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  Subjects -> CHEMISTRY (Total: 792 journals)
    - ANALYTICAL CHEMISTRY (47 journals)
    - CHEMISTRY (552 journals)
    - CRYSTALLOGRAPHY (22 journals)
    - ELECTROCHEMISTRY (24 journals)
    - INORGANIC CHEMISTRY (41 journals)
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    - PHYSICAL CHEMISTRY (64 journals)

CHEMISTRY (552 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: 17)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 25)
ACS Nano     Full-text available via subscription   (Followers: 289)
ACS Photonics     Full-text available via subscription   (Followers: 5)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 8)
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: 4)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 4)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 5)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 8)
Advanced Functional Materials     Hybrid Journal   (Followers: 35)
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: 14)
Advances in Drug Research     Full-text available via subscription   (Followers: 16)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 7)
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: 15)
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: 4)
Afrique Science : Revue Internationale des Sciences et Technologie     Open Access   (Followers: 1)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Alchemy     Open Access   (Followers: 3)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 4)
AMB Express     Open Access   (Followers: 1)
American Journal of Applied Sciences     Open Access   (Followers: 29)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 179)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 11)
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: 3)
Analyst     Full-text available via subscription   (Followers: 35)
Angewandte Chemie     Hybrid Journal   (Followers: 17)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 232)
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: 12)
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: 19)
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: 221)
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: 10)
Carbon     Hybrid Journal   (Followers: 54)
Catalysis for Sustainable Energy     Open Access   (Followers: 2)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 5)
Catalysis Science and Technology     Free   (Followers: 4)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 4)
Catalysts     Open Access   (Followers: 7)
Cellulose     Hybrid Journal   (Followers: 5)

        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  [2571 journals]
  • Synthesis of (R)- or (S)-valinol using ω-transaminases in aqueous and
           organic media
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20
      Author(s): Christine S. Fuchs , Robert C. Simon , Waander Riethorst , Ferdinand Zepeck , Wolfgang Kroutil
      Valinol is part of numerous pharmaceuticals and has various other important applications. Optically pure valinol (ee >99%) was prepared employing different ω-transaminases from the corresponding prochiral hydroxy ketone. By the choice of the enzyme the (R)- as well as the (S)-enantiomer were accessible. Reductive amination was performed in organic solvent (MTBE) using 2-propyl amine as amine donor whereas alanine was applied in or in aqueous medium. Transformations in phosphate buffer were successfully performed even at 200mM substrate concentration (20.4g/L) leading to 99% (R) and 94% (S) conversion with perfect optical purity (>99% ee).
      Graphical abstract image

      PubDate: 2014-10-12T08:24:19Z
       
  • Bacterial Anabaena variabilis phenylalanine ammonia lyase: A biocatalyst
           with broad substrate specificity
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20
      Author(s): Sarah L. Lovelock , Nicholas J. Turner
      Phenylalanine ammonia lyases (PALs) catalyse the regio- and stereoselective hydroamination of cinnamic acid analogues to yield optically enriched α-amino acids. Herein, we demonstrate that a bacterial PAL from Anabaena variabilis (AvPAL) displays significantly higher activity towards a series of non-natural substrates than previously described eukaryotic PALs. Biotransformations performed on a preparative scale led to the synthesis of the 2-chloro- and 4-trifluoromethyl-phenylalanine derivatives in excellent ee, highlighting the enormous potential of bacterial PALs as biocatalysts for the synthesis of high value, non-natural amino acids.
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      PubDate: 2014-10-12T08:24:19Z
       
  • Controlling substrate specificity and product regio- and
           stereo-selectivities of P450 enzymes without mutagenesis
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20
      Author(s): Vanja Polic , Karine Auclair
      P450 enzymes (P450s) are well known for their ability to oxidize unactivated CH bonds with high regio- and stereoselectivity. Hence, there is emerging interest in exploiting P450s as potential biocatalysts. Although bacterial P450s typically show higher activity than their mammalian counterparts, they tend to be more substrate selective. Most drug-metabolizing P450s on the other hand, display remarkable substrate promiscuity, yet product prediction remains challenging. Protein engineering is one established strategy to overcome these issues. A less explored, yet promising alternative involves substrate engineering. This review discusses the use of small molecules for controlling the substrate specificity and product selectivity of P450s. The focus is on two approaches, one taking advantage of non-covalent decoy molecules, and the other involving covalent substrate modifications.
      Graphical abstract image

      PubDate: 2014-10-12T08:24:19Z
       
  • Whole-cell biotransformation with recombinant cytochrome P450 for the
           selective oxidation of Grundmann’s ketone
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20
      Author(s): Alba Hernández-Martín , Clemens J. von Bühler , Florian Tieves , Susana Fernández , Miguel Ferrero , Vlada B. Urlacher
      25-Hydroxy-Grundmann’s ketone is a key building block in the chemical synthesis of vitamin D3 and its derivatives through convergent routes. Generally, the chemical synthesis of this compound involves tedious procedures and results in a mixture of several products. Recently, the selective hydroxylation of Grundmann’s ketone at position C25 by cytochrome P450 (CYP) 154E1 from Thermobifida fusca YX was described. In this study a recombinant whole-cell biocatalyst was developed and applied for hydroxylation of Grundmann’s ketone. Biotransformation was performed by Escherichia coli cells expressing CYP154E1 along with two redox partner systems, Pdx/PdR and YkuN/FdR. The system comprising CYP154E1/Pdx/PdR showed the highest production of 25-hydroxy-Grundmann’s ketone and resulted in 1.1mM (300mgL−1) product concentration.
      Graphical abstract image

      PubDate: 2014-10-12T08:24:19Z
       
  • Editorial board
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20




      PubDate: 2014-10-12T08:24:19Z
       
  • Graphical contents list
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20




      PubDate: 2014-10-12T08:24:19Z
       
  • Natural, engineered, and artificial biocatalysts for organic synthesis
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20
      Author(s): Rudi Fasan



      PubDate: 2014-10-12T08:24:19Z
       
  • Synthesis of fluorinated analogues of sphingosine-1-phosphate antagonists
           as potential radiotracers for molecular imaging using positron emission
           tomography
    • Abstract: Publication date: 1 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 19
      Author(s): Vysakh Pushpa Prasad , Stefan Wagner , Petra Keul , Sven Hermann , Bodo Levkau , Michael Schäfers , Günter Haufe
      Sphingosine-1-phosphate (S1P) receptors play major roles in cardiovascular, immunological and neurological diseases. The recent approval of the sphingolipid drug Fingolimod (Gilenya®), a sphingosine-1-phosphate agonist for relapsing multiple sclerosis, in 2010 exemplifies the potential for targeting sphingolipids for the treatment of human disorders. Moreover, non-invasive in vivo imaging of S1P receptors that are not available till now would contribute to the understanding of their role in specific pathologies and is therefore of preclinical interest. Based on fluorinated analogues of the S1P1 receptor antagonist W146 showing practically equal in vitro potency as the lead structure, the first S1P receptor antagonist [18F]-radiotracer has been synthesized and tested for in vivo imaging of the S1P1 receptor using positron emission tomography (PET). Though the tracer is serum stable, initial in vivo images show fast metabolism and subsequent accumulation of free [18F]fluoride in the bones.
      Graphical abstract image

