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CHEMISTRY (603 journals)                  1 2 3 4 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 5)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 25)
ACS Catalysis     Full-text available via subscription   (Followers: 28)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 15)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 23)
ACS Macro Letters     Full-text available via subscription   (Followers: 21)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 36)
ACS Nano     Full-text available via subscription   (Followers: 178)
ACS Photonics     Full-text available via subscription   (Followers: 7)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 19)
Acta Chemica Iasi     Open Access   (Followers: 1)
Acta Chimica Sinica     Full-text available via subscription  
Acta Chimica Slovaca     Open Access   (Followers: 1)
Acta Chromatographica     Full-text available via subscription   (Followers: 8)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 5)
Acta Scientifica Naturalis     Open Access   (Followers: 1)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 6)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 4)
Advanced Functional Materials     Hybrid Journal   (Followers: 44)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 52)
Advances in Chemical Science     Open Access   (Followers: 11)
Advances in Chemistry     Open Access   (Followers: 10)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 15)
Advances in Drug Research     Full-text available via subscription   (Followers: 21)
Advances in Enzyme Research     Open Access   (Followers: 5)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 12)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 16)
Advances in Nanoparticles     Open Access   (Followers: 12)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 14)
Advances in Polymer Science     Hybrid Journal   (Followers: 39)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 16)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 16)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Science and Technology     Full-text available via subscription   (Followers: 6)
African Journal of Bacteriology Research     Open Access  
African Journal of Chemical Education     Open Access   (Followers: 2)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 7)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Alchemy : Jurnal Penelitian Kimia     Open Access  
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 63)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 13)
American Journal of Chemistry     Open Access   (Followers: 23)
American Journal of Plant Physiology     Open Access   (Followers: 12)
American Mineralogist     Full-text available via subscription   (Followers: 8)
Anadolu University Journal of Science and Technology     Open Access  
Analyst     Full-text available via subscription   (Followers: 41)
Angewandte Chemie     Hybrid Journal   (Followers: 135)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 183)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 1)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 3)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 7)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 10)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 14)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Full-text available via subscription  
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 5)
Applied Spectroscopy     Full-text available via subscription   (Followers: 23)
Applied Surface Science     Hybrid Journal   (Followers: 23)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 2)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Atomization and Sprays     Full-text available via subscription   (Followers: 3)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 6)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 8)
Biochemistry     Full-text available via subscription   (Followers: 241)
Biochemistry Insights     Open Access   (Followers: 4)
Biochemistry Research International     Open Access   (Followers: 5)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 9)
Bioinspired Materials     Open Access   (Followers: 3)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access  
Biomacromolecules     Full-text available via subscription   (Followers: 17)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 11)
Biomedical Chromatography     Hybrid Journal   (Followers: 7)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 2)
BioNanoScience     Partially Free   (Followers: 4)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 110)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 89)
Bioorganic Chemistry     Hybrid Journal   (Followers: 9)
Biopolymers     Hybrid Journal   (Followers: 17)
Biosensors     Open Access   (Followers: 1)
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: 3)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 26)
Bulletin of the Korean Chemical Society     Hybrid Journal   (Followers: 1)
C - Journal of Carbon Research     Open Access   (Followers: 2)
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 2)
Canadian Journal of Chemistry     Full-text available via subscription   (Followers: 8)
Canadian Mineralogist     Full-text available via subscription   (Followers: 3)
Carbohydrate Research     Hybrid Journal   (Followers: 27)
Carbon     Hybrid Journal   (Followers: 67)
Catalysis for Sustainable Energy     Open Access   (Followers: 5)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 7)
Catalysis Science and Technology     Free   (Followers: 6)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 6)
Cellulose     Hybrid Journal   (Followers: 5)
Cereal Chemistry     Full-text available via subscription   (Followers: 4)
ChemBioEng Reviews     Full-text available via subscription  
ChemCatChem     Hybrid Journal   (Followers: 7)
Chemical and Engineering News     Free   (Followers: 10)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 64)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 21)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 18)
Chemical Reviews     Full-text available via subscription   (Followers: 141)
Chemical Science     Open Access   (Followers: 18)
Chemical Technology     Open Access   (Followers: 12)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 4)
Chemical Week     Full-text available via subscription   (Followers: 7)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 53)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 25)
ChemInform     Hybrid Journal   (Followers: 7)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 5)
Chemistry & Biology     Full-text available via subscription   (Followers: 29)
Chemistry & Industry     Hybrid Journal   (Followers: 4)
Chemistry - A European Journal     Hybrid Journal   (Followers: 127)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 14)
Chemistry and Materials Research     Open Access   (Followers: 15)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 4)
Chemistry in Education     Open Access   (Followers: 2)
Chemistry International     Hybrid Journal   (Followers: 1)
Chemistry Letters     Full-text available via subscription   (Followers: 45)
Chemistry of Materials     Full-text available via subscription   (Followers: 159)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 8)
Chemistry-Didactics-Ecology-Metrology     Open Access  
ChemistryOpen     Open Access   (Followers: 1)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 2)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 15)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 6)
ChemPlusChem     Hybrid Journal  
ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 3)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 10)
Chromatographia     Hybrid Journal   (Followers: 24)
Chromatography Research International     Open Access   (Followers: 5)
Clay Minerals     Full-text available via subscription   (Followers: 8)
Cogent Chemistry     Open Access  
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 9)
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 7)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 3)
Combustion Science and Technology     Hybrid Journal   (Followers: 18)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 1)
Composite Interfaces     Hybrid Journal   (Followers: 4)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 2)
Comptes Rendus Chimie     Full-text available via subscription  
Comptes Rendus Physique     Full-text available via subscription   (Followers: 1)
Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 9)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 10)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 10)
Coordination Chemistry Reviews     Full-text available via subscription  
Copernican Letters     Open Access  
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 5)
Crystal Structure Theory and Applications     Open Access   (Followers: 2)
CrystEngComm     Full-text available via subscription   (Followers: 9)
Current Catalysis     Hybrid Journal   (Followers: 1)
Current Metabolomics     Hybrid Journal   (Followers: 3)
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 7)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 14)
Current Research in Chemistry     Open Access   (Followers: 7)
Current Science     Open Access   (Followers: 44)
Dalton Transactions     Full-text available via subscription   (Followers: 17)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)
Diamond and Related Materials     Hybrid Journal   (Followers: 11)
Dislocations in Solids     Full-text available via subscription  
Doklady Chemistry     Hybrid Journal  
Drying Technology: An International Journal     Hybrid Journal   (Followers: 3)
Eclética Química     Open Access   (Followers: 1)
Ecological Chemistry and Engineering S     Open Access   (Followers: 2)
Ecotoxicology and Environmental Contamination     Open Access  
Educación Química     Open Access   (Followers: 1)
Education for Chemical Engineers     Hybrid Journal   (Followers: 4)
EDUSAINS     Open Access  
Elements     Full-text available via subscription   (Followers: 1)
Environmental Chemistry     Hybrid Journal   (Followers: 5)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 2)

        1 2 3 4 | Last

Journal Cover Bioorganic & Medicinal Chemistry
  [SJR: 1.064]   [H-I: 119]   [110 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0968-0896
   Published by Elsevier Homepage  [3039 journals]
  • Cyclen-based Gd3+ complexes as MRI contrast agents: Relaxivity enhancement
           and ligand design
    • Authors: Haroon Ur Rashid; Marco Antonio Utrera Martines; Juliana Jorge; Paula Martin de Moraes; Muhammad Naveed Umar; Kamin Khan; Hanif Ur Rehman
      Pages: 5663 - 5684
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Haroon Ur Rashid, Marco Antonio Utrera Martines, Juliana Jorge, Paula Martin de Moraes, Muhammad Naveed Umar, Kamin Khan, Hanif Ur Rehman
      Magnetic Resonance Imaging (MRI) is a noninvasive radiology technique used to examine the internal organs of human body. It is useful for the diagnosis of structural abnormalities in the body. Contrast agents are used to increase the sensitivity of this technique. 1,4,7,10-Tetraazacyclododecane (cyclen) is a macrocyclic tetraamine. Its derivatives act as useful ligands to produce stable complexes with Gd3+ ion. Such chelates are investigated as MRI contrast agents. Free Gd3+ ion is extremely toxic for in vivo use. Upon complexation with a cyclen-based ligand, it is trapped in the preformed central cavity of the ligand resulting in the formation of a highly stable Gd3+-chelate. Better kinetic and thermodynamic stability of cyclen-based MRI contrast agents decrease their potential toxicity for in vivo use. Consequently, such agents have proved to be safest for clinical applications. Relaxivity is the most important parameter used to measure the effectiveness of a contrast agent. A number of factors influence this parameter. This article elucidates detailed strategies to increase relaxivity of cyclen-based MRI contrast agents. 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) are two key ligands derived from cyclen. They also act as building blocks for the synthesis of novel ligands. A few important methodologies for the synthesis of DOTA and DO3A derivatives are described. Moreover, the coordination geometry of chelates formed by these ligands and their derivatives is discussed as well. Novel ligands can be developed by the appropriate derivatization of DOTA and DO3A. Gd3+-chelates of such ligands prove to be useful MRI contrast agents of enhanced relaxivity, greater stability, better clearance, lesser toxicity and higher water solubility.
      Graphical abstract image

      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.069
  • ArgTX-636, a polyamine isolated from spider venom: A novel class of
           melanogenesis inhibitors
    • Authors: Marion Verdoni; Hermine Roudaut; Harold De Pomyers; Didier Gigmes; Denis Bertin; José Luis; Abd Haq Bengeloune; Kamel Mabrouk
      Pages: 5685 - 5692
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Marion Verdoni, Hermine Roudaut, Harold De Pomyers, Didier Gigmes, Denis Bertin, José Luis, Abd Haq Bengeloune, Kamel Mabrouk
      To discover new molecules with an inhibitory activity of melanogenesis a hundred of scorpions, snakes, spiders and amphibians venoms were screened for their capacity to inhibit mushroom tyrosinase using 3,4-l-dihydroxyphenylalanine (l-DOPA) as substrate. The Argiope lobata spider venom proved to be the most active. HPLC fraction containing Argiotoxine-636 (ArgTX-636), a polyamine known for its numerous biological activities, was found to also show a good regulation activity of melanogenesis by inhibiting DOPA and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) oxidases activities, wore by tyrosinase (TYR) and tyrosinase-related protein 1 (TRP-1), respectively. Our results demonstrate that ArgTX-636 reduced the mushroom tyrosinase activity in a dose-dependent way with a maximal half inhibitory concentration (IC50) value of 8.34μM, when l-DOPA is used as substrate. The Lineweaver–Burk study showed that ArgTX-636 is a mixed type inhibitor of the diphenolase activity. Moreover, ArgTX-636 inhibits DHICA oxydase activity of mushroom tyrosinase activity with IC50 at 41.3μM. ArgTX-636 has no cytotoxicity in B16F10 melanoma cells at concentrations up to 42.1μM. The effect of ArgTX-636 on melanogenesis showed that melanin production in B16F10 melanoma cell decreased by approximatively 70% compared to untreated cells. ArgTX-636 displayed no significant effect on the TYR expression while the protein level of TRP-1 decreased in B16F10 cells. Thus, ArgTX-636 could have particular interest for cosmetic and/or pharmaceutical use in order to reduce important dermatoses in black and mixed skins.
      Graphical abstract image

