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  Subjects -> CHEMISTRY (Total: 814 journals)
    - ANALYTICAL CHEMISTRY (49 journals)
    - CHEMISTRY (566 journals)
    - CRYSTALLOGRAPHY (22 journals)
    - ELECTROCHEMISTRY (25 journals)
    - INORGANIC CHEMISTRY (41 journals)
    - ORGANIC CHEMISTRY (46 journals)
    - PHYSICAL CHEMISTRY (65 journals)

CHEMISTRY (566 journals)                  1 2 3 4 5 6 | Last

2D Materials     Hybrid Journal   (Followers: 4)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 31)
ACS Catalysis     Full-text available via subscription   (Followers: 25)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 13)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 8)
ACS Macro Letters     Full-text available via subscription   (Followers: 20)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 25)
ACS Nano     Full-text available via subscription   (Followers: 355)
ACS Photonics     Full-text available via subscription   (Followers: 6)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 9)
Acta Chemica Iasi     Open Access  
Acta Chimica Sinica     Full-text available via subscription  
Acta Chimica Slovaca     Open Access   (Followers: 6)
Acta Chromatographica     Full-text available via subscription   (Followers: 10)
Acta Facultatis Medicae Naissensis     Open Access   (Followers: 1)
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 5)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 4)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 5)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 10)
Advanced Functional Materials     Hybrid Journal   (Followers: 38)
Advances in Chemical Engineering and Science     Open Access   (Followers: 23)
Advances in Chemical Science     Open Access   (Followers: 9)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 15)
Advances in Drug Research     Full-text available via subscription   (Followers: 18)
Advances in Enzyme Research     Open Access  
Advances in Fluorine Science     Full-text available via subscription   (Followers: 7)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 13)
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: 9)
Advances in Polymer Science     Hybrid Journal   (Followers: 39)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 10)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 4)
African Journal of Chemical Education     Open Access   (Followers: 1)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 5)
Afrique Science : Revue Internationale des Sciences et Technologie     Open Access   (Followers: 1)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 1)
Alchemy     Open Access   (Followers: 3)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 4)
AMB Express     Open Access  
American Journal of Applied Sciences     Open Access   (Followers: 31)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 213)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 12)
American Journal of Chemistry     Open Access   (Followers: 18)
American Journal of Plant Physiology     Open Access   (Followers: 10)
American Mineralogist     Full-text available via subscription   (Followers: 7)
Analyst     Full-text available via subscription   (Followers: 36)
Angewandte Chemie     Hybrid Journal   (Followers: 18)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 273)
Annales UMCS, Chemia     Open Access   (Followers: 2)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 1)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 2)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 4)
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: 11)
Anti-Infective Agents     Hybrid Journal   (Followers: 1)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 4)
Applied Spectroscopy     Full-text available via subscription   (Followers: 12)
Applied Surface Science     Hybrid Journal   (Followers: 20)
Arabian Journal of Chemistry     Full-text available via subscription   (Followers: 6)
ARKIVOC     Open Access   (Followers: 1)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 4)
Autophagy     Full-text available via subscription   (Followers: 1)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 6)
Biochemistry     Full-text available via subscription   (Followers: 261)
Biochemistry Insights     Open Access   (Followers: 4)
Biochemistry Research International     Open Access   (Followers: 4)
BioChip Journal     Hybrid Journal   (Followers: 1)
Bioinorganic Chemistry and Applications     Open Access   (Followers: 4)
Bioinspired Materials     Open Access  
Biointerface Research in Applied Chemistry     Open Access   (Followers: 1)
Biointerphases     Open Access  
Biomacromolecules     Full-text available via subscription   (Followers: 17)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 5)
Biomedical Chromatography     Hybrid Journal   (Followers: 7)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 2)
BioNanoScience     Partially Free   (Followers: 4)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 30)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 24)
Bioorganic Chemistry     Hybrid Journal   (Followers: 5)
Biopolymers     Hybrid Journal   (Followers: 14)
Biosensors     Open Access   (Followers: 3)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 1)
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 1)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 13)
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 3)
Canadian Journal of Chemistry     Full-text available via subscription   (Followers: 6)
Canadian Mineralogist     Full-text available via subscription   (Followers: 1)
Carbohydrate Research     Hybrid Journal   (Followers: 11)
Carbon     Hybrid Journal   (Followers: 55)
Catalysis for Sustainable Energy     Open Access   (Followers: 2)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 6)
Catalysis Science and Technology     Free   (Followers: 4)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 4)
Catalysts     Open Access   (Followers: 7)

        1 2 3 4 5 6 | Last

Journal Cover   Bioorganic & Medicinal Chemistry
  [32 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0968-0896
   Published by Elsevier Homepage  [2589 journals]
  • The use of a conformational cathepsin D-derived epitope for vaccine
           development against Schistosoma mansoni
    • Abstract: Publication date: 15 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 6
      Author(s): Abdullah A.H. Ahmad Fuaad , Romain Roubille , Mark S. Pearson , Darren A. Pickering , Alex C. Loukas , Mariusz Skwarczynski , Istvan Toth
      Schistosomiasis is caused by the infection from Schistosoma species. Among these, Schistosoma mansoni is one of the major species that infects millions of people worldwide. The use of praziquantel is effective in clearing the infestation but treatment of a large and widespread population in endemic areas is unsustainable. Thus, synergistic approach of using drug and vaccination can serve as an alternative to the current treatment. In this study, we have developed vaccine candidates that composed of three components: a B-cell epitope derived from S. mansoni cathepsin D protein (Sm-CatD) flanked by GCN4 helix promoting peptide; a promiscuous T-helper epitope (P25); and a lipid core peptide system, in attempt to develop self-adjuvanting vaccine candidates against the schistosome. Physicochemical properties of the vaccine candidates were analysed and antibodies to each construct were raised in BALB/c mice. The vaccine candidates were able to self-assemble into particles that induced high titres of IgG without the use of additional adjuvant. The antibody levels were comparable to that induced by peptide formulated with strong but toxic Freund’s adjuvant. The integration of a GCN4 sequence induced the helical conformation of the epitope, while the addition of the T helper peptide was very effective in inducing consistent IgG-specific antibodies response amongst mice. These findings are particularly encouraging for the development of efficient and immunogenic vaccine against schistosomiasis.
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      PubDate: 2015-02-27T08:28:43Z
       
  • Design, synthesis and SAR studies of GABA uptake inhibitors derived from
           2-substituted pyrrolidine-2-yl-acetic acids
    • Abstract: Publication date: 15 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 6
      Author(s): Tobias Steffan , Thejavathi Renukappa-Gutke , Georg Höfner , Klaus T. Wanner
      In this paper, we disclose the design and synthesis of a series of 2-substituted pyrrolidine-2-yl-acetic acid as core structures and the N-arylalkyl derivatives thereof as potential GABA transport inhibitors. The 2-position in the side chain of pyrrolidine-2-yl-acetic acid derivatives was substituted with alkyl, hydroxy and amino groups to modulate the activity and selectivity to mGAT1 and mGAT4 proteins. SAR studies of the compounds performed for the four mouse GABA transporter proteins (mGAT1–mGAT4) implied significant potencies and subtype selectivities for 2-hydroxy-2-pyrrolidine-2-yl-acetic acid derivatives. The racemate rac-(u)-13c exhibited the highest potency (pIC50 5.67) at and selectivity for mGAT1 in GABA uptake assays. In fact, the potency of rac-(u)-13c at hGAT-1 (pIC50 6.14) was even higher than its potency at mGAT1. These uptake results for rac-(u)-13c are in line with the binding affinities to the aforesaid proteins mGAT1 (pK i 6.99) and hGAT-1 (pK i 7.18) determined by MS Binding Assay based on NO711 as marker quantified by LC–ESI-MS–MS analysis. Interestingly, the 2-hydroxy-2-pyrrolidine-2-yl-acetic acid rac-(u)-13d containing 2-{[tris(4-methoxyphenyl)]methoxy} ethyl group at the nitrogen atom of the pyrrolidine ring showed high potency at mGAT4 and a comparatively better selectivity for this protein (>15 against mGAT3) than the well known mGAT4 uptake inhibitor (S)-SNAP-5114.
      Graphical abstract image