      PubDate: 2014-10-12T08:24:19Z
       
  • Synthesis and biological evaluation of 1,2,3-triazole linked
           aminocombretastatin conjugates as mitochondrial mediated apoptosis
           inducers
    • Abstract: Publication date: 1 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 19
      Author(s): Ahmed Kamal , Bajee Shaik , V. Lakshma Nayak , Burri Nagaraju , Jeevak Sopanrao Kapure , M. Shaheer Malik , Thokhir Basha Shaik , B. Prasad
      A series of 1,2,3-triazole linked aminocombretastatin conjugates were synthesized and evaluated for cytotoxicity, inhibition of tubulin polymerization and apoptosis inducing ability. Most of the conjugates exhibited significant anticancer activity against some representative human cancer cell lines and two of the conjugates 6d and 7c displayed potent cytotoxicity with IC50 values of 53nM and 44nM against A549 human lung cancer respectively, and were comparable to combretastatin A-4 (CA-4). SAR studies revealed that 1-benzyl substituted triazole moiety with an amide linkage at 3-position of B-ring of the combretastatin subunit are more active compared to 2-position. G2/M cell cycle arrest was induced by these conjugates 6d and 7c and the tubulin polymerization assay (IC50 of 1.16μM and 0.95μM for 6d and 7c, respectively) as well as immunofluorescence analysis showed that these conjugates effectively inhibit microtubule assembly at both molecular and cellular levels in A549 cells. Colchicine competitive binding assay suggested that these conjugates bind at the colchicine binding site of tubulin as also observed from the docking studies. Further, mitochondrial membrane potential, ROS generation, caspase-3 activation assay, Hoechst staining and DNA fragmentation analysis revealed that these conjugates induce cell death by apoptosis.
      Graphical abstract image

      PubDate: 2014-10-12T08:24:19Z
       
  • Design, synthesis and biological evaluation of novel
           6H-benzo[c]chromen-6-one, and 7,8,9,10-tetrahydro-benzo[c]chromen-6-one
           derivatives as potential cholinesterase inhibitors
    • Abstract: Publication date: 1 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 19
      Author(s): Hayrettin Ozan Gulcan , Serdar Unlu , İlker Esiringu , Tugba Ercetin , Yasemin Sahin , Demet Oz , Mustafa Fethi Sahin
      Hydroxylated 6H-benzo[c]chromen-6-one derivatives (i.e., urolithins) are the main bioavailable metabolites, and biomarkers of ellagitannins present in various nutrition. Although these dietaries, the sources of urolithins, are employed in folk medicine as cognitive enhancer in the treatment of Alzheimer’s Disease, urolithins have negligible potential to inhibit acetylcholinesterase and butyrylcholinesterase enzymes, the validated targets of Alzheimer’s Disease. Therefore, within this research, a series of 6H-benzo[c]chromen-6-one, and 7,8,9,10-tetrahydro-benzo[c]chromen-6-one derivatives has been designed, synthesized, and their biological activities were evaluated as potential acetylcholinesterase and butyrylcholinesterase inhibitors. The compounds synthesized exerted comparable activity in comparison to rivastigmine, galantamine, and donepezil both in in vitro and in vivo studies.
      Graphical abstract image

      PubDate: 2014-10-12T08:24:19Z
       
  • Editorial board
    • Abstract: Publication date: 1 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 19




      PubDate: 2014-10-12T08:24:19Z
       
  • Graphical contents list
    • Abstract: Publication date: 1 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 19




      PubDate: 2014-10-12T08:24:19Z
       
  • Quinazoline–sulfonamides with potent inhibitory activity against the
           α-carbonic anhydrase from Vibrio cholerae
    • Abstract: Publication date: 1 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 19
      Author(s): Ahmed M. Alafeefy , Mariangela Ceruso , Abdul-Malek S. Al-Tamimi , Sonia Del Prete , Clemente Capasso , Claudiu T. Supuran
      Thirteen novel sulfonamide derivatives incorporating the quinazoline scaffold were synthesized by simple, eco-friendly procedures. These compounds were tested for their ability to inhibit the α-carbonic anhydrases (CA, EC 4.2.1.1) from Vibrio cholerae (VchCA) as well as the human α-CA isoforms, hCA I and hCA II. Nine compounds were highly effective, nanomolar inhibitors of the pathogenic enzyme VchCA. Three of them were also highly effective sub-nanomolar inhibitors of the cytosolic isoform II. The best VchCA inhibitor had a K I of 2.7nM. Many of these developed compounds showed high selectivity for inhibition of the bacterial over the mammalian CA isoforms, with one compound possessing selectivity ratios as high as 97.9 against hCA I and 9.7 against hCA II. Compound 9d was another highly effective VchCA inhibitor presenting a selectivity ratio of 99.1 and 8.1 against hCA I and hCA II, respectively. These results suggest that sulfonamides with quinazoline backbone could be considered suitable tools to better understand the role of bacterial CAs in pathogenesis.
      Graphical abstract image

      PubDate: 2014-10-12T08:24:19Z
       
  • Design, Synthesis and Structure-Activity Relationship Studies of
           Morpholino-1H-phenalene Derivatives That Antagonize Mcl-1/Bcl-2
    • Abstract: Publication date: Available online 2 October 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Xiangqian Li , Xiaomeng Liang , Ting Song , Pengchen Su , Zhichao Zhang
      We report herein characteristic studies of Mcl-1 and Bcl-2 dual inhibitors. It was found that a protruding carbonyl group forming hydrogen bond with R263 plays a predominant role compared with the hydrophobic group that occupies the p2 pocket. A series of dual inhibitors representing different parts of the morpholino-1H-phenalene were designed, synthesized and evaluated.
      Graphical abstract image

      PubDate: 2014-10-12T08:24:19Z
       
  • Synthesis, insecticidal activities and SAR of novel phthalamides targeting
           calcium channel
    • Abstract: Publication date: Available online 2 October 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Youwei Chen , Yuxin Li , Li Pan , Jingbo Liu , Yingying Wan , Wei Chen , Lixia Xiong , Na Yang , Haibin Song , Zhengming Li
      In order to find novel and environmental friendly insecticides targeting the ryanodine receptor, three series of novel phthalamides containing heptafluoroisopropyl group, low fluorine atoms group and non-fluorine group were designed and synthesized. 35 novel structures of three series were obtained. Insectcidal activities of title compounds against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella) indicated that most of title compounds showed moderate to high activities at the tested concentration. The structure-activity relationship (SAR) was discussed in detail. During synthesizing title compounds B8, C7, D1, D9, D12, their corresponding positional isomers (B8’, C7’, D1’, D9’, D12’) were afforded, and their structures were confirmed by 2D NMR. The calcium-imaging technique was also applied to investigate the effects of compounds B2, B10, C4 and C5 on the intracellular calcium ion concentration ([Ca2+]i), which indicated that they released stored calcium ions from endoplasmic reticulum, which denoted that some compounds are potential modulators of the insect ryanodine receptor(RyR).
      Graphical abstract image

      PubDate: 2014-10-12T08:24:19Z
       
  • A Bicyclic Peptide Scaffold Promotes Phosphotyrosine Mimicry and Cellular
           Uptake
    • Abstract: Publication date: Available online 2 October 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Justin S. Quartararo , Matthew R. Eshelman , Leila Peraro , Hongtao Yu , James D. Baleja , Yu-Shan Lin , Joshua A. Kritzer
      While peptides are promising as probes and therapeutics, targeting intracellular proteins will require greater understanding of highly structured, cell-internalized scaffolds. We recently reported BC1, an 11-residue bicyclic peptide that inhibits the Src homology 2 (SH2) domain of growth factor receptor-bound protein 2 (Grb2). In this work, we describe the unique structural and cell uptake properties of BC1 and similar cyclic and bicyclic scaffolds. These constrained scaffolds are taken up by mammalian cells despite their net neutral or negative charges, while unconstrained analogs are not. The mechanism of uptake is shown to be energy-dependent and endocytic, but distinct from that of Tat. The solution structure of BC1 was investigated by NMR and MD simulations, which revealed discrete water-binding sites on BC1 that reduce exposure of backbone amides to bulk water. This represents an original and potentially general strategy for promoting cell uptake.
      Graphical abstract image