      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.08.023
  • Conjugation of N-acylhydrazone and 1,2,4-oxadiazole leads to the
           identification of active antimalarial agents
    • Authors: José Maurício dos Santos Filho; Diogo Manoel Alves de Queiroz e Silva; Taís Soares Macedo; Helena Mariana Pitangueira Teixeira; Diogo Rodrigo Magalhaes Moreira; Soura Challal; Jean-Luc Wolfender; Emerson Ferreira Queiroz; Milena Botelho Pereira Soares
      Pages: 5693 - 5701
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): José Maurício dos Santos Filho, Diogo Manoel Alves de Queiroz e Silva, Taís Soares Macedo, Helena Mariana Pitangueira Teixeira, Diogo Rodrigo Magalhaes Moreira, Soura Challal, Jean-Luc Wolfender, Emerson Ferreira Queiroz, Milena Botelho Pereira Soares
      Malaria, caused by several Plasmodium species, is the major life-threatening parasitic infection worldwide. Due to the parasite resistance to quinoline based drugs, the search for antimalarial agents is necessary. Here, we report the structural design, synthesis and antiparasitic evaluation of two novel series of 1,2,4-oxadiazoles in conjugation to N-acylhydrazones, both groups recognized as privileged structures, as well as the studies on the antimalarial activity of 16 previous described analogues. By varying substituents attached to the phenyl ring, it was possible to retain, enhance or increase the antiparasitic activity in comparison to the nonsubstituted derivatives. Replacement of substituted aryl rings by ferrocenyl and cinnamyl moieties attached in the N-acylhydrazone ablated the antiparasitic response, evidencing the structural features associated with the activity. Active compounds exhibited in vitro potency similar to mefloquine, but not all inhibited β-hematin formation. Additionally, the active compounds displayed low cytotoxicity in HepG2 cells and did not cause hemolysis in uninfected erythrocytes. In Plasmodium berghei-infected mice, the compounds reduced parasitemia but exhibited limited efficacy in increasing mice survival when compared to chloroquine, suggesting that pharmacological improvement is still necessary.
      Graphical abstract image

      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.013
  • In vivo effective dibenzo[b,d]furan-1-yl-thiazoles as novel PDE-4
    • Authors: Gopalan Balasubramanian; Sukunath Narayanan; Lavanya Andiappan; Thirunavukkarasu Sappanimuthu; Saravanan Thirunavukkarasu; Shamundeeswari Sundaram; Saravanakumar Natarajan; Naresh Sivaraman; Sridharan Rajagopal; Fakrudeen Ali Ahamed Nazumudeen; Sanjeev Saxena; Santosh L. Vishwakarma; Shridhar Narayanan; Ganapavarapu V.R. Sharma; Chidambaram V. Srinivasan; Narasimhan Kilambi
      Pages: 5702 - 5716
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Gopalan Balasubramanian, Sukunath Narayanan, Lavanya Andiappan, Thirunavukkarasu Sappanimuthu, Saravanan Thirunavukkarasu, Shamundeeswari Sundaram, Saravanakumar Natarajan, Naresh Sivaraman, Sridharan Rajagopal, Fakrudeen Ali Ahamed Nazumudeen, Sanjeev Saxena, Santosh L. Vishwakarma, Shridhar Narayanan, Ganapavarapu V.R. Sharma, Chidambaram V. Srinivasan, Narasimhan Kilambi
      Herein we report the synthesis, PDE-4B and TNF-α inhibitory activities of a few dibenzo[b,d]furan-1-yl-thiazole derivatives. The hydroxycyclohexanol amide derivatives 14, 18, 24, 29, 31 and 33 exhibited promising in vitro PDE-4B and TNF-α inhibitory activities. Compound 24 showed good systemic availability in preclinical animal models and was also found to be non-toxic (exploratory mutagenicity test). Further it exhibited promising results in in vivo asthma/COPD and Uveitis models.
      Graphical abstract image

      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.011
  • Pyrazolo[1,5a]pyrimidines as a new class of FUSE binding protein 1 (FUBP1)
    • Authors: Stefanie Hauck; Kerstin Hiesinger; Sabrina Khageh Hosseini; Janosch Achenbach; Ricardo M. Biondi; Ewgenij Proschak; Martin Zörnig; Dalibor Odadzic
      Pages: 5717 - 5729
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Stefanie Hauck, Kerstin Hiesinger, Sabrina Khageh Hosseini, Janosch Achenbach, Ricardo M. Biondi, Ewgenij Proschak, Martin Zörnig, Dalibor Odadzic
      The transcriptional regulator FUSE binding protein 1 (FUBP1) is aberrantly upregulated in various malignancies, fulfilling its oncogenic role by the deregulation of critical genes involved in cell cycle control and apoptosis regulation. Thus, the pharmaceutical inhibition of this protein would represent an encouraging novel targeted chemotherapy. Here, we demonstrate the identification and initial optimization of a pyrazolo[1,5a]pyrimidine-based FUBP1 inhibitor derived from medium throughput screening, which interferes with the binding of FUBP1 to its single stranded target DNA FUSE. We were able to generate a new class of FUBP1 interfering molecules with in vitro and biological activity. In biophysical assays, we could show that our best inhibitor, compound 6, potently inhibits the binding of FUBP1 to the FUSE sequence with an IC50 value of 11.0μM. Furthermore, hepatocellular carcinoma cells exhibited sensitivity towards the treatment with compound 6, resulting in reduced cell expansion and induction of cell death. Finally, we provide insights into the corresponding SAR landscape, leading to a prospective enhancement in potency and cellular efficacy.
      Graphical abstract image

      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.015
  • Synthesis and evaluation of the structural elements in alkylated
           tetrahydroisoquinolines for binding to CNS receptors
    • Authors: Edward Ofori; Xue Y. Zhu; Jagan R. Etukala; Barbara A. Bricker; Seth Y. Ablordeppey
      Pages: 5730 - 5740
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Edward Ofori, Xue Y. Zhu, Jagan R. Etukala, Barbara A. Bricker, Seth Y. Ablordeppey
      Diseases of the CNS are often complex and involve multiple receptor systems and thus, the treatment options for these diseases must focus on targeting the multiple receptors implicated in the various disorders. Schizophrenia and depression are examples of such diseases and their pharmacotherapy thus depends on agents which target multiple receptors including the dopamine, serotonin and even cholinergic receptors at the same time. In our previous campaign to find multi-receptor ligands, we have identified the benzothiazole 1a as an initial lead molecule. In the current work, we have expanded the structure affinity relationship (SAFIR) of 1a resulting in the identification of a partially restrained butyrophenone 3j as a potent and selective dual 5-HT1A and 5-HT7 receptor ligand. It is expected that compound 3j may serve as a new lead for further development in our search for newer and novel ligands with the potential to treat diseases of CNS origin.
      Graphical abstract image

      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.019
  • Synthesis and pharmacological evaluation of conformationally constrained
           glutamic acid higher homologues
    • Authors: Lucia Tamborini; Gregorio Cullia; Birgitte Nielsen; Carlo De Micheli; Paola Conti; Andrea Pinto
      Pages: 5741 - 5747
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Lucia Tamborini, Gregorio Cullia, Birgitte Nielsen, Carlo De Micheli, Paola Conti, Andrea Pinto
      Homologation of glutamic acid chain together with conformational constraint is a commonly used strategy to achieve selectivity towards different types of glutamate receptors. In the present work, starting from two potent and selective unnatural amino acids previously developed by us, we investigated the effects on the activity/selectivity profile produced by a further increase in the distance between the amino acidic moiety and the distal carboxylate group. Interestingly, the insertion of an aromatic ring as a spacer produced a low micromolar affinity NMDA ligand that might represent a lead for the development of a new class of NMDA antagonists.
      Graphical abstract image