      PubDate: 2015-02-27T08:28:43Z
       
  • Synthesis of dansyl-labeled probe of thiophene analogue of annonaceous
           acetogenins for visualization of cell distribution and growth inhibitory
           activity toward human cancer cell lines
    • Abstract: Publication date: 15 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 6
      Author(s): Naoto Kojima , Yuki Suga , Takuya Matsumoto , Tetsuaki Tanaka , Akinobu Akatsuka , Takao Yamori , Shingo Dan , Hiroki Iwasaki , Masayuki Yamashita
      The convergent synthesis of the dansyl-labeled probe of the thiophene-3-carboxamide analogue of annonaceous acetogenins, which shows potent antitumor activity, was accomplished by two asymmetric alkynylations of the 2,5-diformyl THF equivalent with an alkyne having a thiophene moiety and another alkyne tagged with a dansyl group. The growth inhibitory profiles toward 39 human cancer cell lines revealed that the probe retained the biological function of its mother compound, and would be useful for studying cellular activity.
      Graphical abstract image

      PubDate: 2015-02-27T08:28:43Z
       
  • Discovery and in vitro and in vivo profiles of
           N-ethyl-N-[2-[3-(5-fluoro-2-pyridinyl)-1H-pyrazol-1-yl]ethyl]-2-(2H-1,2,3-triazol-2-yl)-benzamide
           as a novel class of dual orexin receptor antagonist
    • Abstract: Publication date: 15 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 6
      Author(s): Ryo Suzuki , Dai Nozawa , Aya Futamura , Rie Nishikawa-Shimono , Masahito Abe , Nobutaka Hattori , Hiroshi Ohta , Yuko Araki , Daiji Kambe , Mari Ohmichi , Seiken Tokura , Takeshi Aoki , Norikazu Ohtake , Hiroshi Kawamoto
      Orexins play an important role in sleep/wake regulation, and orexin receptor antagonists are a focus of novel therapy for the treatment of insomnia. We identified 27e (TASP0428980) as a potent dual orexin receptor antagonist through the systematic modification of our original designed lead A. We demonstrated the potent sleep-promoting effects of 27e at ip dose of 3mg/kg in a rat polysomnogram study. 27e exhibited relatively short half-life profiles in rats and dogs. Furthermore, accumulating evidence regarding ADME profiles indicates that the predicted human half-life of 27e should be 1.2–1.4h. These data indicated that 27e has a short-acting hypnotic property, suggesting that 27e might be useful for treating primary insomnia while exhibiting a low risk of next-day residual somnolence. Thus, 27e and its related compounds should be further evaluated to enable advancement to clinical trials.
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      PubDate: 2015-02-27T08:28:43Z
       
  • Synthesis and biological activity of novel mono-indole and mono-benzofuran
           inhibitors of bacterial transcription initiation complex formation
    • Abstract: Publication date: Available online 25 February 2015
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Marcin Mielczarek , Ruth V. Thomas , Cong Ma , Hakan Kandemir , Xiao Yang , Mohan Bhadbhade , David StC. Black , Renate Griffith , Peter J. Lewis , Naresh Kumar
      Our ongoing research focused on targeting transcription initiation in bacteria has resulted in synthesis of several classes of mono-indole and mono-benzofuran inhibitors that targeted the essential protein-protein interaction between RNA polymerase core and σ 70/σ A factors in bacteria. In this study, the reaction of indole-2-, indole-3-, indole-7- and benzofuran-2-glyoxyloyl chlorides with amines and hydrazines afforded a variety of glyoxyloylamides and glyoxyloylhydrazides. Similarly, condensation of 2- and 7-trichloroacetylindoles with amines and hydrazines delivered amides and hydrazides. The novel molecules were found to inhibit the RNA polymerase-σ 70/σ A interaction as measured by ELISA, and also inhibited the growth of both Gram-positive and Gram-negative bacteria in culture. Structure-activity relationship (SAR) studies of the mono-indole and mono-benzofuran inhibitors suggested that the hydrophilic-hydrophobic balance is an important determinant of biological activity.
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      PubDate: 2015-02-27T08:28:43Z
       
  • Synthesis, structure–activity relationships, and anticonvulsant
           activities of 2-amino-4H-pyrido[3,2-e][1,3]thiazin-4-one derivatives as
           orally active AMPA receptor antagonists
    • Abstract: Publication date: Available online 25 February 2015
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Hiroshi Inami , Jun-ichi Shishikura , Tomoyuki Yasunaga , Kazushige Ohno , Hiroshi Yamashita , Kota Kato , Shuichi Sakamoto
      As part of a program aimed at discovering orally active 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonists, we screened our compound library and identified 2-[allyl(4-methylphenyl)amino]-4H-pyrido[3,2-e][1,3]thiazin-4-one (7) as a lead compound that inhibited kainate-induced neurotoxicity mediated by AMPA receptors in rat hippocampal cultures. Structure–activity relationship studies of a series of 2-amino-4H-pyrido[3,2-e][1,3]thiazin-4-one derivatives revealed that substituents on the phenyl ring attached to the 2-amino group and the 4H-pyrido[3,2-e][1,3]thiazin-4-one ring system play an important role in inhibitory activity against kainate-induced neurotoxicity. Several analogs bearing a phenyl group with a 4-substituent or five- or six-membered ring fused at the 3,4-positions exhibited potent inhibitory activity against kainate-induced neurotoxicity. Further, some of these compounds exhibited significant suppression of maximal electroshock seizure in mice following oral administration. Of these compounds, 2-[(4-chlorophenyl)(methyl)amino]-4H-pyrido[3,2-e][1,3]thiazin-4-one (16i) (YM928) demonstrated the most potent inhibitory effect with an ED50 value of 7.4 mg/kg.
      Graphical abstract image

      PubDate: 2015-02-27T08:28:43Z
       
  • Design, synthesis, and structure-activity relationships of
           1-ethylpyrazole-3-carboxamide compounds as novel hypoxia-inducible factor
           (HIF)-1 inhibitors
    • Abstract: Publication date: Available online 25 February 2015
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Yorinobu Yasuda , Takeaki Arakawa , Yumi Nawata , Sayaka Shimada , Shinya Oishi , Nobutaka Fujii , Shinichi Nishimura , Akira Hattori , Hideaki Kakeya
      Hypoxia-inducible factor (HIF)-1 is well known as a promising target for cancer chemotherapy. By screening an in-house chemical library using a hypoxia-responsive luciferase reporter gene assay, we identified CLB-016 (1) containing 1-ethylpyrazole-3-carboxamide as a HIF-1 inhibitor (IC50 = 19.1 μM). In a subsequent extensive structure-activity relationship (SAR) study, we developed compound 11Ae with an IC50 value of 8.1 μM against HIF-1-driven luciferase activity. Compounds 1 and 11Ae were shown to significantly suppress the HIF-1-mediated hypoxia response, including carbonic anhydrase IX (CAIX) gene expression and migration of human sarcoma HT1080 cells. These results revealed 1-ethylpyrazole-3-carboxamide as a novel scaffold to develop promising anti-cancer drugs targeting the HIF-1 signaling pathway.
      Graphical abstract image

      PubDate: 2015-02-27T08:28:43Z
       
  • Strategies to make Protein Serine/Threonine (PP1, Calcineurin) and
           Tyrosine Phosphatases (PTP1B) druggable: achieving specificity by
           targeting substrate and regulatory protein interaction sites
    • Abstract: Publication date: Available online 26 February 2015
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Wolfgang Peti , Rebecca Page
      The established dogma is that protein Serine/Threonine (PSPs) and Tyrosine (PTPs) Phosphatases are unattainable drug targets. This is because natural product inhibitors of PSP active sites are lethal, while the active sites of PTPs are exceptionally conserved and charged, making it nearly impossible to develop PTP inhibitors that are selective. However, due to a series of recent structural and functional studies, this view of phosphatases is about to undergo a radical change. Rather than target active sites, these studies have demonstrated that targeting PSP/PTP protein (substrate/regulatory) interaction sites, which are distal from the active sites, are highly viable and suitable drugs targets. This is especially true for Calcineurin (CN), in which the blockbuster immunosuppressant drugs FK506 and cyclosporine A were recently demonstrated to bind and block one of the key CN substrate interaction sites, the LxVP site. Additional studies show that this approach—targeting substrate and/or regulatory protein interaction sites—also holds incredible promise for protein phosphatase 1 (PP1)-related diseases. Finally, domains outside PTP catalytic domains have also recently been demonstrated to directly alter PTP activity. Collectively, these novel insights offer new, transformative perspectives for the therapeutic targeting of PSPs by interfering with the binding of PIPs or substrates and PTPs by targeting allosteric sites outside their catalytic domains.
      Graphical abstract image

