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Sample records for acyclic nucleoside phosphonates

  1. Enantiopurity analysis of new types of acyclic nucleoside phosphonates by capillary electrophoresis with cyclodextrins as chiral selectors.

    Science.gov (United States)

    Solínová, Veronika; Kaiser, Martin Maxmilián; Lukáč, Miloš; Janeba, Zlatko; Kašička, Václav

    2014-02-01

    CE methods have been developed for the chiral analysis of new types of six acyclic nucleoside phosphonates, nucleotide analogs bearing [(3-hydroxypropan-2-yl)-1H-1,2,3-triazol-4-yl]phosphonic acid, 2-[(diisopropoxyphosphonyl)methoxy]propanoic acid, or 2-(phosphonomethoxy)propanoic acid moieties attached to adenine, guanine, 2,6-diaminopurine, uracil, and 5-bromouracil nucleobases, using neutral and cationic cyclodextrins as chiral selectors. With the exception of the 5-bromouracil-derived acyclic nucleoside phosphonate with a 2-(phosphonomethoxy)propanoic acid side chain, the R and S enantiomers of the other five acyclic nucleoside phosphonates were successfully separated with sufficient resolutions, 1.51-2.94, within a reasonable time, 13-28 min, by CE in alkaline BGEs (50 mM sodium tetraborate adjusted with NaOH to pH 9.60, 9.85, and 10.30, respectively) containing 20 mg/mL β-cyclodextrin as the chiral selector. A baseline separation of the R and S enantiomers of the 5-bromouracil-derived acyclic nucleoside phosphonate with 2-(phosphonomethoxy)propanoic acid side chain was achieved within a short time of 7 min by CE in an acidic BGE (20:40 mM Tris/phosphate, pH 2.20) using 60 mg/mL quaternary ammonium β-cyclodextrin chiral selector. The developed methods were applied for the assessment of the enantiomeric purity of the above acyclic nucleoside phosphonates. The preparations of all these compounds were found to be synthesized in pure enantiomeric forms. Using UV absorption detection at 206 nm, their concentration detection limits were in the low micromolar range.

  2. Synthesis of some novel hydrazono acyclic nucleoside analogues

    Directory of Open Access Journals (Sweden)

    Mohammad N. Soltani Rad

    2010-05-01

    Full Text Available The syntheses of novel hydrazono acyclic nucleosides similar to miconazole scaffolds are described. In this series of acyclic nucleosides, pyrimidine as well as purine and other azole derivatives replaced the imidazole function in miconazole and the ether group was replaced with a hydrazone moiety using phenylhydrazine. To interpret the dominant formation of (E-hydrazone derivatives rather than (Z-isomers, PM3 semiempirical quantum mechanic calculations were carried out which indicated that the (E-isomers had the lower heats of formation.

  3. Acyclic Immucillin Phosphonates. Second-Generation Inhibitors of Plasmodium falciparum Hypoxanthine- Guanine-Xanthine Phosphoribosyltransferase

    Energy Technology Data Exchange (ETDEWEB)

    Hazelton, Keith Z. [Yeshiva Univ., New York, NY (United States); Ho, Meng-Chaio [Yeshiva Univ., New York, NY (United States); Cassera, Maria B. [Yeshiva Univ., New York, NY (United States); Clinch, Keith [Industrial Research Ltd., Lower Hutt (New Zealand); Crump, Douglas R. [Industrial Research Ltd., Lower Hutt (New Zealand); Rosario Jr., Irving [Yeshiva Univ., New York, NY (United States); Merino, Emilio F. [Yeshiva Univ., New York, NY (United States); Almo, Steve C. [Yeshiva Univ., New York, NY (United States); Tyler, Peter C. [Industrial Research Ltd., Lower Hutt (New Zealand); Schramm, Vern L. [Yeshiva Univ., New York, NY (United States)

    2012-06-22

    We found that Plasmodium falciparum is the primary cause of deaths from malaria. It is a purine auxotroph and relies on hypoxanthine salvage from the host purine pool. Purine starvation as an antimalarial target has been validated by inhibition of purine nucleoside phosphorylase. Hypoxanthine depletion kills Plasmodium falciparum in cell culture and in Aotus monkey infections. Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) from P. falciparum is required for hypoxanthine salvage by forming inosine 5'-monophosphate, a branchpoint for all purine nucleotide synthesis in the parasite. We present a class of HGXPRT inhibitors, the acyclic immucillin phosphonates (AIPs), and cell permeable AIP prodrugs. The AIPs are simple, potent, selective, and biologically stable inhibitors. The AIP prodrugs block proliferation of cultured parasites by inhibiting the incorporation of hypoxanthine into the parasite nucleotide pool and validates HGXPRT as a target in malaria.

  4. The preparation of trisubstituted alkenyl nucleoside phosphonates under ultrasound-assisted olefin cross-metathesis.

    Science.gov (United States)

    Sari, Ozkan; Hamada, Manabu; Roy, Vincent; Nolan, Steven P; Agrofoglio, Luigi A

    2013-09-01

    Intermolecular ultrasound-assisted olefin cross-metathesis is reported. This approach allows an easy access to challenging trisubstituted alkenyl nucleoside phosphonates. Regioselective chemoenzymatic deacetylation and Mitsunobu coupling are also described.

  5. The preparation of trisubstituted alkenyl nucleoside phosphonates under ultrasound-assisted olefin cross-metathesis.

    Science.gov (United States)

    Sari, Ozkan; Hamada, Manabu; Roy, Vincent; Nolan, Steven P; Agrofoglio, Luigi A

    2013-09-01

    Intermolecular ultrasound-assisted olefin cross-metathesis is reported. This approach allows an easy access to challenging trisubstituted alkenyl nucleoside phosphonates. Regioselective chemoenzymatic deacetylation and Mitsunobu coupling are also described. PMID:23961760

  6. Synthesis of conformationally locked L-deoxythreosyl phosphonate nucleosides built on a bicyclo[3.1.0]hexane template.

    Science.gov (United States)

    Saneyoshi, Hisao; Deschamps, Jeffrey R; Marquez, Victor E

    2010-11-19

    Two conformationally locked versions of l-deoxythreosyl phosphonate nucleosides (2 and 3) were synthesized to investigate the preference of HIV reverse transcriptase for a conformation displaying either a fully diaxial or fully diequatorial disposition of substituents. Synthesis of the enantiomeric 4-(6-amino-9H-purin-9-yl)bicyclo[3.1.0]hexan-2-ol carbocyclic nucleoside precursors (diaxially disposed) proceeded straightforwardly from commercially available (1R,4S)-4-hydroxy-2-cyclopent-2-enyl-1-yl acetate employing a hydroxyl-directed Simmons-Smith cyclopropanation that culminated with a Mitsunobu coupling of the purine base. For the more complicated 1-(6-amino-9H-purin-9-yl)bicyclo[3.1.0]hexan-3-ol carbocyclic nucleoside precursors (diequatorially disposed), the obligatory linear approach required the syntheses of key 1-aminobicyclo[3.1.0.]hexan-3-yl benzoate precursors that were assembled via the amide variant of the Kulinkovich reaction involving the intramolecular cyclopropanation of a substituted δ-vinylamide. Completion of the purine ring was achieved by conventional approaches but with much improved yields through the use of a microwave reactor. The syntheses of the phosphonates and the corresponding diphosphates were achieved by conventional means. None of the diphosphates, which were supposed to act as nucleoside triphosphate mimics, could compete with dATP even when present in a 10-fold excess. PMID:20964394

  7. Milestones in the discovery of antiviral agents: nucleosides and nucleotides

    Directory of Open Access Journals (Sweden)

    Erik de Clercq

    2012-12-01

    Full Text Available In this review article, a number of milestones in the antiviral research field on nucleosides and nucleotides are reviewed in which the author played a significant part, especially in the initial stages of their development. Highlighted are the amino acyl esters of acyclovir, particularly valacyclovir (VACV, brivudin (BVDU and the valine ester of Cf1743 (FV-100, the 2′,3′-dideoxynucleosides (nucleoside reverse transcriptase inhibitors, NRTIs, the acyclic nucleoside phosphonates (S-HPMPA, (S-HPMPC (cidofovir and alkoxyalkyl esters thereof (HDP-, ODE-CDV, adefovir and adefovir dipivoxil, tenofovir and tenofovir disoproxil fumarate (TDF, combinations containing TDF and emtricitabine, i.e., Truvada®, Atripla®, Complera®/Eviplera® and the Quad pill, and the phosphonoamidate derivatives GS-7340, GS-9131, GS-9191 and GS-9219.

  8. Counting acyclic hypergraphs

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Acyclic hypergraphs are analogues of forests in graphs. They arevery useful in the design of databases. The number of distinct acyclic uniform hypergraphs with n labeled vertices is studied. With the aid of the principle of inclusion-exclusion, two formulas are presented. One is the explicit formula for strict (d)-connected acyclic hypergraphs, the other is the recurrence formula for linear acyclic hypergraphs.

  9. Subquivers of mutation-acyclic quivers are mutation-acyclic

    CERN Document Server

    Warkentin, Matthias

    2011-01-01

    Quiver mutation plays a crucial role in the definition of cluster algebras by Fomin and Zelevinsky. It induces an equivalence relation on the set of all quivers without loops and two-cycles. A quiver is called mutation-acyclic if it is mutation-equivalent to an acyclic quiver. The aim of this note is to show that full subquivers of mutation-acyclic quivers are mutation-acyclic.

  10. Enumeration of Maximum Acyclic Hypergraphs

    Institute of Scientific and Technical Information of China (English)

    Jian-fang Wang; Hai-zhu Li

    2002-01-01

    Acyclic hypergraphs are analogues of forests in graphs. They are very useful in the design of databases. In this article, the maximum size of an acyclic hypergraph is determined and the number of maximum r-uniform acyclic hypergraphs of order n is shown to be ( n t-1 )(n(r-1)-r2 +2r)n-r-1.

  11. Nucleoside Sensing

    OpenAIRE

    Thomas Schrader; Frank-Gerrit Klärner; Michael Fokkens

    2006-01-01

    A rigid molecular clip comprising bisphosphonate binding sites and aromatic sidewalls forming an electron-rich cavity is able to distinguish between nucleosides and nucleotides in aqueous solution. Neutral nucleosides as well as antibiotics derived thereof are drawn into the unpolar interior of the cleft and lead to substantial upfield-shifts in the 1H NMR spectrum. Nucleoside drugs can therefore be detected with high selectivity in the presence of their phosphorylated pendants or nucleic acids.

  12. ON ACYCLIC AND CYCLIC HYPERGRAPHS

    Institute of Scientific and Technical Information of China (English)

    LI Haizhu; WANG Jianfang

    2002-01-01

    So far, the acyclic hypergraph has two different definitions. One is based onthe cyclomatic number of the hypergraph, whereas the other arises from the acyclic schemaof the relational database in the computer science. In this paper, it is first proved thatthese two definitions coincide with each other completely. Then we prove that a hypergraphH is not acyclic, or cyclic, if and only if it contains a special partial hypergraph namedhypercircuit. In addition, we show that H has l(H) different hypercircuits, where l(H) isa parameter used to decide whether H is acyclic or cyclic.

  13. Backdoors to Acyclic SAT

    CERN Document Server

    Gaspers, Serge

    2011-01-01

    Backdoor sets, a notion introduced by Williams et al. in 2003, are certain sets of "key" variables of a CNF formula F that make it easy to solve the formula; by assigning truth values to the variables in a backdoor set, the formula gets reduced to one or several polynomial-time solvable formulas. More specifically, a weak backdoor set of F is a set X of variables such that there exits a truth assignment t to X that reduces F to a satisfiable formula F[t] that belongs to a polynomial-time decidable base class C. A strong backdoor set is a set X of variables such that for all assignments t to X, the reduced formula F[t] belongs to C. We study the problem of finding backdoor sets of size at most k with respect to the base class of CNF formulas with acyclic incidence graphs, taking k as the parameter. We show that 1. the detection of weak backdoor sets is W[2]-hard in general but fixed-parameter tractable for r-CNF formulas, for any fixed r>=3, and 2. the detection of strong backdoor sets is fixed-parameter appro...

  14. Some inequalities for orderings of acyclic digraphs

    CERN Document Server

    Bier, Thomas

    2011-01-01

    For any acyclic ordering $g$ of a finite acyclic digraph $D$ we obtain a lower bound inequality for the inner product of its $e-$vector and $g.$ Here the $e-$vector is defined to be the difference of the indegree and the outdegree of the underlying acyclic digraph. This gives a lower bound on the functional $ T_e(f) = ,$ defined on the set of all acyclic orderings of $D.$ The class of acyclic digraphs which admit an acyclic ordering attaining the lower bound is determined as the class of posets of order dimension two.

  15. A Scalable Acyclic Graph Generator

    CERN Document Server

    Gupta, Sandeep

    2012-01-01

    Acyclic graphs, much like scale-free graphs, appear in many areas of computation and engineering. These include, but are not limited to, knowledge representation, binary decision diagrams, dependency graphs, semantic web, and, binaries of computer programs. In the field of life-sciences and bio-informatics, in particular, such structures are used to create ontologies that represent the compendium of factual information and are central towards organizing and cataloging scientific data. I show why most naive generators might produce degenerate (bipartite graphs) and propose a generator that can produce a stochastic acyclic graph satisfying constraints on the in-degree, the out-degree, the depth, and the path-length (distribution of random walks from source to sink) attributes of the resulting dag. I provide suit of distribution functions that yield non-degenerate real-world acyclic graphs.

  16. On Acyclicity of Games with Cycles

    DEFF Research Database (Denmark)

    Andersson, Daniel; Gurvich, Vladimir; Hansen, Thomas Dueholm

    2009-01-01

    We study restricted improvement cycles (ri-cycles) in finite positional n-person games with perfect information modeled by directed graphs (digraphs) that may contain cycles. We obtain criteria of restricted improvement acyclicity (ri-acyclicity) in two cases: for n = 2 and for acyclic digraphs. We...

  17. Convex sets in acyclic digraphs

    CERN Document Server

    Balister, P; Gutin, G

    2007-01-01

    A non-empty set $X$ of vertices of an acyclic digraph is called connected if the underlying undirected graph induced by $X$ is connected and it is called convex if no two vertices of $X$ are connected by a directed path in which some vertices are not in $X$. The set of convex sets (connected convex sets) of an acyclic digraph $D$ is denoted by $\\sco(D)$ ($\\scc(D)$) and its size by $\\co(D)$ ($\\cc(D)$). Gutin, Johnstone, Reddington, Scott, Soleimanfallah, and Yeo (Proc. ACiD'07) conjectured that the sum of the sizes of all (connected) convex sets in $D$ equals $\\Theta(n \\cdot \\co(D))$ ($\\Theta(n \\cdot \\cc(D))$) where $n$ is the order of $D$. In this paper we exhibit a family of connected acyclic digraphs with $\\sum_{C\\in \\sco(D)}|C| = o(n\\cdot \\co(D))$ and $\\sum_{C\\in \\scc(D)}|C| = o(n\\cdot \\cc(D))$. We also show that the number of connected convex sets of order $k$ in any connected acyclic digraph of order $n$ is at least $n-k+1$. This is a strengthening of a theorem by Gutin and Yeo.

  18. [Amino(iminiomethyl]phosphonate

    Directory of Open Access Journals (Sweden)

    Ting-Hai Yang

    2010-09-01

    Full Text Available The title compound, CH5N2O3P, exists as a zwitterion. The N atom of the imino group is protonated and the phosphonic acid group is deprotonated. The molecular geometry about the central C atom of this zwitterionic species was found to be strictly planar with the sum of the three angles about C being precisely 360°. In the crystal, the molecules are interlinked by O—H...O and N—H...O hydrogen-bonding interactions, forming a three-dimensional supramolecular network structure.

  19. Higher-dimensional normalisation strategies for acyclicity

    CERN Document Server

    Guiraud, Yves

    2010-01-01

    We introduce acyclic track polygraphs, a notion of complete categorical cellular models for small categories: they are polygraphs containing generators, with additional invertible cells for relations and higher-dimensional globular syzygies. We give a rewriting method to realise such a model by proving that a convergent presentation canonically extends to an acyclic track polygraph. For that, we introduce normalising strategies, defined as homotopically coherent ways to relate each cell of a track polygraph to its normal form, and we prove that acyclicity is equivalent to the existence of a normalisation strategy.

  20. Algorithms for Junctions in Directed Acyclic Graphs

    CERN Document Server

    Ferreira, Carlos Eduardo

    2012-01-01

    Given a pair of distinct vertices u, v in a graph G, we say that s is a junction of u, v if there are in G internally vertex disjoint directed paths from s to u and from s to v. We show how to characterize junctions in directed acyclic graphs. We also consider the two problems in the following and derive efficient algorithms to solve them. Given a directed acyclic graph G and a vertex s in G, how can we find all pairs of vertices of G such that s is a junction of them? And given a directed acyclic graph G and k pairs of vertices of G, how can we preprocess G such that all junctions of k given pairs of vertices could be listed quickly? All junctions of k pairs problem arises in an application in Anthropology and we apply our algorithm to find such junctions on kinship networks of some brazilian indian ethnic groups.

  1. The Algebra of Directed Acyclic Graphs

    OpenAIRE

    Fiore, Marcelo; Campos, Marco Devesas

    2013-01-01

    We give an algebraic presentation of directed acyclic graph structure, introducing a symmetric monoidal equational theory whose free PROP we characterise as that of finite abstract dags with input/output interfaces. Our development provides an initial-algebra semantics for dag structure.

  2. Removal and Recovery of Phosphonate Antiscalants

    OpenAIRE

    Boels, L.

    2012-01-01

    In reverse osmosis (RO) desalination processes, the use of phosphonates prevents scaling, thus allowing for a higher product water recovery, which increases the efficiency of the process. However, a major concern associated with their use in RO desalination is the high cost and environmental impacts associated with the discharge of the waste brine or membrane concentrate containing phosphonates. Therefore, technologies are needed that can remove and recover phosphonate antiscalants from membr...

  3. Nucleotides, Nucleosides, and Nucleobases

    DEFF Research Database (Denmark)

    Jensen, Kaj Frank; Dandanell, Gert; Hove-Jensen, Bjarne;

    2008-01-01

    We review literature on the metabolism of ribo- and deoxyribonucleotides, nucleosides, and nucleobases in Escherichia coli and Salmonella,including biosynthesis, degradation, interconversion, and transport. Emphasis is placed on enzymology and regulation of the pathways, at both the level of gene...

  4. Acyclic 6-choosability of planar graphs without adjacent short cycles

    Institute of Scientific and Technical Information of China (English)

    WANG WeiFan; ZHANG Ge; CHEN Min

    2014-01-01

    A proper vertex coloring of a graph G is acyclic if G contains no bicolored cycles.Given a list assignment L={L(v)|v∈V}of G,we say that G is acyclically L-colorable if there exists a proper acyclic coloringπof G such thatπ(v)∈L(v)for all v∈V.If G is acyclically L-colorable for any list assignment L with|L(v)|k for all v∈V(G),then G is acyclically k-choosable.In this paper,we prove that every planar graph G is acyclically 6-choosable if G does not contain 4-cycles adjacent to i-cycles for each i∈{3,4,5,6}.This improves the result by Wang and Chen(2009).

  5. Acyclic Edge Coloring of Planar Graphs without Adjacent Triangles

    Institute of Scientific and Technical Information of China (English)

    Dezheng XIE; Yanqing WU

    2012-01-01

    An acyclic edge coloring of a graph G is a proper edge coloring such that there are no bichromatic cycles.The acyclic edge chromatic number of a graph G is the minimum number k such that there exists an acyclic edge coloring using k colors and is denoted by x'a(G).In this paper we prove that x'a(G)≤ Δ(G)+ 5 for planar graphs G without adjacent triangles.

  6. Synthesis of novel castor oil phosphonates

    Science.gov (United States)

    Castor oil has served as a versatile hydroxy fatty acid (HFA); its principle component, ricinoleic acid, can be isolated from castor oil and has been modified extensively for a number of applications. Additionally, phosphonates and their corresponding phosphonic acids are a functional moiety that ha...

  7. Bayesian Discovery of Linear Acyclic Causal Models

    CERN Document Server

    Hoyer, Patrik O

    2012-01-01

    Methods for automated discovery of causal relationships from non-interventional data have received much attention recently. A widely used and well understood model family is given by linear acyclic causal models (recursive structural equation models). For Gaussian data both constraint-based methods (Spirtes et al., 1993; Pearl, 2000) (which output a single equivalence class) and Bayesian score-based methods (Geiger and Heckerman, 1994) (which assign relative scores to the equivalence classes) are available. On the contrary, all current methods able to utilize non-Gaussianity in the data (Shimizu et al., 2006; Hoyer et al., 2008) always return only a single graph or a single equivalence class, and so are fundamentally unable to express the degree of certainty attached to that output. In this paper we develop a Bayesian score-based approach able to take advantage of non-Gaussianity when estimating linear acyclic causal models, and we empirically demonstrate that, at least on very modest size networks, its accur...