      PubDate: 2014-10-12T08:24:19Z
       
  • Ferrier sulfamidoglycosylation of glycals catalyzed by nitrosononium
           tetrafluoroborate: towards new carbonic anhydrase glycoinhibitors
    • Abstract: Publication date: Available online 2 October 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Joanna Ombouma , Daniela Vullo , Claudiu T. Supuran , Jean-Yves Winum
      Ferrier sulfamidoglycosylation of glycals catalyzed by nitrosonium tetrafluoroborate allowed the preparation of hydroxysulfamide glycosides in good yields with a good α stereoselectivity. A variety of mono-saccharide derivatives was synthesized using this new methodology leading to selective and powerful glycoinhibitors of the tumour associated carbonic anhydrases (CA, EC 4.2.1.1) isoforms CA IX and CA XII.
      Graphical abstract image Highlights

      PubDate: 2014-10-12T08:24:19Z
       
  • N-Methylthioacetylation of RYYRIK-NH2 with Enhanced Specific Binding
           Affinity and High Antagonist Activity for Nociceptin ORL1 Receptor
    • Abstract: Publication date: Available online 2 October 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Jinglan Li , Hirokazu Nishimura , Ayami Matsushima , Yasuyuki Shimohigashi
      Antagonists of the neuropeptide nociceptin are expected to be potential analgesic and antineuropathic drugs acting on ORL1 GPCR receptors. The peptide library-based antagonist Ac-RYYRIK-NH2 inhibits the nociceptin activity mediated through ORL1, but preserves a considerably high level of agonist activity. We previously reported that the N-terminal acyl group is important for interaction with specific receptors, and developed isovarelyl-RYYRIK-NH2, which exhibits strong antagonist activity with negligible agonist activity. In the present study, in order to obtain a more potent antagonist, we further modified the isovarelyl group by replacing its Cβ atom with an oxygen, nitrogen, or sulfur atom to give the methyl group improved interaction ability. The methyl group bound to such heteroatoms was expected to enhance the hydrophobic interaction between the peptide and the ORL1 receptor. The RYYRIK-NH2 peptide with a methylthioacetyl group, CH3SCH2CO, revealed a higher receptor-binding affinity with strong antagonist activity, and the results suggested the presence of a receptor aromatic group as a complementary residue of this CH3S group.
      Graphical abstract image

      PubDate: 2014-10-12T08:24:19Z
       
  • Synthesis and evaluation of bivalent ligands for binding to the human
           melanocortin-4 receptor
    • Abstract: Publication date: Available online 2 October 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Steve M. Fernandes , Yeon Sun Lee , Robert J. Gillies , Victor J. Hruby
      Membrane proteins, especially G-protein coupled receptors (GPCRs), are interesting and important theragnostic targets since many of them serve in intracellular signaling critical for all aspects of health and disease. The potential utility of designed bivalent ligands as targeting agents for cancer diagnosis and/or therapy can be evaluated by determining their binding to the corresponding receptors. As proof of concept, GPCR cell surface proteins are shown to be targeted specifically using multivalent ligands. We designed, synthesized, and tested a series of bivalent ligands targeting the over-expressed human melanocortin 4 receptor (hMC4R) in human embryonic kidney (HEK) 293 cells. Based on our data suggesting an optimal linker length of 25±10 Å inferred from the bivalent melanocyte stimulating hormone (MSH) agonist, the truncated heptapeptide, referred to as MSH(7): Ac-Ser-Nle-Glu-His-D-Phe-Arg-Trp-NH2 was used to construct a set of bivalent ligands incorporating a hMC4R antagonist, SHU9119: Ac-Nle-c[Asp-His-2′-D-Nal-Arg-Trp-Lys]-NH2 and another set of bivalent ligands containing the SHU9119 antagonist pharmacophore on both side of the optimized linkers. These two binding motifs within the bivalent constructs were conjoined by semi-rigid (Pro-Gly)3 units with or without the flexible poly(ethylene glycol) (PEGO) moieties. Lanthanide-based competitive binding assays showed bivalent ligands binds to the hMC4R with up to 240-fold higher affinity than the corresponding linked monovalent ligands.
      Graphical abstract image

      PubDate: 2014-10-12T08:24:19Z
       
  • Inhibition of Myeloperoxidase: Evaluation of 2H-Indazoles and
           1H-Indazolones
    • Abstract: Publication date: Available online 2 October 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Aaron Roth , Sean Ott , Kelli M. Farber , Teresa A. Palazzo , Wayne E. Conrad , Makhluf J. Haddadin , Dean J. Tantillo , Carroll E. Cross , Jason P. Eiserich , Mark J. Kurth
      Myeloperoxidase (MPO) produces hypohalous acids as a key component of the innate immune response; however, release of these acids extracellularly results in inflammatory cell and tissue damage. The two-step, one-pot Davis-Beirut reaction was used to synthesize a library of 2H-indazoles and 1H-indazolones as putative inhibitors of MPO. A structure-activity relationship study was undertaken wherein compounds were evaluated utilizing taurine-chloramine and MPO-mediated H2O2 consumption assays. Docking studies as well as toxicophore and Lipinski analyses were performed. Fourteen compounds were found to be potent inhibitors with IC50 values <1 μM, suggesting these compounds could be considered as potential modulators of pro-oxidative tissue injury pertubated by the inflammatory MPO:H2O2:HOCl/ HOBr system.
      Graphical abstract image

      PubDate: 2014-10-12T08:24:19Z
       
  • Synthesis and analysis of potential α1,3-fucosyltransferase
           inhibitors
    • Abstract: Publication date: Available online 2 October 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Katrin Seelhorst , Tomas Piernitzki , Nathalie Lunau , Chris Meier , Ulrich Hahn
      Fucosyltransferases catalyze the transfer of l-fucose from an activated GDP-β-l-fucose to various acceptor molecules such as N-acetyllactosamine. Frequently fucosylation is the final step within the glycosylation machinery, and the resulting glycans are involved in various cellular processes such as cell-cell recognition, adhesion and inflammation or tumor metastasis. The selective blocking of these interactions would thus be a potential promising therapeutic strategy. The syntheses and analyses of various potential α1,3-fucosyltransferase inhibitors derived from GDP-β-l-fucose containing a triazole linker unit is summarized and the observed inhibitory effect was compared with that of small molecules such as GDP or fucose. To examine their specificity and selectivity, all inhibitors were tested with human α1,3-fucosyltransferase IX and Helicobacter pylori α1,3-fucosyltransferase, which is to date the only α1,3-fucosyltransferase with a known high resolution structure. Specific inhibitors which inhibit either H. pylori α1,3-fucosyltransferase or human fucosyltransferase IX with K i values in the micromolar range were identified. In that regard, acetylated GDP-galactose derivative Ac-3 turned out to inhibit H. pylori α1,3-fucosyltransferase but not human fucosyltransferase IX, whereas GDP-6-amino-β-l-fucose 17 showed an appreciably better inhibitory effect on fucosyltransferase IX activity than on that of H. pylori fucosyltransferase.
      Graphical abstract image

      PubDate: 2014-10-12T08:24:19Z
       
  • Identification of Novel Thiadiazoloacrylamide Analogues as Inhibitors of
           Dengue-2 Virus NS2B/NS3 Protease
    • Abstract: Publication date: Available online 5 October 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Hailong Liu , Ruoming Wu , Yanyan Sun , Yan Ye , Jing Chen , Xiaomin Luo , Xu Shen , Hong Liu
      Dengue virus is endemic throughout tropical and subtropical regions, and cause severe epidemic diseases. The NS2B/NS3 protease is a promising drug target for dengue virus. Herein, we report the discovery and modification of a novel class of thiadiazoloacrylamide derivatives with potent inhibitory activity against the NS2B/NS3 protease. Thiadiazolopyrimidinone 1 was firstly determined as a new chemical structure against NS2B/NS3 from a commercial compound library. Then, we sought to identify similar compounds with the thiadiazoloacrylamide core that would exhibit better activity. A series of analogues were synthesized and fourteen of them were identified with strong inhibitory activities, in which the nitrile group in the linker part was discovered as an essential group for the inhibitory activity. The best of these (8b) demonstrated an IC50 at 2.24 μM based on in vitro DENV2 NS2B-NS3pro assays.
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      PubDate: 2014-10-12T08:24:19Z
       