      PubDate: 2015-02-27T08:28:43Z
       
  • Development of a time-resolved fluorescence probe for evaluation of
           competitive binding to the cholecystokinin 2 receptor
    • Abstract: Publication date: Available online 26 February 2015
      Source:Bioorganic & Medicinal Chemistry
      Author(s): N.G.R. Dayan Elshan , Thanuja Jayasundera , Craig S. Weber , Ronald M. Lynch , Eugene A. Mash
      The synthesis, characterization, and use of Eu-DTPA-PEGO-Trp-Nle-Asp-Phe-NH2 (Eu-DTPA-PEGO-CCK4), a luminescent probe targeted to cholecystokinin 2 receptor (CCK2R, aka CCKBR), are described. The probe was prepared by solid phase synthesis. A K d value of 17 ± 2 nM was determined by means of saturation binding assays using HEK-293 cells that overexpress CCK2R. The probe was then used in competitive binding assays against Ac-CCK4 and three new trivalent CCK4 compounds. Repeatable and reproducible binding assay results were obtained. Given its ease of synthesis, purification, receptor binding properties, and utility in competitive binding assays, Eu-DTPA-PEGO-CCK4 could become a standard tool for high-throughput screening of compounds in development targeted to cholecystokinin receptors.
      Graphical abstract image

      PubDate: 2015-02-27T08:28:43Z
       
  • Synthesis and biological evaluation of 3-phenyl-3-aryl carboxamido
           propanoic acid derivatives as small molecule inhibitors of retinoic acid
           4-hydroxylase (CYP26A1)
    • Abstract: Publication date: 15 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 6
      Author(s): Dongmei Zhao , Bin Sun , Jinhong Ren , Fengrong Li , Shuai Song , Xuejiao Lv , Chenzhou Hao , Maosheng Cheng
      All-trans-retinoic acid (ATRA), the biologically active metabolite of vitamin A, is used medicinally for the treatment of hyperproliferative diseases and cancers. However, it is easily metabolized. In this study, the leading compound S8 was found based on virtual screening. To improve the activity of the leading compound S8, a series of novel S8 derivatives were designed, synthesized and evaluated for their in vitro biological activities. All of the prepared compounds showed that substituting the 5-chloro-3-methyl-1-phenyl-1H-pyrazole group for the 2-tertbutyl-5-methylfuran scaffold led to a clear increase in the biological activity. The most promising compound 32, with a CYP26A1 IC50 value of 1.36μM (compared to liarozole (IC50 =2.45μM) and S8 (IC50 =3.21μM)) displayed strong inhibitory and differentiation activity against HL60 cells. In addition, the study focused on the effect of β-phenylalanine, which forms the coordination bond with the heme of CYP26A1. These studies suggest that the compound 32 can be used as an appropriate candidate for future development.
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      PubDate: 2015-02-27T08:28:43Z
       
  • Design, synthesis and evaluation of XZH-5 analogues as STAT3 inhibitors
    • Abstract: Publication date: 15 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 6
      Author(s): Philias Daka , Aiguo Liu , Chamini Karunaratne , Erika Csatary , Cameron Williams , Hui Xiao , Jiayuh Lin , Zhenghu Xu , Richard C. Page , Hong Wang
      Inhibition of the signaling pathways of signal transducer and activator of transcription 3 (STAT 3) has shown to be a promising strategy to combat cancer. In this paper we report the design, synthesis and evaluation of a novel class of small molecule inhibitors, that is, XZH-5 and its analogues, as promising leads for further development of STAT3 inhibitors. Preliminary SARs was established for XZH-5 and its derivatives; and the binding modes were predicted by molecular docking. Lead compounds with IC50 as low as 6.5μM in breast cancer cell lines and 7.6μM in pancreatic cancer cell lines were identified.
      Graphical abstract image

      PubDate: 2015-02-27T08:28:43Z
       
  • Spectral and biological evaluation of a synthetic antimicrobial peptide
           derived from 1-aminocyclohexane carboxylic acid
    • Abstract: Publication date: 15 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 6
      Author(s): J.J. Abercrombie , Kai P. Leung , Hanbo Chai , Rickey P. Hicks
      Ac-GF(A6c)G(A6c)K(A6c)G(A6c)F(A6c)G(A6c)GK(A6c)KKKK-amide (A6c=1-aminocyclohexane carboxylic acid) is a synthetic antimicrobial peptide (AMP) that exhibits in vitro inhibitory activity against drug resistant strains of Staphylococcus aureus, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter aerogenes, and Enterococcus faecium at concentrations ranging from 10.9 to 43μM. Spectroscopic investigations were conducted to determine how this AMP interacts with simple membrane model systems in order to provide insight into possible mechanisms of action. CD and 2D-1H NMR experiments indicated this AMP on binding to SDS and DPC micelles adopts conformations with varying percentages of helical and random coil conformers. CD investigations in the presence of three phospholipid SUVs consisting of POPC, 4:1 POPC/POPG, and 60% POPE/21%POPG/19%POPC revealed: (1) The interactions occurring with POPC SUVs have minimal effect on the conformational diversity of the AMP yielding conformations similar to those observed in buffer. (2) The interactions with 4:1 POPC/POPG, and 60% POPE/21%POPG/19%POPC SUVs exhibited a greater influence on the percentage of different conformers contributing to the CD spectra. (3) The presence of a high of percentage of helical conformers was not observed in the presence of SUVs as was the case with micelles. This data indicates that the diversity of surface bound conformations adopted by this AMP are very different from the diversity of conformations adopted by this AMP on insertion into the lipid bilayer. CD spectra of this AMP in the presence of SUVs consisting of LPS isolated from P. aeruginosa, K. pneumoniae and Escherichia coli exhibited characteristics associated with various helical conformations.
      Graphical abstract image

      PubDate: 2015-02-27T08:28:43Z
       
  • Design, synthesis, and biological evaluation of a series of bifunctional
           ligands of opioids/SSRIs
    • Abstract: Publication date: 15 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 6
      Author(s): Mehr-un-Nisa , Munawar A. Munawar , Yeon Sun Lee , David Rankin , Jawaria Munir , Josephine Lai , Misbahul A. Khan , Victor J. Hruby
      A series of opioid and serotonin re-uptake inhibitors (SSRIs) bifunctional ligands have been designed, synthesized, and tested for their activities and efficacies at μ-, δ- and κ opioid receptors and SSRIs receptors. Most of the compounds showed high affinities for μ- and δ-opioid receptors and lower affinities for SSRIs and κ opioid receptors. A docking study on the μ-opioid receptor binding pocket has been carried out for ligands 3–11. The ligands 7 and 11 have displayed the highest binding profiles for the μ-opioid receptor binding site with ΔG bind (−12.14kcal/mol) and K i value (1.0nM), and ΔG bind (−12.41kcal/mol) and K i value (0.4nM), respectively. Ligand 3 was shown to have the potential of dual acting serotonin/norepinephrine re-uptake inhibitor (SNRI) antidepressant activity in addition to opioid activities, and thus could be used for the design of multifunctional ligands in the area of a novel approach for the treatment of pain and depression.
      Graphical abstract image

      PubDate: 2015-02-27T08:28:43Z
       
  • Bis-3-chloropiperidines containing bridging lysine linkers: Influence of
           side chain structure on DNA alkylating activity
    • Abstract: Publication date: 15 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 6
      Author(s): Ivonne Zuravka , Rolf Roesmann , Alice Sosic , Richard Göttlich , Barbara Gatto
      A series of bis-3-chloropiperidines containing lysine linkers was synthesised as DNA alkylating model compounds by using a bidirectional synthetic strategy. These novel piperidine mustard based agents have been evaluated for their alkylating properties towards nucleic acids and were shown to alkylate and cleave DNA with strong preference for guanine residues. Our studies reveal that the introduction of aromatic groups in the side chain of the lysine linker has an impact on DNA alkylating activity. Analysis by ESI mass spectrometry enabled the verification of the reactive aziridinium ion formation. Overall, the results confirm our recently proposed reaction mechanism of bis-3-chloropiperidines.
      Graphical abstract image