  8. On network coding for acyclic networks with delays

    CERN Document Server

    Prasad, K

    2011-01-01

    Problems related to network coding for acyclic, instantaneous networks (where the edges of the acyclic graph representing the network are assumed to have zero-delay) have been extensively dealt with in the recent past. The most prominent of these problems include (a) the existence of network codes that achieve maximum rate of transmission, (b) efficient network code constructions, and (c) field size issues. In practice, however, networks have transmission delays. In network coding theory, such networks with transmission delays are generally abstracted by assuming that their edges have integer delays. Note that using enough memory at the nodes of an acyclic network with integer delays can effectively simulate instantaneous behavior, which is probably why only acyclic instantaneous networks have been primarily focused on thus far. In this work, we elaborate on issues ((a), (b) and (c) above) related to network coding for acyclic networks with integer delays, which have till now been overlooked. We show that the...

  9. Nucleoside Inhibitors of Zika Virus.

    Science.gov (United States)

    Eyer, Luděk; Nencka, Radim; Huvarová, Ivana; Palus, Martin; Joao Alves, Maria; Gould, Ernest A; De Clercq, Erik; Růžek, Daniel

    2016-09-01

    There is growing evidence that Zika virus (ZIKV) can cause devastating infant brain defects and other neurological disorders in humans. However, no specific antiviral therapy is available at present. We tested a series of 2'-C- or 2'-O-methyl-substituted nucleosides, 2'-C-fluoro-2'-C-methyl-substituted nucleosides, 3'-O-methyl-substituted nucleosides, 3'-deoxynucleosides, derivatives with 4'-C-azido substitution, heterobase-modified nucleosides, and neplanocins for their ability to inhibit ZIKV replication in cell culture. Antiviral activity was identified when 2'-C-methylated nucleosides were tested, suggesting that these compounds might represent promising lead candidates for further development of specific antivirals against ZIKV. PMID:27234417

  10. Phosphonate Based High Nuclearity Magnetic Cages.

    Science.gov (United States)

    Sheikh, Javeed Ahmad; Jena, Himanshu Sekhar; Clearfield, Abraham; Konar, Sanjit

    2016-06-21

    Transition metal based high nuclearity molecular magnetic cages are a very important class of compounds owing to their potential applications in fabricating new generation molecular magnets such as single molecular magnets, magnetic refrigerants, etc. Most of the reported polynuclear cages contain carboxylates or alkoxides as ligands. However, the binding ability of phosphonates with transition metal ions is stronger than the carboxylates or alkoxides. The presence of three oxygen donor sites enables phosphonates to bridge up to nine metal centers simultaneously. But very few phosphonate based transition metal cages were reported in the literature until recently, mainly because of synthetic difficulties, propensity to result in layered compounds, and also their poor crystalline properties. Accordingly, various synthetic strategies have been followed by several groups in order to overcome such synthetic difficulties. These strategies mainly include use of small preformed metal precursors, proper choice of coligands along with the phosphonate ligands, and use of sterically hindered bulky phosphonate ligands. Currently, the phosphonate system offers a library of high nuclearity transition metal and mixed metal (3d-4f) cages with aesthetically pleasing structures and interesting magnetic properties. This Account is in the form of a research landscape on our efforts to synthesize and characterize new types of phosphonate based high nuclearity paramagnetic transition metal cages. We quite often experienced synthetic difficulties with such versatile systems in assembling high nuclearity metal cages. Few methods have been emphasized for the self-assembly of phosphonate systems with suitable transition metal ions in achieving high nuclearity. We highlighted our journey from 2005 until today for phosphonate based high nuclearity transition metal cages with V(IV/V), Mn(II/III), Fe(III), Co(II), Ni(II), and Cu(II) metal ions and their magnetic properties. We observed that

  11. Acyclic Preference Systems in P2P Networks

    CERN Document Server

    Gai, Anh-Tuan; Mathieu, Fabien; De Montgolfier, Fabien; Reynier, Julien; Viennot, Laurent

    2007-01-01

    In this work we study preference systems natural for the Peer-to-Peer paradigm. Most of them fall in three categories: global, symmetric and complementary. All these systems share an acyclicity property. As a consequence, they admit a stable (or Pareto efficient) configuration, where no participant can collaborate with better partners than their current ones. We analyze the representation of the such preference systems and show that any acyclic system can be represented with a symmetric mark matrix. This gives a method to merge acyclic preference systems and retain the acyclicity. We also consider such properties of the corresponding collaboration graph, as clustering coefficient and diameter. In particular, studying the example of preferences based on real latency measurements, we observe that its stable configuration is a small-world graph.

  12. [Purine nucleoside phosphorylase].

    Science.gov (United States)

    Pogosian, L G; Akopian, Zh I

    2013-01-01

    Purine nucleoside phosphorylase (PNP) is one of the most important enzymes of the purine metabolism, wich promotes the recycling of purine bases. Nowadays is the actual to search for effective inhibitors of this enzyme which is necessary for creation T-cell immunodeficient status of the organism in the organs and tissues transplantation, and chemotherapy of a number pathologies as well. For their successful practical application necessary to conduct in-depth and comprehensive study of the enzyme, namely a structure, functions, and an affinity of the reaction mechanism. In the review the contemporary achievements in the study of PNP from various biological objects are presented. New data describing the structure of PNP are summarised and analysed. The physiological role of the enzyme is discussed. The enzyme basic reaction mechanisms and actions are considered. The studies on enzyme physicochemical, kinetic, and catalytic research are presented. PMID:24479338

  13. Carboranyl Nucleosides & Oligonucleotides for Neutron Capture Therapy Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Schinazi, Raymond F.

    2004-12-01

    This proposal enabled us to synthesize and develop boron-rich nucleosides and oligonucleotide analogues for boron neutron capture therapy (BNCT) and the treatment of various malignancies. First, we determined the relationship between structure, cellular accumulation and tissue distribution of 5-o-carboranyl-2'-deoxyuridine (D-CDU) and its derivatives D-ribo-CU and 5-o-carboranyluracil (CU), to potentially target brain and other solid tumors for neutron capture therapy. Synthesized carborane containing nucleoside derivatives of CDU, D- and L-enantiomers of CDU, D-ribo-CU and CU were used. We measured tissue disposition in xenografted mice bearing 9479 human prostate tumors xenografts and in rats bearing 9L gliosarcoma isografts in their flanks and intracranially. The accumulation of D-CDU, 1-({beta}-L-arabinosyl)-5-o-carboranyluracil, D-ribo-CU, and CU were also studied in LnCap human prostate tumor cells and their retention was measured in male nude mice bearing LnCap and 9479 human prostate tumor xenografts. D-CDU, D-ribo-CU and CU levels were measured after administration in mice bearing 9479 human prostate tumors in their flanks. D-CDU achieved high cellular concentrations in LnCap cells and up to 2.5% of the total cellular compound was recovered in the 5'-monophosphorylated form. D-CDU cellular concentrations were similar in LnCap and 9479 tumor xenografts. Studies in tumor bearing animals indicated that increasing the number of hydroxyl moieties in the sugar constituent of the carboranyl nucleosides lead to increased rate and extent of renal elimination, a decrease in serum half-lives and an increased tissue specificity. Tumor/brain ratios were greatest for CDU and D-ribo-CU, while tumor/prostate ratios were greatest with CU. CDU and D-ribo-CU have potential for BNCT of brain malignancies, while CU may be further developed for prostate cancer. A method was developed for the solid phase synthesis of oligonucleotides containing (ocarboran-1-yl-methyl)phosphonate

  14. Peramivir Phosphonate Derivatives as Influenza Neuraminidase Inhibitors.

    Science.gov (United States)

    Wang, Peng-Cheng; Fang, Jim-Min; Tsai, Keng-Chang; Wang, Shi-Yun; Huang, Wen-I; Tseng, Yin-Chen; Cheng, Yih-Shyun E; Cheng, Ting-Jen Rachel; Wong, Chi-Huey

    2016-06-01

    Peramivir is a potent neuraminidase (NA) inhibitor for treatment of influenza infection by intravenous administration. By replacing the carboxylate group in peramivir with a phosphonate group, phosphono-peramivir (6a), the dehydration and deoxy derivatives (7a and 8a) as well as their corresponding monoalkyl esters are prepared from a pivotal intermediate epoxide 12. Among these phosphonate compounds, the dehydration derivative 7a that has a relatively rigid cyclopentene core structure exhibits the strongest inhibitory activity (IC50 = 0.3-4.1 nM) against several NAs of wild-type human and avian influenza viruses (H1N1, H3N2, H5N1, and H7N9), although the phosphonate congener 6a is unexpectedly less active than peramivir. The inferior binding affinity of 6a is attributable to the deviated orientations of its phosphonic acid and 3-pentyl groups in the NA active site as inferred from the NMR, X-ray diffraction, and molecular modeling analyses. Compound 7a is active to the oseltamivir-resistant H275Y strains of H1N1 and H5N1 viruses (IC50 = 73-86 nM). The phosphonate monoalkyl esters (6b, 6c, 7b, 7c, 8b, and 8c) are better anti-influenza agents (EC50 = 19-89 nM) than their corresponding phosphonic acids (EC50 = 50-343 nM) in protection of cells from the viral infection. The phosphonate monoalkyl esters are stable in buffer solutions (pH 2.0-7.4) and rabbit serum; furthermore, the alkyl group is possibly tuned to attain the desired pharmacokinetic properties. PMID:27167096

  15. Exploring the randomness of Directed Acyclic Networks

    CERN Document Server

    Goñi, Joaquín; Solé, Ricard V; Rodríguez-Caso, Carlos

    2010-01-01

    The feed-forward relationship naturally observed in time-dependent processes and in a diverse number of real systems -such as some food-webs and electronic and neural wiring- can be described in terms of so-called directed acyclic graphs (DAGs). An important ingredient of the analysis of such networks is a proper comparison of their observed architecture against an ensemble of randomized graphs, thereby quantifying the {\\em randomness} of the real systems with respect to suitable null models. This approximation is particularly relevant when the finite size and/or large connectivity of real systems make inadequate a comparison with the predictions obtained from the so-called {\\em configuration model}. In this paper we analyze four methods of DAG randomization as defined by the desired combination of topological invariants (directed and undirected degree sequence and component distributions) aimed to be preserved. A highly ordered DAG, called \\textit{snake}-graph and a Erd\\:os-R\\'enyi DAG were used to validate ...

  16. Approved Antiviral Drugs over the Past 50 Years.

    Science.gov (United States)

    De Clercq, Erik; Li, Guangdi

    2016-07-01

    Since the first antiviral drug, idoxuridine, was approved in 1963, 90 antiviral drugs categorized into 13 functional groups have been formally approved for the treatment of the following 9 human infectious diseases: (i) HIV infections (protease inhibitors, integrase inhibitors, entry inhibitors, nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and acyclic nucleoside phosphonate analogues), (ii) hepatitis B virus (HBV) infections (lamivudine, interferons, nucleoside analogues, and acyclic nucleoside phosphonate analogues), (iii) hepatitis C virus (HCV) infections (ribavirin, interferons, NS3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors), (iv) herpesvirus infections (5-substituted 2'-deoxyuridine analogues, entry inhibitors, nucleoside analogues, pyrophosphate analogues, and acyclic guanosine analogues), (v) influenza virus infections (ribavirin, matrix 2 protein inhibitors, RNA polymerase inhibitors, and neuraminidase inhibitors), (vi) human cytomegalovirus infections (acyclic guanosine analogues, acyclic nucleoside phosphonate analogues, pyrophosphate analogues, and oligonucleotides), (vii) varicella-zoster virus infections (acyclic guanosine analogues, nucleoside analogues, 5-substituted 2'-deoxyuridine analogues, and antibodies), (viii) respiratory syncytial virus infections (ribavirin and antibodies), and (ix) external anogenital warts caused by human papillomavirus infections (imiquimod, sinecatechins, and podofilox). Here, we present for the first time a comprehensive overview of antiviral drugs approved over the past 50 years, shedding light on the development of effective antiviral treatments against current and emerging infectious diseases worldwide. PMID:27281742

  17. Actinide phosphonate complexes in aqueous solutions

    International Nuclear Information System (INIS)

    Complexes formed by actinides with carboxylic acids, polycarboxylic acids, and aminopolycarboxylic acids play a central role in both the basic and process chemistry of the actinides. Recent studies of f-element complexes with phosphonic acid ligands indicate that new ligands incorporating doubly ionizable phosphonate groups (-PO3H2) have many properties which are unique chemically, and promise more efficient separation processes for waste cleanup and environmental restoration. Simple diphosphonate ligands form much stronger complexes than isostructural carboxylates, often exhibiting higher solubility as well. In this manuscript recent studies of the thermodynamics and kinetics of f-element complexation by 1,1 and 1,2 diphosphonic acid ligands are described

  18. Renal transepithelial transport of nucleosides.

    Science.gov (United States)

    Nelson, J A; Vidale, E; Enigbokan, M

    1988-01-01

    Previous work from this and other laboratories has suggested that the mammalian kidney has unique mechanisms for handling purine nucleosides. For example, in humans and in mice, adenosine undergoes net renal reabsorption whereas deoxyadenosine is secreted [Kuttesch and Nelson: Cancer Chemother. Pharmacol. 8, 221 (1982)]. The relationships between these renal transport systems and classical renal organic cation and anion, carbohydrate, and cell membrane nucleoside transport carriers are not established. To investigate possible relationships between such carriers, we have tested effects of selected classical transport inhibitors on the renal clearances of adenosine, deoxyadenosine, 5'-deoxy-5-fluorouridine (5'-dFUR), and 5-fluorouracil in mice. The secretion of deoxyadenosine and 5'-dFUR, but not the reabsorption of adenosine or 5-fluorouracil, was prevented by the classical nucleoside transport inhibitors, dipyridamole and nitrobenzylthioinosine. Cimetidine, an inhibitor of the organic cation secretory system, also inhibited the secretion of 5'-dFUR, although it did not inhibit deoxyadenosine secretion in earlier studies [Nelson et al.: Biochem. Pharmacol. 32, 2323 (1983)]. The specific inhibitor of glucose renal reabsorption, phloridzin, failed to inhibit the reabsorption of adenosine or the secretion of deoxyadenosine. Failure of the nucleoside transport inhibitors and phloridzin to prevent adenosine reabsorption suggests that adenosine reabsorption may occur via a unique process. On the other hand, inhibition of the net secretion of deoxyadenosine and 5'-dFUR by dipyridamole and nitrobenzylthioinosine implies a role for the carrier that is sensitive to these compounds in the renal secretion (active transport) of these nucleosides.

  19. Acyclic edge colorings of planar graphs and series parallel graphs

    Institute of Scientific and Technical Information of China (English)

    HOU JianFeng; WU JianLiang; LIU GuiZhen; LIU Bin

    2009-01-01

    A proper edge coloring of a graph G is called acyclic if there is no 2-colored cycle in G.The acyclic edge chromatic number of G,denoted by a'(G),is the least number of colors in an acyclic edge coloring of G.Alon et al.conjectured that a'(G) ≤△(G) +2 for any graphs.For planar graphs G with girth g(G),we prove that a'(G) ≤ max{2△(G)-2,△(G) +22} if g(G) ≥3,a'(G)≤△(G)+2if g(G) ≥ 5,a'(G) ≤△(G)+1 if g(G) ≥ 7,and a'(G)=△(G) if g(G) ≥ 16 and △(G) ≥ 3.For series-parallel graphs G,we have a'(G) ≤ △(G) +1.

  20. Removal and Recovery of Phosphonate Antiscalants

    NARCIS (Netherlands)

    Boels, L.

    2012-01-01

    In reverse osmosis (RO) desalination processes, the use of phosphonates prevents scaling, thus allowing for a higher product water recovery, which increases the efficiency of the process. However, a major concern associated with their use in RO desalination is the high cost and environmental impacts

  1. Inverse Eigenvalue Problems for Two Special Acyclic Matrices

    Directory of Open Access Journals (Sweden)

    Debashish Sharma

    2016-03-01

    Full Text Available In this paper, we study two inverse eigenvalue problems (IEPs of constructing two special acyclic matrices. The first problem involves the reconstruction of matrices whose graph is a path, from given information on one eigenvector of the required matrix and one eigenvalue of each of its leading principal submatrices. The second problem involves reconstruction of matrices whose graph is a broom, the eigen data being the maximum and minimum eigenvalues of each of the leading principal submatrices of the required matrix. In order to solve the problems, we use the recurrence relations among leading principal minors and the property of simplicity of the extremal eigenvalues of acyclic matrices.

  2. Synthesis and Early Development of Hexadecyloxypropyl-cidofovir: An Oral Antipoxvirus Nucleoside Phosphonate

    Directory of Open Access Journals (Sweden)

    Karl Y. Hostetler

    2010-09-01

    Full Text Available Hexadecyloxypropyl-cidofovir (HDP-CDV is a novel ether lipid conjugate of (S-1-(3-hydroxy-2-phosphonoylmethoxypropyl-cytosine (CDV which exhibits a remarkable increase in antiviral activity against orthopoxviruses compared with CDV. In contrast to CDV, HDP-CDV is orally active and lacks the nephrotoxicity of CDV itself. Increased oral bioavailability and increased cellular uptake is facilitated by the lipid portion of the molecule which is responsible for the improved activity profile. The lipid portion of HDP-CDV is cleaved in the cell, releasing CDV which is converted to CDV diphosphate, the active metabolite. HDP-CDV is a highly effective agent against a variety of orthopoxvirus infections in animal models of disease including vaccinia, cowpox, rabbitpox and ectromelia. Its activity was recently demonstrated in a case of human disseminated vaccinia infection after it was added to a multiple drug regimen. In addition to the activity against orthopoxviruses, HDP-CDV (CMX001 is active against all double stranded DNA viruses including CMV, HSV-1, HSV-2, EBV, adenovirus, BK virus, orf, JC, and papilloma viruses, and is under clinical evaluation as a treatment for human infections with these agents.

  3. New acyclic diterpenic acids from yacon (Smallanthus sonchifolius) leaves.

    Science.gov (United States)

    Mercado, María I; Coll Aráoz, María V; Grau, Alfredo; Catalán, César A N

    2010-11-01

    Two new acyclic diterpenoids, smaditerpenic acid E (1a) and F (2a), along with nineteen melampolide-type sesquiterpene lactones, six of them not previously reported in yacon, were isolated from the methylene chloride leaf rinse extract. Their structures were elucidated from 1D and 2D NMR experiments and gas chromatography coupled to mass spectrometry. PMID:21213966

  4. Diversity and abundance of phosphonate biosynthetic genes in nature

    OpenAIRE

    Yu, Xiaomin; Doroghazi, James R.; Janga, Sarath C.; Zhang, Jun Kai; Circello, Benjamin; Griffin, Benjamin M.; Labeda, David P.; Metcalf, William W.

    2013-01-01

    Phosphonic acids are organophosphorus molecules containing direct carbon–phosphorus bonds that are often perceived as biological rarities. The data presented here show that the ability to synthesize diverse phosphonates is both widespread and relatively common among microbes. These findings are consistent with recent evidence suggesting that phosphonates are important intermediates in the global phosphorus cycle. Moreover, they support the idea that these molecules play a significant role in ...

  5. Designer discodermolide segments via ozonolysis of vinyl phosphonates.

    Science.gov (United States)

    Mollat du Jourdin, Xavier; Noshi, Mohammad; Fuchs, P L

    2009-02-01

    To apply our collection of enantiopure 7-ring vinyl sulfones to probe the anticancer SAR of a series of computer-designed (+)-discodermolide analogs, the ozonolytic reactivity of transposed cyclic vinyl phosphonates was explored. Successful preparation of the desired aldehyde-esters and lactones from vinyl phosphonates via an oxidative cleavage-phosphite/methanol exchange sequence is described.

  6. Understanding Model Counting for beta-acyclic CNF-formulas

    OpenAIRE

    Brault-Baron, Johann; Capelli, Florent; Mengel, Stefan

    2015-01-01

    We show that SAT on beta-acyclic CNF-formulas can be solved in polynomial time. In contrast to previous algorithms for other structurally restricted classes of formulas, our algorithm does not proceed by dynamic programming. Instead, it works along an elimination order, solving a weighted version of constraint satisfaction. We give evidence that this deviation from more standard algorithms is no coincidence by showing that it is outside of the framework recently proposed by Saether et al. (SA...