      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.029
  • (1S,2E,4S,7E,11E)-2,7,11-Cembratriene-4,6-diol semisynthetic analogs as
           novel c-Met inhibitors for the control of c-Met-dependent breast
    • Authors: Hassan Y. Ebrahim; Mohamed M. Mohyeldin; Mohammad M. Hailat; Khalid A. El Sayed
      Pages: 5748 - 5761
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Hassan Y. Ebrahim, Mohamed M. Mohyeldin, Mohammad M. Hailat, Khalid A. El Sayed
      (1S,2E,4S,6R,7E,11E)-2,7,11-Cembratriene-4,6-diol (1) and its 4-epi-analog (2) are the cembranoid precursors to several key flavor ingredients in most Nicotiana (tobacco) species. Nearly 40–60% of 1 and 2 are purposely degraded during the commercial tobacco fermentation. However, 1 and 2 display promising bioactivities, including anticancer. Breast cancer is the most diagnosed cancer in women and ranked second female disease killer. The receptor tyrosine kinase c-Met correlates with aggressiveness of certain breast cancer phenotypes and thus considered a valid therapeutic target. This study reports the discovery and optimization of the tobacco-based cembranoid 1 as a novel c-Met inhibitory scaffold using combined structure- and ligand-based approaches. 1 displayed antiproliferative, anti-migratory and anti-invasive effects against the c-Met overexpressing MDA-MB-231 breast cancer cells at moderate μM concentrations. The Z′-LYTE kinase platform and Western blot analysis identified c-Met as a potential macromolecular target. Rationally designed carbamate analogs were proposed to probe additional targeted c-Met interactions and improve the cellular potency. The 6-phenyl carbamate 3 showed enhanced c-Met inhibitory activity. Structure–activity relationships of different substituents on the 3’s phenyl moiety were studied. The most active analog 20 showed potent in vitro anticancer activity against the MDA-MB-231 breast cancer cells at low μM concentrations, with minimal toxicity on the non-tumorigenic MCF-10A mammary epithelial cells. Cembranoid 20 potently inhibited the c-Met catalytic activity in Z′-LYTE kinase assay and various cellular c-Met-driven signaling pathways. Furthermore, 20 displayed a robust antitumor activity in a breast cancer xenograft athymic mouse model and thus promoted to the lead rank. Cembranoids are novel c-Met inhibitors appropriate for future use to control c-Met dependent malignancies.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.032
  • Synthesis and evaluation of dihydropyrimidinone-derived selenoesters as
           multi-targeted directed compounds against Alzheimer’s disease
    • Authors: Flavio A.R. Barbosa; Rômulo F.S. Canto; Sumbal Saba; Jamal Rafique; Antonio L. Braga
      Pages: 5762 - 5770
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Flavio A.R. Barbosa, Rômulo F.S. Canto, Sumbal Saba, Jamal Rafique, Antonio L. Braga
      This paper describes the synthesis and evaluation of new dihydropyrimidinone (DHPM)-derived selenoesters as potential multi-targeted agents for the treatment of Alzheimer’s disease. A series of DHPM-derived selenoesters were obtained with high structural diversity through a short and modular synthetic route. The antioxidant activity was evaluated by TBARS and iron chelation assays. These compounds were also evaluated as acetylcholinesterase inhibitors (AChEi). The compounds demonstrated good antioxidant activity, since they presented excellent lipid peroxidation inhibition and good iron chelation activity. In addition, they showed acetylcholinesterase inhibition activity and some of them presented activity superior to that of the standard drug galantamine. The in silico predictions showed that the compound 1h may present a good pharmacokinetic profile. Therefore, the series of DHPM-derived selenoesters described herein displayed good potential for the development of antioxidant and anticholinesterasic agents in the search for new multi-targeted therapeutics for the treatment of Alzheimer’s disease.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.031
  • Structure-based design of a new series of
           N-(piperidin-3-yl)pyrimidine-5-carboxamides as renin inhibitors
    • Authors: Yasuhiro Imaeda; Michiko Tawada; Shinkichi Suzuki; Masaki Tomimoto; Mitsuyo Kondo; Naoki Tarui; Tsukasa Sanada; Ray Kanagawa; Gyorgy Snell; Craig A. Behnke; Keiji Kubo; Takanobu Kuroita
      Pages: 5771 - 5780
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Yasuhiro Imaeda, Michiko Tawada, Shinkichi Suzuki, Masaki Tomimoto, Mitsuyo Kondo, Naoki Tarui, Tsukasa Sanada, Ray Kanagawa, Gyorgy Snell, Craig A. Behnke, Keiji Kubo, Takanobu Kuroita
      The action of the aspartyl protease renin is the rate-limiting initial step of the renin-angiotensin-aldosterone system. Therefore, renin is a particularly promising target for blood pressure as well as onset and progression of cardiovascular and renal diseases. New pyrimidine derivatives 5–14 were designed in an attempt to enhance the renin inhibitory activity of compound 3 identified by our previous fragment-based drug design approach. Introduction of a basic amine essential for interaction with the two aspartic acids in the catalytic site and optimization of the S1/S3 binding elements including an induced-fit structural change of Leu114 (‘Leu-in’ to ‘Leu-out’) by a rational structure-based drug design approach led to the discovery of N-(piperidin-3-yl)pyrimidine-5-carboxamide 14, a 65,000-fold more potent renin inhibitor than compound 3. Surprisingly, this remarkable enhancement in the inhibitory activity of compound 14 has been achieved by the overall addition of only seven heavy atoms to compound 3. Compound 14 demonstrated excellent selectivity over other aspartyl proteases and moderate oral bioavailability in rats.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.030
  • Design, synthesis and biological evaluation of lapachol derivatives
           possessing indole scaffolds as topoisomerase I inhibitors
    • Authors: Chong Zhang; Yan Qu; Bingxuan Niu
      Pages: 5781 - 5786
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Chong Zhang, Yan Qu, Bingxuan Niu
      A series of novel lapachol derivatives possessing indole scaffolds was designed and synthesized. The in vitro anti-proliferative activity of these novel compounds was evaluated in Eca109 and Hela cell lines. Almost all the tested compounds showed manifested potent inhibitory activity against the two tested cancer cell lines. Topo I-mediated DNA relaxation activity indicated that these novel compounds have potent Topoisomerase I inhibition activity. The most potent compounds 4n and 4k demonstrated more cytotoxicity than camptothecin and was comparable to camptothecin in inhibitory activities on Topoisomerase I in our biological assay. In addition, the Hoechst 33342 staining method also showed that the complex can induce Hela cell apoptosis.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.034
  • Discovery of a novel chimeric ubenimex–gemcitabine with potent oral
           antitumor activity
    • Authors: Yuqi Jiang; Jinning Hou; Xiaoyang Li; Yongxue Huang; Xuejian Wang; Jingde Wu; Jian Zhang; Wenfang Xu; Yingjie Zhang
      Pages: 5787 - 5795
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Yuqi Jiang, Jinning Hou, Xiaoyang Li, Yongxue Huang, Xuejian Wang, Jingde Wu, Jian Zhang, Wenfang Xu, Yingjie Zhang
      Herein, a novel mutual prodrug BC-A1 was discovered by integrating ubenimex and gemcitabine into one molecule. Biological characterization revealed that compound BC-A1 could maintain both the anti-CD13 activity of ubenimex and the cytotoxic activity of gemcitabine in vitro. Further characterization also demonstrated that compound BC-A1 exhibited significant anti-invasion and anti-angiogenesis effects in vitro. The preliminary stability test of BC-A1 revealed that it could release gemcitabine in vitro. The in vivo anti-tumor results in liver cancer showed that at the same dosage, oral administration of BC-A1 was as potent as intraperitoneal administration of gemcitabine. This warranted the further research and development of the orally active prodrug BC-A1 because gemcitabine can not be orally administrated in clinic.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.033
  • Tautomeric and non-tautomeric N-substituted 2-iminobenzimidazolines as new
           lead compounds for the design of anti-influenza drugs: An in vitro study
    • Authors: Vladimir V. Zarubaev; Anatolii S. Morkovnik; Liudmila N. Divaeva; Liubov’ A. Karpinskaya; Gennadii S. Borodkin
      Pages: 5796 - 5803
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Vladimir V. Zarubaev, Anatolii S. Morkovnik, Liudmila N. Divaeva, Liubov’ A. Karpinskaya, Gennadii S. Borodkin
      A series of 1,3-disubstituted 2-iminobenzimidazolines as well as a number of their tautomeric analogs were synthesized. The synthesized compounds were tested for their cytotoxicity against MDCK cells and for inhibiting activity against influenza virus A/California/07/09 (H1N1)pdm09. Based on the results obtained, 50% cytotoxic concentration (CC50), 50% inhibiting concentration (IC50) and selectivity index (SI) were calculated for each compound. It was found that some of synthesized benzimidazole derivatives (7 of 22, 32%) possess strong virus-inhibiting activity against pandemic influenza virus (IC50’s in low micromolar range) with quite moderate cytotoxicity (CC50 in the range of thousands micromoles). Due to their high selectivity (highest SI’s=50–83) these compounds are of significant interest for further in vivo experiments as well as for further structural optimization and drug development.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.036
  • On the stability and biological behavior of cyclometallated Pt(IV)
           complexes with halido and aryl ligands in the axial positions
    • Authors: Anna Escolà; Margarita Crespo; Concepción López; Josefina Quirante; Anusha Jayaraman; Ibrahim H. Polat; Josefa Badía; Laura Baldomà; Marta Cascante
      Pages: 5804 - 5815
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Anna Escolà, Margarita Crespo, Concepción López, Josefina Quirante, Anusha Jayaraman, Ibrahim H. Polat, Josefa Badía, Laura Baldomà, Marta Cascante
      A series of cyclometallated platinum(IV) compounds (3a, 3a′ and 3b′) with a meridional [C,N,N′] terdentate ligand, featuring an halido and an aryl group in the axial positions has been evaluated for electrochemical reduction and preliminary biological behavior against a panel of human adenocarcinoma (A-549 lung, HCT-116 colon, and MCF-7 breast) cell lines and the normal bronquial epithelial BEAS-2B cells. Cathodic reduction potentials (shifting from −1.463 to −1.570V) reveal that the platinum(IV) compounds under study would be highly reluctant to be reduced in a biological environment. Actually ascorbic acid was not able to reduce complex 3a′, the most prone to be reduced according its reduction potential, over a period of one week. These results suggest an intrinsic activity for the investigated platinum(IV) complexes (3a, 3a′ and 3b′), which exhibit a remarkable cytotoxicity effectiveness (with IC50 values in the low micromolar range), even greater than that of cisplatin. The IC50 for A-549 lung cells and clog P values were found to follow the same trend: 3b′ > 3a′ > 3a. However, no correlation was observed between reduction potential and in vitro activity. As a representative example, cyclometallated platinum(IV) compound 3a′, exercise its antiproliferative activity directly over non-microcytic A-549 lung cancer cells through a mixture of cell cycle arrest (13% arrest at G1 phase and 46% arrest at G2 phase) and apoptosis induction (increase of early apoptosis by 30 times with regard to control). To gain further insights into the mode of action of the investigated platinum(IV) complexes, drug uptake, cathepsin B inhibition and ROS generation were also evaluated. Interestingly an increased ROS generation could be related with the antiproliferative activity of the cyclometallated platinum(IV) series under study in the cisplatin-resistant A-549 lung and HCT-116 cancer cell lines.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.037
  • Direct protein–protein conjugation by genetically introducing
           bioorthogonal functional groups into proteins
    • Authors: Sanggil Kim; Wooseok Ko; Bong Hyun Sung; Sun Chang Kim; Hyun Soo Lee
      Pages: 5816 - 5822
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Sanggil Kim, Wooseok Ko, Bong Hyun Sung, Sun Chang Kim, Hyun Soo Lee
      Proteins often function as complex structures in conjunction with other proteins. Because these complex structures are essential for sophisticated functions, developing protein–protein conjugates has gained research interest. In this study, site-specific protein–protein conjugation was performed by genetically incorporating an azide-containing amino acid into one protein and a bicyclononyne (BCN)-containing amino acid into the other. Three to four sites in each of the proteins were tested for conjugation efficiency, and three combinations showed excellent conjugation efficiency. The genetic incorporation of unnatural amino acids (UAAs) is technically simple and produces the mutant protein in high yield. In addition, the conjugation reaction can be conducted by simple mixing, and does not require additional reagents or linker molecules. Therefore, this method may prove very useful for generating protein–protein conjugates and protein complexes of biochemical significance.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.035
  • Exploration of bivalent ligands targeting putative mu opioid receptor and
           chemokine receptor CCR5 dimerization
    • Authors: Christopher K. Arnatt; Bethany A. Falls; Yunyun Yuan; Thomas J. Raborg; Ruturaj R. Masvekar; Nazira El-Hage; Dana E. Selley; Anthony V. Nicola; Pamela E. Knapp; Kurt F. Hauser; Yan Zhang
      Pages: 5969 - 5987
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Christopher K. Arnatt, Bethany A. Falls, Yunyun Yuan, Thomas J. Raborg, Ruturaj R. Masvekar, Nazira El-Hage, Dana E. Selley, Anthony V. Nicola, Pamela E. Knapp, Kurt F. Hauser, Yan Zhang
      Modern antiretroviral therapies have provided HIV-1 infected patients longer lifespans and better quality of life. However, several neurological complications are now being seen in these patients due to HIV-1 associated injury of neurons by infected microglia and astrocytes. In addition, these effects can be further exacerbated with opiate use and abuse. One possible mechanism for such potentiation effects of opiates is the interaction of the mu opioid receptor (MOR) with the chemokine receptor CCR5 (CCR5), a known HIV-1 co-receptor, to form MOR–CCR5 heterodimer. In an attempt to understand this putative interaction and its relevance to neuroAIDS, we designed and synthesized a series of bivalent ligands targeting the putative CCR5–MOR heterodimer. To understand how these bivalent ligands may interact with the heterodimer, biological studies including calcium mobilization inhibition, binding affinity, HIV-1 invasion, and cell fusion assays were applied. In particular, HIV-1 infection assays using human peripheral blood mononuclear cells, macrophages, and astrocytes revealed a notable synergy in activity for one particular bivalent ligand. Further, a molecular model of the putative CCR5–MOR heterodimer was constructed, docked with the bivalent ligand, and molecular dynamics simulations of the complex was performed in a membrane-water system to help understand the biological observation.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.059
  • Design, synthesis and evaluation of small molecule CD4-mimics as entry
           inhibitors possessing broad spectrum anti-HIV-1 activity
    • Authors: Francesca Curreli; Dmitry S. Belov; Ranjith R. Ramesh; Naisargi Patel; Andrea Altieri; Alexander V. Kurkin; Asim K. Debnath
      Pages: 5988 - 6003
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Francesca Curreli, Dmitry S. Belov, Ranjith R. Ramesh, Naisargi Patel, Andrea Altieri, Alexander V. Kurkin, Asim K. Debnath
      Since our first discovery of a CD4-mimic, NBD-556, which targets the Phe43 cavity of HIV-1 gp120, we and other groups made considerable progress in designing new CD4-mimics with viral entry-antagonist property. In our continued effort to make further progress we have synthesized twenty five new analogs based on our earlier reported viral entry antagonist, NBD-11021. These compounds were tested first in HIV-1 Env-pseudovirus based single-cycle infection assay as well as in a multi-cycle infection assay. Four of these new compounds showed much improved antiviral potency as well as cytotoxicity. We selected two of the best compounds 45A (NBD-14009) and 46A (NBD-14010) to test against a panel of 51 Env-pseudotyped HIV-1 representing diverse subtypes of clinical isolates. These compounds showed noticeable breadth of antiviral potency with IC50 of as low as 150nM. These compounds also inhibited cell-to-cell fusion and cell-to-cell HIV-1 transmission. The study is expected to pave the way of designing more potent and selective HIV-1 entry inhibitors targeted to the Phe43 cavity of HIV-1 gp120.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.057
  • Inhibition of the metastatic progression of breast and colorectal cancer
           in vitro and in vivo in murine model by the oxidovanadium(IV) complex with
    • Authors: Luciana G. Naso; Iker Badiola; Joana Marquez Clavijo; María Valcarcel; Clarisa Salado; Evelina G. Ferrer; Patricia A.M. Williams
      Pages: 6004 - 6011
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Luciana G. Naso, Iker Badiola, Joana Marquez Clavijo, María Valcarcel, Clarisa Salado, Evelina G. Ferrer, Patricia A.M. Williams
      The anticancer and antimetastatic behavior of the flavonoid luteolin and its oxidovanadium(IV) complex [VO(lut)(H2O)2]Na·3H2O (VOlut) has been investigated. Considering that the complex displayed strong anticancer activity on MDAMB231 human breast cancer cell line we herein determined through in vitro assays that the complex would probably reduce breast cancer cell metastasis in a higher extent than the natural antioxidant. In the CT26 colon cancer cell line a stronger anticancer effect has also been determined for the complex (IC50 0.9μM) and in addition it did not exert toxic effects on normal colon epithelial cells at concentrations up to 10μM. Working with a murine model of highly aggressive, orthotopic colon cancer model (CT26 cancer cell lines) it has been determined that the complex might prevent metastatic dissemination of the colon cancer cells to the liver. The flavonoid luteolin also exerted anticancer effects (at a low degree, IC50 5.9μM) on CT26 cell line and produced a 24% reduction of colon cancer liver metastasis.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.058
  • Biological evaluation of tetracationic compounds based on two
           1,4-diazabicyclo[2.2.2]octane moieties connected by different linkers
    • Authors: Ekaterina A. Burakova; Irina V. Saranina; Nina V. Tikunova; Zhanna K. Nazarkina; Pavel P. Laktionov; Lubov’ A. Karpinskaya; Vadim B. Anikin; Vladimir V. Zarubaev; Vladimir N. Silnikov
      Pages: 6012 - 6020
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Ekaterina A. Burakova, Irina V. Saranina, Nina V. Tikunova, Zhanna K. Nazarkina, Pavel P. Laktionov, Lubov’ A. Karpinskaya, Vadim B. Anikin, Vladimir V. Zarubaev, Vladimir N. Silnikov
      A series of 1,4-diazabicyclo[2.2.2]octane derivatives differing by linker moiety was evaluated for activity against several strains of both Gram-positive and Gram-negative bacteria including drug-resistant strains, one strain of fungus and influenza virus A/Puerto Rico/8/34 (H1N1). All compounds exhibited high antibacterial activity against all bacteria except Proteus vulgaris. The minimum inhibitory concentrations (MICs) of compound 1c with an o-phenylenebismethyl linker and compound 1e with a propylene aliphatic linker were found to be low and were comparable or better to the reference drug ciprofloxacin for Pseudomonas aeruginosa and Staphylococcus aureus. Additionally, a time-kill assay was performed to examine the bactericidal kinetics. Compounds 1c and 1e displayed rapid killing effects against St. aureus and Ps. aeruginosa after 2h. Furthermore, compounds 1a–c with aromatic linkers and compound 1e showed the highest antiviral activity.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.064
  • Methylene versus carbonyl bridge in the structure of new tubulin
           polymerization inhibitors with tricyclic A-rings
    • Authors: Iuliana-Monica Moise; Elena Bîcu; Joëlle Dubois; Amaury Farce; Benoît Rigo; Alina Ghinet
      Pages: 6021 - 6030
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Iuliana-Monica Moise, Elena Bîcu, Joëlle Dubois, Amaury Farce, Benoît Rigo, Alina Ghinet
      The phenothiazine group has been identified as a suitable A ring in the structure of tubulin polymerization inhibitors. In our search to identify more potent inhibitors, a study of different isosteric tricyclic groups as new potential A rings was first realized and permitted to identify 1-azaphenothiazine and iminodibenzyl as favorable modulations providing compounds with improved activity against tubulin. An investigation of the methylene group as the connector between the A and B rings revealed that the “CH2” bridge was tolerated, improving the biological potency when the A unit was of phenothiazine, 1-azaphenothiazine or iminodibenzyl type. Molecules 6–8 and 12 showed increased biological activity in comparison to parent phenstatin 2 on COLO 205 colon cancer cell line. The most antineoplastic agent in the current study was phenothiazine 5 displaying a GI50 of 25nM against the melanoma MDA-MB-435 cell line.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.063
  • Multitarget-directed oxoisoaporphine derivatives:
           Anti-acetylcholinesterase, anti-β-amyloid aggregation and enhanced
           autophagy activity against Alzheimer’s disease
    • Authors: Shenqi Wei; Wei Chen; Jingfang Qin; Yingzi Huangli; Li Wang; Yue Shen; Huang Tang
      Pages: 6031 - 6039
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Shenqi Wei, Wei Chen, Jingfang Qin, Yingzi Huangli, Li Wang, Yue Shen, Huang Tang
      A series of 8- and 11-substituted oxoisoaporphine derivatives have been designed, synthesized, and tested for their ability to inhibit cholinesterase (ChE) in vitro and in vivo, and self-induced β-amyloid (Aβ) aggregation. Their autophagy activity and blood–brain barrier (BBB) permeability were also assessed. The new derivatives exhibited high AChE inhibitory activity in vivo and in intro. Over half the derivatives exhibited a significant in vitro inhibitory activity toward the self-induced Aβ aggregation. While, treatment of SH-SY5Y cells overexpressing the Swedish mutant form of human β-amyloid precursor protein (APPsw) with derivatives was associated with significant reduction of Aβ secretion levels. Moreover, one-third of the synthetic compounds were predicted to be able to cross the BBB to reach their targets in the central nervous system (CNS) according to a parallel artificial membrane permeation assay for BBB. Compounds 5b and 6b were chosen for assessing their autophagy activity. The fluorescence intensity of the BC12921 was decreased significantly after treatment with compounds. The result encourages us to study such compounds thoroughly and systematically.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.061
  • Synthesis, photophysical properties and biological evaluation of
           β-alkylaminoporphyrin for photodynamic therapy
    • Authors: Ping-Yong Liao; Xin-Rong Wang; Ying-Hua Gao; Xiang-Hua Zhang; Li-Jun Zhang; Chun-Hong Song; Dan-Ping Zhang; Yi-Jia Yan; Zhi-Long Chen
      Pages: 6040 - 6047
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Ping-Yong Liao, Xin-Rong Wang, Ying-Hua Gao, Xiang-Hua Zhang, Li-Jun Zhang, Chun-Hong Song, Dan-Ping Zhang, Yi-Jia Yan, Zhi-Long Chen
      A series of β-alkylaminoporphyrins conjugated with different amines at β position (D1–D3) or with electron-donating and electron-withdrawing substituents at phenyl position (D4–D6) were synthesized. Their photophysical and photochemical properties, intracellular localization, photocytotoxicities in vitro and vivo were also investigated. All target compounds exhibited no cytotoxicities in the dark and excellent photocytotoxicities against HeLa cells. Among them, D6 showed the highest phototoxicity and the lowest dark toxicity, which was more phototoxic than Hematoporphyrin monomethyl ether (HMME). In addition, D6 exhibited best photodynamic antitumor efficacy on BALB/c nude mice bearing HeLa tumor. Therefore, D6 is a powerful and promising antitumor photosensitizer for photodynamic therapy.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.060
  • Triethylated chromones with substituted naphthalenes as tubulin inhibitors
    • Authors: Kyoko Nakagawa-Goto; Yukako Taniguchi; Yurie Watanabe; Akifumi Oda; Emika Ohkoshi; Ernest Hamel; Kuo-Hsiung Lee; Masuo Goto
      Pages: 6048 - 6057
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Kyoko Nakagawa-Goto, Yukako Taniguchi, Yurie Watanabe, Akifumi Oda, Emika Ohkoshi, Ernest Hamel, Kuo-Hsiung Lee, Masuo Goto
      Previously synthesized 2-(benzo[b]thiophene-3′-yl)-6,8,8-triethyldesmosdumotin B (1, TEDB-TB) and 2-(naphth-1′-yl)-6,8,8-triethyldesmosdumotin B (2) showed potent activity against multiple human tumor cell lines, including a multidrug-resistant (MDR) subline, by targeting spindle formation and/or the microtubule network. Consequently, ester analogues of hydroxylated naphthyl substituted TEBDs (3–5) were prepared and evaluated for their effects on tumor cell proliferation and on tubulin assembly. Among all new compounds, compound 6, a 4′-acetoxynaphthalen-1′-yl derivative, displayed the most potent antiproliferative activity (IC50 0.2–5.7μM). Selected analogues were confirmed to be tubulin assembly inhibitors in cell-free and cell-based assays using MDR tumor cells. The new analogues partially inhibited colchicine binding to tubulin, suggesting their binding mode would be different from that of colchicine. This observation was supported by computational docking model analyses. Thus, the newly synthesized triethylated chromones with esterified naphthalene groups have good potential for development as a new class of mitotic inhibitors that target tubulin.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.062
  • Synthesis of novel tetrazole derivatives and evaluation of their
           antifungal activity
    • Authors: Edyta Łukowska-Chojnacka; Jolanta Mierzejewska; Małgorzata Milner-Krawczyk; Małgorzata Bondaryk; Monika Staniszewska
      Pages: 6058 - 6065
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Edyta Łukowska-Chojnacka, Jolanta Mierzejewska, Małgorzata Milner-Krawczyk, Małgorzata Bondaryk, Monika Staniszewska
      With the appearance of the antifungal resistance, novel antifungal agents need to be identified. In this context new 2,5-disubstituted tetrazole derivatives containing benzothiazole, benzoxazole or phenylsulfonyl moiety were synthesized by N-alkylation of aryltetrazole with 2-[(3-chloropropyl)sulfanyl]-1,3-benzothiazole or 2-[(3-chloropropyl)sulfanyl]-1,3-benzoxazole and Michael-type addition of aryltetrazole to phenyl vinyl sulfone. The chemical structures of the synthesized compounds were confirmed by means of 1H NMR, 13C NMR, IR and HRMS spectral data. The compounds were tested against the moulds: Fusarium sambucinum, Fusarium oxysporum, Colletotrichum coccodes, Aspergillus niger, and the yeast Candida albicans. The results showed that among the moulds only C. coccodes was significantly sensitive to all the structures examined. All the tetrazole derivatives acted at the same level against C. albicans and demonstrated a high cell growth inhibition (97–99%) at the concentrations ranging from 16 to 0.0313μg/mL. The mode of action of 2-({3-[5-(4-chlorophenyl)-2H-tetrazol-2-yl]propyl}sulfanyl)-1,3-benzoxazole (5c) and 2-({3-[5-(2-chlorophenyl)-2H-tetrazol-2-yl]propyl}sulfanyl)-1,3-benzoxazole (5d) was established by verifying fungal growth in the presence of osmotic protector-sorbitol. The effect of compound 5c or 5d combined with Fluconazole was determined using the checkerboard method. The calculated fractional inhibitory concentration index (FIC) indicated antagonism (FIC >1). Additionally, survival experiments with lepidopteran Galleria mellonella treated with compounds 5c and 5d were performed and demonstrated the lack of toxicity of these compounds.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.066
  • Novel approach of fragment-based lead discovery applied to renin
    • Authors: Michiko Tawada; Shinkichi Suzuki; Yasuhiro Imaeda; Hideyuki Oki; Gyorgy Snell; Craig A. Behnke; Mitsuyo Kondo; Naoki Tarui; Toshimasa Tanaka; Takanobu Kuroita; Masaki Tomimoto
      Pages: 6066 - 6074
      Abstract: Publication date: 15 November 2016
      Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
      Author(s): Michiko Tawada, Shinkichi Suzuki, Yasuhiro Imaeda, Hideyuki Oki, Gyorgy Snell, Craig A. Behnke, Mitsuyo Kondo, Naoki Tarui, Toshimasa Tanaka, Takanobu Kuroita, Masaki Tomimoto
      A novel approach was conducted for fragment-based lead discovery and applied to renin inhibitors. The biochemical screening of a fragment library against renin provided the hit fragment which showed a characteristic interaction pattern with the target protein. The hit fragment bound only to the S1, S3, and S3SP (S3 subpocket) sites without any interactions with the catalytic aspartate residues (Asp32 and Asp215 (pepsin numbering)). Prior to making chemical modifications to the hit fragment, we first identified its essential binding sites by utilizing the hit fragment’s substructures. Second, we created a new and smaller scaffold, which better occupied the identified essential S3 and S3SP sites, by utilizing library synthesis with high-throughput chemistry. We then revisited the S1 site and efficiently explored a good building block attaching to the scaffold with library synthesis. In the library syntheses, the binding modes of each pivotal compound were determined and confirmed by X-ray crystallography and the library was strategically designed by structure-based computational approach not only to obtain a more active compound but also to obtain informative Structure Activity Relationship (SAR). As a result, we obtained a lead compound offering synthetic accessibility as well as the improved in vitro ADMET profiles. The fragments and compounds possessing a characteristic interaction pattern provided new structural insights into renin’s active site and the potential to create a new generation of renin inhibitors. In addition, we demonstrated our FBDD strategy integrating highly sensitive biochemical assay, X-ray crystallography, and high-throughput synthesis and in silico library design aimed at fragment morphing at the initial stage was effective to elucidate a pocket profile and a promising lead compound.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.09.065
  • A novel curcumin derivative which inhibits P-glycoprotein, arrests cell
           cycle and induces apoptosis in multidrug resistance cells
    • Authors: Vanessa Lopes-Rodrigues; Ana Oliveira; Marta Correia-da-Silva; Madalena Pinto; Raquel T. Lima; Emília Sousa; M. Helena Vasconcelos
      Abstract: Publication date: Available online 19 November 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Vanessa Lopes-Rodrigues, Ana Oliveira, Marta Correia-da-Silva, Madalena Pinto, Raquel T. Lima, Emília Sousa, M. Helena Vasconcelos
      Cancer multidrug resistance (MDR) is a major limitation to the success of cancer treatment and is highly associated with the overexpression of drug efflux pumps such as P-glycoprotein (P-gp). In order to achieve more effective chemotherapeutic treatments, it is important to develop P-gp inhibitors to block/decrease its activity. Curcumin (1) is a secondary metabolite isolated from the turmeric of Curcuma longa L.. Diverse biological activities have been identified for this compound, particularly, MDR modulation in various cancer cell models. However, curcumin (1) has low chemical stability, which severely limits its application. In order to improve stability and P-gp inhibitory effect, two potential more stable curcumin derivatives were synthesized as building blocks, followed by several curcumin derivatives. These compounds were then analyzed in terms of antitumor and anti-P-gp activity, in two MDR and sensitive tumour lines (from chronic myeloid leukemia and non-small cell lung cancer). We identified from a series of curcumin derivatives a novel curcumin derivative (1,7-bis(3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)hepta-1,6-diene-3,5-dione, 10) with more potent antitumor and anti-P-gp activity than curcumin (1). This compound (10) was shown to promote cell cycle arrest (at the G2/M phase) and induce apoptosis in the MDR chronic myeloid leukemia cell line. Therefore it is a really interesting P-gp inhibitor due to its ability to inhibit both P-gp function and expression.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.11.023
  • Discovery of 4-sulfamoyl-phenyl-β-lactams as a new class of potent
           carbonic anhydrase isoforms I, II, IV and VII inhibitors: the first
           example of subnanomolar CA IV inhibitors
    • Authors: Srinivas Angapelly; P.V. Sri Ramya; Andrea Angeli; Simona Maria Monti; Martina Buonanno; Mallika Alvala; Cladiu T. Supuran; Mohammed Arifuddin
      Abstract: Publication date: Available online 19 November 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Srinivas Angapelly, P.V. Sri Ramya, Andrea Angeli, Simona Maria Monti, Martina Buonanno, Mallika Alvala, Cladiu T. Supuran, Mohammed Arifuddin
      A series of benzenesulfonamides incorporating 1,3,4-trisubstituted-β-lactam moieties was prepared from sulfanilamide Schiff bases and in situ obtained ketenes, by using the Staudinger cycloaddition reaction. The new compounds were assayed as inhibitors of four human isoforms of the metalloenzyme carbonic anhydrase (hCA, EC involved in various physiological/pathological conditions, hCA I, II, IV and VII. Excellent inhibitory activity was observed against all these isoforms, as follows: hCA I, involved in some eye diseases was inhibited with KIs in the range of 7.3 – 917 nM; hCA II, an antiglaucoma drug target, with KIs in the range of 0.76 – 163 nM. hCA IV, an isoform involved in several pathological conditions such as glaucoma, retinitis pigmentosa and edema was potently inhibited by the lactam-sulfonamides, with KIs in the range of 0.53 – 51.0 nM, whereas hCA VII, a recently validated anti-neuropathic pain target was the most inhibited isoform by these derivatives, with KIs in the range of 0.68 – 9.1 nM. The structure-activity relationship for inhibiting these CAs with the new lactam-sulfonamides is discussed in detail
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.11.027
  • Enhanced potency of bivalent small molecule gp41 inhibitors
    • Authors: Vladimir Sofiyev; Hardeep Kaur; Beth A. Snyder; Priscilla A. Hogan; Roger G. Ptak; Peter Hwang; Miriam Gochin
      Abstract: Publication date: Available online 19 November 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Vladimir Sofiyev, Hardeep Kaur, Beth A. Snyder, Priscilla A. Hogan, Roger G. Ptak, Peter Hwang, Miriam Gochin
      Low molecular weight peptidomimetic inhibitors with hydrophobic pocket binding properties and moderate fusion inhibitory activity against HIV-1 gp41-mediated cell fusion were elaborated by increasing the available surface area for interacting with the heptad repeat-1 (HR1) coiled coil on gp41. Two types of modifications were tested: 1) increasing the overall hydrophobicity of the molecules with an extension that could interact in the HR1 groove, and 2) forming symmetrical dimers with two peptidomimetic motifs that could potentially interact simultaneously in two hydrophobic pockets on the HR1 trimer. The latter approach was more successful, yielding 40 – 60 times improved potency against HIV fusion over the monomers. Biophysical characterization, including equilibrium binding studies by fluorescence and kinetic analysis by Surface Plasmon Resonance, revealed that inhibitor potency was better correlated to off-rates than to binding affinity. Binding and kinetic data could be fit to a model of bidentate interaction of dimers with the HR1 trimer as an explanation for the slow off-rate, albeit with minimal cooperativity due to the highly flexible ligand structures. The strong cooperativity observed in fusion inhibitory activity of the dimers implied accentuated potency due to the transient nature of the targeted intermediate. Optimization of monomer, dimer or higher order structures has the potential to lead to highly potent non-peptide fusion inhibitors by targeting multiple hydrophobic pockets.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.11.010
  • Synthesis and binding monitoring of a new nanomolar PAMAM-based matrix
           metalloproteinases inhibitor (MMPIs)
    • Authors: Linda Cerofolini; Veronica Baldoneschi; Elisa Dragoni; Andrea Storai; Marianna Mamusa; Debora Berti; Marco Fragai; Barbara Richichi; Cristina Nativi
      Abstract: Publication date: Available online 19 November 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Linda Cerofolini, Veronica Baldoneschi, Elisa Dragoni, Andrea Storai, Marianna Mamusa, Debora Berti, Marco Fragai, Barbara Richichi, Cristina Nativi
      Dendrimers are efficient drug delivery systems particularly useful in ocular diseases. In particular, low generation PAMAM dendrimers are non-toxic and non-immunogenic and they provide an enhancement of the residence time of drugs in the eyes. In this context, the synthesis of the PAMAM-based matrix metalloproteinases inhibitor 5, is reported. In particular, we demonstrated that 5 strongly binds (18.0 nM ± 2.5 nM) MMP-9, the most relevant MMP responsible of ocular surface damages in induced dry eyes syndrome (DES).
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.11.028
  • Design, Synthesis and Biological Evaluation of Alkylamino Biphenylamides
           as Hsp90 C-Terminal Inhibitors
    • Authors: Gaurav Garg; Huiping Zhao; Brian S.J. Blagg
      Abstract: Publication date: Available online 19 November 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Gaurav Garg, Huiping Zhao, Brian S.J. Blagg
      Hsp90 is a promising therapeutic target for the development of anti-cancer agents due to its integral role in the stability and function of proteins associated with all ten hallmarks of cancer. Novobiocin, a coumarin antibiotic, was the first natural product identified that targeted the Hsp90 C-terminal domain and manifested anti-proliferative activity (SKBr3 IC50 ∼ 700 μM). Subsequent structural investigations on novobiocin led to analogues with significantly improved anti-proliferative activity against multiple cancer cell lines. In an effort to develop more efficacious and diverse analogues, it was recently found that the coumarin ring of novobiocin could be replaced with the biphenyl core without compromising activity. Based on these prior studies, a series of alkylamino biphenylamides was designed, synthesized and evaluated for anti-proliferative activity against two breast cancer cell lines. SAR studies demonstrated that the incorporation of an alkylamino side chain onto the biphenyl core improved anti-proliferative activity and resulted in compounds that exhibit sub-micromolar to mid-nanomolar activity through Hsp90 inhibition. Importantly, these studies indicate the presence of a hydrophilic region about the central core that can be exploited for the design of new inhibitors.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.11.030
  • Synthesis, antioxidant and antichagasic properties of a selected series of
    • Authors: Natalia Robledo-O’Ryan; Maria João Matos; Saleta Vazquez-Rodriguez; Lourdes Santana; Eugenio Uriarte; Mauricio Moncada-Basualto; Francisco Mura; Michel Lapier; Juan Diego Maya; Claudio Olea-Azar
      Abstract: Publication date: Available online 19 November 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Natalia Robledo-O’Ryan, Maria João Matos, Saleta Vazquez-Rodriguez, Lourdes Santana, Eugenio Uriarte, Mauricio Moncada-Basualto, Francisco Mura, Michel Lapier, Juan Diego Maya, Claudio Olea-Azar
      Oxidative stress is involved in several parasitic diseases such as Chagas. Agents able to selectively modulate biochemical processes involved in the disease represent promising multifunctional agents for the delay or abolishment of the progression of this pathology. In the current work, differently substituted hydroxy-3-arylcoumarins are described, exerting both antioxidant and trypanocidal activity. Among the compounds synthesized, compound 8 showed the most interesting profile, presenting a moderate scavenging ability for peroxyl radicals (ORAC-FL=2.23) and a high degree of selectivity toward epimastigotes stage of the parasite T. cruzi (IC50 = 1.31 μM), higher than Nifurtimox (drug currently used for treatment of Chagas disease). Interestingly, the current study revealed that small structural changes in the hydroxy-3-arylcoumarin core allow modulating both activities, suggesting that this scaffold has desirable properties for the development of promising classes of antichagasic compounds. 2009 Elsevier Ltd. All rights reserved.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.11.033
  • Cyclic citrulinated MBP87-99 peptide stimulates T cell responses:
           implications in triggering disease
    • Authors: Vasso Apostolopoulos; George Deraos; Minos-Timotheos Matsoukas; Stephanie Day; Lily Stojanovska; Theodore Tselios; Maria-Eleni Androutsou; John Matsoukas
      Abstract: Publication date: Available online 19 November 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Vasso Apostolopoulos, George Deraos, Minos-Timotheos Matsoukas, Stephanie Day, Lily Stojanovska, Theodore Tselios, Maria-Eleni Androutsou, John Matsoukas
      Amino acid mutations to agonist peptide epitopes of myelin proteins have been used to modulate immune responses and experimental autoimmune encephalomyelitis (EAE, animal model of multiple sclerosis). Such amino acid alteration are termed, altered peptide ligands (APL). We have shown that the agonist myelin basic protein (MBP) 87-99 epitope (MBP87-99) with crucial T cell receptor (TCR) substitutions at positions 91 and 96 (K91,P96 (TCR contact residues) to R91,A96; [R91,A96]MBP87-99) results in altered T cell responses and inhibits EAE symptoms. In this study, the role of citrulination of arginines in [R91,A96]MBP87-99 peptide analog was determined using in vivo experiments in combination with computational studies. The immunogenicity of linear [Cit91,A96,Cit97]MBP87-99 and its cyclic analog - cyclo(87-99)[Cit91,A96,Cit97]MBP87-99 when conjugated to the carrier mannan (polysaccharide) were studied in SJL/J mice. It was found that mannocylated cyclo(87-99)[Cit91,A96,Cit97]MBP87-99 peptide induced strong T cell proliferative responses and IFN-gamma cytokine secretion compared with the linear one. Moreover, the interaction of linear and cyclic peptide analogs with the major histocompatibility complex (MHC II, H2-IAs) and TCR was analyzed using molecular dynamics simulations at the receptor level, in order to gain a better understanding of the molecular recognition mechanisms that underly the different immunological profiles of citrulinated peptides compared to its agonist native counterpart MBP87-99 epitope. The results demonstrate that the citrulination of arginine in combination with the backbone conformation of mutated linear and cyclic analogs are significant elements for the immune response triggering the induction of pro-inflammatory cytokines.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.11.029
  • Synthesis, Evaluation and Molecular Modelling Studies of
           2-(Carbazol-3-yl)-2-oxoacetamide Analogues as a New Class of Potential
           Pancreatic Lipase Inhibitors
    • Authors: S.N.C. Sridhar; Ginson George; P.O. Venkataramana Reddy; Mukund P. Tantak; Dalip Kumar; Atish T. Paul
      Abstract: Publication date: Available online 18 November 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): S.N.C. Sridhar, Ginson George, P.O. Venkataramana Reddy, Mukund P. Tantak, Dalip Kumar, Atish T. Paul
      A series of twenty-four 2-(carbazol-3-yl)-2-oxoacetamide analogues were synthesized, characterized and evaluated for their PL inhibitory activities. Porcine PL was used against 4-nitrophenyl butyrate and tributyrin as substrates during the PL inhibition assay. Compounds 7e, 7f and 7p exhibited potential PL inhibitory activity (IC50 values of 6.31, 8.72 and 9.58 μM, respectively in method A; and Xi50 of 21.85, 21.94 and 26.2, respectively in method B). Further, inhibition kinetics of 7e, 7f and 7p against PL revealed their competitive nature of inhibition. A comparison of the inhibition profiles of the top three compounds in method B and C, provided a preliminary idea of covalent bonding of the compounds with Ser 152 of PL. Molecular docking studies of the compounds 7a-x into the active site of human PL (PDB ID: 1LPB) was in agreement with the in vitro results, and highlighted probable covalent bond formation with Ser 152 apart from hydrophobic interactions with the lid domain. Molecular dynamics simulation of 7e complexed with PL, further confirmed the role of aromatic groups in stabilising the ligand (RMSD ⩽ 4 Å). The present study led to the identification of 2-(carbazol-3-yl)-2-oxoacetamide analogues 7a-x as a new class of potential PL inhibitors.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.11.031
  • Computer design, synthesis, and bioactivity analyses of drugs like
           Fingolimod used in the treatment of Multiple Sclerosis
    • Authors: Gurbet Çelik Turgut; Doğukan Doyduk; Yılmaz Yıldırır; Serkan Yavuz; Atilla Akdemir; Ali Dişli; Alaaddin Şen
      Abstract: Publication date: Available online 18 November 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Gurbet Çelik Turgut, Doğukan Doyduk, Yılmaz Yıldırır, Serkan Yavuz, Atilla Akdemir, Ali Dişli, Alaaddin Şen
      Multiple Sclerosis (MS) is a very common disease of vital importance. In the MS treatment, some drugs such as fingolimod which help to protect nerves from damage are used. The main goal of the drug therapy in MS is to take control of the inflammation which leads to the destruction of myelin and axons in nerve cell and thus prevent and stop the progression of the disease. Fingolimod (FTY720) is an orally active immunomodulatory drug that has been used for the treatment of relapsing-remitting multiple sclerosis. It is a sphingosine-1-phosphate receptor modulator which prevents lymphocytes from contributing to an autoimmune reaction by inhibiting egress of lymphocytes them from lymph nodes. In this study, we have computer designed, synthesized and characterized two novel derivatives of FTY720, F1-12h and F2-9, and have determined their underlying mechanism of their beneficial effect in SH-SY5Y, SK-N-SH, and U-118MG cell lines. For this purpose, we first determined the regulation of the cAMP response element (CRE) activity and cAMP concentration by F1-12h and F2-9 together with FTY720 using pGL4.29 luciferase reporter assay and cAMP immunoassay, respectively. Then, we have determined their effect on MS- and GPCR-related gene expression profiles using custom arrays along with FTY720 treatment at non-toxic doses (EC10). It was found that both derivatives significantly activate CRE and increase cAMP concentration in all three cell lines, indicating that they activate cAMP pathway through cell surface receptors as FTY720 does. Furthermore, F1-12h and F2-9 modulate the expression of the pathway related genes that are important in inflammatory signaling, cAMP signaling pathway, cell migration as well as diverse receptor and transcription factors. Expression of the genes involved in myelination was also increased by the treatment with F1-12h and F2-9. In summary, our data demonstrate that the two novel FTY720 derivatives act as anti-inflammatory ultimately by influencing the gene expression via the cAMP and downstream transcription factor CRE pathway. In conclusion, F1-12h and F2-9 might contribute future therapies for autoimmune diseases such as multiple sclerosis.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.11.015
  • N-Propargylpiperidines with Naphthalene-2-Carboxamide or
           Naphthalene-2-Sulfonamide Moieties: Potential Multifunctional
           Anti-Alzheimer’s Agents
    • Authors: Urban Košak; Damijan Knez; Nicolas Coquelle; Boris Brus; Anja Pišlar; Florian Nachon; Xavier Brazzolotto; Janko Kos; Jacques-Philippe Colletier; Stanislav Gobec
      Abstract: Publication date: Available online 19 November 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Urban Košak, Damijan Knez, Nicolas Coquelle, Boris Brus, Anja Pišlar, Florian Nachon, Xavier Brazzolotto, Janko Kos, Jacques-Philippe Colletier, Stanislav Gobec
      In the brains of patients with Alzheimer’s disease, the enzymatic activities of butyrycholinesterase (BChE) and monoamine oxidase B (MAO-B) are increased. While BChE is a viable therapeutic target for alleviation of symptoms caused by cholinergic hypofunction, MAO-B is a potential therapeutic target for prevention of neurodegeneration in Alzheimer’s disease. Starting with piperidine-based selective human (h)BChE inhibitors and propargylamine-based MAO inhibitors, we have designed, synthesized and biochemically evaluated a series of N-propargylpiperidines. All of these compounds inhibited hBChE with good selectivity over the related enzyme, acetylcholinesterase, and crossed the blood-brain barrier in a parallel artificial membrane permeation assay. The crystal structure of one of the inhibitors (compound 3) in complex with hBChE revealed its binding mode. Three compounds (4, 5, 6) showed concomitant inhibition of MAO-B. Additionally, the most potent hBChE inhibitor 7 and dual BChE and MAO-B inhibitor 6 were non-cytotoxic and protected neuronal SH-SY5Y cells from toxic amyloid β-peptide species.
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      PubDate: 2016-11-20T00:57:56Z
      DOI: 10.1016/j.bmc.2016.11.032
  • Design and synthesis of purine analogues as highly specific ligands for
           FcyB, a ubiquitous fungal nucleobase transporter
    • Authors: Nikolaos Lougiakis; Efthymios-Spyridon Gavriil; Markelos Kairis; Georgia Sioupouli; George Lambrinidis; Dimitra Benaki; Emilia Krypotou; Emmanuel Mikros; Panagiotis Marakos; Nicole Pouli; George Diallinas
      Abstract: Publication date: Available online 22 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Nikolaos Lougiakis, Efthymios-Spyridon Gavriil, Markelos Kairis, Georgia Sioupouli, George Lambrinidis, Dimitra Benaki, Emilia Krypotou, Emmanuel Mikros, Panagiotis Marakos, Nicole Pouli, George Diallinas
      In the course of our study on fungal purine transporters, a number of new 3-deazapurine analogues have been rationally designed, based on the interaction of purine substrates with the Aspergillus nidulans FcyB carrier, and synthesized following an effective synthetic procedure. Certain derivatives have been found to specifically inhibit FcyB-mediated [3H]-adenine uptake. Molecular simulations have been performed, suggesting that all active compounds interact with FcyB through the formation of hydrogen bonds with Asn163, while the insertion of hydrophobic fragments at position 9 and N6 of 3-deazaadenine enhanced the inhibition.
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      PubDate: 2016-09-24T05:12:28Z
      DOI: 10.1016/j.bmc.2016.09.055
  • Insights into tyrosinase inhibition by compounds isolated from Greyia
           radlkoferi Syzsyl using biological activity, molecular docking and gene
           expression analysis
    • Authors: Namrita Lall; Elizabeth Mogapi; Marco Nuno de Canha; Bridget Crampton; Mabatho Nqephe; Ahmed Hussein; Vivek Kumar
      Abstract: Publication date: Available online 22 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Namrita Lall, Elizabeth Mogapi, Marco Nuno de Canha, Bridget Crampton, Mabatho Nqephe, Ahmed Hussein, Vivek Kumar
      Greyia radlkoferi ethanol extract and its five compounds were tested for their inhibitory activity against the mushroom tyrosinase enzyme and melanin production on melanocytes. The crude extract showed significant tyrosinase inhibition with IC50 of 17.96μg/ml. This is the first report of the isolation of these 5 compounds from Greyia radlkoferi. 2’, 4’, 6’-trihydroxydihydrochalcone showed the highest tyrosinase inhibition at 17.70μg/ml (68.48μM), with low toxicity when compared with crude extract. This compound is therefore, a key component in the crude extract, which is responsible for tyrosinase inhibitory activity. The RT-qPCR indicated that the mechanism of action is most likely post transcriptional. Further, the molecular docking study showed that tyrosinase inhibitory activity depends on interaction of the compound with Cu2+ ions at the active site. This is the first report of the tyrosinase inhibitory activity of the G. radlkoferi extract and molecular insights on interaction of its compounds with Cu2+ ions as the driving factor for tyrosinase inhibition. These results suggest that the extract of G. radlkoferi and the compound 2’, 4’, 6’-trihydroxydihydrochalcone have great potential to be further developed as pharmaceutical or cosmetic agents for use against dermatological disorders associated with melanin.
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      PubDate: 2016-09-24T05:12:28Z
      DOI: 10.1016/j.bmc.2016.09.054
  • Neuroprotective effects of benzyloxy substituted small molecule monoamine
           oxidase B inhibitors in Parkinson’s disease
    • Authors: Zhimin Wang; Jiajia Wu; Xuelian Yang; Pei Cai; Qiaohong Liu; Kelvin D.G. Wang; Lingyi Kong; Xiaobing Wang
      Abstract: Publication date: Available online 21 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Zhimin Wang, Jiajia Wu, Xuelian Yang, Pei Cai, Qiaohong Liu, Kelvin D.G. Wang, Lingyi Kong, Xiaobing Wang
      The benzyloxy substituted small molecules are well-known highly potent monoamine oxidase B inhibitors, but their therapeutic potential against Parkinson’s disease have not been investigated in detail. In this paper, a series of representative benzyloxy substituted derivatives were synthesized and evaluated for MAO-A/B inhibition. In addition, their neuroprotective effects were investigated in 6-OHDA- and rotenone-treated PC12 cells. It was observed that most of the compounds exhibited a marked increase in survival of PC12 cells which treated with the neurotoxins. Among them, 13 exhibited remarkable and balanced neuroprotective potency. The protective effects of 13 against neurotoxins-induced apoptosis were confirmed with flow cytometry and staining methods. Furthermore, 13 also showed good BBB permeability and low toxicity according to in vitro BBB prediction and in vivo acute toxicity test. The results indicated that 13 is an effective and promising candidate to be further developed as disease-modifying drug for Parkinson’s disease therapy.
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      PubDate: 2016-09-24T05:12:28Z
      DOI: 10.1016/j.bmc.2016.09.050
  • Synthesis and Pin1 inhibitory activity of thiazole derivatives
    • Authors: Hailong Zhao; Guonan Cui; Jing Jin; Xiaoguang Chen; Bailing Xu
      Abstract: Publication date: Available online 21 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Hailong Zhao, Guonan Cui, Jing Jin, Xiaoguang Chen, Bailing Xu
      Pin1 (Protein interacting with NIMA1) is a peptidyl prolyl cis-trans isomerase (PPIase) which specifically catalyze the conformational conversion of the amide bond of pSer/Thr-Pro motifs in its subtrate proteins and is a novel promising anticancer target. A series of new thiazole derivatives were designed and synthesized, and their inhibitory activites were measured agaist human Pin1 using a protease-coupled enzyme assay. Of all the tested compounds, a number of thiazole derivatives bearing an oxalic acid group at 4-position were found to be potent Pin1 inhibitors with IC50 values at low micromolar level. The detailed structure–activity relationships were analyzed and the binding features of compound 10b (IC50 5.38 μM) was predicted using CDOCKER program. The results of this research would provide informative guidance for further optimizing thiazole derivatives as potent Pin1 inhibitors.
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      PubDate: 2016-09-24T05:12:28Z
      DOI: 10.1016/j.bmc.2016.09.049
  • Synthesis and Topoisomerases Inhibitory Activity of heteroaromatic
    • Authors: Kyung-Hwa Jeon; Han-Bit Yu; Soo Yeon Kwak; Youngjoo Kwon; Younghwa Na
      Abstract: Publication date: Available online 21 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Kyung-Hwa Jeon, Han-Bit Yu, Soo Yeon Kwak, Youngjoo Kwon, Younghwa Na
      The critical role of nuclear enzyme topoisomerase enzymes during cell proliferation process guided topoisomerases to be one of the major targets for anticancer drug development. We have designed and synthesized 22 heteroaromatic ring incorporated chalcone derivatives substituted with epoxide or thioepoxide. Topoisomerase enzyme inhibitory activity and cytotoxic tests were also conducted to evaluate compounds’ pharmacological efficacy. In the topoisomerase I inhibitory test, compound 1 was most active one, 24% of inhibition at 20 μM, among all the compounds but it was lower than camptothecin. Compounds 9, 11, and 13 inhibited the function of topoisomerase II more strongly than etoposide with almost same magnitude (around 90% and 30% inhibition at 100 and 20 μM, respectively) which were higher than those of etoposide (72% and 18% inhibition). In the cytotoxicity test, compound 9 inhibited T47D cancer cell growth with the IC50 value of 6.61 ± 0.21 μM. On the other hand, compound 13 (IC50: 4.32 ± 0.18 μM) effectively suppressed MDA-MB468 cancer cell growth.
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      PubDate: 2016-09-24T05:12:28Z
      DOI: 10.1016/j.bmc.2016.09.051
  • Synthesis and Biological Evaluation of Furocoumarin Derivatives on Melanin
           Synthesis in Murine B16 Cells for the Treatment of Vitiligo
    • Authors: Chao Niu; Guang Xian Pang; Gen Li; Jun Dou; Li Fei Nie; Helimay Himit; Madina Kabas; Haji Akber Aisa
      Abstract: Publication date: Available online 23 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Chao Niu, Guang Xian Pang, Gen Li, Jun Dou, Li Fei Nie, Helimay Himit, Madina Kabas, Haji Akber Aisa
      Furocoumarins, isolated from Psoralen corylifolia L., were found to be the most effective drug in the treatment of vitiligo nowadays. Twenty-five furocoumarin derivatives were thus designed and synthesized in order to improve the melanogenesis in B16 cells for the first time. Among them, twenty-three compounds were more potent than the positive control (8-MOP), the commonly used drug for vitiligo in clinic. Noticeably, compounds 6m (350.5%) and 6p (313.1%) based on the scaffold of 6k (2H-benzofuro[2,3-h]chromen-2-one) were nearly 3-fold stronger than 8-MOP (114.50%). The in vitro melanin synthesis evaluation of these structurally diverse analogues had also led to an outline of structure-activity relationship.
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      PubDate: 2016-09-24T05:12:28Z
      DOI: 10.1016/j.bmc.2016.09.056
  • Design, Synthesis, and Evaluation of Novel Porcupine Inhibitors Featuring
           a Fused 3-ring System Based on the “Reversed” Amide Scaffold
    • Authors: Zhixiang Xu; Xiangxiang Xu; Ruadhan O’Laoi; Haikuo Ma; Jiyue Zheng; Shuaishuai Chen; Lusong Luo; Zhilin Hu; Sudan He; Jiajun Li; Hongjian Zhang; Xiaohu Zhang
      Abstract: Publication date: Available online 17 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Zhixiang Xu, Xiangxiang Xu, Ruadhan O’Laoi, Haikuo Ma, Jiyue Zheng, Shuaishuai Chen, Lusong Luo, Zhilin Hu, Sudan He, Jiajun Li, Hongjian Zhang, Xiaohu Zhang
      The Wnt signaling pathway is an essential signal transduction pathway which leads to the regulation of cellular processes such as proliferation, differentiation and migration. Aberrant Wnt signaling is known to have an association with multiple cancers. Porcupine is an enzyme that catalyses the addition of palmitoleate to a serine residue in Wnt proteins, a process which is required for the secretion of Wnt proteins. Here we report the synthesis and structure-activity-relationship of the novel porcupine inhibitors based on a “reversed” amide scaffold. The leading compound 53 was as potent as the clinical compound LGK974 in a cell based STF reporter gene assay. Compound 53 potently inhibited the secretion of Wnt3A, therefore was confirmed to be a porcupine inhibitor. Furthermore, compound 53 showed excellent chemical and plasma stabilities. However, the clearance of compound 53 in liver microsomal tests was moderate to high, and the solubility of compound 53 was suboptimal. Collective efforts toward further optimization of this novel tricyclic template to develop better porcupine inhibitors will be subsequently undertaken and reported in due course.
      Graphical abstract image