      PubDate: 2015-02-27T08:28:43Z
       
  • 6,7-Dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives as
           selective inhibitors of PI3Kα
    • Abstract: Publication date: 15 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 6
      Author(s): Yong Yin , Yan-Qing Zhang , Biao Jin , Shao Sha , Xun Wu , Chetan B. Sangani , She-Feng Wang , Fang Qiao , Ai-Min Lu , Peng-Cheng Lv , Hai-Liang Zhu
      Twenty eight 6,7-dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives were synthesized and evaluated their biological activities as PI3K inhibitors. Biological evaluation against four human tumor cell lines revealed that most target compounds showed impressively better antiproliferative activities than that of LY294002. Among these compounds, compound 25 exhibited the most potent and selective activity for PI3Kα, with the IC50 value of 0.016μM, an approximately 30-fold increase in comparison with LY294002, it also has an increased potency of approximately 11-fold for PI3Kβ. It indicated the potential of developing 6,7-dihydrobenzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine derivatives as the new PI3Kα selective inhibitors for tumor treatment.
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      PubDate: 2015-02-27T08:28:43Z
       
  • QSAR model as a random event: A case of rat toxicity
    • Abstract: Publication date: 15 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 6
      Author(s): Alla P. Toropova , Andrey A. Toropov , Emilio Benfenati , Danuta Leszczynska , Jerzy Leszczynski
      Quantitative structure—property/activity relationships (QSPRs/QSARs) can be used to predict physicochemical and/or biochemical behavior of substances which were not studied experimentally. Typically predicted values for chemicals in the training set are accurate since they were used to build the model. QSPR/QSAR models must be validated before they are used in practice. Unfortunately, the majority of the suggested approaches of the validation of QSPR/QSAR models are based on consideration of geometrical features of clusters of data points in the plot of experimental versus calculated values of an endpoint. We believe these geometrical criteria can be more useful if they are analyzed for several splits into the training and test sets. In this way, one can estimate the reproducibility of the model with various splits and better evaluate model reliability. The probability of the correct prediction of an endpoint for external validation set (in the series of the above-mentioned splits) can provide an useful way to evaluate the domain of applicability of the model.
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      PubDate: 2015-02-27T08:28:43Z
       
  • 3-Oxoisoxazole-2(3H)-carboxamides and isoxazol-3-yl carbamates:
           Resistance-breaking acetylcholinesterase inhibitors targeting the malaria
           mosquito, Anopheles gambiae
    • Abstract: Publication date: 15 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 6
      Author(s): Astha Verma , Dawn M. Wong , Rafique Islam , Fan Tong , Maryam Ghavami , James M. Mutunga , Carla Slebodnick , Jianyong Li , Elisabet Viayna , Polo C.-H. Lam , Maxim M. Totrov , Jeffrey R. Bloomquist , Paul R. Carlier
      To identify potential selective and resistance-breaking mosquitocides against the African malaria vector Anopheles gambiae, we investigated the acetylcholinesterase (AChE) inhibitory and mosquitocidal properties of isoxazol-3-yl dimethylcarbamates (15), and the corresponding 3-oxoisoxazole-2(3H)-dimethylcarboxamide isomers (14). In both series, compounds were found with excellent contact toxicity to wild-type susceptible (G3) strain and multiply resistant (Akron) strain mosquitoes that carry the G119S resistance mutation of AChE. Compounds possessing good to excellent toxicity to Akron strain mosquitoes inhibit the G119S mutant of An. gambiae AChE (AgAChE) with k i values at least 10- to 600-fold higher than that of propoxur, a compound that does not kill Akron mosquitoes at the highest concentration tested. On average, inactivation of WT AgAChE by dimethylcarboxamides 14 was 10–20 fold faster than that of the corresponding isoxazol-3-yl dimethylcarbamates 15. X-ray crystallography of dimethylcarboxamide 14d provided insight into that reactivity, a finding that may explain the inhibitory power of structurally-related inhibitors of hormone-sensitive lipase. Finally, human/An. gambiae AChE inhibition selectivities of these compounds were low, suggesting the need for additional structural modification.
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      PubDate: 2015-02-27T08:28:43Z
       
  • Synthesis and biological evaluation of 4-nitroindole derivatives as 5-HT2A
           receptor antagonists
    • Abstract: Publication date: 15 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 6
      Author(s): Faisal Hayat , Ambily Nath Indu Viswanath , Ae Nim Pae , Hyewhon Rhim , Woo-Kyu Park , Hea-Young Park Choo
      A novel series of 4-nitroindole sulfonamides containing a methyleneamino-N,N-dimethylformamidine were prepared. The binding of these compounds to 5-HT2A and 5-HT2C was evaluated, and most of the compounds showed IC50 values of less than 1μM, and exhibited high selectivity for the 5-HT2C receptor. However, little selectivity was observed in the functional assay for 5-HT6 receptors. The computational modeling studies further validated the biological results and also demonstrated a reasonable correlation between the activity of compounds and the mode of superimposition with specified pharmacophoric features.
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      PubDate: 2015-02-27T08:28:43Z
       
  • Editorial board
    • Abstract: Publication date: 15 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 6




      PubDate: 2015-02-27T08:28:43Z
       
  • Graphical contents list
    • Abstract: Publication date: 15 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 6




      PubDate: 2015-02-27T08:28:43Z
       
  • Synthesis of the O-linked hexasaccharide containing
           β-d-Galp-(1→2)-d-Galf in Trypanosoma cruzi mucins. Differences
           on sialylation by trans-sialidase of the two constituent hexasaccharides
    • Abstract: Publication date: 15 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 6
      Author(s): Rosalía Agustí , M. Eugenia Giorgi , Verónica M. Mendoza , Gustavo A. Kashiwagi , Rosa M. de Lederkremer , Carola Gallo-Rodriguez
      The hexasaccharide β-d-Galp-(1→2)-[β-d-Galp-(1→3)]-β-d-Galp-(1→6)-[β-d-Galp(1→2)-β-d-Galf(1→4)]-d-GlcNAc (10) and its β-d-Galf-(1→2)-β-d-Galf containing isomer (7) are the largest carbohydrates in mucins of some strains of Trypanosoma cruzi. The terminal β-d-Galp units are sites of sialylation by the parasite trans-sialidase. Hexasaccharide 10 was chemically synthesized for the first time by a [3+3] nitrilium based convergent approach, using the trichloroacetimidate method of glycosylation. The 1H NMR spectrum of its alditol was identical to the spectrum of the product released by β-elimination from the parasite mucin. The trans-sialylation reaction studied on the benzyl glycoside of 10 showed two monosialylated products whose relative abundance changed with time. On the other hand, only one product was produced by sialylation of the benzyl glycoside of 7. A preparative synthesis of the latter and spectroscopic analysis of the product unequivocally established the sialylation site at the less hindered (1→3)-linked galactopyranose.
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      PubDate: 2015-02-27T08:28:43Z
       
  • Structural development of stapled short helical peptides as vitamin D
           receptor (VDR)–coactivator interaction inhibitors
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Takashi Misawa , Yosuke Demizu , Megumi Kawamura , Nanako Yamagata , Masaaki Kurihara
      We developed several stabilized helical heptapeptides (DPI-01–10) composed of l-leucine residues, an α,α-disubstituted α-amino acid (α-aminoisobutyric acid [Aib] or hydroxymethylserine [Hms]), and a stapled side chain as inhibitors of vitamin D receptor (VDR)–coactivator interactions. The inhibitory activity of these peptides against VDR–coactivator interactions was evaluated using a receptor cofactor assay system, and DPI-08 demonstrated strong activity (IC50: 3.2μM).
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      PubDate: 2015-02-20T11:48:20Z
       
  • Discovery of biphenyl-based VEGFR-2 inhibitors. Part 3: Design, synthesis
           and 3D-QSAR studies
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Wen Lu , Pengfei Li , Yuanyuan Shan , Ping Su , Jinfeng Wang , Yaling Shi , Jie Zhang
      VEGFR-2 plays an essential role in angiogenesis and is a central target for anticancer drug discovery. In order to develop novel VEGFR-2 inhibitors, we designed and synthesized 33 biphenyl amides based on our previously reported lead compound. The biological results indicated that four compounds (18b, 20e, 20h and 20j) are potent VEGFR-2 inhibitors which are comparable to positive control. Compound 18b displayed the most potent VEGFR-2 inhibition with IC50 value of 2.02nM. Moreover, it exhibited promising antiproliferative activity against MCF-7 and SMMC-7721 cells with IC50 values of 1.47μM and 5.98μM, respectively. Molecular docking and 3D-QSAR studies were also carried out. The results indicated that these biphenyl amides could serve as promising leads for further optimization as novel VEGFR-2 inhibitors.
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      PubDate: 2015-02-20T11:48:20Z
       