  • γ-Hydroxyethyl piperidine iminosugar and N-alkylated derivatives: A
           study of their activity as glycosidase inhibitors and as immunosuppressive
           agents
    • Abstract: Publication date: Available online 7 October 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Pramod R. Markad , Dhiraj P. Sonawane , Sougata Ghosh , Balu A. Chopade , Navnath Kumbhar , Thierry Louat , Jean Herman , Mark Waer , Piet Herdewijn , Dilip D. Dhavale
      An efficient and practical strategy for the synthesis of (3R,4s,5S)-4-(2-hydroxyethyl) piperidine-3,4,5-triol and its N-alkyl derivatives 8a–f, starting from the d-glucose, is reported. The chiral pool methodology involves preparation of the C-3-allyl-α-d-ribofuranodialdose 10, which was converted to the C-5-amino derivative 11 by reductive amination. The presence of C-3-allyl group gives an easy access to the requisite hydroxyethyl substituted compound 13. Intramolecular reductive aminocyclization of C-5 amino group with C-1 aldehyde provided the γ-hydroxyethyl substituted piperidine iminosugar 8a that was N-alkylated to get N-alkyl derivatives 8b–f. Iminosugars 8a–f were screened against glycosidase enzymes. Amongst synthetic N-alkylated iminosugars, 8b and 8c were found to be α-galactosidase inhibitors while 8d and 8e were selective and moderate α-mannosidase inhibitors. In addition, immunomodulatory activity of compounds 8a–f was examined. These results were substantiated by molecular docking studies using AUTODOCK 4.2 programme.
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      PubDate: 2014-10-12T08:24:19Z
       
  • A site-selective, irreversible inhibitor of the DNA replication auxiliary
           factor proliferating cell nuclear antigen (PCNA)
    • Abstract: Publication date: Available online 8 October 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Benjamin J. Evison , Marcelo L. Actis , Zhexiang Wu , Youming Shao , Richard J. Heath , Lei Yang , Naoaki Fujii
      Proliferating cell nuclear antigen (PCNA) assumes an indispensable role in supporting cellular DNA replication and repair by organizing numerous protein components of these pathways via a common PCNA-interacting sequence motif called a PIP-box. Given the multifunctional nature of PCNA, the selective inhibition of PIP-box–mediated interactions may represent a new strategy for the chemosensitization of cancer cells to existing DNA-directed therapies; however, promiscuous blockage of these interactions may also be universally deleterious. To address these possibilities, we utilized a chemical strategy to irreversibly block PIP-box–mediated interactions. Initially, we identified and validated PCNA methionine 40 (M40) and histidine 44 (H44) as essential residues for PCNA/PIP-box interactions in general and, more specifically, for efficient PCNA loading onto chromatin within cells. Next, we created a novel small molecule incorporating an electrophilic di-chloro platinum moiety that preferentially alkylated M40 and H44 residues. The compound, designated T2Pt, covalently cross-linked wild-type but not M40A/H44A PCNA, irreversibly inhibited PCNA/PIP-box interactions, and mildly alkylated plasmid DNA in vitro. In cells, T2Pt persistently induced cell cycle arrest, activated ATR-Chk1 signaling and modestly induced DNA strand breaks, features typical of cellular replication stress. Despite sustained activation of the replication stress response by the compound and its modestly genotoxic nature, T2Pt demonstrated little activity in clonogenic survival assays as a single agent, yet sensitized cells to cisplatin. The discovery of T2Pt represents an original effort directed at the development of irreversible PCNA inhibitors and sets the stage for the discovery of analogues more selective for PCNA over other cellular nucleophiles.
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      PubDate: 2014-10-12T08:24:19Z
       
  • Synthesis and evaluation of the antiplasmodial activity of novel
           indeno[2,1-c]quinoline derivatives
    • Abstract: Publication date: Available online 10 October 2014
      Source:Bioorganic & Medicinal Chemistry
      Author(s): Anna Barteselli , Silvia Parapini , Nicoletta Basilico , Danilo Mommo , Anna Sparatore
      With the aim to explore the potentiality of new chemical scaffolds for the design of new antimalarials, a set of new indeno[2,1-c]quinolines bearing different basic heads has been synthesized and tested in vitro against chloroquine sensitive (CQ-S) and chloroquine resistant (CQ-R) strains of Plasmodium falciparum. Most of the synthesized compounds exhibited a moderate antiplasmodial activity, inhibiting the growth of both CQ-S and CQ-R strains of P. falciparum with IC50 ranging from 0.24 to 6.9μM and with a very low resistance index. The most potent compounds (1.2–1.3-fold the CQ on the W-2 strain) can be considered as promising ‘lead compounds’ to be further optimized to improve efficacy and selectivity against Plasmodia.
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      PubDate: 2014-10-12T08:24:19Z
       
  • Intramolecular C(sp3)H amination of arylsulfonyl azides with engineered
           and artificial myoglobin-based catalysts
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20
      Author(s): Melanie Bordeaux , Ritesh Singh , Rudi Fasan
      The direct conversion of aliphatic CH bonds into CN bonds provides an attractive approach to the introduction of nitrogen-containing functionalities in organic molecules. Following the recent discovery that cytochrome P450 enzymes can catalyze the cyclization of arylsulfonyl azide compounds via an intramolecular C(sp3)H amination reaction, we have explored here the CH amination reactivity of other hemoproteins. Various heme-containing proteins, and in particular myoglobin and horseradish peroxidase, were found to be capable of catalyzing this transformation. Based on this finding, a series of engineered and artificial myoglobin variants containing active site mutations and non-native Mn- and Co-protoporphyrin IX cofactors, respectively, were prepared to investigate the effect of these structural changes on the catalytic activity and selectivity of these catalysts. Our studies showed that metallo-substituted myoglobins constitute viable CH amination catalysts, revealing a distinctive reactivity trend as compared to synthetic metalloporphyrin counterparts. On the other hand, amino acid substitutions at the level of the heme pocket were found to be beneficial toward improving the stereo- and enantioselectivity of these Mb-catalyzed reactions. Mechanistic studies involving kinetic isotope effect experiments indicate that CH bond cleavage is implicated in the rate-limiting step of myoglobin-catalyzed amination of arylsulfonyl azides. Altogether, these studies indicate that myoglobin constitutes a promising scaffold for the design and development of CH amination catalysts.
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      PubDate: 2014-10-12T08:24:19Z
       
  • Redox self-sufficient whole cell biotransformation for amination of
           alcohols
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20
      Author(s): Stephanie Klatte , Volker F. Wendisch
      Whole cell biotransformation is an upcoming tool to replace common chemical routes for functionalization and modification of desired molecules. In the approach presented here the production of various non-natural (di)amines was realized using the designed whole cell biocatalyst Escherichia coli W3110/pTrc99A-ald-adh-ta with plasmid-borne overexpression of genes for an l-alanine dehydrogenase, an alcohol dehydrogenase and a transaminase. Cascading alcohol oxidation with l-alanine dependent transamination and l-alanine dehydrogenase allowed for redox self-sufficient conversion of alcohols to the corresponding amines. The supplementation of the corresponding (di)alcohol precursors as well as amino group donor l-alanine and ammonium chloride were sufficient for amination and redox cofactor recycling in a resting buffer system. The addition of the transaminase cofactor pyridoxal-phosphate and the alcohol dehydrogenase cofactor NAD+ was not necessary to obtain complete conversion. Secondary and cyclic alcohols, for example, 2-hexanol and cyclohexanol were not aminated. However, efficient redox self-sufficient amination of aliphatic and aromatic (di)alcohols in vivo was achieved with 1-hexanol, 1,10-decanediol and benzylalcohol being aminated best.
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      PubDate: 2014-10-12T08:24:19Z
       