      PubDate: 2016-09-20T13:35:09Z
      DOI: 10.1016/j.bmc.2016.09.041
  • Investigation of Bombesin peptide as a targeting ligand for the gastrin
           releasing peptide (GRP) receptor
    • Authors: Anjuman Ara Begum; Peter M. Moyle; Istvan Toth
      Abstract: Publication date: Available online 16 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Anjuman Ara Begum, Peter M. Moyle, Istvan Toth
      Gastrin releasing peptide (GRP) receptor (GRPR), a bombesin family receptor, is overexpressed in many cancers including breast, prostate, pancreatic and lung. The targeting of therapeutics to GRPR can be achieved using the full-length (14 amino acid) GRP analogue Bombesin (BBN) or the truncated BBN(6-14) sequence, both of which bind GRPR with high affinity and specificity. In this study, we have investigated the level of GRPR expression in various cancerous (Caco-2, HeLa, LNCap, MDA-MB-231, and PC-3) and non-cancerous (WPMY-1) cell lines using a western blotting approach. Such information is currently lacking in the literature, and is therefore of importance for the in vitro assessment of GRPR targeted therapeutics. Of the cell lines assessed, the PC-3 (prostate cancer) and Caco-2 (colon cancer) cell lines demonstrated the highest and lowest levels of GRPR expression respectively. Using this information, we further investigated the cellular uptake of carboxyfluorescein-labelled BBN and BBN(6-14) peptides by flow cytometry and confocal microscopy using cell lines that express GRPR (Caco-2, HeLa, PC-3). The uptake of each of these peptides was similar, suggesting that the shorter BBN(6-14) peptide is sufficient for GRPR targeting. Further, the uptake of these peptides could be inhibited by competition with unlabelled BBN peptides, suggesting their cellular uptake is GRPR-mediated, while the level of BBN uptake (as measured by flow cytometry) was found to be directly proportional to the level of GRPR expression. Overall, the information obtained from these studies provides useful information for the in vitro assessment of GRPR targeted therapeutics.
      Graphical abstract image