  7. Acyclic Preference Systems in P2P Networks

    OpenAIRE

    Gai, Anh-Tuan; Lebedev, Dmitry; Mathieu, Fabien; de Montgolfier, Fabien; Reynier, Julien; Viennot, Laurent

    2007-01-01

    The original publication is available at www.springerlink.com International audience In this work we study preference systems suitable for the Peer-to-Peer paradigm. Most of them fall in one of the three following categories: global, symmetric and complementary. All these systems share an acyclicity property. As a consequence, they admit a stable (or Pareto efficient) configuration, where no participant can collaborate with better partners than their current ones. We analyze the represe...

  8. A sequential growth dynamics for a directed acyclic dyadic graph

    CERN Document Server

    Krugly, Alexey L

    2011-01-01

    A model of discrete spacetime on a microscopic level is considered. It is a directed acyclic dyadic graph. This is the particular case of a causal set. The goal of this model is to describe particles as some repetitive symmetrical self-organized structures of the graph without any reference to continuous spacetime. The dynamics of the model is considered. This dynamics is stochastic sequential additions of new vertexes. Growth of the graph is a Markovian process. This dynamics is a consequence of a causality principle.

  9. Chemoselective recognition with phosphonate cavitands: the ephedrine over pseudoephedrine case.

    Science.gov (United States)

    Biavardi, Elisa; Ugozzoli, Franco; Massera, Chiara

    2015-02-25

    Complete discrimination of ephedrine and pseudoephedrine, both in solution and in the solid state, was achieved with a phosphonate cavitand receptor. The molecular origin of the epimer discrimination was revealed by the crystal structure of the respective complexes.

  10. A General and Efficient CuBr2-Catalyzed N-Arylation of Secondary Acyclic Amides

    Institute of Scientific and Technical Information of China (English)

    王满刚; 于华; 尤心稳; 吴军; 商志才

    2012-01-01

    A general and efficient Cu(II)-catalyzed cross-coupling method is reported for the preparation of acyclic tertiary amides. Generally moderate to excellent yields and functional group tolerance were obtained with secondary acyclic amides and aryl halides as substrates in toluene.

  11. A Distributed Algorithm for Determining Minimal Covers of Acyclic Database Schemes

    Institute of Scientific and Technical Information of China (English)

    叶新铭

    1994-01-01

    Acyclic databases possess several desirable properties for their design and use.A distributed algorithm is proposed for determining a minimal cover of an alpha-,beta-,gamma-,or Berge-acyclic database scheme over a set of attributes in a distributed environment.

  12. Towards Optimal Event Detection and Localization in Acyclic Flow Networks

    KAUST Repository

    Agumbe Suresh, Mahima

    2012-01-03

    Acyclic flow networks, present in many infrastructures of national importance (e.g., oil & gas and water distribution systems), have been attracting immense research interest. Existing solutions for detecting and locating attacks against these infrastructures, have been proven costly and imprecise, especially when dealing with large scale distribution systems. In this paper, to the best of our knowledge for the first time, we investigate how mobile sensor networks can be used for optimal event detection and localization in acyclic flow networks. Sensor nodes move along the edges of the network and detect events (i.e., attacks) and proximity to beacon nodes with known placement in the network. We formulate the problem of minimizing the cost of monitoring infrastructure (i.e., minimizing the number of sensor and beacon nodes deployed), while ensuring a degree of sensing coverage in a zone of interest and a required accuracy in locating events. We propose algorithms for solving these problems and demonstrate their effectiveness with results obtained from a high fidelity simulator.

  13. On Event Detection and Localization in Acyclic Flow Networks

    KAUST Repository

    Suresh, Mahima Agumbe

    2013-05-01

    Acyclic flow networks, present in many infrastructures of national importance (e.g., oil and gas and water distribution systems), have been attracting immense research interest. Existing solutions for detecting and locating attacks against these infrastructures have been proven costly and imprecise, particularly when dealing with large-scale distribution systems. In this article, to the best of our knowledge, for the first time, we investigate how mobile sensor networks can be used for optimal event detection and localization in acyclic flow networks. We propose the idea of using sensors that move along the edges of the network and detect events (i.e., attacks). To localize the events, sensors detect proximity to beacons, which are devices with known placement in the network. We formulate the problem of minimizing the cost of monitoring infrastructure (i.e., minimizing the number of sensors and beacons deployed) in a predetermined zone of interest, while ensuring a degree of coverage by sensors and a required accuracy in locating events using beacons. We propose algorithms for solving the aforementioned problem and demonstrate their effectiveness with results obtained from a realistic flow network simulator.

  14. Worst-case Behaviour of History Based Pivot Rules on Acyclic Unique Sink Orientations of Hypercubes

    CERN Document Server

    Aoshima, Yoshikazu; Deering, Theresa; Matsumoto, Yoshitake; Moriyama, Sonoko

    2011-01-01

    An acyclic USO on a hypercube is formed by directing its edges in such as way that the digraph is acyclic and each face of the hypercube has a unique sink and a unique source. A path to the global sink of an acyclic USO can be modeled as pivoting in a unit hypercube of the same dimension with an abstract objective function, and vice versa. In such a way, Zadeh's 'least entered rule' and other history based pivot rules can be applied to the problem of finding the global sink of an acyclic USO. In this paper we present some theoretical and empirical results on the worst case behaviour of various history based pivot rules for this problem. In particular, we investigate whether or not they can follow a Hamiltonian path on an acyclic USO.

  15. Pan-pathway based interaction profiling of FDA-approved nucleoside and nucleobase analogs with enzymes of the human nucleotide metabolism.

    Directory of Open Access Journals (Sweden)

    Louise Egeblad

    Full Text Available To identify interactions a nucleoside analog library (NAL consisting of 45 FDA-approved nucleoside analogs was screened against 23 enzymes of the human nucleotide metabolism using a thermal shift assay. The method was validated with deoxycytidine kinase; eight interactions known from the literature were detected and five additional interactions were revealed after the addition of ATP, the second substrate. The NAL screening gave relatively few significant hits, supporting a low rate of "off target effects." However, unexpected ligands were identified for two catabolic enzymes guanine deaminase (GDA and uridine phosphorylase 1 (UPP1. An acyclic guanosine prodrug analog, valaciclovir, was shown to stabilize GDA to the same degree as the natural substrate, guanine, with a ΔT(agg around 7°C. Aciclovir, penciclovir, ganciclovir, thioguanine and mercaptopurine were also identified as ligands for GDA. The crystal structure of GDA with valaciclovir bound in the active site was determined, revealing the binding of the long unbranched chain of valaciclovir in the active site of the enzyme. Several ligands were identified for UPP1: vidarabine, an antiviral nucleoside analog, as well as trifluridine, idoxuridine, floxuridine, zidovudine, telbivudine, fluorouracil and thioguanine caused concentration-dependent stabilization of UPP1. A kinetic study of UPP1 with vidarabine revealed that vidarabine was a mixed-type competitive inhibitor with the natural substrate uridine. The unexpected ligands identified for UPP1 and GDA imply further metabolic consequences for these nucleoside analogs, which could also serve as a starting point for future drug design.

  16. Synthesis of Nucleoside Derivatives Containing Benzophenoxazinone Moiety

    Institute of Scientific and Technical Information of China (English)

    Yu GAO; Wu Xin ZOU; Ling WU; Jin Shui LI; Ji Tao WANG; Ji Ben MENG

    2004-01-01

    Two new nucleoside derivatives containing benzophenoxazinone moiety were synthesized. Their luminescence spectra show that they have strong near infrared fluorescence. Our study provides a new method for direct introduction of near infrared fluorescent probe to bioactive molecules.

  17. $\\ell_0$-penalized maximum likelihood for sparse directed acyclic graphs

    CERN Document Server

    van de Geer, Sara

    2012-01-01

    We consider the problem of regularized maximum likelihood estimation for the structure and parameters of a high-dimensional, sparse directed acyclic graphical (DAG) model with Gaussian distribution, or equivalently, of a Gaussian structural equation model. We show that the $\\ell_0$-penalized maximum likelihood estimator of a DAG has about the same number of edges as the minimal-edge I-MAP (a DAG with minimal number of edges representing the distribution), and that it converges in Frobenius norm. We allow the number of nodes $p$ to be much larger than sample size $n$ but assume a sparsity condition and that any representation of the true DAG has at least a fixed proportion of its non-zero edge weights above the noise level. Our results do not rely on the restrictive strong faithfulness condition which is required for methods based on conditional independence testing such as the PC-algorithm.

  18. Insights into phosphate cooperativity and influence of substrate modifications on binding and catalysis of hexameric purine nucleoside phosphorylases.

    Directory of Open Access Journals (Sweden)

    Priscila O de Giuseppe

    Full Text Available The hexameric purine nucleoside phosphorylase from Bacillus subtilis (BsPNP233 displays great potential to produce nucleoside analogues in industry and can be exploited in the development of new anti-tumor gene therapies. In order to provide structural basis for enzyme and substrates rational optimization, aiming at those applications, the present work shows a thorough and detailed structural description of the binding mode of substrates and nucleoside analogues to the active site of the hexameric BsPNP233. Here we report the crystal structure of BsPNP233 in the apo form and in complex with 11 ligands, including clinically relevant compounds. The crystal structure of six ligands (adenine, 2'deoxyguanosine, aciclovir, ganciclovir, 8-bromoguanosine, 6-chloroguanosine in complex with a hexameric PNP are presented for the first time. Our data showed that free bases adopt alternative conformations in the BsPNP233 active site and indicated that binding of the co-substrate (2'deoxyribose 1-phosphate might contribute for stabilizing the bases in a favorable orientation for catalysis. The BsPNP233-adenosine complex revealed that a hydrogen bond between the 5' hydroxyl group of adenosine and Arg(43* side chain contributes for the ribosyl radical to adopt an unusual C3'-endo conformation. The structures with 6-chloroguanosine and 8-bromoguanosine pointed out that the Cl(6 and Br(8 substrate modifications seem to be detrimental for catalysis and can be explored in the design of inhibitors for hexameric PNPs from pathogens. Our data also corroborated the competitive inhibition mechanism of hexameric PNPs by tubercidin and suggested that the acyclic nucleoside ganciclovir is a better inhibitor for hexameric PNPs than aciclovir. Furthermore, comparative structural analyses indicated that the replacement of Ser(90 by a threonine in the B. cereus hexameric adenosine phosphorylase (Thr(91 is responsible for the lack of negative cooperativity of phosphate binding

  19. Formation of nucleoside 5'-polyphosphates from nucleotides and trimetaphosphate.

    Science.gov (United States)

    Lohrmann, R

    1975-12-29

    When solutions of nucleoside 5'-phosphates and trimetaphosphate are dried out at room temperature, nucleoside 5'-polyphosphates are formed. The Mg++ ion shows a superior catalytic function in this reaction when compared with other divalent metal ions. Starting with nucleoside 5'-phosphates, Mg++ and trimetaphosphate, the predominant products in the nucleoside 5'-polyphosphate series pnN are p4N, P7N and p10N. Nucleoside 5'-diphosphates yield p5N and p8N, nucleoside 5'-triphosphates give p6N and p9N. The prebiological relevance of these reactions is discussed. PMID:1541

  20. SOME RECENT FINDINGS IN THE BIOTECHNOLOGY OF BIOLOGICALLY IMPORTANT NUCLEOSIDES

    Directory of Open Access Journals (Sweden)

    A. Mikhailopulo

    2013-08-01

    Full Text Available Some recent findings in the biotechnology of biologically important nucleosides will be discussed, viz., (i a new strategy of the cascade one-pot transformation of D-pentoses into nucleosides based on the extension and deepening of the knowledge of the mechanism of functioning of the ribokinase, phosphopentomutase, and uridine, thymidine and purine nucleoside (PNP phosphorylases, and the role of different factors (structural, electronic, stereochemical in the glycoside bond formation, (ii the modern chemistries of the chemo-enzymatic syntheses of nucleosides, (iii the transglycosylation reaction using natural and sugar modified nucleosides as donors of carbohydrate residues and heterocyclic bases as acceptors catalyzed by nucleoside phosphorylases (NP.

  1. Novel and Convenient Method for the Preparation of Phosphonate Peptides and Phosphonamidate Peptides

    Institute of Scientific and Technical Information of China (English)

    XU Jia-Xi; FU Nan-Yan; GAO Yuan-He; ZHNAG Qi-Han; DUAN Li-Fang

    2003-01-01

    @@ Phosphonate and phosphonamidate peptides are phosphorus analogues of natural peptides. They have been great used as stable mimetics of tetrahedral transition states as enzyme inhibitors and as haptens for catalytic antibody research in recent years. Although several methods are available for the preparation of phosphonate peptides and phosphonamidate peptides, all of them use phosphonic acid derivatives as starting materials. The overall yields from the synthesis of phosphonic acid derivatives to desired peptides are not satisfactory in most cases.

  2. The Existence Condition of γ-Acyclic Database Schemes with MVDs Constraints

    Institute of Scientific and Technical Information of China (English)

    郝忠孝; 姚春龙

    2002-01-01

    It is very important to use database technology for a large-scale system such as ERP and MIS. A good database design may improve the performance of the system. Some researches show that a γ-acyclic database scheme has many good properties, e.g., each connected join expression is monotonous, which helps to improve query performance of the database system. Thus what conditions are needed to generate a γ-acyclic database scheme for a given relational scheme? In this paper, the sufficient and necessary condition of the existence of γ-acyclic, join-lossless and dependencies-preserved database schemes meeting 4NF is given.

  3. Two new acyclic diterpene-y-lactones from the leaves of Salix matsudana

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Two new acyclic diterpene-(-lactones named hanliuine III (1) and hanliuine IV (2) were isolated from leaves of Salix matsudana (Chinese name "hanliu"). Their structures were deduced from spectral data.

  4. Prebiotic phosphorylation of nucleosides in formamide

    Science.gov (United States)

    Schoffstall, A. M.

    1976-01-01

    Results are presented for an experimental study intended to assess phosphorylation under neither aqueous nor dry thermal conditions. Instead, phosphorylations were attempted in possible nonaqueous prebiotic solvents. Formamide appeared to be the most obvious candidate for phosphorylation studies. Three main classes of phosphorylated products were formed in formamide solution: adenosine monophosphates, cyclic adenosine phosphate, and adenosine diphosphates. Experiments were designed to investigate the extent of phosphorylation of nucleosides in formamide, the relative amounts of nucleoside monophosphate, diphosphates and cyclic phosphate formed and the relative effectiveness of different sources of phosphate as phosphorylating agents in formamide. Reaction variables were temperature, nature of the phosphate or condensed phosphate, nucleoside, concentration of reactants and possible effects of additives. Product identification was based on qualitative and quantitative thin layer chromatography.

  5. Titanium-zirconium-phosphonate hybrid film on 6061 aluminum alloy

    Institute of Scientific and Technical Information of China (English)

    Shuanghong WANG; Lei WANG; Changsheng LIU

    2011-01-01

    Three titanium-zirconium-phosphonate hybrid films were formed on AA6061 aluminum alloy by immersing in fluorotitanic acid and fluorozirconic acid based solution containing different phosphonic acids for protective coatings of aluminium alloy. The corrosion resistance of three hybrid films as the substitute for chromate film were evaluated and compared. The neutral salt spray test was explored,the immersion test was conducted and electrochemical test was also executed. The hybrid films exhibited well-pleasing corrosion resistance and adhesion to epoxy resin paints. It was found out that the hybrid films could efficiently be a substitute for chromate based primer over aluminium alloy.

  6. XPS investigation of DNA binding to zirconium-phosphonate surfaces.

    Science.gov (United States)

    Lane, Sarah M; Monot, Julien; Petit, Marc; Bujoli, Bruno; Talham, Daniel R

    2007-07-01

    The surface coverage of phosphorylated oligonucleotides immobilized on a zirconium-phosphonate surface was analyzed using X-ray photoelectron spectroscopy (XPS). By quantifying the intensity of the N 1s signal originating from the oligonucleotide and the Zr 3d peak from the metal-phosphonate surface, the surface coverage of the oligonucleotide could be calculated with a modified substrate-overlayer model. We found relatively low surface coverages indicating that once covalently bound via the terminal phosphate the polymer chain further physisorbs to the surface limiting the adsorption of additional molecules.

  7. Synthesis and stereochemistry of 6-membered ring phosphonates

    Directory of Open Access Journals (Sweden)

    Michael D. Pungente

    2012-03-01

    Full Text Available Background: Organophosphorus compounds have important industrial and biomedical applications as pharmaceutical and agrochemical agents, as well as transition state analogs for the production of monoclonal antibodies. Methods: Two diastereomers of a 6-membered ring, cyclic phenyl phosphonate were synthesized in 8 steps from 1,3-butanediol. Results: The stereochemistry of the diastereomers was elucidated on the basis of H NMR nuclear Overhauser effects (NOE difference experiments. Conclusions: Such cyclic phosphonates may have utility serving as transition state analogs for the production of monoclonal antibodies.

  8. Synthesis of Nucleoside Triphosphates from 2'-3'-Protected Nucleosides Using Trimetaphosphate.

    Science.gov (United States)

    Mohamady, Samy; Taylor, Scott D

    2016-02-01

    Chemists have been attempting to triphosphorylate nucleosides and other alcohols using trimetaphosphate (TriMP) since the 1960s. However, this route appears to have been abandoned due to poor yields. The first practical syntheses of nucleoside triphosphates (NTPs) are reported using TriMP as the key reagent. This was achieved by reacting the tetrabutylammonium salt of TriMP with mesitylenesulfonyl chloride in the presence of DABCO in pyridine followed by the addition of an appropriately protected nucleoside and phthalimide. Quenching the reaction with aqueous buffer followed by hydrolysis of the OH protecting groups gave the NTPs in good yield. PMID:26759914

  9. Structural Interactions within Lithium Salt Solvates. Acyclic Carbonates and Esters

    Energy Technology Data Exchange (ETDEWEB)

    Afroz, Taliman [North Carolina State Univ., Raleigh, NC (United States); Seo, D. M. [North Carolina State Univ., Raleigh, NC (United States); Han, Sang D. [North Carolina State Univ., Raleigh, NC (United States); Boyle, Paul D. [North Carolina State Univ., Raleigh, NC (United States); Henderson, Wesley A. [North Carolina State Univ., Raleigh, NC (United States); Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

    2015-03-06

    Solvate crystal structures serve as useful models for the molecular-level interactions within the diverse solvates present in liquid electrolytes. Although acyclic carbonate solvents are widely used for Li-ion battery electrolytes, only three solvate crystal structures with lithium salts are known for these and related solvents. The present work, therefore, reports six lithium salt solvate structures with dimethyl and diethyl carbonate: (DMC)2:LiPF6, (DMC)1:LiCF3SO3, (DMC)1/4:LiBF4, (DEC)2:LiClO4, (DEC)1:LiClO4 and (DEC)1:LiCF3SO3 and four with the structurally related methyl and ethyl acetate: (MA)2:LiClO4, (MA)1:LiBF4, (EA)1:LiClO4 and (EA)1:LiBF4.

  10. Amberlyst-15 catalyzed synthesis of alkyl/aryl/heterocyclic phosphonates

    Institute of Scientific and Technical Information of China (English)

    U.M. Rao Kunda; V.N. Reddy Mudumala; C.S. Reddy Gangireddy; B.R. Nemallapudi; K.N. Sandip; S.R. Cirandur

    2011-01-01

    A novel and efficient procedure for the synthesis of alkyl phosphonates through one pot condensation of alkyl halide and tri-alkyl/aryl phosphite in the presence of Amberlyst-15 as catalyst under solvent free conditions was applied. It demonstrated several advantages such as good yields of products, simple operation, convenient separation and inexpensive catalyst.

  11. Synthesis of biologically active phosphonates from Lesquerella oil

    Science.gov (United States)

    Bisphosphonates and vinyl phosphonates are two classes of compounds that have much potential, namely as pharmaceutical agents and synthetic building blocks. Previous studies have shown success in synthesizing these compounds from hydroxy fatty acids (HFAs) found in Ricinus communis, commonly known a...

  12. Flame retardant properties of triazine phosphonates derivative with cotton fabric

    Science.gov (United States)

    The flame retardant behavior of a cotton fabric treated with phosphorus-nitrogen containing triazine compound was evaluated. It was found that cyanuric chloride (2,4,6-trichloro-1,3,5-triazine) is an excellent starting material for the preparation of phosphonates flame retardants that interacts wel...