  • Characterization of the N-oxygenase AurF from Streptomyces thioletus
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20
      Author(s): Emmanuel Chanco , Yoo Seong Choi , Ning Sun , Michael Vu , Huimin Zhao
      AurF catalyzes the N-oxidation of p-aminobenzoic acid to p-nitrobenzoic acid in the biosynthesis of the antibiotic aureothin. Here we report the characterization of AurF under optimized conditions to explore its potential use in biocatalysis. The pH optimum of the enzyme was established to be 5.5 using phenazine methosulfate (PMS)/NADH as the enzyme mediator system, showing ∼10-fold higher activity than previous reports in literature. Kinetic characterization at optimized conditions give a K m of 14.7±1.1μM, a k cat of 47.5±5.4min−1 and a k cat/K m of 3.2±0.4μM−1 min−1. PMS/NADH and the native electron transfer proteins showed significant formation of the p-hydroxylaminobenzoic acid intermediate, however H2O2 produced mostly p-nitrobenzoic acid. Alanine scanning identified the role of important active site residues. The substrate specificity of AurF was examined and rationalized based on the protein crystal structure. Kinetic studies indicate that the K m is the main determinant of AurF activity toward alternative substrates.
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      PubDate: 2014-10-12T08:24:19Z
       
  • Enzymatic preparation of cis and trans-3-amino-4-hydroxytetrahydrofurans
           and cis-3-amino-4-hydroxypyrrolidines
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20
      Author(s): Ángela Villar-Barro , Vicente Gotor , Rosario Brieva
      The lipase catalyzed resolution of cis and trans-3-amino-4-hydroxytetrahydrofurans and cis-3-amino-4-hydroxypyrrolidines have been studied. For all the heterocycles, the best enantioselectivity was obtained using Candida antarctica lipases A and B as catalysts in hydrolytic processes. The absolute configuration of the optically pure obtained heterocycles has been assigned.
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      PubDate: 2014-10-12T08:24:19Z
       
  • Enzymatic resolution of racemates with a ‘remote’ stereogenic
           center as an efficient tool in drug, flavor and vitamin synthesis
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20
      Author(s): Maria Alfaro Blasco , Harald Gröger
      The enantioselective recognition of ‘remote’ stereogenic centers represents a scientific task in organic chemistry being also of current interest in the pharmaceutical industry. This is due to a range of pharmaceutically relevant molecules or intermediates thereof bearing a stereogenic center, which is separated from the functional group by a larger non-chiral moiety such as, for example, a longer sequence of bonds of at least three carbon or hetero-atoms or by a planar aromatic moiety. Notably, biocatalysis turned out to provide an excellent solution for a range of challenging syntheses in this field. For example, efficient enzymatic resolution processes of racemates with such a ‘remote’ stereogenic center were developed for the synthesis of pelitrexol, lasofoxifene and (S)-monastrol. In general, good yields accompanied by high enantioselectivities were obtained, thus underlining the tremendous potential of enzymes to recognize and enantioselectively transform enantiomers of racemates with ‘remote’ stereogenic centers. Such or similar types of stereoselective recognitions of ‘remote’ stereogenic centers by means of enzymes have been also reported in the field of flavor and vitamin synthesis. Thus, biocatalysis represents a promising solution for the efficient approach to enantiomerically pure complex chiral molecules with stereogenic centers being located apart from the functional group, and it can be expected that enzymatic resolution will be increasingly applied when searching for an efficient and also technically feasible process for also novel complex chiral molecules bearing a ‘remote’ stereogenic center.
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      PubDate: 2014-10-12T08:24:19Z
       
  • In situ formation of H2O2 for P450 peroxygenases
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20
      Author(s): Caroline E. Paul , Ekaterina Churakova , Elmer Maurits , Marco Girhard , Vlada B. Urlacher , Frank Hollmann
      An in situ H2O2 generation approach to promote P450 peroxygenases catalysis was developed through the use of the nicotinamide cofactor analogue 1-benzyl-1,4-dihydronicotinamide (BNAH) and flavin mononucleotide (FMN). Final productivity could be enhanced due to higher enzyme stability at low H2O2 concentrations. The H2O2 generation represented the rate-limiting step, however it could be easily controlled by varying both FMN and BNAH concentrations. Further characterization can result in an optimized ratio of FMN/BNAH/O2/biocatalyst enabling high reaction rates while minimizing H2O2-related inactivation of the enzyme.
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      PubDate: 2014-10-12T08:24:19Z
       
  • Regio- and stereoselective hydroxylation of 10-undecenoic acid with a
           light-driven P450 BM3 biocatalyst yielding a valuable synthon for natural
           product synthesis
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20
      Author(s): Mallory Kato , Daniel Nguyen , Melissa Gonzalez , Alejandro Cortez , Sarah E. Mullen , Lionel E. Cheruzel
      We report herein the selective hydroxylation of 10-undecenoic acid with a light-activated hybrid P450 BM3 enzyme. Under previously developed photocatalytic reaction conditions, only a monohydroxylated product is detected by gas chromatography. Hydroxylation occurs exclusively at the allylic position as confirmed from a synthesized authentic standard. Investigation into the stereochemistry of the reaction indicates that the R enantiomer is obtained in 85% ee. The (R)-9-hydroxy-10-undecenoic acid obtained enzymatically is a valuable synthon en route to various natural products further expanding the light-activated P450 BM3 biocatalysis and highlighting the advantages over traditional methods.
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      PubDate: 2014-10-12T08:24:19Z
       
  • Neocarzinostatin-based hybrid biocatalysts with a RNase like activity
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20
      Author(s): Agathe Urvoas , Wadih Ghattas , Jean-Didier Maréchal , Frédéric Avenier , Felix Bellande , Wei Mao , Rémy Ricoux , Jean-Pierre Mahy
      A new zinc(II)-cofactor coupled to a testosterone anchor, zinc(II)-N,N-bis(2-pyridylmethyl)-1,3-diamino-propa-2-ol-N′(17′-succinimidyltestosterone) (Zn-Testo-BisPyPol) 1-Zn has been synthesized and fully characterized. It has been further associated with a neocarzinostatin variant, NCS-3.24, to generate a new artificial metalloenzyme following the so-called ‘Trojan horse’ strategy. This new 1-Zn-NCS-3.24 biocatalyst showed an interesting catalytic activity as it was found able to catalyze the hydrolysis of the RNA model HPNP with a good catalytic efficiency (k cat/K M =13.6M−1 s−1 at pH 7) that places it among the best artificial catalysts for this reaction. Molecular modeling studies showed that a synergy between the binding of the steroid moiety and that of the BisPyPol into the protein binding site can explain the experimental results, indicating a better affinity of 1-Zn for the NCS-3.24 variant than testosterone and testosterone-hemisuccinate themselves. They also show that the artificial cofactor entirely fills the cavity, the testosterone part of 1-Zn being bound to one the two subdomains of the protein providing with good complementarities whereas its metal ion remains widely exposed to the solvent which made it a valuable tool for the catalysis of hydrolysis reactions, such as that of HPNP. Some possible improvements in the ‘Trojan horse’ strategy for obtaining better catalysts of selective reactions will be further studied.
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      PubDate: 2014-10-12T08:24:19Z
       
  • Catalyst design in oxidation chemistry; from KMnO4 to artificial
           metalloenzymes
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20
      Author(s): Megan V. Doble , Andrew C.C. Ward , Peter J. Deuss , Amanda G. Jarvis , Paul C.J. Kamer
      Oxidation reactions are an important part of the synthetic organic chemist’s toolkit and continued advancements have, in many cases, resulted in high yields and selectivities. This review aims to give an overview of the current state-of-the-art in oxygenation reactions using both chemical and enzymatic processes, the design principles applied to date and a possible future in the direction of hybrid catalysts combining the best of chemical and natural design.
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      PubDate: 2014-10-12T08:24:19Z
       