  • Synthesis and structure–activity relationships of novel
           phenoxyacetamide inhibitors of the Pseudomonas aeruginosa type III
           secretion system (T3SS)
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): John D. Williams , Matthew C. Torhan , Venugopal R. Neelagiri , Carson Brown , Nicholas O. Bowlin , Ming Di , Courtney T. McCarthy , Daniel Aiello , Norton P. Peet , Terry L. Bowlin , Donald T. Moir
      The increasing prevalence of drug-resistant bacterial infections is driving the discovery and development not only of new antibiotics, but also of inhibitors of virulence factors that are crucial for in vivo pathogenicity. One such virulence factor is the type III secretion system (T3SS), which plays a critical role in the establishment and dissemination of Pseudomonas aeruginosa infections. We have recently described the discovery and characterization of a series of inhibitors of P. aeruginosa T3SS based on a phenoxyacetamide scaffold. To better characterize the factors involved in potent T3SS inhibition, we have conducted a systematic exploration of this structure, revealing several highly responsive structure–activity relationships indicative of interaction with a specific target. Most of the structural features contributing to potency were additive, and combination of those features produced optimized inhibitors with IC50 values <1μM.
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      PubDate: 2015-02-20T11:48:20Z
       
  • Synthesis of new ligands for targeting the S1P1 receptor
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Stefanie S. Schilson , Petra Keul , Rizwan S. Shaikh , Michael Schäfers , Bodo Levkau , Günter Haufe
      Sphingosine-1-phosphate (S1P) influences various fundamental biological processes by interacting with a family of five G protein-coupled receptors (S1P1–5). FTY720, a sphingosine analogue, which was approved for treatment of relapsing forms of multiple sclerosis, is phosphorylated in vivo and acts as an agonist of four of the five S1P receptor subtypes. Starting from these lead structures we developed new agonists for the S1P1 receptor. The biological activity was tested in vivo and promising ligands were fluorinated at different positions to identify candidates for positron emission tomography (PET) imaging after [18F]-labelling. The radioligands shall enable the imaging of S1P1 receptor expression in vivo and thus may serve as novel imaging markers of S1P-related diseases.
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      PubDate: 2015-02-20T11:48:20Z
       
  • Dibenzosuberyl substituted polyamines and analogs of clomipramine as
           effective inhibitors of trypanothione reductase; molecular docking, and
           assessment of trypanocidal activities
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Mary C. O’Sullivan , Timothy B. Durham , Hannah E. Valdes , Kelly L. Dauer , Nicholas J. Karney , Andrew C. Forrestel , Cyrus J. Bacchi , Jerome F. Baker
      Trypanothione reductase (TR) is an enzyme critical to the maintenance of the thiol redox balance in trypanosomatids, including the genera Trypanosoma and Leishmania that are parasites responsible for several serious diseases. Analogs of clomipramine were prepared since clomipramine is reported to inhibit TR and cure mice infected with trypanosomes, however its psychotropic activity precludes its use as an anti-trypanosomal therapeutic. The clomipramine analogs contained a tricyclic dibenzosuberyl moiety. Additionally a series of polyamines with N-dibenzosuberyl substituents were prepared. All compounds studied were competitive inhibitors of TR and showed trypanocidal activities against Trypanosoma brucei in vitro. The analogs of clomipramine were poor inhibitors of TR, whereas the polyamine derivatives were effective TR inhibitors with the most potent compound, N 4,N 8-bis(dibenzosuberyl)spermine (7), having a K i value of 0.26μM. However, compound (7) did not prolong the lives of mice infected with trypanosomes. Analysis of docking studies indicated: the tricyclic groups of inhibitors bind at four distinct hydrophobic regions in the active site of TR; the importance of the chlorine substituent of clomipramine in binding to TR; and binding of the dibenzosuberyl groups of (7) occur at separate and distinct hydrophobic regions within the active site of TR.
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      PubDate: 2015-02-20T11:48:20Z
       
  • Computer-aided discovery of aminopyridines as novel JAK2 inhibitors
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Chao Zhao , Su Hui Yang , Daulat Bikram Khadka , Yifeng Jin , Kyung-Tae Lee , Won-Jea Cho
      The Janus kinase 2 (JAK2)-mediated signaling pathway plays an important role in controlling cell survival, proliferation, and differentiation. In recent years, genetic, biological, and physiological evidence has established JAK2 inhibitors as effective chemotherapeutic agents for the treatment of many different cancers. For this reason, we sought to identify novel small molecule inhibitors of JAK2. Using Surflex-Dock software, we tested 3010 compounds with known chemical structures in silico for their ability to interact with the JAK2 ATP-binding pocket. We selected the 10 highest-scoring compounds and tested their abilities to inhibit JAK2 activity in vitro. Compound 1a (ethyl 1-(5-((3-methoxyphenyl)carbamoyl)-3-nitropyridin-2-yl)piperidine-4-carboxylate) was identified. Optimization of 1a using docking studies led to the discovery of compounds 1b and 1d, potent JAK2 inhibitors. Furthermore, as V-shaped kinase inhibitors can curve around the protein backbone and access deep into the pocket, we developed a new series of compounds with a non-linear sulfonamide bond. Nine compounds were prepared and evaluated for JAK2 inhibitory effects. Compounds 7e (IC50 =6.9μM) and 7h (IC50 =12.2μM) showed better JAK2 inhibition, validating our design approach. This study successfully applied virtual screening for hit discovery, and a docking study for hit optimization. In addition, a novel approach to drug discovery, combining structure- and shape-based drug design, facilitated the design of more potent JAK2 inhibitors. The methods provide a guide for future development of inhibitors targeting JAK2 and other kinases.
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      PubDate: 2015-02-20T11:48:20Z
       
  • Enantioselective synthesis of dictyoceratin-A (smenospondiol) and -C,
           hypoxia-selective growth inhibitors from marine sponge
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Yuji Sumii , Naoyuki Kotoku , Akinori Fukuda , Takashi Kawachi , Yuta Sumii , Masayoshi Arai , Motomasa Kobayashi
      Total syntheses of (+)-dictyoceratin-C (1) and (+)-dictyoceratin-A (smenospondiol) (2), hypoxia-selective growth inhibitors isolated from marine sponge, were executed. The absolute stereochemistry of the each compound was determined through the enantioselective total syntheses of them. It revealed that the unnatural enantiomers of them also exhibited the hypoxia-selective growth inhibitory activity against human prostate cancer DU-145 cells.
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      PubDate: 2015-02-20T11:48:20Z
       
  • Design and synthesis of a novel candidate compound NTI-007 targeting
           sodium taurocholate cotransporting polypeptide
           [NTCP]–APOA1–HBx–Beclin1-mediated autophagic pathway in
           HBV therapy
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Jin Zhang , Lei-lei Fu , Mao Tian , Hao-qiu Liu , Jing-jing Li , Yan Li , Jun He , Jian Huang , Liang Ouyang , Hui-yuan Gao , Jin-hui Wang
      Sodium taurocholate cotransporting polypeptide (NTCP) is a multiple transmembrane transporter predominantly expressed in the liver, functioning as a functional receptor for HBV. Through our continuous efforts to identify NTCP as a novel HBV target, we designed and synthesized a series of new compounds based on the structure of our previous compound NT-5. Molecular docking and MD simulation validated that a new compound named NTI-007 can tightly bind to NTCP, whose efficacy was also measured in vitro virological examination and cytotoxicity studies. Furthermore, autophagy was observed in NTI-007 incubated HepG2.2.15 cells, and results of q-PCR and Western blotting revealed that NTI-007 induced autophagy through NTCP–APOA1–HBx–Beclin1-mediated pathway. Taken together, considering crucial role of NTCP in HBV infection, NTCP-mediated autophagic pathway may provide a promising strategy of HBV therapy and given efficacy of NTI-007 triggering autophagy. Our study suggests pre-clinical potential of this compound as a novel anti-HBV drug candidate.
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      PubDate: 2015-02-20T11:48:20Z
       
