasidines A (1) and B (2), from Alstonia scholaris featuring unprecedented skeleton with two indole moieties bridged by a sugar, represented a novel bisindole type having strictosamide-glucopyranose-picraline scaffold. Both compounds exhibited selective cytotoxicity against human glioma stem cells (GSCs) and induced caspase-3 dependent extrinsic apoptosis by increasing the expression of interleukin 1 (IL-1), tumor necrosis factor (TNF-α), and the cleaved caspase-3, while damaged the unlimited proliferation and self-renewal capacity of GSCs. This finding might provide new type of leads for the selective killing of human glioma stem cells.
      Graphical abstract image

      PubDate: 2018-02-25T21:23:56Z
      DOI: 10.1016/j.bmc.2018.02.024
       
 
 
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