  • Artificial enzymes with protein scaffolds: Structural design and
           modification
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20
      Author(s): Takashi Matsuo , Shun Hirota
      Recent development in biochemical experiment techniques and bioinformatics has enabled us to create a variety of artificial biocatalysts with protein scaffolds (namely ‘artificial enzymes’). The construction methods of these catalysts include genetic mutation, chemical modification using synthetic molecules and/or a combination of these methods. Designed evolution strategy based on the structural information of host proteins has become more and more popular as an effective approach to construct artificial protein-based biocatalysts with desired reactivities. From the viewpoint of application of artificial enzymes for organic synthesis, recently constructed artificial enzymes mediating oxidation, reduction and C–C bond formation/cleavage are introduced in this review article.
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      PubDate: 2014-10-12T08:24:19Z
       
  • Engineering strictosidine synthase: Rational design of a small, focused
           circular permutation library of the β-propeller fold enzyme
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20
      Author(s): Eva Fischereder , Desiree Pressnitz , Wolfgang Kroutil , Stefan Lutz
      Strictosidine synthases catalyze the formation of strictosidine, a key intermediate in the biosynthesis of a large variety of monoterpenoid indole alkaloids. Efforts to utilize these biocatalysts for the preparation of strictosidine analogs have however been of limited success due to the high substrate specificity of these enzymes. We have explored the impact of a protein engineering approach called circular permutation on the activity of strictosidine synthase from the Indian medicinal plant Rauvolfia serpentina. To expedite the discovery process, our study departs from the usual process of creating a random protein library, followed by extensive screening. Instead, a small, focused library of circular permutated variants of the six bladed β-propeller protein was prepared, specifically probing two regions which cover the enzyme active site. The observed activity changes suggest important roles of both regions in protein folding, stability and catalysis.
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      PubDate: 2014-10-12T08:24:19Z
       
  • Pichia stipitis OYE 2.6 variants with improved catalytic efficiencies from
           site-saturation mutagenesis libraries
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20
      Author(s): Athéna Patterson-Orazem , Bradford Sullivan , Jon D. Stewart
      An earlier directed evolution project using alkene reductase OYE 2.6 from Pichia stipitis yielded 13 active site variants with improved properties toward three homologous Baylis–Hillman adducts. Here, we probed the generality of these improvements by testing the wild-type and all 13 variants against a panel of 16 structurally-diverse electron-deficient alkenes. Several substrates were sterically demanding, and as hoped, creating additional active site volume yielded better conversions for these alkenes. The most impressive improvement was found for 2-butylidenecyclohexanone. The wild-type provided less than 20% conversion after 24h; a triple mutant afforded more than 60% conversion in the same time period. Moreover, even wild-type OYE 2.6 can reduce cyclohexenones with very bulky 4-substituents efficiently.
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      PubDate: 2014-10-12T08:24:19Z
       
  • Turning a monocovalent flavoprotein into a bicovalent flavoprotein by
           structure-inspired mutagenesis
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20
      Author(s): Malgorzata M. Kopacz , Marco W. Fraaije
      A recently discovered class of bicovalent flavoproteins is an interesting group of enzymes because of their unusual cofactor binding mode, their open active sites and the bulky substrates they can accept. Through a sequence comparison study we have identified a conserved sequence region in bicovalent flavoproteins that is different from monocovalent flavoproteins. Based on this and the available structural information we have designed mutants of the prototype monocovalent flavoprotein, 6-hydroxy-d-nicotine oxidase (6HDNO), in order to introduce a second cofactor-protein linkage. Two amino acid replacements, namely histidine 130 to a cysteine and leucine 138 to a histidine, were sufficient to create a bicovalent 6HDNO. The introduced cysteine forms a covalent bond with FAD as found in natural bicovalent flavoproteins, while the second mutation was found to be essential to facilitate the formation of the cysteinyl linkage. This points to an important role of the introduced histidine in stabilizing a negative charge of the isoalloxazine ring during covalent flavinylation. The His130Cys/Leu138His 6HDNO is still active and shows a higher midpoint redox potential when compared to wild-type 6HDNO. This agrees well with the previous studies that have shown that bicovalent flavoenzymes have extremely high redox potentials
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      PubDate: 2014-10-12T08:24:19Z
       
  • Application of engineered cytochrome P450 mutants as biocatalysts for the
           synthesis of benzylic and aromatic metabolites of fenamic acid NSAIDs
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20
      Author(s): Harini Venkataraman , Marlies C.A. Verkade-Vreeker , Luigi Capoferri , Daan P. Geerke , Nico P.E. Vermeulen , Jan N.M. Commandeur
      Cytochrome P450 BM3 mutants are promising biocatalysts for the production of drug metabolites. In the present study, the ability of cytochrome P450 BM3 mutants to produce oxidative metabolites of structurally related NSAIDs meclofenamic acid, mefenamic acid and tolfenamic acid was investigated. A library of engineered P450 BM3 mutants was screened with meclofenamic acid (1) to identify catalytically active and selective mutants. Three mono-hydroxylated metabolites were identified for 1. The hydroxylated products were confirmed by NMR analysis to be 3′-OH-methyl-meclofenamic acid (1a), 5-OH-meclofenamic acid (1b) and 4′-OH-meclofenamic acid (1c) which are human relevant metabolites. P450 BM3 variants containing V87I and V87F mutation showed high selectivity for benzylic and aromatic hydroxylation of 1 respectively. The applicability of these mutants to selectively hydroxylate structurally similar drugs such as mefenamic acid (2) and tolfenamic acid (3) was also investigated. The tested variants showed high total turnover numbers in the order of 4000–6000 and can be used as biocatalysts for preparative scale synthesis. Both 1 and 2 could undergo benzylic and aromatic hydroxylation by the P450 BM3 mutants, whereas 3 was hydroxylated only on aromatic rings. The P450 BM3 variant M11 V87F hydroxylated the aromatic ring at 4′ position of all three drugs tested with high regioselectivity. Reference metabolites produced by P450 BM3 mutants allowed the characterisation of activity and regioselectivity of metabolism of all three NSAIDs by thirteen recombinant human P450s. In conclusion, engineered P450 BM3 mutants that are capable of benzylic or aromatic hydroxylation of fenamic acid containing NSAIDs, with high selectivity and turnover numbers have been identified. This shows their potential use as a greener alternative for the generation of drug metabolites.
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      PubDate: 2014-10-12T08:24:19Z
       
  • Recent advances in biocatalyst discovery, development and applications
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20
      Author(s): Guang Yang , Yousong Ding
      Enzymes catalyze a wide range of biotransformations and have a great potential as environmentally friendly alternatives to classical chemical catalysts in various industrial applications. Recently, advanced techniques and strategies in enzyme discovery and engineering have led to the significant expansion of the quantity and functional diversity of biocatalysts, which has further allowed broader uses of biocatalysts in new processes, especially those traditionally enabled only by chemical catalysts. Here we highlight some of these recent advances with the focus on new approaches in biocatalyst discovery and development, and discuss new applications of selected biocatalysts including transaminases, cytochrome P450s, and Baeyer–Villiger monooxygenases.
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      PubDate: 2014-10-12T08:24:19Z
       