  • A peptide affinity reagent for isolating an intact and catalytically
           active multi-protein complex from mammalian cells
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Hinnerk Saathoff , Mattias Brofelth , Anne Trinh , Benjamin L. Parker , Daniel P. Ryan , Jason K.K. Low , Sarah R. Webb , Ana P.G. Silva , Joel P. Mackay , Nicholas E. Shepherd
      We have developed an approach for directly isolating an intact multi-protein chromatin remodeling complex from mammalian cell extracts using synthetic peptide affinity reagent 4. FOG1(1–15), a short peptide sequence known to target subunits of the nucleosome remodeling and deacetylase (NuRD) complex, was joined via a 35-atom hydrophilic linker to the StreptagII peptide. Loading this peptide onto Streptactin beads enabled capture of the intact NuRD complex from MEL cell nuclear extract. Gentle biotin elution yielded the desired intact complex free of significant contaminants and in a form that was catalytically competent in a nucleosome remodeling assay. The efficiency of 4 in isolating the NuRD complex was comparable to other reported methods utilising recombinantly produced GST–FOG1(1–45).
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      PubDate: 2015-02-20T11:48:20Z
       
  • Discovery and structure–activity relationship studies of
           N6-benzoyladenine derivatives as novel BRD4 inhibitors
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Tomomi Noguchi-Yachide , Taki Sakai , Yuichi Hashimoto , Takao Yamaguchi
      Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that bind to acetylated lysines in histones. Among them, BRD4 is a candidate target molecule of therapeutic agents for diverse diseases, including cancer and inflammatory disease. As a part of our continuing structural development studies of thalidomide to obtain a broad spectrum of biological modifiers based on the ‘multi-template’ approach, in this work we focused on BRD4-inhibitory activity, and discovered that N6-benzoyladenine derivatives exhibit this activity. Structure–activity relationship studies led to N6-(2,4,5-trimethoxybenzoyl)adenine (29), which exhibits potent BRD4 bromodomain1 inhibitory activity with an IC50 value of 0.427μM. N6-Benzoyladenine appears to be a new chemical scaffold for development of BRD4 inhibitors.
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      PubDate: 2015-02-20T11:48:20Z
       
  • Rat hormone sensitive lipase inhibition by cyclipostins and their analogs
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Elena Vasilieva , Supratik Dutta , Raj K. Malla , Benjamin P. Martin , Christopher D. Spilling , Cynthia M. Dupureur
      Cyclipostins are bicyclic lipophilic phosphate natural products. We report here that synthesized individual diastereomers of cyclipostins P and R have nanomolar IC50s toward hormone sensitive lipase (HSL). The less potent diastereomers of these compounds have 10-fold weaker IC50s. The monocyclic phosphate analog of cyclipostin P is nearly as potent as the bicyclic natural product. Bicyclic phosphonate analogs of both cyclipostins exhibit IC50s similar to those of the weaker diastereomer phosphates (about 400nM). The monocyclic phosphonate analog of cyclipostin P has similar potency. A series of monocyclic phosphonate analogs in which a hydrophobic tail extends from the lactone side of the ring are considerably poorer inhibitors, with IC50s around 50μM. Finally cyclophostin, a related natural product inhibitor of acetylcholinesterase (AChE) that lacks the hydrocarbon tail of cyclipostins, is not active against HSL. These results indicate a critical SAR for these compounds, the hydrophobic tail. The smaller lactone ring is not critical to activity, a similarity shared with cyclophostin and AChE. The HSL kinetics of inhibition for the cyclipostin P trans diastereomer were examined in detail. The reaction is irreversible with a K I of 40nM and a rate constant for inactivation of 0.2min−1. These results are similar to those observed for cyclophostin and AChE.
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      PubDate: 2015-02-20T11:48:20Z
       
  • Design, synthesis, and biological evaluation of air-stable
           nafuredin-γ analogs as complex I inhibitors
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Masaki Ohtawa , Mari Matsunaga , Keiko Fukunaga , Risa Shimizu , Eri Shimizu , Shiho Arima , Junko Ohmori , Kiyoshi Kita , Kazuro Shiomi , Satoshi Omura , Tohru Nagamitsu
      Nafuredin-γ (2), converted from nafuredin (1) under mild basic conditions, demonstrates potent and selective inhibitory activity against helminth complex I. However, 2 is unstable in air because the conjugated dienes are oxygen-labile. To address this, we designed and synthesized air-stable nafuredin-γ analogs. Although the complex I inhibitory activities of all the new nafuredin-γ analogs were lower than that of 2, all were in the high nM range (IC50: 300–820nM).
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      PubDate: 2015-02-20T11:48:20Z
       
  • Rational design, synthesis and structure–activity relationships of
           4-alkoxy- and 4-acyloxy-phenylethylenethiosemicarbazone analogues as novel
           tyrosinase inhibitors
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Ao You , Jie Zhou , Senchuan Song , Guoxun Zhu , Huacan Song , Wei Yi
      In continuing our program aimed to search for potent compounds as highly efficient tyrosinase inhibitors, here a series of novel 4-alkoxy- and 4-acyloxy-phenylethylenethiosemicarbazone analogues were designed, synthesized and their biological activities on mushroom tyrosinase were evaluated. Notably, most of compounds displayed remarkable tyrosinase inhibitory activities with IC50 value of lower than 1.0μM. Furthermore, the structure–activity relationships (SARs) were discussed and the inhibition mechanism and the inhibitory kinetics of selected compounds 7k and 8d were also investigated. Taken together, these results suggested that such compounds could serve as the promising candidates for the treatment of tyrosinase-related disorders and further development of such compounds might be of great interest.
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      PubDate: 2015-02-20T11:48:20Z
       
  • Design, synthesis and evaluation of
           chromone-2-carboxamido-alkylbenzylamines as multifunctional agents for the
           treatment of Alzheimer’s disease
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Qiang Liu , Xiaoming Qiang , Yan Li , Zhipei Sang , Yuxing Li , Zhenghuai Tan , Yong Deng
      A series of chromone-2-carboxamido-alkylbenzylamines were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer’s disease (AD). The results showed that most of these compounds exhibited good multifunctional activities. Among them, compound 49 displayed excellent inhibitory potency toward acetylcholinesterase (AChE), moderate anti-oxidative activity, selective biometal chelating, and possessed good inhibitory effects on self-induced and Cu2+-induced Aβ aggregation. Both kinetic analysis of AChE inhibition and molecular modeling study indicated that 49 was a mixed-type inhibitor, binding simultaneously to the catalytic active site and peripheral anionic site of AChE. These results suggested that 49 might be a potential multifunctional agent for AD treatment.
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      PubDate: 2015-02-20T11:48:20Z
       
  • Graphical contents list
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5




      PubDate: 2015-02-20T11:48:20Z
       
  • Editorial board
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5




      PubDate: 2015-02-20T11:48:20Z
       
  • Synthesis of (+)-crocacin D and simplified bioactive analogues
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Adele E. Pasqua , Frank D. Ferrari , James J. Crawford , William G. Whittingham , Rodolfo Marquez
      The total synthesis of (+)-crocacin D has been achieved in 15 steps (9 isolated intermediates) and 14% overall yield from commercially available starting materials and using (+)-crocacin C as a key intermediate. A number of simplified analogues and their biological activities are also reported.
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      PubDate: 2015-02-20T11:48:20Z
       
  • Scaffold hopping: Exploration of acetanilide-containing uracil analogues
           as potential NNRTIs
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Denis A. Babkov , Vladimir T. Valuev-Elliston , Maria P. Paramonova , Alexander A. Ozerov , Alexander V. Ivanov , Alexander O. Chizhov , Anastasia L. Khandazhinskaya , Sergey N. Kochetkov , Jan Balzarini , Dirk Daelemans , Christophe Pannecouque , Katherine L. Seley-Radtke , Mikhail S. Novikov
      In order to identify novel nonnucleoside inhibitors of HIV-1 reverse transcriptase two series of amide-containing uracil derivatives were designed as hybrids of two scaffolds of previously reported inhibitors. Subsequent biological evaluation confirmed acetamide uracil derivatives 15a–k as selective micromolar NNRTIs with a first generation-like resistance profile. Molecular modeling of the most active compounds 15c and 15i was employed to provide insight on their inhibitory properties and direct future design efforts.
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      PubDate: 2015-02-20T11:48:20Z
       