  13. PEG-bis phosphonic acid based ionic supramolecular structures

    DEFF Research Database (Denmark)

    Gonzalez, Lidia; Skov, Anne Ladegaard; Hvilsted, Søren

    2014-01-01

    A number of supramolecular structures are prepared by mixing stoichiometric amounts of a phosphonic acid terminated poly(ethylene glycol) with propargyl amine, hexamethylene diamine, tris(2-aminoethyl)amine, and the first generation of a poly(propylene imine) dendrimer in turn at room temperature...

  14. Structure-activity-relationships (SAR) in pyrimidine nucleoside transport

    International Nuclear Information System (INIS)

    Several series of pyrimidine nucleosides were evaluated as part of a larger program to develop non-invasive brain imaging agents. The interaction of these antitumor/antiviral nucleosides with an NBMPR-sensitive murine erythroctye nucleoside transporter was evaluated by determining their inhibitory effect (Ki) on zero-trans influx of thymidine. Within each series of compounds, which had F, Cl, Br or I as halogen substituents, an increase in size of the halogen atom or a decrease in electronegativity decreased affinity for the transporter. Partition coefficients (P) of these pyrimidine nucleosides were measured to determine their potential to diffuse across the blood-brain-barrier (BBB). Most of the pyrimidine nucleosides had lower P values (log P i for nucleosides with a particular sugar moiety. Within a nucleoside series with a given sugar component, the binding affinity for the transporter was inversely proportional to lipophilicity. 25 refs., 2 tabs., 4 figs

  15. Acyclic edge colorings of planar graphs and series-parallel graphs

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    A proper edge coloring of a graph G is called acyclic if there is no 2-colored cycle in G. The acyclic edge chromatic number of G, denoted by a (G), is the least number of colors in an acyclic edge coloring of G. Alon et al. conjectured that a (G) Δ(G) + 2 for any graphs. For planar graphs G with girth g(G), we prove that a (G) max{2Δ(G) + 2, Δ(G) + 22} if g(G) 3, a (G) Δ(G) + 2 if g(G) 5, a (G) Δ(G) + 1 if g(G) 7, and a (G) = Δ(G) if g(G) 16 and Δ(G) 3. For series-parallel graphs G, we have a (G) Δ(G) + 1.

  16. An Upper Bound for the Adjacent Vertex Distinguishing Acyclic Edge Chromatic Number of a Graph

    Institute of Scientific and Technical Information of China (English)

    Xin-sheng Liu; Ming-qiang An; Yang Gao

    2009-01-01

    A proper k-edge coloring of a graph G is called adjacent vertex distinguishing acyclic edge coloring if there is no 2-colored cycle in G and the color set of edges incident to u is not equal to the color set of edges incident to v,where uv ∈ E(G).The adjacent vertex distinguishing acyclic edge chromatic number of G,denoted by χαα(G),is the minimal number of colors in an adjacent vertex distinguishing acyclic edge coloring of G.In this paper we prove that if G(V,E)is a graph with no isolated edges,then χαα(G)≤32△.

  17. Acyclic cucurbit[n]uril molecular containers enhance the solubility and bioactivity of poorly soluble pharmaceuticals

    Science.gov (United States)

    Ma, Da; Hettiarachchi, Gaya; Nguyen, Duc; Zhang, Ben; Wittenberg, James B.; Zavalij, Peter Y.; Briken, Volker; Isaacs, Lyle

    2012-06-01

    The solubility characteristics of 40-70% of new drug candidates are so poor that they cannot be formulated on their own, so new methods for increasing drug solubility are highly prized. Here, we describe a new class of general-purpose solubilizing agents—acyclic cucurbituril-type containers—which increase the solubility of ten insoluble drugs by a factor of between 23 and 2,750 by forming container-drug complexes. The containers exhibit low in vitro toxicity in human liver, kidney and monocyte cell lines, and outbred Swiss Webster mice tolerate high doses of the container without sickness or weight loss. Paclitaxel solubilized by the acyclic cucurbituril-type containers kills cervical and ovarian cancer cells more efficiently than paclitaxel alone. The acyclic cucurbituril-type containers preferentially bind cationic and aromatic drugs, but also solubilize neutral drugs such as paclitaxel, and represent an attractive extension of cyclodextrin-based technology for drug solubilization and delivery.

  18. Extraction of uranium from aqueous solution by phosphonic acid-imbedded polyurethane foam

    International Nuclear Information System (INIS)

    Phenylphosphonic acid was imbedded into the matrix of the polyurethane foam during the fabrication process of the polymer. The extraction of uranium by phosphonic acid-imbedded polyurethane foam and blank polyurethane (i.e., foam without phosphonic acid functional groups) was investigated. Phosphonic acid-imbedded foam showed superior extractability of uranium from solutions with pH = 7.0 ± 1.5 over a wide range of temperatures. (author)

  19. Synthesis of 1,4-Diazepine Nucleosides

    OpenAIRE

    M Zia-Ul-Haq; Hameed, Shahid

    2002-01-01

    The phenolic b-diketones I prepared by modified Baker-Venkataraman rearrangement were converted to the flavones II in acidic medium which on treatment with aqueous ethylenediamine/propylenediamine gave diazepine derivatives III. After coupling with acetobromo sugars in the presence of mercuric cyanide and nitromethane, deacetylation in methanolic ammonia yielded nucleosides V. The structures of all the intermediates and final products were confirmed with the help of modern spectrosc...

  20. ADO-phosphonic acid self-assembled monolayer modified dielectrics for organic thin film transistors

    Science.gov (United States)

    Zhefeng, Li; Xianye, Luo

    2014-10-01

    This study explores a strategy of using the phosphonic acid derivative (11-((12-(anthracen-2-yl)dodecyl)oxy)-11-oxoundecyl) phosphonic acid (ADO-phosphonic acid) as self-assembled monolayers (SAMs) on a Si/SiO2 surface to induce the crystallization of rubrene in vacuum deposited thin film transistors, which showed a field-effect mobility as high as 0.18 cm2/(V·s). It is found that ADO-phosphonic acid SAMs play a unique role in modulating the morphology of rubrene to form a crystalline film in the thin-film transistors.

  1. Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates.

    Science.gov (United States)

    Haji, Mohammad

    2016-01-01

    Multicomponent reactions (MCRs) are one of the most important processes for the preparation of highly functionalized organic compounds in modern synthetic chemistry. As shown in this review, they play an important role in organophosphorus chemistry where phosphorus reagents are used as substrates for the synthesis of a wide range of phosphorylated heterocycles. In this article, an overview about multicomponent reactions used for the synthesis of heterocyclic compounds bearing a phosphonate group on the ring is given. PMID:27559377

  2. Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

    Science.gov (United States)

    2016-01-01

    Summary Multicomponent reactions (MCRs) are one of the most important processes for the preparation of highly functionalized organic compounds in modern synthetic chemistry. As shown in this review, they play an important role in organophosphorus chemistry where phosphorus reagents are used as substrates for the synthesis of a wide range of phosphorylated heterocycles. In this article, an overview about multicomponent reactions used for the synthesis of heterocyclic compounds bearing a phosphonate group on the ring is given. PMID:27559377

  3. Characterisation of Campylobacter jejuni genes potentially involved in phosphonate degradation

    Directory of Open Access Journals (Sweden)

    Hartley Lauren E

    2009-06-01

    Full Text Available Abstract Potential biological roles of the Campylobacter jejuni genes cj0641, cj0774c and cj1663 were investigated. The proteins encoded by these genes showed sequence similarities to the phosphonate utilisation PhnH, K and L gene products of Escherichia coli. The genes cj0641, cj0774c and cj1663 were amplified from the pathogenic C. jejuni strain 81116, sequenced, and cloned into pGEM-T Easy vectors. Recombinant plasmids were used to disrupt each one of the genes by inserting a kanamycin resistance (KmR cassette employing site-directed mutagenesis or inverse PCR. Campylobacter jejuni 81116 isogenic mutants were generated by integration of the mutated genes into the genome of the wild-type strain. The C. jejuni mutants grew on primary isolation plates, but they could not be purified by subsequent passages owing to cell death. The mutant C. jejuni strains survived and proliferated in co-cultures with wild-type bacteria or in media in which wild-type C. jejuni had been previously grown. PCR analyses of mixed wild-type/mutant cultures served to verify the presence of the mutated gene in the genome of a fraction of the total bacterial population. The data suggested that each mutation inactivated a gene essential for survival. Rates of phosphonate catabolism in lysates of E. coli strain DH5α were determined using proton nuclear magnetic resonance spectroscopy. Whole-cell lysates of the wild-type degraded phosphonoacetate, phenylphosphonate and aminomethylphosphonate. Significant differences in the rates of phosphonate degradation were observed between lysates of wild-type E. coli, and of bacteria transformed with each one of the vectors carrying one of the C. jejuni genes, suggesting that these genes were involved in phosphonate catabolism.

  4. Phosphonate Biosynthesis and Catabolism: A Treasure Trove of Unusual Enzymology

    OpenAIRE

    Peck, Spencer C.; van der Donk, Wilfred A.

    2013-01-01

    Natural product biosynthesis has proven a fertile ground for the discovery of novel chemistry. Herein we review the progress made in elucidating the biosynthetic pathways of phosphonate and phosphinate natural products such as the antibacterial compounds dehydrophos and fosfomycin, the herbicidal phosphinothricin-containing peptides, and the antimalarial compound FR-900098. In each case, investigation of the pathway has yielded unusual, and often unprecedented, biochemistry. Likewise, recent ...

  5. Hierarchical mesostructured titanium phosphonates with unusual uniform lines of macropores.

    Science.gov (United States)

    Ma, Tian-Yi; Lin, Xiu-Zhen; Zhang, Xue-Jun; Yuan, Zhong-Yong

    2011-04-01

    Organic-inorganic hybrid materials of mesostructured titanium phosphonates with unusual uniform lines of macropores were synthesized by using bis(hexamethylenetriamine) penta(methylenephosphonic acid) (BHMTPMP) as the coupling molecule, through a one-pot hydrothermal process without any surfactant assistance. A wormhole-like mesostructure and many uniform parallel lines of macropores divided by solid ridges in the same direction were confirmed by N(2) sorption, SEM and TEM observations. This novel macropore architecture has never been observed in other metal phosphonate materials, which may be directly related to the structure nature of BHMTPMP with extra long alkyl chains. The structural characterization of FT-IR and MAS NMR revealed the integrity of organic groups inside the hybrid framework. The hybrid materials were also used as adsorbents for heavy metal ions and CO(2), in order to clarify the impacts of the organic contents and organic types on the physicochemical properties of the synthesized hierarchical macro-/mesoporous phosphonate materials. PMID:21344079

  6. Morphology and Proton Transport in Humidified Phosphonated Peptoid Block Copolymers

    Science.gov (United States)

    2016-01-01

    Polymers that conduct protons in the hydrated state are of crucial importance in a wide variety of clean energy applications such as hydrogen fuel cells and artificial photosynthesis. Phosphonated and sulfonated polymers are known to conduct protons at low water content. In this paper, we report on the synthesis phosphonated peptoid diblock copolymers, poly-N-(2-ethyl)hexylglycine-block-poly-N-phosphonomethylglycine (pNeh-b-pNpm), with volume fractions of pNpm (ϕNpm) values ranging from 0.13 to 0.44 and dispersity (Đ) ≤ 1.0003. The morphologies of the dry block copolypeptoids were determined by transmission electron microscopy and in both the dry and hydrated states by synchrotron small-angle X-ray scattering. Dry samples with ϕNpm > 0.13 exhibited a lamellar morphology. Upon hydration, the lowest molecular weight sample transitioned to a hexagonally packed cylinder morphology, while the others maintained their dry morphologies. Water uptake of all of the ordered samples was 8.1 ± 1.1 water molecules per phosphonate group. In spite of this, the proton conductivity of the ordered pNeh-b-pNpm copolymers ranged from 0.002 to 0.008 S/cm. We demonstrate that proton conductivity is maximized in high molecular weight, symmetric pNeh-b-pNpm copolymers. PMID:27134312

  7. Phosphonate biosynthesis and catabolism: a treasure trove of unusual enzymology.

    Science.gov (United States)

    Peck, Spencer C; van der Donk, Wilfred A

    2013-08-01

    Natural product biosynthesis has proven a fertile ground for the discovery of novel chemistry. Herein we review the progress made in elucidating the biosynthetic pathways of phosphonate and phosphinate natural products such as the antibacterial compounds dehydrophos and fosfomycin, the herbicidal phosphinothricin-containing peptides, and the antimalarial compound FR-900098. In each case, investigation of the pathway has yielded unusual, and often unprecedented, biochemistry. Likewise, recent investigations have uncovered novel ways to cleave the CP bond to yield phosphate under phosphorus starvation conditions. These include the discovery of novel oxidative cleavage of the CP bond catalyzed by PhnY and PhnZ as well as phosphonohydrolases that liberate phosphate from phosphonoacetate. Perhaps the crown jewel of phosphonate catabolism has been the recent resolution of the longstanding problem of the C-P lyase responsible for reductively cleaving the CP bond of a number of different phosphonates to release phosphate. Taken together, the strides made on both metabolic and catabolic fronts illustrate an array of fascinating biochemistry. PMID:23870698

  8. Reactions of unsaturated compounds. CXXIV. Claisen rearrangement of allyl and propargyloxydienyl phosphonates

    Energy Technology Data Exchange (ETDEWEB)

    Dangyan, Yu.M.; Tirakyan, M.R.; Panosyan, G.A.; Badanyan, Sh.O.

    1986-12-20

    O,O-Dialkyl-1-ethylidene-2-allyl(propargyl)oxy-2-butenyl phosphonates have been obtained from vinylallenyl phosphonates and undergo thermal Claisen rearrangement to form highly unsaturated ketophosphonates. Comprehensive coupling constant and chemical shift figures from an NMR analysis are given.

  9. Novel and Convenient Approach to Synthesis of AZT/d4T H-phosphonates

    Institute of Scientific and Technical Information of China (English)

    LIN, Chang-Xue(林长学); FU, Hua(付华); TU, Guang-Zhong(涂光忠); ZHAO, Yu-Fen(赵玉芬)

    2004-01-01

    A convenient, efficient and general method has been developed for synthesis of H-phosphonate mono and diesters of AZT and d4T through one-pot reaction of phosphonic acid with AZT or d4T and different alcohols using pivaloyl chloride as condensing agent under mild conditions.

  10. Hybridization accompanying FRET event in labeled natural nucleoside-unnatural nucleoside containing chimeric DNA duplexes.

    Science.gov (United States)

    Bag, Subhendu Sekhar; Das, Suman K; Pradhan, Manoj Kumar; Jana, Subhashis

    2016-09-01

    Förster resonance energy transfer (FRET) is a highly efficient strategy in illuminating the structures, structural changes and dynamics of DNA, proteins and other biomolecules and thus is being widely utilized in studying such phenomena, in designing molecular/biomolecular probes for monitoring the hybridization event of two single stranded DNA to form duplex, in gene detection and in many other sensory applications in chemistry, biology and material sciences. Moreover, FRET can give information about the positional status of chromophores within the associated biomolecules with much more accuracy than other methods can yield. Toward this end, we want to report here the ability of fluorescent unnatural nucleoside, triazolylphenanthrene ((TPhen)BDo) to show FRET interaction upon hybridization with fluorescently labeled natural nucleosides, (Per)U or (OxoPy)U or (Per)U, forming two stable chimeric DNA duplexes. The pairing selectivity and the thermal duplex stability of the chimeric duplexes are higher than any of the duplexes with natural nucleoside formed. The hybridization results in a Förster resonance energy transfer (FRET) from donor triazolylphenanthrene of (TPhen)BDo to acceptor oxopyrene of (OxoPy)U and/or to perylene chromophore of (Per)U, respectively, in two chimeric DNA duplexes. Therefore, we have established the FRET process in two chimeric DNA duplexes wherein a fluorescently labeled natural nucleoside ((OxoPy)U or (Per)U) paired against an unnatural nucleoside ((TPhen)BDo) without sacrificing the duplex stability and B-DNA conformation. The hybridization accompanying FRET event in these classes of interacting fluorophores is new. Moreover, there is no report of such designed system of chimeric DNA duplex. Our observed phenomenon and the design can potentially be exploited in designing more of such efficient FRET pairs for useful application in the detection and analysis of biomolecular interactions and in material science application.

  11. Phosphonates as alternative to tributyl phosphate for the separation of actinides from fission products

    Energy Technology Data Exchange (ETDEWEB)

    Vyas, Chirag K.; Joshirao, Pranav M.; Manchanda, Vijay K. [Sungkyunkwan Univ., Suwon (Korea, Republic of). Dept. of Energy Science; Rao, C.V.S. Brahmmananda; Jayalakshmi, S. [Indira Gandhi Centre for Atomic Research, Kalpakkam (India). Fuel Chemistry Div.

    2015-06-01

    The present work investigates the role of increase in the basicity of organophosphorus extractant (dialkylalkyl phosphonates) on the uptake of actinides and fission products vis-a-vis tributyl phosphate (TBP), currently employed as a universal extractant. Two dialkylalkyl phosphonates viz. dibutylpropyl phosphonate (DBPrP) and dibutylpentyl phosphonate (DBPeP) were synthesized, characterized and evaluated for their solvent extraction behavior towards U(VI), Th(IV), Eu(III) and Tc(VII) in nitric acid medium ranging from 0.01-6 M. It was observed that increasing the basicity of the phosphoryl oxygen enhanced the uptake of the actinides and the distribution coefficient values were significantly larger as compared to TBP. The limiting organic concentration (LOC) value was estimated for Th(IV) for these extractants and compared with the TBP system. The separation factors of actinides with phosphonates over Tc(VII) are distinctly better than that with TBP.

  12. Structural variations in layered alkaline earth metal cyclohexyl phosphonates

    Indian Academy of Sciences (India)

    Ramaswamy Murugavel; Nayanmoni Gogoi

    2009-06-01

    Two series of alkaline earth metal cyclohexyl phosphonates, M(C6H11PO3H)2(H2O) (M = Ca, Sr and Ba) (1–3) and M(C6H11PO3)(H2O) (M = Mg, Ca, Sr, and Ba) (4–7) have been synthesized under mild reaction conditions. All new compounds have been characterized using elemental analysis, IR, TGA and powder X-ray diffraction techniques. The molecular structure of compound 2 determined using single crystal X-ray diffraction technique reveals a layered polymeric structure.

  13. An improved method for the enzymatic transformation of nucleosides into 5'-monophosphates.

    Science.gov (United States)

    Barai, Vladimir N; Kvach, Sergei V; Zinchenko, Anatoli I; Mikhailopulo, Igor A

    2004-12-01

    An improved method to transform nucleosides into 5'-monophosphates using nucleoside phosphotransferase from Erwinia herbicola is reported. The method is based on the shift in the equilibrium state of the reaction to the formation of desired product due to its precipitation by Zn2+. Under optimal conditions, the extent of nucleoside transformations into nucleoside-5'-monophosphates were 41-91% (mol). PMID:15672226

  14. Lanthanide phosphonates: Synthesis, thermal stability and magnetic characterization

    Energy Technology Data Exchange (ETDEWEB)

    Amghouz, Z., E-mail: amghouz.uo@uniovi.es [Departamentos de Quimica Fisica y Analitica y Quimica Organica e Inorganica, Universidad de Oviedo - CINN, 33006 Oviedo (Spain); Garcia, J.R.; Garcia-Granda, S. [Departamentos de Quimica Fisica y Analitica y Quimica Organica e Inorganica, Universidad de Oviedo - CINN, 33006 Oviedo (Spain); Clearfield, A. [Department of Chemistry, Texas A and M University, College Station, TX 77842-3012 (United States); Rodriguez Fernandez, J.; Pedro, I. de [CITIMAC, Facultad de Ciencias, Universidad de Cantabria, 39005 Santander (Spain); Blanco, J.A. [Departamento de Fisica, Universidad de Oviedo, 33007 Oviedo (Spain)

    2012-09-25

    Highlights: Black-Right-Pointing-Pointer Report of the complete series of lanthanide 1,4-phenylbis(phosphonate). Black-Right-Pointing-Pointer Synthesis under conventional hydrothermal synthesis or microwave-assisted hydrothermal synthesis. Black-Right-Pointing-Pointer Cation size is the key factor for the structural and particles size variations. Black-Right-Pointing-Pointer Thermal behaviour is characterized by unusual very high thermal stability. - Abstract: Series of novel organic-inorganic hybrids materials based on trivalent lanthanides (Ln = Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu) and 1,4-phenylbis(phosphonate) obtained under hydrothermal conditions either by oven heat or microwave irradiation. The anhydrous compounds containing La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, and Ho, are isostructural. However, the compounds based on Y, Er, Tm, Yb, and Lu are hydrated and their structures have not yet been solved. The series of compounds are characterized by PXRD, TEM, SEM-EDX and thermal analyses (TG-MS and DSC). TEM study show a variable particles size with a minimum mean-particle size of ca. 30 nm. These compounds exhibit unusual very high thermal stability. The size of particles and the thermal stability are depending on lanthanide(III) cation features. All the investigated materials show paramagnetic behaviour. The magnetic susceptibility data follow a Curie-Weiss laws with paramagnetic effective moments in good agreement with those expected for Ln{sup 3+} free ions.