  • Influence of azide incorporation on binding affinity by small papain
           inhibitors
    • Abstract: Publication date: 15 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 20
      Author(s): Angelique E.M. Wammes , Tom G. Hendriks , Helene I.V. Amatdjais-Groenen , Marloes A. Wijdeven , Jan C.M. van Hest , Floris L. van Delft , Tina Ritschel , Floris P.J.T. Rutjes
      In order to develop affinity-based biosensor platforms, appropriate ligands with a functional handle for immobilization onto a biosensor surface are required. To this end, a library of papain inhibitors was designed and synthesized, containing different azide linkers for subsequent immobilization by ‘click’ chemistry, in this particular case by copper-free, strain-promoted azide–alkyne cycloaddition (SPAAC). Furthermore, a molecular docking study was performed to obtain a better insight as to at which position such azide handles could be tolerated without affecting binding affinity. Although the azide moiety is small, in some cases its introduction strongly influenced the binding affinity. For one class of inhibitors a swapped binding mode was proposed to explain the results. In addition, a specific site for linker introduction was identified, which did not significantly affect the binding affinity.
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      PubDate: 2014-10-12T08:24:19Z
       
  • Synthesis, anti-cancer and anti-inflammatory activity of novel
           2-substituted isoflavenes
    • Abstract: Publication date: 1 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 19
      Author(s): Eleanor Eiffe , Eddy Pasquier , Maria Kavallaris , Cristan Herbert , David StC Black , Naresh Kumar
      Fifteen novel 2-substituted isoflavenes were synthesised via nucleophilic addition to isoflavylium salts. Twelve of the newly synthesised isoflavenes, along with the unsubstituted parent isoflavene, were tested in cell viability assays against the SHEP neuroblastoma and MDA-MB-231 breast adenocarcinoma cell lines. While the 2-substituted isoflavenes displayed a range of anti-proliferative activities, in most cases they were less active that the unsubstituted isoflavene (IC50 =9.9μM vs SHEP; IC50 =33μM vs MDA-MB-231). However, compound 7f, derived from the reaction between isoflavylium salt 5 and para-methoxyacetophenone, showed improved anti-proliferative activity against breast cancer cells (IC50 =7.6μM). Furthermore, compound 7f, as well as analogues 7a, 7c, 11d and 14, inhibited the production of interleukin-6 in LPS-activated RAW 264.7 cells.
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      PubDate: 2014-10-12T08:24:19Z
       
  • Pyrazolone–quinazolone hybrids: A novel class of human
           4-hydroxyphenylpyruvate dioxygenase inhibitors
    • Abstract: Publication date: 1 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 19
      Author(s): Yu-Ling Xu , Hong-Yan Lin , Run-Jie Cao , Ze-Zhong Ming , Wen-Chao Yang , Guang-Fu Yang
      4-Hydroxyphenylpyruvate dioxygenase (HPPD), converting 4-hydroxyphenylpyruvate acid to homogentisate, is an important target for treating type I tyrosinemia and alkaptonuria due to its significant role in tyrosine catabolism. However, only one commercial drug, NTBC, also known as nitisinone, has been available for clinical use so far. Herein, we have elucidated the structure-based design of a series of pyrazolone–quinazolone hybrids that are novel potent human HPPD inhibitors through the successful integration of various techniques including computational simulations, organic synthesis, and biochemical characterization. Most of the new compounds displayed potent inhibitory activity against the recombinant human HPPD in nanomolar range. Compounds 3h and 3u were identified as the most potent candidates with K i values of around 10 nM against human HPPD, about three-fold more potent than NTBC. Molecular modeling indicated that the interaction between the pyrazolone ring and ferrous ion, and the hydrophobic interaction of quinazolone with its surrounding residues, such as Phe347 and Phe364, contributed greatly to the high potency of these inhibitors. Therefore, compounds 3h and 3u could be potentially useful for the treatment of type I tyrosinemia and other diseases with defects in tyrosine degradation.
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      PubDate: 2014-10-12T08:24:19Z
       
  • Hepatocyte-targeting gene delivery using a lipoplex composed of
           galactose-modified aromatic lipid synthesized with click chemistry
    • Abstract: Publication date: 1 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 19
      Author(s): Mizuha Sakashita , Shinichi Mochizuki , Kazuo Sakurai
      Highly efficient drug carriers targeting hepatocyte is needed for treatment for liver diseases such as liver cirrhosis and virus infections. Galactose or N-acetylgalactosamine is known to be recognized and incorporated into the cells through asialoglycoprotein receptor (ASGPR) that is exclusively expressed on hepatocyte and hepatoma. In this study, we synthesized a galactose-modified lipid with aromatic ring with click chemistry. To make a complex with DNA, termed ‘lipoplex’, we prepared a binary micelle composed of cationic lipid; dioleoyltrimethylammoniumpropane (DOTAP) and galactose-modified lipid (D/Gal). We prepared lipoplex from plasmid DNA (pDNA) and D/Gal and examined the cell specificity and transfection efficiency. The lipoplex was able to interact with ASGPR immobilized on gold substrate in the quartz-crystal microbalance (QCM) sensor cell. The lipoplex induced high gene expression to HepG2 cells, a human hepatocellular carcinoma cell line, but not to A549 cells, a human alveolar adenocarcinoma cell line. The treatment with asialofetuin, which is a ligand for ASGPR and would work as a competitive inhibitor, before addition of the lipoplexes decreased the expression to HepG2 cells. These results indicate that D/Gal lipoplex was incorporated into HepG2 cells preferentially through ASGPR and the uptake was caused by galactose specific receptor. This delivery system to hepatocytes may overcome the problems for gene therapy and be used for treatment of hepatitis and hepatic cirrhosis.
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      PubDate: 2014-10-12T08:24:19Z
       
  • Synthesis of non-prenyl analogues of baccharin as selective and potent
           inhibitors for aldo-keto reductase 1C3
    • Abstract: Publication date: 1 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 19
      Author(s): Satoshi Endo , Dawei Hu , Toshiyuki Matsunaga , Yoko Otsuji , Ossama El-Kabbani , Mahmoud Kandeel , Akira Ikari , Akira Hara , Yukio Kitade , Naoki Toyooka
      Inhibitors of a human member (AKR1C3) of the aldo-keto reductase superfamily are regarded as promising therapeutics for the treatment of prostatic and breast cancers. Baccharin [3-prenyl-4-(dihydrocinnamoyloxy)cinnamic acid], a component of propolis, was shown to be both potent (K i 56nM) and highly isoform-selective inhibitor of AKR1C3. In this study, a series of derivatives of baccharin were synthesized by replacing the 3-prenyl moiety with aryl and alkyl ether moieties, and their inhibitory activities for the enzyme were evaluated. Among them, two benzyl ether derivatives, 6m and 6n, showed an equivalent inhibitory potency to baccharin. The molecular docking of 6m in AKR1C3 has allowed the design and synthesis of (E)-3-{3-[(3-hydroxybenzyl)oxy]-4-[(3-phenylpropanoyl)oxy]phenyl}acrylic acid (14) with improved potency (K i 6.4nM) and selectivity comparable to baccharin. Additionally, 14 significantly decreased the cellular metabolism of androsterone and cytotoxic 4-oxo-2-nonenal by AKR1C3 at much lower concentrations than baccharin.
      Graphical abstract image

      PubDate: 2014-10-12T08:24:19Z
       
  • Prodrug oncrasin-266 improves the stability, pharmacokinetics, and safety
           of NSC-743380
    • Abstract: Publication date: 1 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 19
      Author(s): Shuhong Wu , Li Wang , Xiao Huang , Mengru Cao , Jing Hu , Hongyu Li , Hui Zhang , Xiaoping Sun , Qing H. Meng , Wayne L. Hofstetter , Jack A. Roth , Stephen G. Swisher , Bingliang Fang
      Through synthetic lethality screening of isogenic cell lines with and without the oncogenic KRAS gene and through lead compound optimization, we recently developed a novel anticancer agent designated NSC-743380 (oncrasin-72) that has promising in vitro and in vivo anticancer activity in a subset of cancer cell lines, including KRAS-mutant cancer cells. However, NSC-743380 tends to form dimers, which dramatically reduces its anticancer activity. To improve the physicochemical properties of NSC-743380, we synthesized a prodrug of NSC-743380, designated oncrasin-266, by modifying NSC-743380 with cyclohexylacetic acid and evaluated its in vitro and in vivo properties. Oncrasin-266 spontaneously hydrolyzed in phosphate-buffered saline in a time-dependent manner and was more stable than NSC-743380 in powder or stock solutions. In vivo administration of oncrasin-266 in mice led to the release of NSC-743380 which improved the pharmacokinetics of NSC-743380. Tissue distribution analysis revealed that oncrasin-266 was deposited in liver, whereas released NSC-743380 was detected in liver, lung, kidney, and subcutaneous tumor. Oncrasin-266 was better tolerated in mice at a higher dose level treatment (150–300mg/kg, ip) than the parent agent was, suggesting that the prodrug reduced the acute toxicity of the parent agent. Our results demonstrated that the prodrug strategy could improve the stability, pharmacokinetic properties, and safety of NSC-743380.
      Graphical abstract image