  • Synthesis of arylpyrazole linked benzimidazole conjugates as potential
           microtubule disruptors
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Ahmed Kamal , Anver Basha Shaik , Sowjanya Polepalli , G. Bharath Kumar , Vangala Santhosh Reddy , Rasala Mahesh , Srujana Garimella , Nishant Jain
      In an attempt to develop potent and selective anticancer agents, a series of twenty arylpyrazole linked benzimidazole conjugates (10a–t) were designed and synthesized as microtubule destabilizing agents. The joining of arylpyrazole to the benzimidazole moiety resulted in a four ring (A, B, C and D) molecular scaffold that comprises of polar heterocyclic rings in the middle associated with rotatable single bonds and substituted aryl rings placed in the opposite directions. These conjugates were evaluated for their ability to inhibit the growth of sixty cancer cell line panel of the NCI. Among these some conjugates like 10a, 10b, 10d, 10e, 10p and 10r exhibited significant growth inhibitory activity against most of the cell lines ranging from 0.3 to 13μM. Interestingly, the conjugate 10b with methoxy group on D-ring expressed appreciable cytotoxic potential. A549 cells treated with some of the potent conjugates like 10a, 10b and 10d arrested cells at G2/M phase apart from activating cyclin-B1 protein levels and disrupting microtubule network. Moreover, these conjugates effectively inhibited tubulin polymerization with IC50 values of 1.3–3.8μM. Whereas, the caspase assay revealed that they activate the casepase-3 leading to apoptosis. Particularly 10b having methoxy substituent induced activity almost 3 folds higher than CA-4. Furthermore, a competitive colchicine binding assay and molecular modeling analysis suggests that these conjugates bind to the tubulin successfully at the colchicine binding site. These investigations reveal that such conjugates having pyrazole and benzimidazole moieties have the potential in the development of newer chemotherapeutic agents.
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      PubDate: 2015-02-20T11:48:20Z
       
  • Discovery of Mer kinase inhibitors by virtual screening using Structural
           Protein–Ligand Interaction Fingerprints
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): C. Da , M. Stashko , C. Jayakody , X. Wang , W. Janzen , S. Frye , D. Kireev
      Mer is a receptor tyrosine kinase implicated in acute lymphoblastic leukemia (ALL), the most common malignancy in children. The currently available data provide a rationale for development of Mer kinase inhibitors as cancer therapeutics that can target both cell autologous and immune-modulatory anti-tumor effects. We have previously reported several series of potent Mer inhibitors and the objective of the current report is to identify a chemically dissimilar back-up series that might circumvent potential, but currently unknown, flaws inherent to the lead series. To this end, we virtually screened a database of ∼3.8million commercially available compounds using high-throughput docking followed by a filter involving Structural Protein–Ligand Interaction Fingerprints (SPLIF). SPLIF permits a quantitative assessment of whether a docking pose interacts with the protein target similarly to an endogenous or known synthetic ligand, and therefore helps to improve both sensitivity and specificity with respect to the docking score alone. Of the total of 62 experimentally tested compounds, 15 demonstrated reliable dose-dependent responses in the Mer in vitro kinase activity assay with inhibitory potencies ranging from 0.46μM to 9.9μM.
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      PubDate: 2015-02-20T11:48:20Z
       
  • Naturally occurring polyphenol, morin hydrate, inhibits enzymatic activity
           of N-methylpurine DNA glycosylase, a DNA repair enzyme with various roles
           in human disease
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Monica Dixon , Jordan Woodrick , Suhani Gupta , Soumendra Krishna Karmahapatra , Stephen Devito , Sona Vasudevan , Sivanesan Dakshanamurthy , Sanjay Adhikari , Venkata M. Yenugonda , Rabindra Roy
      Interest in the mechanisms of DNA repair pathways, including the base excision repair (BER) pathway specifically, has heightened since these pathways have been shown to modulate important aspects of human disease. Modulation of the expression or activity of a particular BER enzyme, N-methylpurine DNA glycosylase (MPG), has been demonstrated to play a role in carcinogenesis and resistance to chemotherapy as well as neurodegenerative diseases, which has intensified the focus on studying MPG-related mechanisms of repair. A specific small molecule inhibitor for MPG activity would be a valuable biochemical tool for understanding these repair mechanisms. By screening several small molecule chemical libraries, we identified a natural polyphenolic compound, morin hydrate, which inhibits MPG activity specifically (IC50 =2.6μM). Detailed mechanism analysis showed that morin hydrate inhibited substrate DNA binding of MPG, and eventually the enzymatic activity of MPG. Computational docking studies with an x-ray derived MPG structure as well as comparison studies with other structurally-related flavonoids offer a rationale for the inhibitory activity of morin hydrate observed. The results of this study suggest that the morin hydrate could be an effective tool for studying MPG function and it is possible that morin hydrate and its derivatives could be utilized in future studies focused on the role of MPG in human disease.
      Graphical abstract image

      PubDate: 2015-02-20T11:48:20Z
       
  • Radiosynthesis and micro-SPECT analysis of triazole-based RGD integrin
           ligands as non-peptide molecular imaging probes for angiogenesis
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Francesca Bianchini , Pierangelo Fabbrizzi , Gloria Menchi , Silvia Raspanti , Anna Bottoncetti , Alessandro Passeri , Elena Andreucci , Antonio Guarna , Lido Calorini , Alberto Pupi , Andrea Trabocchi
      Taking advantage of click chemistry, we synthesized triazole-containing RGD peptidomimetics capable of binding to αvβ3 integrin with diverse potency, and selected 125I-labeled compounds proved to interact in vitro and in vivo with αvβ3 integrin expressed by melanoma cells. Two 125I-compounds containing either 2-aminobenzimidazole or 2-aminopyridine groups as the arginine bioisostere with the capacity to selectively bind cells of highly expressing αvβ3 melanoma xenografts were found using micro-SPECT imaging studies.
      Graphical abstract image

      PubDate: 2015-02-20T11:48:20Z
       
  • Synthesis and pharmacological characterization of 2-aminobenzaldehyde
           oxime analogs as dual inhibitors of neutrophil elastase and proteinase 3
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Tsong-Long Hwang , Wen-Hui Wang , Ting-Yi Wang , Huang-Ping Yu , Pei-Wen Hsieh
      Proteinase 3 (Pr3), and human neutrophil elastase (HNE) are two major neutrophilic serine proteases (NsPs) expressed in neutrophil azurophil granules. Emerging data suggest that excessive release of proteases mediates tissue damage, and therefore prolonged neutrophil accumulation has an important role in the pathogenesis of many diseases. Thus, HNE and Pr3 inhibitors may prove to be targets for the generation of agents in the treatment of neutrophilic inflammatory disease. Sivelestat is the only commercially available selective HNE inhibitor. Therefore, sivelestat was chosen as the model structure in an attempt to obtain more potent anti-NsPs agents. In the present study, a series 2-aminobenzaldehyde oxime and 2-aminobenzoate analogs were synthesized and their inhibitory effects on NsPs (CatG, Pr3, and HNE) were determined, respectively. The results of structure–activity relationships studies concluded that a hydroxyl oxime moiety plays an important role in ligand–enzyme affinity through hydrogen bonding. As compound 6 had more potency and showed dual inhibitory effects on NE and Pr3, both in vitro and in vivo experiments were carried out to evaluate its selectivity, effects in cell-based assays, and efficacy in models of inflammation and damage. Compound 6 had the potential to reduce paw edema induced by LPS and HNE, as well as acute lung injury, and may be approved as a candidate for the development of new agents in the treatment of neutrophilic inflammatory diseases.
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      PubDate: 2015-02-20T11:48:20Z
       