  15. Regulation of the survival and differentiation of hepatic stem/progenitor cells by acyclic retinoid.

    Science.gov (United States)

    Kamiya, Akihide

    2015-01-01

    During embryonic liver development, hepatic stem/progenitor cells (HpSCs) have a high proliferative ability and bipotency to differentiate into hepatocytes and cholangiocytes. Retinoic acid is a derivative of vitamin A and is involved in the proliferation and differentiation of stem/progenitor cells in several tissues. However, whether retinoic acid regulates the characteristics of HpSCs in the normal liver is still unknown. A recent study has shown that acyclic retinoid regulates the survival and proliferation of HpSCs derived from mouse foetal liver. Acyclic retinoid suppressed the expansion of CD29(+)CD49f(+) HpSCs through the induction of hepatocytic differentiation and progression of apoptosis. PMID:26021438

  16. [Synthesis of acyclic 1,3-polyols and its application to structural study of natural products].

    Science.gov (United States)

    Mori, Y

    1993-06-01

    A 1,3-polyhydroxylated chain is often found on the backbone of biologically important natural products. The acyclic nature and the regular array of many hydroxyl groups are main obstacles to structural and synthetic studies, and many efforts have been made to this end. We have developed a new general synthetic method of 1,3-polyols based on the coupling of a chiral dithiane, a four-carbon unit, and an epoxide, followed by 1,3-diastereoselective reduction. We applied the method to the synthesis of polymethoxy-1-alkenes isolated from blue-green algae to establish their absolute stereochemistry. Moreover, a general procedure for assigning the absolute stereochemistry of acyclic 1,3-polyols by the difference circular dichroism (CD) method have been established. Combination of the method and a reiterative degradation enables one to determine the absolute configuration of 1,3-polyols, even if the relative stereochemistry is unknown. PMID:8355146

  17. Regulation of the survival and differentiation of hepatic stem/progenitor cells by acyclic retinoid

    OpenAIRE

    Kamiya, Akihide

    2015-01-01

    During embryonic liver development, hepatic stem/progenitor cells (HpSCs) have a high proliferative ability and bipotency to differentiate into hepatocytes and cholangiocytes. Retinoic acid is a derivative of vitamin A and is involved in the proliferation and differentiation of stem/progenitor cells in several tissues. However, whether retinoic acid regulates the characteristics of HpSCs in the normal liver is still unknown. A recent study has shown that acyclic retinoid regulates the surviva...

  18. Extraction studies of actinides by diisoamyl alkyl and dibutyl phenyl phosphonates from nitric acid media

    International Nuclear Information System (INIS)

    Organophosphonates are more basic than phosphates and hence were reported as superior extractants than phosphates for extraction of uranium and thorium. The extraction of metals by neutral phosphorus based extractants is due to the basic nature of phosphoryl oxygen and mainly depends on the nature of substituents attached to the phosphorus atom. Hence, there is scope to develop phosphonate extractants having tailor-made properties for actinide separation and recovery. Diisoamyl butyl, amyl and hexyl phosphonates were synthesized by the Michaelis-Beeker reaction while dibutylphenyl phosphonate (DBPP) were synthesized from their corresponding aryl phosphorichloridate and alcohol in presence of a base

  19. Palladium-Catalyzed Modification of Unprotected Nucleosides, Nucleotides, and Oligonucleotides

    Directory of Open Access Journals (Sweden)

    Kevin H. Shaughnessy

    2015-05-01

    Full Text Available Synthetic modification of nucleoside structures provides access to molecules of interest as pharmaceuticals, biochemical probes, and models to study diseases. Covalent modification of the purine and pyrimidine bases is an important strategy for the synthesis of these adducts. Palladium-catalyzed cross-coupling is a powerful method to attach groups to the base heterocycles through the formation of new carbon-carbon and carbon-heteroatom bonds. In this review, approaches to palladium-catalyzed modification of unprotected nucleosides, nucleotides, and oligonucleotides are reviewed. Polar reaction media, such as water or polar aprotic solvents, allow reactions to be performed directly on the hydrophilic nucleosides and nucleotides without the need to use protecting groups. Homogeneous aqueous-phase coupling reactions catalyzed by palladium complexes of water-soluble ligands provide a general approach to the synthesis of modified nucleosides, nucleotides, and oligonucleotides.

  20. Base-Modified Nucleosides as Chemotherapeutic Agents: Past and Future.

    Science.gov (United States)

    Burke, Matthew P; Borland, Kayla M; Litosh, Vladislav A

    2016-01-01

    Nucleoside and nucleobase antimetabolites have substantially impacted treatment of cancer and infections. Their close resemblance to natural analogs gives them the power to interfere with a variety of intracellular targets, which on one hand gives them high potency, but on the other hand incurs severe side effects, especially of the chemotherapeutics used against malignancies. Therefore, the development of novel nucleoside analogs with widened therapeutic windows represents an attractive target to synthetic organic and medicinal chemists. This review discusses the current antimetabolite drugs: 5- fluorouracil, 6-mercaptopurine, 6-thioguanine, Cladribine, Vidaza, Decitabine, Emtricitabine, Abacavir, Sorivudine, Clofarabine, Fludarabine, and Nelarabine; gives insight into the nucleoside drug candidates that are being developed; and outlines the approaches to nucleobase modifications that may help discover novel bioactive nucleoside analogs with the mechanism of action focused on termination of DNA synthesis, which is expected to diminish the off-target toxicity in non-proliferating human cells. PMID:26369814

  1. Current prodrug strategies for improving oral absorption of nucleoside analogues

    Directory of Open Access Journals (Sweden)

    Youxi Zhang

    2014-04-01

    Full Text Available Nucleoside analogues are first line chemotherapy in various severe diseases: AIDS (acquired immunodeficiency disease syndrome, cytomegalovirus infections, cancer, etc. However, many nucleoside analogues exhibit poor oral bioavailability because of their high polarity and low intestinal permeability. In order to get around this drawback, prodrugs have been utilized to improve lipophilicity by chemical modification of the parent drug. Alternatively, prodrugs targeting transporters present in the intestine have been applied to promote the transport of the nucleoside analogues. Valacyclovir and valganciclovir are two classic valine ester prodrugs transported by oligopeptide transporter 1. The ideal prodrug achieves delivery of a parent drug by attaching a non-toxic moiety that is stable during transport, but is readily degraded to the parent drug once at the target. This article presents advances of prodrug approaches for enhancing oral absorption of nucleoside analogues.

  2. Crystal structure of a concentrative nucleoside transporter from Vibrio cholerae at 2.4;#8201;Å

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, Zachary Lee; Cheong, Cheom-Gil; Lee, Seok-Yong (Duke)

    2012-07-11

    Nucleosides are required for DNA and RNA synthesis, and the nucleoside adenosine has a function in a variety of signalling processes. Transport of nucleosides across cell membranes provides the major source of nucleosides in many cell types and is also responsible for the termination of adenosine signalling. As a result of their hydrophilic nature, nucleosides require a specialized class of integral membrane proteins, known as nucleoside transporters (NTs), for specific transport across cell membranes. In addition to nucleosides, NTs are important determinants for the transport of nucleoside-derived drugs across cell membranes. A wide range of nucleoside-derived drugs, including anticancer drugs (such as Ara-C and gemcitabine) and antiviral drugs (such as zidovudine and ribavirin), have been shown to depend, at least in part, on NTs for transport across cell membranes. Concentrative nucleoside transporters, members of the solute carrier transporter superfamily SLC28, use an ion gradient in the active transport of both nucleosides and nucleoside-derived drugs against their chemical gradients. The structural basis for selective ion-coupled nucleoside transport by concentrative nucleoside transporters is unknown. Here we present the crystal structure of a concentrative nucleoside transporter from Vibrio cholerae in complex with uridine at 2.4 {angstrom}. Our functional data show that, like its human orthologues, the transporter uses a sodium-ion gradient for nucleoside transport. The structure reveals the overall architecture of this class of transporter, unravels the molecular determinants for nucleoside and sodium binding, and provides a framework for understanding the mechanism of nucleoside and nucleoside drug transport across cell membranes.

  3. Urinary nucleosides as biological markers for patients with colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    Yu-Fang Zheng; Jun Yang; Xin-Jie Zhao; Bo Feng; Hong-Wei Kong; Ying-Jie Chen; Shen Lv; Min-Hua Zheng; Guo-Wang Xu

    2005-01-01

    AIM: Fourteen urinary nucleosides, primary degradation products of tRNA, were evaluated to know the potential as biological markers for patients with colorectal cancer.METHODS: The concentrations of 14 kinds of urinary nucleosides from 52 patients with colorectal cancer, 10patients with intestinal villous adenoma and 60 healthy adults were determined by column switching high performance liquid chromatography method.RESULTS: The mean levels of 12 kinds of urinary nucleosides (except uridine and guanosine) in the patients with colorectal cancer were significantly higher than those in patients with intestinal villous adenoma or the healthy adults. Using the levels of 14 kinds of urinary nucleosides as the data vectors for principal component analysis, 71% (37/52) patients with colorectal cancer were correctly classified from healthy adults, in which the identification rate was much higher than that of CEA method (29%).Only 10% (1/10) of patients with intestinal villous adenoma were indistinguishable from patients with colorectal cancer. The levels of m1G, Pseu and m1A were positively related with tumor size and Duke's stages of colorectal cancer. When monitoring the changes in urinary nucleoside concentrations of patients with colorectal cancer associated with surgery, it was found that the overall correlations with clinical assessment were 84% (27/32)and 91% (10/11) in response group and progressive group, respectively.CONCLUSION: These findings indicate that urinary nucleosides determined by column switching high performance liquid chromatography method may be useful as biological markers for colorectal cancer.

  4. Synthesis of coumarin or ferrocene labeled nucleosides via Staudinger ligation

    Directory of Open Access Journals (Sweden)

    Kois Pavol

    2006-11-01

    Full Text Available Abstract Background Reaction of azides with triaryl phosphines under mild conditions gives iminophosphoranes which can react with almost any kind of electrophilic reagent, e.g. aldehydes/ketones to form imines or esters to form amides. This so-called Staudinger ligation has been employed in a wide range of applications as a general tool for bioconjugation including specific labeling of nucleic acids. Results A new approach for the preparation of labeled nucleosides via intermolecular Staudinger ligation is described. Reaction of azidonucleosides with triphenylphosphine lead to iminophosphorane intermediates, which react subsequently with derivatives of coumarin or ferrocene to form coumarin or ferrocene labeled nucleosides. Fluorescent properties of coumarin labeled nucleosides are determined. Conclusion New coumarin and ferrocene labeled nucleosides were prepared via intermolecular Staudinger ligation. This reaction joins the fluorescent coumarin and biospecific nucleoside to the new molecule with promising fluorescent and electrochemical properties. The isolated yields of products depend on the structure of azidonucleoside and carboxylic acids. A detailed study of the kinetics of the Staudinger ligation with nucleoside substrates is in progress.

  5. Phosphonated nanocelluloses from sequential oxidative-reductive treatment-Physicochemical characteristics and thermal properties.

    Science.gov (United States)

    Sirviö, Juho Antti; Hasa, Tapani; Ahola, Juha; Liimatainen, Henrikki; Niinimäki, Jouko; Hormi, Osmo

    2015-11-20

    Nanocellulosic materials with good thermal stability are highly desirable for applications, such as reinforcement and filler agents in composites. In the present work, phosphonated cellulose was utilized to obtain nanocelluloses with good thermal stability and potential intumescent properties. Phosphonated cellulose was synthetized from birch pulp via sequential periodate oxidation and reductive amination using a bisphosphonate group-containing amine, sodium alendronate, as a phosphonating reagent. After high-pressure homogenization, bisphosphonate cellulose nanofibres or nanocrystals were obtained, depending on the initial oxidation degree. Nanofibres had a typical diameter of 3.8nm and length of several micrometers, whereas nanocrystals exhibited a width of about 6nm and an average length of 103-129nm. All nanocelluloses exhibited cellulose I crystalline structures and high transparency in water solutions. Phosphonated nanocelluloses exhibited good thermal stability and a greater amount of residual char was formed at 700°C compared to birch pulp and mechanically produced, non-chemically modified NFC. PMID:26344310

  6. Insights into the Coordination Chemistry of Phosphonate Derivatives of Hetero-poly-oxo-tungstates

    International Nuclear Information System (INIS)

    The coordination properties of vacant bis-phosphonate derivatives of poly-oxo-metalates, with easily tunable functions, have been explored. The preparation and crystallographic structure of their La3+ and Zr4+ complexes are described herein. (authors)

  7. A database study of intermolecular NH...O hydrogen bonds for carboxylates, sulfonates and monohydrogen phosphonates

    International Nuclear Information System (INIS)

    A search of the Cambridge Structural Database (CSD, version 5.05, 1993) was performed in order to compare the geometrical features of the hydrogen bonds involving on the one hand amino groups and on the other hand carboxylates, sulfonates or monohydrogen phosponates. Phosphonates were not considered because only four entries containing amino and phosphonate moieities were located in the CSD. The hydroxylic group of monohydrogen phosphonates primarily acts as a hydrogen-bond donor. The three moieties under study show NH..O hydrogen bonds with similar geometrical features. This statistical analysis has focused on the hydrogen-bond distances and angles and on the distributions of the H atoms around the acceptor O atoms of carboxylates, sulfonates or monohydrogen phosphonates. (orig.)

  8. A Green Synthesis of 1-Aminoalkyl Phosphonates Under Microwave Irradiation without Any Catalysts and Solvent

    Institute of Scientific and Technical Information of China (English)

    GU,Da-Gong; ZHOU,Min-Feng; SHI,Hai-Bing; JI,Shun-Jun

    2004-01-01

    @@ The synthesis of 1-aminoalkyl phosphonates has been developed during past 20 years. 1-Aminoalkyl phosphonates have received much attentions as an important substrate in the synthesis of phosphonopeptides. It is reported that 1-aminoalkyl phosphonates can be used as enzyme inhibitors, antibiotics and pharmacological agents, herbicides and haptens of catalytic antibolies. Many papers mention that synthesis of 1-aminoalkyl phosphonates is convenient by using a base or an acid as a catalyst. For example, Lewis acids such as SnCl2, SnCl4, ZnCl2, MgBr2, INCl3 or acids alumia can be used as a catalyst in this reaction. It is found that the product can be obtained from a mixture of aldehydes, amine and dithyl phosphite under microwave irradiation in yields of 80%~95%.

  9. Synthesis and crystal structure of ethyl benzimidazole-2-yl phosphonate

    Institute of Scientific and Technical Information of China (English)

    HU, Fang-Zhong; WENG, Lin-Hong; YANG, Hua-Zheng; ZOU, Xiao-Mao

    2000-01-01

    When N-cyanoimido- ( O, O-diethyl ) phosphonyl/ S-methyl thiocarbonate (1) was treated with o-phenylenediamine in the presence of Et3N in ethanol, diethyl benzimidazole-2-yl recrys phonate(2) was obtained and hydrolyzed during the recrys tallization in MeOH/H2O, generating ethyl benzimidazole-2-yl phosphonate(3). The crystal structure of compound 3 was determined by X-ray diffraction method. The crystals belong to monoclinic, space rgoup C2/c, a=1.78408(18), b=O. 83725(9), c=1.67401(18) nm, β= 118.997(2)°, v=2. 1870(4) nm3, z=8, Dc=1.374g/cm3, F(000)=944.The final R and wR are 0.0499 and 0.1436, respectively. The mechanism of the above reaction is also discussed.

  10. Evaluation of follicular oxidant-antioxidant balance and oxidative damage during reproductive acyclicity in water buffalo (Bubalus bubalis)

    Institute of Scientific and Technical Information of China (English)

    M H Jan; G Singh; M Sarkar; G K Das; F A Khan; J Singh; S T Bashir; S Khan; J K Prasad; S Mehrotra; M C Pathak

    2014-01-01

    Objective:To investigate changes in follicular fluid concentrations of reactive oxygen species (ROS) and total antioxidant capacity(TAC) and degree of oxidative damage to follicular cells, using protein carbonyl(PC) as marker of oxidative stress, were investigated during reproductive acyclicity in buffalo.Methods:Follicular fluid was aspirated from follicles grouped into three classes depending upon their diameter [small(5.0-7.0 mm), medium(7.1-10.0 mm), and large (>10.0 mm)].Progesterone and estradiol were estimated to determine functional status(P:E ratio) of the follicles.Results:Acyclic buffaloes had greater concentrations ofROS(P<0.001) andPC (P=0.0412) and lower concentrations ofTAC(P=0.0280) than cyclic buffaloes.An interesting novel finding was the complete absence of lowP:E functionally active follicles in acyclic buffaloes. Results indicated a pronounced follicular fluid oxidant-antioxidant imbalance and oxidative damage to follicular cells during acyclicity in buffalo.Conclusion:In conclusion, this study provided evidence about role of oxidative stress in pathogenesis of reproductive acyclicity.

  11. 平面图的无圈边染色%Acyclic Edge Colouring of Pianar Graphs

    Institute of Scientific and Technical Information of China (English)

    段娟娟; 丁伟

    2011-01-01

    Let G=(V,E) be any finite graph.A mapping C:E→[k]is called an acyclic edge colouring of G,if any two adjacent edges have different colours and there are no bichromatic cycles in G.In other words,the subgraph induced by the union of any two colour classes is a forest.The minimum number k of colours,such that G has an acyclic edge k-colouring is called the acyclic chromatic index of G,denoted by X′a(G).Alon et al.conjectured that for any graph G it holds that X′a(G)≤Δ(G)+2;here Δ(G) stands for the maximum degree of G.In this paper weprove the planar graphs with girth at least 4,then X′a≤Δ(G)+4.%利用差值转移的方法证明了,如果g(G)≥4则有X′a≤Δ(G)+4.图G=(V,E)是简单图,映射C:E→[k],被称作是图G的一个无圈k边染色.如果任意相邻的两个边染有不同的颜色,以及图G中不含有2-色圈,换句话说即图G中任何染两种颜色的边的导出子图是一棵森林.

  12. Hollow cobalt phosphonate spherical hybrid as high-efficiency Fenton catalyst

    Science.gov (United States)

    Zhu, Yun-Pei; Ren, Tie-Zhen; Yuan, Zhong-Yong

    2014-09-01

    Organic-inorganic hybrid of cobalt phosphonate hollow nanostructured spheres were prepared in a water-ethanol system through a mild hydrothermal process in the absence of any templates using diethylenetriamine penta(methylene phosphonic acid) as bridging molecule. SEM, TEM and N2 sorption characterization confirmed a hollow spherical micromorphology with well-defined porosity. The structure and chemical states of the hybrid materials were investigated by FT-IR, XPS and thermogravimetric analysis, revealing the homogeneous integrity of inorganic and organic units inside the network. As a heterogeneous catalyst, hollow cobalt phosphonate material exhibited considerable catalytic oxidizing decomposition of methylene blue with sulfate radicals as compared to cobalt phosphonate nanoparticles synthesized in single water system, which could be attributed to enhanced mass transfer and high surface area for the hollow material. Some operational parameters, including pH and reaction temperature, were found to influence the oxidation process. The present results suggest that cobalt phosphonate material can perform as an efficient heterogeneous catalyst for the degradation of organic contaminants, providing insights into the rational design and development of alternative catalysts for wastewater treatment.Organic-inorganic hybrid of cobalt phosphonate hollow nanostructured spheres were prepared in a water-ethanol system through a mild hydrothermal process in the absence of any templates using diethylenetriamine penta(methylene phosphonic acid) as bridging molecule. SEM, TEM and N2 sorption characterization confirmed a hollow spherical micromorphology with well-defined porosity. The structure and chemical states of the hybrid materials were investigated by FT-IR, XPS and thermogravimetric analysis, revealing the homogeneous integrity of inorganic and organic units inside the network. As a heterogeneous catalyst, hollow cobalt phosphonate material exhibited considerable

  13. A Practical Approach for Scalable Conjunctive Query Answering on Acyclic {EL}^+ Knowledge Base

    Science.gov (United States)

    Mei, Jing; Liu, Shengping; Xie, Guotong; Kalyanpur, Aditya; Fokoue, Achille; Ni, Yuan; Li, Hanyu; Pan, Yue

    Conjunctive query answering for {EL}^{++} ontologies has recently drawn much attention, as the Description Logic {EL}^{++} captures the expressivity of many large ontologies in the biomedical domain and is the foundation for the OWL 2 EL profile. In this paper, we propose a practical approach for conjunctive query answering in a fragment of {EL}^{++}, namely acyclic {EL}^+, that supports role inclusions. This approach can be implemented with low cost by leveraging any existing relational database management system to do the ABox data completion and query answering. We conducted a preliminary experiment to evaluate our approach using a large clinical data set and show our approach is practical.