      PubDate: 2016-09-20T13:35:09Z
      DOI: 10.1016/j.bmc.2016.09.039
  • Sobetirome Prodrug Esters with Enhanced Blood-Brain Barrier Permeability
    • Authors: Andrew T. Placzek; Skylar J. Ferrara; Meredith D. Hartley; Hannah S. Sanford-Crane; James M. Meinig; Thomas S. Scanlan
      Abstract: Publication date: Available online 16 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Andrew T. Placzek, Skylar J. Ferrara, Meredith D. Hartley, Hannah S. Sanford-Crane, James M. Meinig, Thomas S. Scanlan
      There is currently great interest in developing drugs that stimulate myelin repair for use in demyelinating diseases such as multiple sclerosis. Thyroid hormone plays a key role in stimulating myelination during development and also controls the expression of important genes involved in myelin repair in adults. Because endogenous thyroid hormone in excess lacks a generally useful therapeutic index, it is not used clinically for indications other than hormone replacement; however, selective thyromimetics such as sobetirome offer a therapeutic alternative. Sobetirome is the only clinical-stage thyromimetic that is known to cross the blood-brain-barrier (BBB) and we endeavored to increase the BBB permeability of sobetirome using a prodrug strategy. Ester prodrugs of sobetirome were prepared based on literature reports of improved BBB permeability with other carboxylic acid containing drugs and BBB permeability was assessed in vivo. One sobetirome prodrug, ethanolamine ester 11, was found to distribute more sobetirome to the brain compared to an equimolar peripheral dose of unmodified sobetirome. In addition to enhanced brain levels, prodrug 11 displayed lower sobetirome blood levels and a brain/serum ratio that was larger than that of unmodified sobetirome. Thus, these data indicate that an ester prodrug strategy applied to sobetirome can deliver increased concentrations of the active drug to the central nervous system (CNS), which may prove useful in the treatment of CNS disorders.
      Graphical abstract image