  • Synthesis, biological evaluation and molecular docking study of novel
           piperidine and piperazine derivatives as multi-targeted agents to treat
           Alzheimer’s disease
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Poonam Meena , Vishal Nemaysh , Manisha Khatri , Apra Manral , Pratibha Mehta Luthra , Manisha Tiwari
      Development of Multi-Target Directed Ligands (MTDLs) has emerged as a promising approach for targeting complex etiology of Alzheimer’s disease (AD). Following this approach, a new series of N′-(4-benzylpiperidin-/piperazin-/benzhydrylpiperazin-1-yl)alkylamine derivatives were designed, synthesized and biologically evaluated as inhibitors of cholinesterases (ChEs), amyloid-beta (Aβ) self aggregation and also for their radical scavenging activity. The in vitro studies showed that the majority of synthesized derivatives strongly inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC50 values in the low-nanomolar range, and were clearly more potent than the reference compound donepezil in this regard. Among them, inhibitors 5h and 5k, strongly inhibited AChE, with IC50 value of 6.83nM and 2.13nM, respectively, and particularly, compound 5k was found to be highly selective for AChE (∼38-fold). Moreover, both kinetic analysis of AChE inhibition and the docking study suggested that 5k binds simultaneously to catalytic active site and peripheral anionic site of AChE. Besides, these compounds also exhibited greater ability to inhibit self-induced Aβ1–42 aggregation at 25μM with percentage inhibition from ∼54% to 89% and specially compound 5k provided highest inhibition (88.81%). Also, the derivatives containing methoxy and hydroxy groups showed potent oxygen radical absorbance capacity (ORAC) ranging from 2.2- to 4.4-fold of the Trolox value. Furthermore, results of ADMET studies suggested that all compounds exhibited appropriate drug like properties. Taken together, these results suggest that 5k might be a promising lead compound for further AD drug development.
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      PubDate: 2015-02-20T11:48:20Z
       
  • Guanine-based amphiphiles: synthesis, ion transport properties and
           biological activity
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Domenica Musumeci , Carlo Irace , Rita Santamaria , Domenico Milano , Paolo Tecilla , Daniela Montesarchio
      Novel amphiphilic guanine derivatives, here named Gua1 and Gua2, have been prepared through few, simple and efficient synthetic steps. In ion transport experiments through phospholipid bilayers, carried out to evaluate their ability to mediate H+ transport, Gua2 showed high activity. When this compound was investigated for ion-selective transport activities, no major differences were observed in the behaviour with cations while, in the case of anions, selective activity was observed in the series I− >Br− >Cl− >F−. The bioactivity of these guanine analogues has been evaluated on a panel of human tumour and non-tumour cell lines in preliminary in vitro cytotoxicity assays, showing a relevant antiproliferative profile for Gua2.
      Graphical abstract image

      PubDate: 2015-02-20T11:48:20Z
       
  • Design, synthesis, and biological evaluation of novel 2-methylpiperazine
           derivatives as potent CCR5 antagonists
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Suwen Hu , Zhilong Wang , Tingjun Hou , Xiaodong Ma , Jing Li , Tao Liu , Xin Xie , Yongzhou Hu
      Three series of novel 2-methylpiperazine derivatives were designed and synthesized using a fragment-assembly strategy. Among them, six compounds (13, 16, 18, 22, 33, and 36) showed potent activity against CCR5 comparable to that of the positive control, maraviroc, in calcium mobilization assay. Moreover, some compounds were selected and further tested for their antiviral activity in HIV-1 single cycle assay. As a result, four compounds (13, 16, 33, and 36) showed antiviral activity at the nanomolar level. Additionally, the potent four compounds showed no cytotoxicity at a concentration of 10μM.
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      PubDate: 2015-02-20T11:48:20Z
       
  • Synthesis and comparative biological evaluation of bifunctional ligands
           for radiotherapy applications of 90Y and 177Lu
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Hyun-Soon Chong , Xiang Sun , Yunwei Chen , Inseok Sin , Chi Soo Kang , Michael R. Lewis , Dijie Liu , Varyanna C. Ruthengael , Yongliang Zhong , Ningjie Wu , Hyun A. Song
      Zevalin® is an antibody-drug conjugate radiolabeled with a cytotoxic radioisotope (90Y) that was approved for radioimmunotherapy (RIT) of B-cell non-Hodgkin’s lymphoma. A bifunctional ligand that displays favorable complexation kinetics and in vivo stability is required for effective RIT. New bifunctional ligands 3p-C-DE4TA and 3p-C-NE3TA for potential use in RIT were efficiently prepared by the synthetic route based on regiospecific ring opening of aziridinium ions with prealkylated triaza- or tetraaza-backboned macrocycles. The new bifunctional ligands 3p-C-DE4TA and 3p-C-NE3TA along with the known bimodal ligands 3p-C-NETA and 3p-C-DEPA were comparatively evaluated for potential use in targeted radiotherapy using β-emitting radionuclides 90Y and 177Lu. The bifunctional ligands were evaluated for radiolabeling kinetics with 90Y and 177Lu, and the corresponding 90Y or 177Lu-radiolabeled complexes were studied for in vitro stability in human serum and in vivo biodistribution in mice. The results of the comparative complexation kinetic and stability studies indicate that size of macrocyclic cavity, ligand denticity, and bimodality of donor groups have a substantial impact on complexation of the bifunctional ligands with the radiolanthanides. The new promising bifunctional chelates in the DE4TA and NE3TA series were rapid in binding 90Y and 177Lu, and the corresponding 90Y- and 177Lu-radiolabeled complexes remained inert in human serum or in mice. The in vitro and in vivo data show that 3p-C-DE4TA and 3p-C-NE3TA are promising bifunctional ligands for targeted radiotherapy applications of 90Y and 177Lu.
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      PubDate: 2015-02-20T11:48:20Z
       
  • Synthesis and biological evaluation of
           3-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-4-(indol-3-yl)-maleimides as
           potent, selective GSK-3β inhibitors and neuroprotective agents
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Qing Ye , Weili Mao , Yubo Zhou , Lei Xu , Qiu Li , Yuanxue Gao , Jing Wang , Chenhui Li , Yazhou Xu , Yuan Xu , Hong Liao , Luyong Zhang , Jianrong Gao , Jia Li , Tao Pang
      A series of novel 3-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-4-(indol-3-yl)-maleimides were designed, prepared and evaluated for their GSK-3β inhibitory activities. Most compounds showed high potency to GSK-3β inhibition with high selectivity. Among them, compounds 7c, 7f, 7h, 7l and 7m significantly reduced GSK-3β substrate Tau phosphorylation at Ser396 in primary neurons, showing the inhibition of cellular GSK-3β. In the in vitro neuronal injury models, compounds 7c, 7f, 7h, 7l and 7m prevented neuronal death against glutamate, oxygen–glucose deprivation and nutrient serum deprivation which are associated with cerebral ischemic stroke. In the in vivo cerebral ischemia animal model, compound 7f reduced infarct size by 15% and improved the neurological deficit following focal cerebral ischemia. These findings may provide new insights into the development of novel GSK-3β inhibitors with potential neuroprotective activity.
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      PubDate: 2015-02-20T11:48:20Z
       
  • Synthesis, structure activity relationship, radiolabeling and preclinical
           evaluation of high affinity ligands for the ion channel of the
           N-methyl-d-aspartate receptor as potential imaging probes for positron
           emission tomography
    • Abstract: Publication date: 1 March 2015
      Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 5
      Author(s): Pieter J. Klein , Johannes A.M. Christiaans , Athanasios Metaxas , Robert C. Schuit , Adriaan A. Lammertsma , Bart N.M. van Berckel , Albert D. Windhorst
      The N-methyl-d-aspartate receptor (NMDAr) is involved in many neurological and psychiatric disorders including Alzheimer’s disease and schizophrenia. Currently, it is not possible to assess NMDAr availability in vivo. The purpose of this study was to develop a positron emission tomography (PET) ligand for the NMDAr ion channel. A series of di- and tri-N-substituted diarylguanidines was synthesized. In addition, in vitro binding affinity for the NMDAr ion channel in rat forebrain membrane fractions was assessed. Compounds 10, 11 and 32 were radiolabeled with either carbon-11 or fluorine-18. Ligands [11C]10 and [18F]32 were evaluated ex vivo in B6C3 mice. Biodistribution studies showed higher uptake of [11C]10 and [18F]32 in forebrain regions compared with cerebellum. In addition, for [11C]10 54% and for [18F]32 70% of activity in the brain at 60min was due to intact tracer. Pre-treatment with MK-801 (0.6mg·kg−1, ip) slightly decreased uptake in NMDAr-specific regions for [18F]32, but not for [11C]10. As such [18F]32 has the best characteristics as a PET tracer for the ion channel of the NMDAr.
      Graphical abstract image

      PubDate: 2015-02-20T11:48:20Z
       
 
 
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