  14. New insights into the synergism of nucleoside analogs with radiotherapy

    International Nuclear Information System (INIS)

    Nucleoside analogs have been frequently used in combination with radiotherapy in the clinical setting, as it has long been understood that inhibition of DNA repair pathways is an important means by which many nucleoside analogs synergize. Recent advances in our understanding of the structure and function of deoxycytidine kinase (dCK), a critical enzyme required for the anti-tumor activity for many nucleoside analogs, have clarified the mechanistic role this kinase plays in chemo- and radio-sensitization. A heretofore unrecognized role of dCK in the DNA damage response and cell cycle machinery has helped explain the synergistic effect of these agents with radiotherapy. Since most currently employed nucleoside analogs are primarily activated by dCK, these findings lend fresh impetus to efforts focused on profiling and modulating dCK expression and activity in tumors. In this review we will briefly review the pharmacology and biochemistry of the major nucleoside analogs in clinical use that are activated by dCK. This will be followed by discussions of recent advances in our understanding of dCK activation via post-translational modifications in response to radiation and current strategies aimed at enhancing this activity in cancer cells

  15. Oxygen isotope signature of UV degradation of glyphosate and phosphonoacetate: Tracing sources and cycling of phosphonates

    International Nuclear Information System (INIS)

    Highlights: • Phosphonate (phon) hydrolysis by UVR (1.2 kW) attained ≥90% completion in 84 h. • Isotope study reveals both ambient H2O and O2 involvements in phon C-P bond cleavage. • Mechanistic models proposed for phon C-P bond cleavage based on O-isotope analysis. • Model equations used to calculate δ18OP-org of original phon P-moiety-useful as a tracer. • Study shows relevance in tracing phon sources and cycling in the environment. -- Abstract: The degradation of phosphonates in the natural environment constitutes a major route by which orthophosphate (Pi) is regenerated from organic phosphorus and recently implicated in marine methane production, with ramifications to environmental pollution issues and global climate change concerns. This work explores the application of stable oxygen isotope analysis in elucidating the C-P bond cleavage mechanism(s) of phosphonates by UV photo-oxidation and for tracing their sources in the environment. The two model phosphonates used, glyphosate and phosphonoacetic acid were effectively degraded after exposure to UV irradiation. The isotope results indicate the involvement of both ambient water and atmospheric oxygen in the C-P bond cleavage and generally consistent with previously posited mechanisms of UV-photon excitation reactions. A model developed to calculate the oxygen isotopic composition of the original phosphonate P-moiety, shows both synthetic phosphonates having distinctly lower values compared to naturally derived organophosphorus compounds. Such mechanistic models, based on O-isotope probing, are useful for tracing the sources and reactions of phosphonates in the environment

  16. Oxygen isotope signature of UV degradation of glyphosate and phosphonoacetate: Tracing sources and cycling of phosphonates

    Energy Technology Data Exchange (ETDEWEB)

    Sandy, Edward H. [State Key Laboratory of Biogeology and Environmental Geology, China University of Geosciences, Wuhan 430074 (China); Department of Geology and Geophysics, Yale University, P.O. Box 208109, New Haven, CT 06520-8109 (United States); Department of Chemistry, University of Sierra Leone, Freetown (Sierra Leone); Blake, Ruth E., E-mail: ruth.blake@yale.edu [Department of Geology and Geophysics, Yale University, P.O. Box 208109, New Haven, CT 06520-8109 (United States); School of Civil and Environmental Engineering, and National “International Cooperation Base on Environment and Energy”, University of Science and Technology Beijing, Beijing 100084 (China); Chang, Sae Jung [Department of Geology and Geophysics, Yale University, P.O. Box 208109, New Haven, CT 06520-8109 (United States); Jun, Yao, E-mail: yaojun@ustb.edu.cn [State Key Laboratory of Biogeology and Environmental Geology, China University of Geosciences, Wuhan 430074 (China); Department of Geology and Geophysics, Yale University, P.O. Box 208109, New Haven, CT 06520-8109 (United States); School of Civil and Environmental Engineering, and National “International Cooperation Base on Environment and Energy”, University of Science and Technology Beijing, Beijing 100084 (China); Yu, Chan [Department of Geology and Geophysics, Yale University, P.O. Box 208109, New Haven, CT 06520-8109 (United States); School of Civil and Environmental Engineering, and National “International Cooperation Base on Environment and Energy”, University of Science and Technology Beijing, Beijing 100084 (China)

    2013-09-15

    Highlights: • Phosphonate (phon) hydrolysis by UVR (1.2 kW) attained ≥90% completion in 84 h. • Isotope study reveals both ambient H{sub 2}O and O{sub 2} involvements in phon C-P bond cleavage. • Mechanistic models proposed for phon C-P bond cleavage based on O-isotope analysis. • Model equations used to calculate δ{sup 18}O{sub P-org} of original phon P-moiety-useful as a tracer. • Study shows relevance in tracing phon sources and cycling in the environment. -- Abstract: The degradation of phosphonates in the natural environment constitutes a major route by which orthophosphate (Pi) is regenerated from organic phosphorus and recently implicated in marine methane production, with ramifications to environmental pollution issues and global climate change concerns. This work explores the application of stable oxygen isotope analysis in elucidating the C-P bond cleavage mechanism(s) of phosphonates by UV photo-oxidation and for tracing their sources in the environment. The two model phosphonates used, glyphosate and phosphonoacetic acid were effectively degraded after exposure to UV irradiation. The isotope results indicate the involvement of both ambient water and atmospheric oxygen in the C-P bond cleavage and generally consistent with previously posited mechanisms of UV-photon excitation reactions. A model developed to calculate the oxygen isotopic composition of the original phosphonate P-moiety, shows both synthetic phosphonates having distinctly lower values compared to naturally derived organophosphorus compounds. Such mechanistic models, based on O-isotope probing, are useful for tracing the sources and reactions of phosphonates in the environment.

  17. Nanolayer formation on titanium by phosphonated gelatin for cell adhesion and growth enhancement

    Directory of Open Access Journals (Sweden)

    Zhou X

    2015-09-01

    Full Text Available Xiaoyue Zhou,1,2,* Shin-Hye Park,1,* Hongli Mao,3 Takashi Isoshima,1 Yi Wang,2 Yoshihiro Ito1,3 1Nano Medical Engineering Laboratory, RIKEN, Wako, Saitama, Japan; 2Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, People’s Republic of China; 3Emergent Bioengineering Materials Research Team, RIKEN Center for Emergent Matter Science, Wako, Saitama, Japan *These authors contributed equally to this work Abstract: Phosphonated gelatin was prepared for surface modification of titanium to stimulate cell functions. The modified gelatin was synthesized by coupling with 3-aminopropylphosphonic acid using water-soluble carbodiimide and characterized by 31P nuclear magnetic resonance and gel permeation chromatography. Circular dichroism revealed no differences in the conformations of unmodified and phosphonated gelatin. However, the gelation temperature was changed by the modification. Even a high concentration of modified gelatin did not form a gel at room temperature. Time-of-flight secondary ion mass spectrometry showed direct bonding between the phosphonated gelatin and the titanium surface after binding. The binding behavior of phosphonated gelatin on the titanium surface was quantitatively analyzed by a quartz crystal microbalance. Ellipsometry showed the formation of a several nanometer layer of gelatin on the surface. Contact angle measurement indicated that the modified titanium surface was hydrophobic. Enhancement of the attachment and spreading of MC-3T3L1 osteoblastic cells was observed on the phosphonated gelatin-modified titanium. These effects on cell adhesion also led to growth enhancement. Phosphonation of gelatin was effective for preparation of a cell-stimulating titanium surface. Keywords: phosphonated gelatin, surface modification, titanium, cell adhesion

  18. Metabolism of pyrimidine bases and nucleosides in the coryneform bacteria Brevibacterium ammoniagenes and Micrococcus luteus.

    OpenAIRE

    Auling, G; Moss, B

    1984-01-01

    The metabolism of exogenous pyrimidine bases and nucleosides was investigated in Brevibacterium ammoniagenes and Micrococcus luteus with fluorinated analogs and radioactive precursors. Salvage of thymine and thymidine was found in M. luteus, but not in B. ammoniagenes. Exogenous uracil or uracil nucleosides, but not cytosine or cytosine nucleosides, were nucleic acid precursors for both bacteria. By examining the possible nucleoside-metabolizing enzymes, it can be suggested that the pyrimidin...

  19. Phosphorylation of purine and pyrimidine nucleosides by isolated rat liver mitochondria

    Directory of Open Access Journals (Sweden)

    Inaba,Kozo

    1975-10-01

    Full Text Available Formation of 5'-AMP, 5'-GMP, 5'-CMP and 5'UMP was confirmed in isolated rat liver mitochondria incubated with alpha-ketoglutarate, inorganic phosphate, purine nucleoside and pyrimidine nucleoside. Increased incorporation of 32Pi into ATP, GTP and UTP was observed by adding purine- and pyrimidine nucleosides. The phosphorylation of nucleosides was inhibited severely by arsenite and affected slightly by the addition of nuclear or post-mitochondrial fraction.

  20. Synthesis and Antiviral Activity of 3-Aminoindole Nucleosides of 2-Acetamido-2-deoxy-D-glucose

    Energy Technology Data Exchange (ETDEWEB)

    Abdelrahman, Adel A. H.; Elessawy, Farag A.; Barakat, Yousif A. [Menoufia Univ., Shebin El-Koam (Egypt); Ellatif, Mona M. Abd [The British Univ. in Egypt, Cairo (Egypt)

    2012-10-15

    A new method for the construction of 3-aminoindole nucleosides of 2-acetamido-2-deoxy-D-glucose based is presented. Nitration and acetylation of the indole nucleosides by acetic anhydride-nitric acid mixture followed by reduction using silver catalyst (SNSM) impregnated on silica gel, afforded the corresponding amino indole nucleosides. The nucleosides were tested for antiviral activity against hepatitis B virus (HBV) to show different degrees of antiviral activities or inhibitory actions.

  1. Molecular orbital studies on the Wagner-Meerwein migration in some acyclic pinacol-pinacolone rearrangements

    Indian Academy of Sciences (India)

    Zodinpuia Pachuau; R H Duncan Lyngdoh

    2004-03-01

    The semi-empirical PM3 SCF-MO method is used to investigate the Wagner-Meerwein migration of various groups during the pinacol-pinacolone rearrangement of some acyclic systems. Pinacol first protonates and dehydrates to form a carbocation that undergoes a 1,2-migration to form a protonated ketone, which then deprotonates to yield the pinacolone product. We study the Wagner-Meerwein migration of hydride, methyl, ethyl, isopropyl, t-butyl, phenyl and heterocylic 2-, 3- and 4-pyridyl groups in various acyclic 1,2-diol (pinacol) systems as they rearrange to pinacolones. This 1,2-migration involves a three-centred moiety in the cationic transition state. The migratory aptitude predicted here follows the order: hydride -butyl > isopropyl > ethyl > methyl > phenyl, which accords well with available experimental data and/or chemical intuition, reflecting also on the ability of the group involved to carry positive charge in the transition state. The structure of the migrating group (whether aliphatic or aromatic) within the transition state also supports the stabilising role of delocalisation of positive charge for reaction feasibility. Geometrical and thermodynamic considerations coincide in assigning the following order to relative ``earliness” of the transition state along the reaction pathway: -butyl > isopropyl > phenyl > methyl > 2-pyridyl > 4-pyridyl.

  2. The genes and enzymes of phosphonate metabolism by bacteria, and their distribution in the marine environment

    Directory of Open Access Journals (Sweden)

    Juan F Villarreal-Chiu

    2012-01-01

    Full Text Available AbstractPhosphonates are compounds that contain the chemically-stable carbon-phosphorus (C-P bond. They are widely distributed amongst more primitive life forms including many marine invertebrates and constitute a significant component of the Dissolved Organic Phosphorus reservoir in the oceans. Virtually all biogenic C-P compounds are synthesized by a pathway in which the key step is the intramolecular rearrangement of phosphoenolpyruvate to phosphonopyruvate. However C-P bond cleavage by degradative microorganisms is catalysed by a number of enzymes – C-P lyases, C-P hydrolases and others of as-yet-uncharacterized mechanism. Expression of some of the pathways of phosphonate catabolism is controlled by ambient levels of inorganic P (Pi but for others it is Pi-independent. Interrogation of currently-available whole-genome bacterial sequences indicates that some 10 % contain genes encoding putative pathways of phosphonate biosynthesis while approximately 40% encode one or more pathways of phosphonate catabolism. Analysis of metagenomic data from the Global Ocean Survey suggests that some 10% and 30%, respectively, of bacterial genomes across the sites sampled encode these pathways. Catabolic routes involving phosphonoacetate hydrolase, C-P lyase(s and an uncharacterized 2-aminoethylphosphonate degradative sequence were predominant. These data indicate the likely importance of phosphonate-P in global biogeochemical P cycling, and by extension its role in marine productivity and in carbon and nitrogen dynamics in the oceans.

  3. Characterization and structure of DhpI, a phosphonate O-methyltransferase involved in dehydrophos biosynthesis

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jin-Hee; Bae, Brian; Kuemin, Michael; Circello, Benjamin T.; Metcalf, William W.; Nair, Satish K.; van der Donk, Wilfred A. (UIUC)

    2012-03-15

    Phosphonate natural products possess a range of biological activities as a consequence of their ability to mimic phosphate esters or tetrahedral intermediates formed in enzymatic reactions involved in carboxyl group metabolism. The dianionic form of these compounds at pH 7 poses a drawback with respect to their ability to mimic carboxylates and tetrahedral intermediates. Microorganisms producing phosphonates have evolved two solutions to overcome this hurdle: biosynthesis of monoanionic phosphinates containing two P-C bonds or esterification of the phosphonate group. The latter solution was first discovered for the antibiotic dehydrophos that contains a methyl ester of a phosphonodehydroalanine group. We report here the expression, purification, substrate scope, and structure of the O-methyltransferase from the dehydrophos biosynthetic gene cluster. The enzyme utilizes S-adenosylmethionine to methylate a variety of phosphonates including 1-hydroxyethylphosphonate, 1,2-dihydroxyethylphosphonate, and acetyl-1-aminoethylphosphonate. Kinetic analysis showed that the best substrates are tripeptides containing as C-terminal residue a phosphonate analog of alanine suggesting the enzyme acts late in the biosynthesis of dehydrophos. These conclusions are corroborated by the X-ray structure that reveals an active site that can accommodate a tripeptide substrate. Furthermore, the structural studies demonstrate a conformational change brought about by substrate or product binding. Interestingly, the enzyme has low substrate specificity and was used to methylate the clinical antibiotic fosfomycin and the antimalaria clinical candidate fosmidomycin, showing its promise for applications in bioengineering.

  4. Synthesis and applications of gem-bis-phosphonates, powerful complexing agents of metals

    International Nuclear Information System (INIS)

    This thesis was devoted to the development of new ways to prepare gem-bis-phosphonates compounds (BPs), and was carried out under the Program of Nuclear and Environmental Toxicology (ToxNuc-E). Two applications of these compounds have been investigated, the preparation of potent ligands of the uranyl ion for a target of decorporation, and the preparation of new anticancer compounds. The first of these applications was the consequence of work done in the laboratory, that have shown the strong uranium-binding properties of bis-phosphonic ligands. The in vivo tests performed on these compounds have shown the tendency of these ligands to cause liver accumulation of uranium, we wanted to address this problem by modifying the method of anchoring of the bis-phosphonates functions. To this end we have developed a new way to access to these compounds using a metal-carbenoid mediated poly-ols and poly-amines insertion, the metal-carbenoid species bearing the bis-phosphonate function. Regarding the preparation of BPs as anticancer agents, we have developed a new synthetic pathway using a phosphine catalyzed α-P addition of phosphorated pro-nucleophiles to alkynyl-phosphonates as a key step. This enabled us to prepare thirty compound whose activity was evaluated on two cell lines (A431 and HuH7). Five of these compounds possess an activity equivalent to that of the compound described as the most active, the Zoledronate. (author)

  5. Phosphonic Acids for Interfacial Engineering of Transparent Conductive Oxides

    KAUST Repository

    Paniagua, Sergio A.

    2016-05-26

    Transparent conducting oxides (TCOs), such as indium tin oxide and zinc oxide, play an important role as electrode materials in organic-semiconductor devices. The properties of the inorganic-organic interface - the offset between the TCO Fermi level and the relevant transport level, the extent to which the organic semiconductor can wet the oxide surface, and the influence of the surface on semiconductor morphology - significantly affect device performance. This review surveys the literature on TCO modification with phosphonic acids (PAs), which has increasingly been used to engineer these interfacial properties. The first part outlines the relevance of TCO surface modification to organic electronics, surveys methods for the synthesis of PAs, discusses the modes by which they can bind to TCO surfaces, and compares PAs to alternative organic surface modifiers. The next section discusses methods of PA monolayer deposition, the kinetics of monolayer formation, and structural evidence regarding molecular orientation on TCOs. The next sections discuss TCO work-function modification using PAs, tuning of TCO surface energy using PAs, and initiation of polymerizations from TCO-tethered PAs. Finally, studies that examine the use of PA-modified TCOs in organic light-emitting diodes and organic photovoltaics are compared. © 2016 American Chemical Society.

  6. Phosphonic Acids for Interfacial Engineering of Transparent Conductive Oxides.

    Science.gov (United States)

    Paniagua, Sergio A; Giordano, Anthony J; Smith, O'Neil L; Barlow, Stephen; Li, Hong; Armstrong, Neal R; Pemberton, Jeanne E; Brédas, Jean-Luc; Ginger, David; Marder, Seth R

    2016-06-22

    Transparent conducting oxides (TCOs), such as indium tin oxide and zinc oxide, play an important role as electrode materials in organic-semiconductor devices. The properties of the inorganic-organic interface-the offset between the TCO Fermi level and the relevant transport level, the extent to which the organic semiconductor can wet the oxide surface, and the influence of the surface on semiconductor morphology-significantly affect device performance. This review surveys the literature on TCO modification with phosphonic acids (PAs), which has increasingly been used to engineer these interfacial properties. The first part outlines the relevance of TCO surface modification to organic electronics, surveys methods for the synthesis of PAs, discusses the modes by which they can bind to TCO surfaces, and compares PAs to alternative organic surface modifiers. The next section discusses methods of PA monolayer deposition, the kinetics of monolayer formation, and structural evidence regarding molecular orientation on TCOs. The next sections discuss TCO work-function modification using PAs, tuning of TCO surface energy using PAs, and initiation of polymerizations from TCO-tethered PAs. Finally, studies that examine the use of PA-modified TCOs in organic light-emitting diodes and organic photovoltaics are compared. PMID:27227316

  7. Subnanomolar antisense activity of phosphonate-peptide nucleic acid (PNA) conjugates delivered by cationic lipids to HeLa cells

    DEFF Research Database (Denmark)

    Shiraishi, Takehiko; Hamzavi, Ramin; Nielsen, Peter E

    2008-01-01

    as inferred from induced luciferase activity as a consequence of pre-mRNA splicing correction by the antisense-PNA. Antisense activity depended on the number of phosphonate moieties and the most potent hexa-bis-phosphonate-PNA showed at least 20-fold higher activity than that of an optimized PNA/DNA hetero...

  8. Structural investigation of the zirconium-titanium based amino trimethylene phosphonate hybrid coating on aluminum alloy

    Institute of Scientific and Technical Information of China (English)

    Shuanghong WANG; Changsheng LIU; Fengjun SHAN

    2009-01-01

    A zirconium-titanium based amino trimethylene phosphonate hybrid coating on AA6061 aluminum alloys was formed by dipping in a fluorotitanate/zirconate acid and amino trimethylene phosphonic acid (ATMP) solution for improving the lacquer adhesion and corrosion resistance as a substitute of chromate coatings. The morphol-ogy and structure of the hybrid coating were studied by means of scanning electror microscopy (SEM) and atomic force microscopy (AFM). The surface compositior and structure characteristics were also investigated by means of X-ray photoelectron spectroscopy (XPS) and Fourier transformation infra-red spectroscopy (FTIR). The results of SEM and AFM show that the hybrid coating present piece particle distrib-ution which is much denser than that of the zirconium-titanium coating. The results of XPS and FTIR indicate that the hybrid coating is a hybrid composite structure composed of both the zirconium-titanium and amino trimethylene phosphonate coat-ings.