      PubDate: 2016-09-20T13:35:09Z
      DOI: 10.1016/j.bmc.2016.09.038
  • Design, Synthesis and Biological Evaluation of Potential Antibacterial
    • Authors: Alaa Sweidan; Marylene Chollet-Krugler; Pierre van de Weghe; Ali Chokr; Sophie Tomasi; Martine Bonnaure-Mallet; Latifa Bousarghin
      Abstract: Publication date: Available online 17 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Alaa Sweidan, Marylene Chollet-Krugler, Pierre van de Weghe, Ali Chokr, Sophie Tomasi, Martine Bonnaure-Mallet, Latifa Bousarghin
      Novel butyrolactone analogues were designed and synthesized based on the known lichen antibacterial compounds, lichesterinic acids (B-10 and B-11), by substituting different functional groups on the butyrolactone ring trying to enhance its activity. All synthesized butyrolactone analogues were evaluated for their in vitro antibacterial activity against Streptococcus gordonii. Among the derivatives, B-12 and B-13 had the lowest MIC of 9.38 μg/mL where they have shown to be stronger bactericidals, by 2-3 times, than the reference antibiotic, doxycycline. These two compounds were then checked for their cytotoxicity against human gingival epithelial cell lines, Ca9-22, and macrophages, THP-1, by MTT and LDH assays which confirmed their safety against the tested cell lines. A preliminary study of the structure-activity relationships unveiled that the functional groups at the C4 position had an important influence on the antibacterial activity. An optimum length of the alkyl chain at the C5 position registered the best antibacterial inhibitory activity however as its length increased the bactericidal effect increased as well. This efficiency was attained by a carboxyl group substitution at the C4 position indicating the important dual role contributed by these two substituents which might be involved in their mechanism of action.
      Graphical abstract image