      PubDate: 2014-10-12T08:24:19Z
       
  • From human immunodeficiency virus non-nucleoside reverse transcriptase
           inhibitors to potent and selective antitrypanosomal compounds
    • Abstract: Publication date: 1 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 19
      Author(s): Muthusamy Venkatraj , Kevin K. Ariën , Jan Heeres , Jurgen Joossens , Bertrand Dirié , Sophie Lyssens , Johan Michiels , Paul Cos , Paul J. Lewi , Guido Vanham , Louis Maes , Pieter Van der Veken , Koen Augustyns
      The presence of a structural recognition motif for the nucleoside P2 transporter in a library of pyrimidine and triazine non-nucleoside HIV-1 reverse transcriptase inhibitors, prompted for the evaluation of antitrypanosomal activity. It was demonstrated that the structure–activity relationship for anti-HIV and antitrypanosomal activity was different. Optimization in the diaryl triazine series led to 6-(mesityloxy)-N 2-phenyl-1,3,5-triazine-2,4-diamine (69), a compound with potent in vitro and moderate in vivo antitrypanosomal activity.
      Graphical abstract image

      PubDate: 2014-10-12T08:24:19Z
       
  • Novel chromogenic aminopeptidase substrates for the detection and
           identification of clinically important microorganisms
    • Abstract: Publication date: 1 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 19
      Author(s): Marie Cellier , Arthur L. James , Sylvain Orenga , John D. Perry , Ari K. Rasul , Shaun N. Robinson , Stephen P. Stanforth
      A series of amino acid derivatives 8–10, 42 and 43 have been prepared as chromogenic enzyme substrates in order to detect aminopeptidase activity in clinically important Gram-negative and Gram-positive bacteria. Enzymatic hydrolysis liberates the amino acid moiety and either a 4-aminophenol or a 4-dialkylaminoaniline derivative which undergoes oxidative coupling with 1-naphthol or a substituted 1-naphthol giving an indophenol dye. Substrates and 1-naphthols were incorporated into an agar-based culture medium and this allowed growth of intensely coloured bacterial colonies based on hydrolysis by specific enzymes. Red/pink coloured colonies were produced by the substrates 8–10 and blue coloured colonies were formed by the substrates 42 and 43. The l-alanyl aminopeptidase substrates 8 targeted l-alanyl aminopeptidase activity and gave coloured colonies with a range of Gram-negative bacteria. Substrates 9 targeted β-alanyl aminopeptidase activity and generated coloured colonies with selected Gram-negative species including Pseudomonas aeruginosa. Three substrates for l-pyroglutamyl acid aminopeptidase (10a, 10c and 43) were hydrolysed by enterococci and Streptococcus pyogenes to generate coloured colonies. Two yeasts were also included in the study, but they did not produce coloured colonies with any of the substrates examined.
      Graphical abstract image

      PubDate: 2014-10-12T08:24:19Z
       
  • Synthesis and evaluation of a 18F-labeled spirocyclic piperidine
           derivative as promising σ1 receptor imaging agent
    • Abstract: Publication date: 1 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 19
      Author(s): Yuan-Yuan Chen , Xia Wang , Jin-Ming Zhang , Winnie Deuther-Conrad , Xiao-Jun Zhang , Yiyun Huang , Yan Li , Jia-Jun Ye , Meng-Chao Cui , Jörg Steinbach , Peter Brust , Bo-Li Liu , Hong-Mei Jia
      Several spirocyclic piperidine derivatives were designed and synthesized as σ1 receptor ligands. In vitro competition binding assays showed that the fluoroalkoxy analogues with small substituents possessed high affinity towards σ1 receptors and subtype selectivity. Particularly for ligand 1′-((6-(2-fluoroethoxy)pyridin-3-yl)methyl)-3H-spiro[2-benzofuran-1,4′-piperidine] (2), high σ1 receptor affinity (K i =2.30nM) and high σ1/σ2 subtype selectivity (142-fold) as well as high σ1/VAChT selectivity (234-fold) were observed. [18F]2 was synthesized using an efficient one-pot, two-step reaction method in a home-made automated synthesis module, with an overall isolated radiochemical yield of 8–10%, a radiochemical purity of higher than 99%, and specific activity of 56–78GBq/μmol. Biodistribution studies of [18F]2 in ICR mice indicated high initial brain uptake and a relatively fast washout. Administration of haloperidol, compound 1 and different concentrations of SA4503 (3, 5, or 10μmol/kg) 5min prior to injection of [18F]2 significantly decreased the accumulation of radiotracer in organs known to contain σ1 receptors. Ex vivo autoradiography in Sprague–Dawley rats demonstrated high accumulation of radiotracer in brain areas with high expression of σ1 receptors. These encouraging results prove that [18F]2 is a suitable candidate for σ1 receptor imaging with PET in humans.
      Graphical abstract image

      PubDate: 2014-10-12T08:24:19Z
       
  • Synthesis of α-l-rhamnosyl ceramide and evaluation of its binding
           with anti-rhamnose antibodies
    • Abstract: Publication date: 1 October 2014
      Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 19
      Author(s): David E. Long , Partha Karmakar , Katherine A. Wall , Steven J. Sucheck
      An α-l-rhamnosyl ceramide (1, α-l-RhaCer) has been prepared that was recognized by anti-l-rhamnose (anti-Rha) antibodies. During these studies we explored the use of an α-l-rhamnosyl thioglycoside and a trichloroacetimidate as a glycosyl donors. Subsequently, the acceptors desired for glycosylation, 3-O-benzoylazidosphingosine or 3-O-alloxycarbonylsphingosine, were prepared from d-xylose. The thioglycoside donor, 2,3,4-tri-O-acetyl-1-(4-tolyl)thio-α-l-rhamnopyranoside, and the trichloroacetimidate donor, 2,3,4-tri-O-acetyl-1-(2,2,2-trichloroethanimidate)-α-l-rhamnopyranoside, were synthesized in 50% and 78% yield overall, respectively. The synthesis of the glycosylation acceptor employed an addition–fragmentation olefination that was successfully carried out in 53% yield. With the successful synthesis of key intermediates, α-l-RhaCer (1) was prepared without any insurmountable obstacles. Anti-Rha antibodies were prepared in BALB/c mice by immunizing them with rhamnose-ovalbumin (Rha-Ova) with Sigma Adjuvant System (SAS) and the anti-l-Rha antibodies were isolated from the blood sera. Liposomes and EL4 tumor cells were used as model systems to demonstrate the ability of 1 to insert into a lipid bilayer. The interaction of the liposomes or the EL4 cells with α-l-RhaCer (1) and anti-Rha antibodies were investigated by fluorescence microscopy and flow cytometry, respectively, to confirm the ability of glycolipid 1 to be displayed on the tumor cell surface as well as the ability to be recognized by anti-Rha antibodies.
      Graphical abstract image

      PubDate: 2014-10-12T08:24:19Z
       
 
 
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