  9. Deoxyribonucleoside kinases activate nucleoside antibiotics in severely pathogenic bacteria

    DEFF Research Database (Denmark)

    Sandrini, Michael; Shannon, O.; Clausen, A.R.;

    2007-01-01

    Common bacterial pathogens are becoming progressively more resistant to traditional antibiotics, representing a major public-health crisis. Therefore, there is a need for a variety of antibiotics with alternative modes of action. In our study, several nucleoside analogs were tested against...... alternative for combating pathogenic bacteria....

  10. Synthesis, bioanalysis and pharmacology of nucleoside and nucleotide analogs

    NARCIS (Netherlands)

    Jansen, R.S.

    2009-01-01

    Nucleoside analogs are an important class of drugs in anticancer and antiviral therapy. The compounds are, however, only active after intracellular conversion to their mono-, di- and triphosphate nucleotide form. In this thesis the development of sensitive liquid chromatography coupled to tandem mas

  11. Novel reactivity of Fhit proteins: catalysts for fluorolysis of nucleoside 5'-phosphoramidates and nucleoside 5'-phosphosulfates to generate nucleoside 5'-phosphorofluoridates.

    Science.gov (United States)

    Wojdyła-Mamoń, Anna M; Zimny, Jarosław; Romanowska, Joanna; Kraszewski, Adam; Stawinski, Jacek; Bieganowski, Paweł; Guranowski, Andrzej

    2015-06-01

    Fragile histidine triad (HIT) proteins (Fhits) occur in all eukaryotes but their function is largely unknown. Human Fhit is presumed to function as a tumour suppressor. Previously, we demonstrated that Fhits catalyse hydrolysis of not only dinucleoside triphosphates but also natural adenosine 5'-phosphoramidate (NH2-pA) and adenosine 5'-phosphosulfate (SO4-pA) as well as synthetic adenosine 5'-phosphorofluoridate (F-pA). In the present study, we describe an Fhit-catalysed displacement of the amino group of nucleoside 5'-phosphoramidates (NH2-pNs) or the sulfate moiety of nucleoside 5'-phosphosulfates (SO4-pNs) by fluoride anion. This results in transient accumulation of the corresponding nucleoside 5'-phosphorofluoridates (F-pNs). Substrate specificity and kinetic characterization of the fluorolytic reactions catalysed by the human Fhit and other examples of involvement of fluoride in the biochemistry of nucleotides are described. Among other HIT proteins, human histidine triad nucleotide-binding protein (Hint1) catalysed fluorolysis of NH2-pA 20 times and human Hint2 40 times more slowly than human Fhit. PMID:25826698

  12. Surface engineering of SPIONs: role of phosphonate ligand multivalency in tailoring their efficacy

    Science.gov (United States)

    Lam, Tina; Avti, Pramod K.; Pouliot, Philippe; Tardif, Jean-Claude; Rhéaume, Éric; Lesage, Frederic; Kakkar, Ashok

    2016-10-01

    We report the design of scaffolds containing mono-, bis-, and tris-phosphonate coordinating groups, and a polyethylene glycol chain, for stabilizing superparamagnetic iron oxide nanoparticles (SPIONs), using simple and versatile chemistry. We demonstrate that the number of anchoring phosphonate sites on the ligand influence the colloidal stability, magnetic and biological properties of SPIONs, and the latter do not solely depend on attaching moieties that can enhance their aqueous dispersion. These parameters can be tailored by the number of conjugation sites on the ligand, as evidenced from dynamic light scattering at various salt concentrations, magnetic relaxivities and cell viability studies.

  13. Yield Improvement and Energy Savings Uing Phosphonates as Additives in Kraft pulping

    Energy Technology Data Exchange (ETDEWEB)

    Ulrike W. Tschirner; Timothy Smith

    2007-03-31

    Project Objective: Develop a commercially viable modification to the Kraft process resulting in energy savings, increased yield and improved bleachability. Evaluate the feasibility of this technology across a spectrum of wood species used in North America. Develop detailed fundamental understanding of the mechanism by which phosphonates improve KAPPA number and yield. Evaluate the North American market potential for the use of phosphonates in the Kraft pulping process. Examine determinants of customer perceived value and explore organizational and operational factors influencing attitudes and behaviors. Provide an economic feasibility assessment for the supply chain, both suppliers (chemical supply companies) and buyers (Kraft mills). Provide background to most effectively transfer this new technology to commercial mills.

  14. Prebiotic chemistry of phosphonic acids: products derived from phosphonoacetaldehyde in the presence of formaldehyde.

    Science.gov (United States)

    De Graaf, R M; Visscher, J; Schwartz, A W

    1998-06-01

    Phosphonoacetaldehyde (PAL), a phosphonic acid analogue of glycolaldehyde phosphate, reacts in the presence of formaldehyde under mildly basic conditions to produce several new products. The reaction proceeds in two stages: a fast aldol condensation of formaldehyde with PAL, and a slower reaction to produce products containing two phosphonic acid groups. We report on the derivatization, isolation by means of HPLC and characterization of these compounds. One of the products is of potential interest as a building block for a prebiotic informational polymer. PMID:9611767

  15. GroupLiNGAM: Linear non-Gaussian acyclic models for sets of variables

    CERN Document Server

    Kawahara, Yoshinobu; Shimizu, Shohei; Washio, Takashi

    2010-01-01

    Finding the structure of a graphical model has been received much attention in many fields. Recently, it is reported that the non-Gaussianity of data enables us to identify the structure of a directed acyclic graph without any prior knowledge on the structure. In this paper, we propose a novel non-Gaussianity based algorithm for more general type of models; chain graphs. The algorithm finds an ordering of the disjoint subsets of variables by iteratively evaluating the independence between the variable subset and the residuals when the remaining variables are regressed on those. However, its computational cost grows exponentially according to the number of variables. Therefore, we further discuss an efficient approximate approach for applying the algorithm to large sized graphs. We illustrate the algorithm with artificial and real-world datasets.

  16. Consensus pursuit of heterogeneous multi-agent systems under a directed acyclic graph

    Institute of Scientific and Technical Information of China (English)

    Yan Jing; Guan Xin-Ping; Luo Xiao-Yuan

    2011-01-01

    This paper is concerned with the cooperative target pursuit problem by multiple agents based on directed acyclic graph. The target appears at a random location and moves only when sensed by the agents, and agents will pursue the target once they detect its existence. Since the ability of each agent may be different, we consider the heterogeneous multi-agent systems.According to the topology of the multi-agent systems, a novel consensus-based control law is proposed, where the target and agents are modeled as a leader and followers, respectively. Based on Mason's rule and signal flow graph analysis, the convergence conditions are provided to show that the agents can catch the target in a finite time. Finally, simulation studies are provided to verify the effectiveness of the proposed approach.

  17. A Directed Acyclic Graph-Large Margin Distribution Machine Model for Music Symbol Classification.

    Science.gov (United States)

    Wen, Cuihong; Zhang, Jing; Rebelo, Ana; Cheng, Fanyong

    2016-01-01

    Optical Music Recognition (OMR) has received increasing attention in recent years. In this paper, we propose a classifier based on a new method named Directed Acyclic Graph-Large margin Distribution Machine (DAG-LDM). The DAG-LDM is an improvement of the Large margin Distribution Machine (LDM), which is a binary classifier that optimizes the margin distribution by maximizing the margin mean and minimizing the margin variance simultaneously. We modify the LDM to the DAG-LDM to solve the multi-class music symbol classification problem. Tests are conducted on more than 10000 music symbol images, obtained from handwritten and printed images of music scores. The proposed method provides superior classification capability and achieves much higher classification accuracy than the state-of-the-art algorithms such as Support Vector Machines (SVMs) and Neural Networks (NNs).

  18. Molecular Motion of the Junction Points in Model Networks Prepared by Acyclic Triene Metathesis.

    Science.gov (United States)

    da Silva, Lucas Caire; Bowers, Clifford R; Graf, Robert; Wagener, Kenneth B

    2016-03-01

    The junction dynamics in a selectively deuterated model polymer network containing junctions on every 21st chain carbon is studied by solid state (2) H echo NMR. Polymer networks are prepared via acyclic triene metathesis of deuteron-labeled symmetric trienes with deuteron probes precisely placed at the alpha carbon relative to the junction point. The effect of decreasing the cross-link density on the junction dynamics is studied by introduction of polybutadiene chains in-between junctions. The networks are characterized by swelling, gel content, and solid state (1) H MAS NMR. Line shape analysis of the (2) H quadrupolar echo spectra reveals that the degree of motion anisotropy and the distribution of motion correlation times depend on the cross-link density and structural heterogeneity of the polymer networks. A detailed model of the junction dynamics at different temperatures is proposed and explained in terms of the intermolecular cooperativity in densely-packed systems. PMID:26787457

  19. Metabolism of acyclic and cyclic N-nitrosamines in cultured human bronchi

    DEFF Research Database (Denmark)

    1977-01-01

    ,N'-dinitrosopiperazine (DNP), N-nitrosopyrrolidine (NPy), and N-nitrosopiperidine (NPd)] labeled with 14C were each then added at 100 mumoles for 24 hours. Measurable CO2 was formed by bronchial explants from: 1) DMN, DEN, and NPy in all 4 patients; 2) DNP in 3 of 4 patients; and 3) NPd in only 1 of 4 patients. In all...... bronchial specimens, these N-nitrosamines and/or their metabolites bound to bronchial mucosal DNA and protein. Binding levels were higher to protein than to DNA. Binding levels of DNP were as high as those with the two acyclic N-nitrosamines DMN and DEN, but binding levels of NPy and NPd were lower. Human...

  20. A Directed Acyclic Graph-Large Margin Distribution Machine Model for Music Symbol Classification

    Science.gov (United States)

    Wen, Cuihong; Zhang, Jing; Rebelo, Ana; Cheng, Fanyong

    2016-01-01

    Optical Music Recognition (OMR) has received increasing attention in recent years. In this paper, we propose a classifier based on a new method named Directed Acyclic Graph-Large margin Distribution Machine (DAG-LDM). The DAG-LDM is an improvement of the Large margin Distribution Machine (LDM), which is a binary classifier that optimizes the margin distribution by maximizing the margin mean and minimizing the margin variance simultaneously. We modify the LDM to the DAG-LDM to solve the multi-class music symbol classification problem. Tests are conducted on more than 10000 music symbol images, obtained from handwritten and printed images of music scores. The proposed method provides superior classification capability and achieves much higher classification accuracy than the state-of-the-art algorithms such as Support Vector Machines (SVMs) and Neural Networks (NNs). PMID:26985826

  1. Bioefficacy of acyclic monoterpenes and their saturated derivatives against the West Nile vector Culex pipiens.

    Science.gov (United States)

    Michaelakis, Antonios; Vidali, Veroniki P; Papachristos, Dimitrios P; Pitsinos, Emmanuel N; Koliopoulos, George; Couladouros, Elias A; Polissiou, Moschos G; Kimbaris, Athanasios C

    2014-02-01

    Twenty acyclic monoterpenes with different functional groups (acetoxy, hydroxyl, carbonyl and carboxyl) bearing a variable number of carbon double bonds were assayed as repellent and larvicidal agents against the West Nile vector Culex pipiens. Seven of them were derivatives that were synthesized through either hydrogenation or oxidation procedures. All repellent compounds were tested at the dose of 1mgcm(-2) and only neral and geranial were also tested at a 4-fold lower dose (0.25mgcm(-2)). Repellency results revealed that geranial, neral, nerol, citronellol, geranyl acetate and three more derivatives dihydrolinalool (3), dihydrocitronellol (5) and dihydrocitronellyl acetate (6) resulted in no landings. Based on the LC50 values the derivative dihydrocitronellyl acetate (6) was the most active of all, resulting in an LC50 value of 17.9mgL(-1). Linalyl acetate, citronellyl acetate, neryl acetate, geranyl acetate, dihydrocitronellol (5), dihydrocitronellal (7), citronellol, dihydrolinalyl acetate (2), citronellic acid and tetrahydrolinalyl acetate (1) were also toxic with LC50 values ranging from 23 to 45mgL(-1). Factors modulating toxicity have been identified, thus providing information on structural requirements for the selected acyclic monoterpenes. The acetoxy group enhanced toxicity, without being significantly affected by the unsaturation degree. Within esters, reduction of the vinyl group appears to decrease potency. Presence of a hydroxyl or carbonyl group resulted in increased activity but only in correlation to saturation degree. Branched alcohols proved ineffective compared to the corresponding linear isomers. Finally, as it concerns acids, data do not allow generalizations or correlations to be made.

  2. Structure of nucleoside diphosphate kinase from pacific shrimp (Litopenaeus vannamei) in binary complexes with purine and pyrimidine nucleoside diphosphates.

    Science.gov (United States)

    López-Zavala, Alonso A; Quintero-Reyes, Idania E; Carrasco-Miranda, Jesús S; Stojanoff, Vivian; Weichsel, Andrzej; Rudiño-Piñera, Enrique; Sotelo-Mundo, Rogerio R

    2014-09-01

    Nucleoside diphosphate kinase (NDK; EC 2.7.4.6) is an enzyme that catalyzes the third phosphorylation of nucleoside diphosphates, leading to nucleoside triphosphates for DNA replication. Expression of the NDK from Litopenaeus vannamei (LvNDK) is known to be regulated under viral infection. Also, as determined by isothermal titration calorimetry, LvNDK binds both purine and pyrimidine deoxynucleoside diphosphates with high binding affinity for dGDP and dADP and with no heat of binding interaction for dCDP [Quintero-Reyes et al. (2012), J. Bioenerg. Biomembr. 44, 325-331]. In order to investigate the differences in selectivity, LvNDK was crystallized as binary complexes with both acceptor (dADP and dCDP) and donor (ADP) phosphate-group nucleoside diphosphate substrates and their structures were determined. The three structures with purine or pyrimidine nucleotide ligands are all hexameric. Also, the binding of deoxy or ribonucleotides is similar, as in the former a water molecule replaces the hydrogen bond made by Lys11 to the 2'-hydroxyl group of the ribose moiety. This allows Lys11 to maintain a catalytically favourable conformation independently of the kind of sugar found in the nucleotide. Because of this, shrimp NDK may phosphorylate nucleotide analogues to inhibit the viral infections that attack this organism.

  3. Two nucleoside uptake systems in Lactococcus lactis: Competition between purine nucleosides and cytidine allows for modulation of intracellular nucleotide pools

    DEFF Research Database (Denmark)

    Martinussen, Jan; Wadskov-Hansen, Steen Lyders Lerche; Hammer, Karin

    2003-01-01

    in Lactococcus lactis were investigated by measuring the uptake of radioactively labeled nucleosides. The K. for for inosine, cytidine, and uridine was determined to be in the micromolar range. Furthermore, it was found that cytidine and inosine are competitive inhibitors of each other, whereas no competition...

  4. Novel and Convenient Approach to the Synthesis of AZT/d4T H-Phosphonates

    Institute of Scientific and Technical Information of China (English)

    LIN Chang-Xue; FU Hua; TU Guang-Zhong; ZHAO Yu-Fen

    2003-01-01

    @@ Intensive efforts have been made to develop effectively chemotherapeutic agents against the human immunodeficiencv virus (HIV). [1] Nucleoside analogues are widelv used as antiviral agents in the treatments of AIDS and the AIDS related complex.[2

  5. Correlation of normal boiling points of dialkylalkyl phosphonates with topological indices on the gas chromatographic retention data

    International Nuclear Information System (INIS)

    Highlights: • Normal boiling points of dialkylalkyl phosphonates measured by using GC technique. • Retention times have been determined by using temperature programmed technique. • Topological indices derived to encode the structural aspects of phosphonates. • QSPR discipline have been developed for predicting normal boiling points. • Statistical characteristics were used for validity of the QSPR discipline. - Abstract: The normal boiling point of twelve dialkylalkyl phosphonates has been determined using gas chromatographic technique. Dibutylhydrogen phosphonate has been used as reference for computing normal boiling point of dialkylalkyl phosphonates. Retention times of dialkylalkyl phosphonates have been measured by using temperature programmed technique. The topological indices namely, odd–even index, atom type index and steric effect index have been designed to capture surface interaction parameters. It was found to exhibit excellent correlation of the topological indices to the normal boiling point of dialkylalkyl phosphonates. Multiple linear regression analysis has been performed for development of quantitative structure property relationships discipline. It exhibited good predictive power (R2 = 0.998)

  6. Correlation of normal boiling points of dialkylalkyl phosphonates with topological indices on the gas chromatographic retention data

    Energy Technology Data Exchange (ETDEWEB)

    Panneerselvam, K., E-mail: kpselvam@igcar.gov.in; Rao, C.V.S. Brahmmananda; Antony, M.P.

    2015-01-20

    Highlights: • Normal boiling points of dialkylalkyl phosphonates measured by using GC technique. • Retention times have been determined by using temperature programmed technique. • Topological indices derived to encode the structural aspects of phosphonates. • QSPR discipline have been developed for predicting normal boiling points. • Statistical characteristics were used for validity of the QSPR discipline. - Abstract: The normal boiling point of twelve dialkylalkyl phosphonates has been determined using gas chromatographic technique. Dibutylhydrogen phosphonate has been used as reference for computing normal boiling point of dialkylalkyl phosphonates. Retention times of dialkylalkyl phosphonates have been measured by using temperature programmed technique. The topological indices namely, odd–even index, atom type index and steric effect index have been designed to capture surface interaction parameters. It was found to exhibit excellent correlation of the topological indices to the normal boiling point of dialkylalkyl phosphonates. Multiple linear regression analysis has been performed for development of quantitative structure property relationships discipline. It exhibited good predictive power (R{sup 2} = 0.998)

  7. The SLC28 (CNT) and SLC29 (ENT) nucleoside transporter families: a 30-year collaborative odyssey.

    Science.gov (United States)

    Young, James D

    2016-06-15

    Specialized nucleoside transporter (NT) proteins are required for passage of nucleosides and hydrophilic nucleoside analogues across biological membranes. Physiologic nucleosides serve as central salvage metabolites in nucleotide biosynthesis, and nucleoside analogues are used as chemotherapeutic agents in the treatment of cancer and antiviral diseases. The nucleoside adenosine modulates numerous cellular events via purino-receptor cell signalling pathways. Human NTs are divided into two structurally unrelated protein families: the SLC28 concentrative nucleoside transporter (CNT) family and the SLC29 equilibrative nucleoside transporter (ENT) family. Human CNTs are inwardly directed Na(+)-dependent nucleoside transporters found predominantly in intestinal and renal epithelial and other specialized cell types. Human ENTs mediate bidirectional fluxes of purine and pyrimidine nucleosides down their concentration gradients and are ubiquitously found in most, possibly all, cell types. Both protein families are evolutionarily old: CNTs are present in both eukaryotes and prokaryotes; ENTs are widely distributed in mammalian, lower vertebrate and other eukaryote species. This mini-review describes a 30-year collaboration with Professor Stephen Baldwin to identify and understand the structures and functions of these physiologically and clinically important transport proteins. PMID:27284054

  8. Adsorption of Phosphonate Antiscalant from Reverse Osmosis Membrane Concentrate onto Granular Ferric Hydroxide

    NARCIS (Netherlands)

    Boels, L.; Keesman, K.J.; Witkamp, G.J.

    2012-01-01

    Adsorptive removal of antiscalants offers a promising way to improve current reverse osmosis (RO) concentrate treatment processes and enables the reuse of the antiscalant in the RO desalination process. This work investigates the adsorption and desorption of the phosphonate antiscalant nitrilotris(m

  9. A comparative study of proton transport properties of zirconium (IV) phosphonates

    Indian Academy of Sciences (India)

    Heemanshu Patel; Uma Chudasama

    2006-12-01

    Novel amorphous zirconium (IV) phosphonates of the class of tetravalent metal acid (TMA) salts have been synthesized by sol–gel method where phosphonates used are hydroxy ethylidene diphosphonic acid (HEDP), amino tri(methylene phosphonic acid) (ATMP) and diethylenetriamine penta(methylenephosphonic acid) (DETPMP) to give ZrHEDP, ZrATMP and ZrDETPMP, respectively. These materials have been characterized for elemental analysis, Zr and P (ICP-AES) and carbon, hydrogen, nitrogen contents (CHN analyser), thermal analysis (TGA, DSC), X-ray analysis and FTIR spectroscopy. Chemical resistivity of these materials has been accessed in acids, bases and organic solvent media. The protons present in the structural hydroxyl groups indicate good potential for TMA salts to exhibit solid state proton conduction. The transport properties of these materials has been explored by measuring specific proton conductance at different temperatures in the range 30–120°C at 10°C intervals, using SOLARTRON DATASET impedance analyser (SI 1260) over a frequency range 1 Hz–10 MHz at a signal level below 1 V. Based on the specific conduction data and Arrhenius plots, a suitable mechanism has been proposed and conductance performance of zirconium phosphonates compared with zirconium phosphate (ZrP).