      PubDate: 2016-09-20T13:35:09Z
      DOI: 10.1016/j.bmc.2016.09.040
  • Synthesis and Structure–Activity Relationships of 1-Benzylindane
           Derivatives as Selective Agonists for Estrogen Receptor Beta
    • Authors: Shigeru Yonekubo; Nobuhiko Fushimi; Takashi Miyagi; Osamu Nakanishi; Kenji Katsuno; Motoyasu Ozawa; Chiaki Handa; Noritaka Furuya; Hideyuki Muranaka
      Abstract: Publication date: Available online 20 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Shigeru Yonekubo, Nobuhiko Fushimi, Takashi Miyagi, Osamu Nakanishi, Kenji Katsuno, Motoyasu Ozawa, Chiaki Handa, Noritaka Furuya, Hideyuki Muranaka
      The estrogen receptor beta (ERβ) selective agonist is considered a promising candidate for the treatment of estrogen deficiency symptoms in ERβ-expressing tissues, without the risk of breast cancer, and multiple classes of compounds have been reported as ERβ selective agonists. Among them, 6-6 bicyclic ring-containing structures (e.g., isoflavone phytoestrogens) are regarded as one of the cyclized analogues of isobutestrol 5b, and suggest that other cyclized scaffolds comprising 5-6 bicyclic rings could also act as selective ERβ ligands. In this study, we evaluated the selective ERβ agonistic activity of 1-(4-hydroxybenzyl)indan-5-ol 7a and studied structure–activity relationship (SAR) of its derivatives. Some functional groups improved the properties of 7a; introduction of a nitrile group on the indane-1-position resulted in higher selectivity for ERβ (12a), and further substitution with a fluoro or a methyl group to the pendant phenyl ring was also preferable (12b, d, and e). Subsequent chiral resolution of 12a identified that R -12a has a superior profile over S -12a. This is comparable to diarylpropionitrile (DPN) 5c, one of the promising selective ERβ agonists and indicates that this indane-based scaffold has the potential to provide better ERβ agonistic probes.
      Graphical abstract image

      PubDate: 2016-09-20T13:35:09Z
      DOI: 10.1016/j.bmc.2016.09.047
  • Design, synthesis and evaluation of anti-CD123 antibody drug conjugates
    • Authors: Bin Li; Weiyu Zhao; Xinfu Zhang; Junfeng Wang; Xiao Luo; Sharyn D. Baker; Craig T. Jordan; Yizhou Dong
      Abstract: Publication date: Available online 17 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Bin Li, Weiyu Zhao, Xinfu Zhang, Junfeng Wang, Xiao Luo, Sharyn D. Baker, Craig T. Jordan, Yizhou Dong
      Leukemia stem cells (LSCs) account for the development of drug resistance and increased recurrence rate in acute myeloid leukemia (AML) patients. Targeted drug delivery to leukemia stem cells remains a major challenge in AML chemotherapy. Overexpressed interleukin-3 receptor alpha chain, CD123, on the surface of leukemia stem cells was reported to be a potential target in AML treatment. Here, we designed and developed an antibody drug conjugate by integrating anti-CD123 antibody with a chemotherapeutic agent, Camptothecin (CPT), via a disulfide linker (CD123-CPT). The linker is biodegradable in the presence of Glutathione (GSH, a endogenous component in cells), which leads to release of CPT. Anti-CD123 antibody conjugates showed significant higher cellular uptake in CD123-overexpressed tumor cells. More importantly, CD123-CPT demonstrated potent inhibitory effects on CD123-overexpressed tumor cells. Consequently, these results provide a promising targeted chemotherapeutical strategy for AML treatment.
      Graphical abstract image

      PubDate: 2016-09-20T13:35:09Z
      DOI: 10.1016/j.bmc.2016.09.043
  • A facile stereoselective synthesis of dispiro-indeno
           pyrrolidine/pyrrolothiazole-thiochroman hybrids and evaluation of their
           antimycobacterial, anticancer and AchE inhibitory activities
    • Authors: Chelliah Bharkavi Sundaravel Vivek Kumar Mohamed Ashraf Ali Hasnah Osman
      Abstract: Publication date: Available online 19 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Chelliah Bharkavi, Sundaravel Vivek Kumar, Mohamed Ashraf Ali, Hasnah Osman, Shanmugam Muthusubramanian, Subbu Perumal
      A facile stereoselective synthesis of novel dispiro indeno pyrrolidine/pyrrolothiazole-thiochroman hybrids has been achieved by 1,3-dipolar cycloaddition of azomethine ylides, generated in situ from ninhydrin and sarcosine/thiaproline, on a series of 3-benzylidenethiochroman-4-ones. The synthesised compounds were screened for their antimycobacterial, anticancer and AchE inhibition activities. Compound 4l (IC50 1.07 μM) has been found to exhibit the most potent antimycobacterial activity compared to cycloserine (12 times), pyrimethamine (37 times) and ethambutol (IC50 < 1.56 μM) and 6l (IC50 = 2.87 μM) is more active than both cycloserine (4 times) and pyrimethamine (12 times). Three compounds, 4a, 6b and 6i, display good anticancer activity against CCRF-CEM cell lines. Compounds 6g and 4g display maximum AchE inhibitory activity with IC50 values of 1.10 and 1.16 μmol/L respectively.
      Graphical abstract image

      PubDate: 2016-09-20T13:35:09Z
  • Synthesis and antimicrobial activity of small cationic amphipathic
           aminobenzamide marine natural product mimics and evaluation of relevance
           against clinical isolates including ESBL-CARBA multi-resistant bacteria
    • Authors: Elizaveta M. Igumnova; Ekaterina Mishchenko; Tor Haug; Hans-Matti Blencke; Johanna U. Ericson Sollid; Elizabeth G. Aarag Fredheim; Silje Lauksund; Klara Stensvåg; Morten B. Strøm
      Abstract: Publication date: Available online 20 September 2016
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Elizaveta M. Igumnova, Ekaterina Mishchenko, Tor Haug, Hans-Matti Blencke, Johanna U. Ericson Sollid, Elizabeth G. Aarag Fredheim, Silje Lauksund, Klara Stensvåg, Morten B. Strøm
      A library of small aminobenzamide derivatives was synthesised to explore a cationic amphipathic motif found in marine natural antimicrobials. The most potent compound E23 displayed minimal inhibitory concentrations (MICs) of 0.5 – 2 μg/ml against several Gram-positive bacterial strains, including methicillin resistant Staphylococcus epidermidis (MRSE). E23 was also potent against 275 clinical isolates including Staphylococcus aureus, Enterococcus spp., Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae, as well as methicillin-resistant S. aureus (MRSA), vancomycin-resistant enterococci (VRE), and ESBL-CARBA multi-resistant Gram-negative bacteria. The study demonstrates how structural motifs found in marine natural antimicrobials can be a valuable source for making novel antimicrobial lead-compounds.
      Graphical abstract image

      PubDate: 2016-09-20T13:35:09Z
      DOI: 10.1016/j.bmc.2016.09.046
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