  10. Enantioselective addition of diphenyl phosphonate to ketimines derived from isatins catalyzed by binaphthyl-modified organocatalysts

    Science.gov (United States)

    Jang, Hee Seung; Kim, Yubin

    2016-01-01

    Summary Chiral binaphthyl-modified squaramide-catalyzed enantioselective addition of diphenyl phosphonate to ketimines derived from isatins has been achieved. This method affords practical and efficient access to chiral 3-amino-3-phosphonyl-substituted oxindole derivatives in high yields with excellent enantioselectivities (up to 99% ee). PMID:27559405

  11. Olefin cross-metathesis for the synthesis of alkenyl acyclonucleoside phosphonates.

    Science.gov (United States)

    Bessières, Maxime; De Schutter, Coralie; Roy, Vincent; Agofoglio, Luigi A

    2014-12-12

    The detailed synthetic protocol for the straightforward, efficient synthesis of various alkenyl acyclonucleosides, including challenging trisubstituted alkenyl acyclonucleoside phosphonates, is described. The key step of those syntheses is an olefin cross-metathesis reaction between two olefins selected based on their reactivity using well-defined ruthenium alkylidene catalysts.

  12. Metal phosphonate hybrid mesostructures: environmentally friendly multifunctional materials for clean energy and other applications.

    Science.gov (United States)

    Ma, Tian-Yi; Yuan, Zhong-Yong

    2011-10-17

    The synthesis of porous hybrid materials has been extended to mesoporous non-silica-based organic-inorganic hybrid materials, in which mesoporous metal phosphonates represent an important family. By using organically bridged polyphosphonic acids as coupling molecules, the homogeneous incorporation of a considerable number of organic functional groups into the metal phosphonate hybrid framework has been realized. Small amounts of organic additives and the pH value of the reaction solution have a large impact on the morphology and textural properties of the resultant hybrid mesoporous metal phosphonate solids. Cationic and nonionic surfactants can be used as templates for the synthesis of ordered mesoporous metal phosphonates. The materials are used as efficient adsorbents for heavy metal ions, CO₂, and aldehydes, as well as in the separation of polycyclic aromatic hydrocarbons. They are also useful photocatalysts under UV and simulated solar light irradiation for organic dye degradation. Further functionalization of the synthesized mesoporous hybrids makes them oxidation and acid catalysts, both with impressive performances in the fields of sustainable energy and environment. PMID:21598407

  13. Upper rim {alpha}-hydroxy-or {alpha}-amino phosphonic acid derivatives of calix (4) ARENES

    Energy Technology Data Exchange (ETDEWEB)

    Markovsky, L.N.; Kalchenko, V.I.; Solovyov, A.V.; Finocchiaro, P.; Failla, S.; Atamas, L.I.; Consiglio, G.; Tsymbal, I.F. [Institute of Organic Chemistry National Academy of Sciences of Ukraine (Ukraine)

    1998-10-01

    The synthesis and some stereochemical peculiarities of calix (4) arenes bearing at the upper rim of macrocycle alpha-hydroxy or alpha-amino phosphonic acid dialkyl ester fragments are described. The formation of the dimeric associates induced by intermolecular hydrogen bonds CH-OH...O=P has been also studied. (Author) 24 refs.

  14. Olefin cross-metathesis for the synthesis of alkenyl acyclonucleoside phosphonates.

    Science.gov (United States)

    Bessières, Maxime; De Schutter, Coralie; Roy, Vincent; Agofoglio, Luigi A

    2014-01-01

    The detailed synthetic protocol for the straightforward, efficient synthesis of various alkenyl acyclonucleosides, including challenging trisubstituted alkenyl acyclonucleoside phosphonates, is described. The key step of those syntheses is an olefin cross-metathesis reaction between two olefins selected based on their reactivity using well-defined ruthenium alkylidene catalysts. PMID:25501590

  15. Metal phosphonate hybrid mesostructures: environmentally friendly multifunctional materials for clean energy and other applications.

    Science.gov (United States)

    Ma, Tian-Yi; Yuan, Zhong-Yong

    2011-10-17

    The synthesis of porous hybrid materials has been extended to mesoporous non-silica-based organic-inorganic hybrid materials, in which mesoporous metal phosphonates represent an important family. By using organically bridged polyphosphonic acids as coupling molecules, the homogeneous incorporation of a considerable number of organic functional groups into the metal phosphonate hybrid framework has been realized. Small amounts of organic additives and the pH value of the reaction solution have a large impact on the morphology and textural properties of the resultant hybrid mesoporous metal phosphonate solids. Cationic and nonionic surfactants can be used as templates for the synthesis of ordered mesoporous metal phosphonates. The materials are used as efficient adsorbents for heavy metal ions, CO₂, and aldehydes, as well as in the separation of polycyclic aromatic hydrocarbons. They are also useful photocatalysts under UV and simulated solar light irradiation for organic dye degradation. Further functionalization of the synthesized mesoporous hybrids makes them oxidation and acid catalysts, both with impressive performances in the fields of sustainable energy and environment.

  16. Understanding the mechanism of action of triazine-phosphonate derivatives as flame retardants for cotton fabrics

    Science.gov (United States)

    Countless hours of research and studies on triazine, phosphonate and their combination have provided insightful information into their flame retardant properties on polymeric systems. However, only limited number of studies shed light on the mechanism of flame retardant cotton fabrics. The purpose...

  17. Amino-Functionalized Layered Crystalline Zirconium Phosphonates: Synthesis, Crystal Structure, and Spectroscopic Characterization.

    Science.gov (United States)

    Taddei, Marco; Sassi, Paola; Costantino, Ferdinando; Vivani, Riccardo

    2016-06-20

    Two new layered zirconium phosphonates functionalized with amino groups were synthesized starting from aminomethylphosphonic acid in the presence of different mineralizers, and their structures were solved from powder X-ray diffraction data. Their topologies are unprecedented in zirconium phosphonate chemistry: the first, of formula ZrH[F3(O3PCH2NH2)], prepared in the presence of hydrofluoric acid, features uncommon ZrO2F4 units and a remarkable thermal stability; the second, of formula Zr2H2[(C2O4)3(O3PCH2NH2)2]·2H2O, prepared in the presence of oxalic acid, is based on ZrO7 units with oxalate anions coordinated to the metal atom, which were never observed before in any zirconium phosphonate. In addition, the structure of another compound based on (2-aminoethyl)phosphonic acid is reported, which was the object of a previously published study. This compound has layered α-type structure with -NH3(+) groups located in the interlayer space. All of the reported compounds were further characterized by means of vibrational spectroscopy, which provided important information on fine structural details that cannot be deduced from the powder X-ray diffraction data. PMID:27254781

  18. Functionalization of SBA-15 mesoporous silica by Cu-phosphonate units: Probing of synthesis route

    International Nuclear Information System (INIS)

    Mesoporous silica SBA-15 containing propyl-copper phosphonate units was investigated. The structure of mesoporous samples was tested by N2 isothermal sorption (BET and BHJ analysis), TEM microscopy and X-Ray scattering. Quantitative analysis EDX has given information about proportions between component atoms in the sample. Quantitative elemental analysis has been carried out to support EDX. To examine bounding between copper atoms and phosphonic units the Raman spectroscopy was carried out. As a support of Raman scattering, the theoretical calculations were made based on density functional theory, with the B3LYP method. By comparison of the calculated vibrational spectra of the molecule with experimental results, distribution of the active units inside silica matrix has been determined. - Graphical abstract: The present study is devoted to mesoporous silica SBA-15 containing propyl-copper phosphonate units. The species were investigated to confirm of synthesis procedure correctness by the micro-Raman technique combined with DFT numerical simulations. Complementary research was carried out to test the structure of mesoporous samples. - Highlights: • SBA-15 silica functionalized with propyl-copper phosphonate units was synthesized. • Synthesis efficiency probed by Raman study supported with DFT simulations. • Homogenous distribution of active units was proved. • Synthesis route enables precise control of distance between copper ions

  19. Seasonal expression of the picocyanobacterial phosphonate transporter gene phnD in the Sargasso Sea

    Directory of Open Access Journals (Sweden)

    Irina N Ilikchyan

    2010-12-01

    Full Text Available In phosphorus-limited marine environments, picocyanobacteria (Synechococcus and Prochlorococcus spp. can hydrolyze naturally occurring phosphonates as a P source. Utilization of 2-aminoethylphosphonate (2-AEP is dependent on expression of the phn genes, encoding functions required for uptake and C-P bond cleavage. Prior work has indicated that expression of picocyanobacterial phnD, encoding the phosphonate binding protein of the phosphonate ABC transporter, is a proxy for the assimilation of phosphonates in natural assemblages of Synechococcus spp. and Prochlorococcus spp (Ilikchyan et al. 2009. In this study, we expand this work to assess seasonal phnD expression in the Sargasso Sea. By RT-PCR, our data confirm that phnD expression is constitutive for the Prochlorococcus spp. detected, but in Synechococcus spp., phnD transcription follows patterns of phosphorus availability in the mixed layer. Specifically, our data suggest that phnD is repressed in the spring when P is bioavailable following deep winter mixing. In the fall, phnD expression follows a depth dependent pattern reflecting depleted P at the surface following summertime drawdown, and elevated P at depth.

  20. Functionalization of SBA-15 mesoporous silica by Cu-phosphonate units: Probing of synthesis route

    Energy Technology Data Exchange (ETDEWEB)

    Laskowski, Lukasz, E-mail: lukasz.laskowski@kik.pcz.pl [Czestochowa University of Technology, Institute of Computational Intelligence, Al. Armii Krajowej 36, 42-201 Czestochowa (Poland); Czestochowa University of Technology, Institute of Physics, Al. Armii Krajowej 19, 42-201 Czestochowa (Poland); Laskowska, Magdalena, E-mail: magdalena.laskowska@onet.pl [Czestochowa University of Technology, Institute of Physics, Al. Armii Krajowej 19, 42-201 Czestochowa (Poland)

    2014-12-15

    Mesoporous silica SBA-15 containing propyl-copper phosphonate units was investigated. The structure of mesoporous samples was tested by N{sub 2} isothermal sorption (BET and BHJ analysis), TEM microscopy and X-Ray scattering. Quantitative analysis EDX has given information about proportions between component atoms in the sample. Quantitative elemental analysis has been carried out to support EDX. To examine bounding between copper atoms and phosphonic units the Raman spectroscopy was carried out. As a support of Raman scattering, the theoretical calculations were made based on density functional theory, with the B3LYP method. By comparison of the calculated vibrational spectra of the molecule with experimental results, distribution of the active units inside silica matrix has been determined. - Graphical abstract: The present study is devoted to mesoporous silica SBA-15 containing propyl-copper phosphonate units. The species were investigated to confirm of synthesis procedure correctness by the micro-Raman technique combined with DFT numerical simulations. Complementary research was carried out to test the structure of mesoporous samples. - Highlights: • SBA-15 silica functionalized with propyl-copper phosphonate units was synthesized. • Synthesis efficiency probed by Raman study supported with DFT simulations. • Homogenous distribution of active units was proved. • Synthesis route enables precise control of distance between copper ions.

  1. A Novel and Fast Purification Method for Nucleoside Transporters.

    Science.gov (United States)

    Hao, Zhenyu; Thomsen, Maren; Postis, Vincent L G; Lesiuk, Amelia; Sharples, David; Wang, Yingying; Bartlam, Mark; Goldman, Adrian

    2016-01-01

    Nucleoside transporters (NTs) play critical biological roles in humans, and to understand the molecular mechanism of nucleoside transport requires high-resolution structural information. However, the main bottleneck for structural analysis of NTs is the production of pure, stable, and high quality native protein for crystallization trials. Here we report a novel membrane protein expression and purification strategy, including construction of a high-yield membrane protein expression vector, and a new and fast purification protocol for NTs. The advantages of this strategy are the improved time efficiency, leading to high quality, active, stable membrane proteins, and the efficient use of reagents and consumables. Our strategy might serve as a useful point of reference for investigating NTs and other membrane proteins by clarifying the technical points of vector construction and improvements of membrane protein expression and purification. PMID:27376071

  2. Mildiomycin: a nucleoside antibiotic that inhibits protein synthesis.

    Science.gov (United States)

    Feduchi, E; Cosín, M; Carrasco, L

    1985-03-01

    Mildiomycin, a new nucleoside antibiotic, selectively inhibits protein synthesis in HeLa cells, and is less active in the inhibition of RNA or DNA synthesis. An increased inhibition of translation by mildiomycin is observed in cultured HeLa cells when they are permeabilized by encephalomyocarditis virus. This observation suggests that this antibiotic does not easily pass through the cell membrane, as occurs with other nucleoside and aminoglycoside antibiotics. The inhibition of translation is also observed in cell-free systems, such as endogenous protein synthesis in a rabbit reticulocyte lysate or the synthesis of polyphenylalanine directed by poly (U). Finally the mode of action of mildiomycin was investigated and the results suggest that the compound blocks the peptidyl-transferase center.

  3. Formation of nucleoside 5'-polyphosphates from nucleotides and trimetaphosphate

    Science.gov (United States)

    Lohrmann, R.

    1975-01-01

    Nucleoside 5'-polyphosphates (N5PP) formed when solutions of nucleoside 5'-phosphates (N5P) and trimetaphosphate (TMP) are dessicated at room temperature are studied by paper chromatography, electrophoresis, and metal catalytic reactions. Divalent Mg ion exhibited superior catalytic function to other divalent metal ions in the reaction. Major reaction products are indicated. The importance of the N5PP series, TMP, and N5-triphosphate as substrates of RNA and DNA synthesis, and under postulated prebiotic conditions likely to obtain during prebiological ages of the earth, is emphasized and discussed. Alternate drying and wetting, evaporation from a prebiotic puddle, concentration of solubles in the remaining liquid phase, metal catalysis, and the role of these substances in the formation of amino acids and long-chain polyphosphates are considered.

  4. Compositions containing nucleosides and manganese and their uses

    Energy Technology Data Exchange (ETDEWEB)

    Daly, Michael J.; Gaidamakova, Elena K.; Matrosova, Vera Y.; Levine, Rodney L.; Wehr, Nancy B.

    2015-11-17

    This invention encompasses methods of preserving protein function by contacting a protein with a composition comprising one or more purine or pyrimidine nucleosides (such as e.g., adenosine or uridine) and an antioxidant (such as e.g., manganese). In addition, the invention encompasses methods of treating and/or preventing a side effect of radiation exposure and methods of preventing a side effect of radiotherapy comprising administration of a pharmaceutically effective amount of a composition comprising one or more purine or pyrimidine nucleosides (such as e.g., adenosine or uridine) and an antioxidant (such as e.g., manganese) to a subject in need thereof. The compositions may comprise D. radiodurans extracts.

  5. A Novel and Fast Purification Method for Nucleoside Transporters

    Science.gov (United States)

    Hao, Zhenyu; Thomsen, Maren; Postis, Vincent L. G.; Lesiuk, Amelia; Sharples, David; Wang, Yingying; Bartlam, Mark; Goldman, Adrian

    2016-01-01

    Nucleoside transporters (NTs) play critical biological roles in humans, and to understand the molecular mechanism of nucleoside transport requires high-resolution structural information. However, the main bottleneck for structural analysis of NTs is the production of pure, stable, and high quality native protein for crystallization trials. Here we report a novel membrane protein expression and purification strategy, including construction of a high-yield membrane protein expression vector, and a new and fast purification protocol for NTs. The advantages of this strategy are the improved time efficiency, leading to high quality, active, stable membrane proteins, and the efficient use of reagents and consumables. Our strategy might serve as a useful point of reference for investigating NTs and other membrane proteins by clarifying the technical points of vector construction and improvements of membrane protein expression and purification. PMID:27376071

  6. Modified Nucleoside Triphosphates for in-vitro Selection Techniques

    Science.gov (United States)

    Iribarren, Adolfo; Dellafiore, María; Montserrat, Javier

    2016-05-01

    The development of SELEX (Selective Enhancement of Ligands by Exponential Enrichment) provides a powerful tool for the search of functional oligonucleotides with the ability to bind ligands with high affinity and selectivity (aptamers) and for the discovery of nucleic acid sequences with diverse enzymatic activities (ribozymes and DNAzymes). This technique has been extensively applied to the selection of natural DNA or RNA molecules but, in order to improve chemical and structural diversity as well as for particular applications where further chemical or biological stability is necessary, the extension of this strategy to modified oligonucleotides is desirable. Taking into account these needs, this review intends to collect the research carried out during the past years, focusing mainly on the use of modified nucleotides in SELEX and the development of mutant enzymes for broadening nucleoside triphosphates acceptance. In addition, comments regarding the synthesis of modified nucleoside triphosphate will be briefly discussed.

  7. Locked and unlocked nucleosides in functional nucleic acids

    DEFF Research Database (Denmark)

    Doessing, Holger; Vester, Birte

    2011-01-01

    Nucleic acids are able to adopt a plethora of structures, many of which are of interest in therapeutics, bio- or nanotechnology. However, structural and biochemical stability is a major concern which has been addressed by incorporating a range of modifications and nucleoside derivatives. This rev...... review summarizes the use of locked nucleic acid (LNA) and un-locked nucleic acid (UNA) monomers in functional nucleic acids such as aptamers, ribozymes, and DNAzymes....

  8. Effects of halides on reaction of nucleosides with ozone.

    Science.gov (United States)

    Suzuki, Toshinori; Kaya, Eriko; Inukai, Michiyo

    2012-01-01

    Ozone (O(3)), a major component of photochemical oxidants, is used recently as a deodorizer in living spaces. It has been reported that O(3) can directly react with DNA, causing mutagenesis in human cells and carcinogenesis in mice. However, little is known about the effects of coexistent ions in the reaction of O(3). In the present study, we analyzed the effects of halides on the reaction of O(3) with nucleosides using reversed-phase high-performance liquid chromatography with ultraviolet detection. When aqueous O(3) solution was added to a nucleoside mixture in potassium phosphate buffer (pH 7.3), the nucleosides were consumed with the following decreasing order of importance: dGuo > Thd > dCyd > dAdo. The effects of addition of fluoride and chloride in the system were slight. Bromide suppressed the reactions of dGuo, Thd, and dAdo but enhanced the reaction of dCyd. The major products were 5-hydroxy-2'-deoxycytidine, 5-bromo-2'-deoxycytidine, and 8-bromo-2'-deoxyguanosine. The time course and pH dependence of the product yield indicated formation of hypobromous acid as the reactive agent. Iodide suppressed all the reactions effectively. The results suggest that bromide may alter the mutation spectrum by O(3) in humans. PMID:22646086

  9. An adenosine nucleoside analogue NITD008 inhibits EV71 proliferation.

    Science.gov (United States)

    Shang, Luqing; Wang, Yaxin; Qing, Jie; Shu, Bo; Cao, Lin; Lou, Zhiyong; Gong, Peng; Sun, Yuna; Yin, Zheng

    2014-12-01

    Enterovirus 71 (EV71), one of the major causative agents of Hand-Foot-Mouth Disease (HFMD), causes severe pandemics and hundreds of deaths in the Asia-Pacific region annually and is an enormous public health threat. However, effective therapeutic antiviral drugs against EV71 are rare. Nucleoside analogues have been successfully used in the clinic for the treatment of various viral infections. We evaluated a total of 27 nucleoside analogues and discovered that an adenosine nucleoside analogue NITD008, which has been reported to be an antiviral reagent that specifically inhibits flaviviruses, effectively suppressed the propagation of different strains of EV71 in RD, 293T and Vero cells with a relatively high selectivity index. Triphosphorylated NITD008 (ppp-NITD008) functions as a chain terminator to directly inhibit the RNA-dependent RNA polymerase activity of EV71, and it does not affect the EV71 VPg uridylylation process. A significant synergistic anti-EV71 effect of NITD008 with rupintrivir (AG7088) (a protease inhibitor) was documented, supporting the potential combination therapy of NITD008 with other inhibitors for the treatment of EV71 infections.

  10. A comparison of enzymatic phosphorylation and phosphatidylation of beta-L- and beta-D-nucleosides.

    Science.gov (United States)

    Birichevskaya, Larisa L; Kvach, Sergei V; Sivets, Grigorii G; Kalinichenko, Elena N; Zinchenko, Anatoly I; Mikhailopulo, Igor A

    2007-04-01

    Enzymatic 5'-monophosphorylation and 5'-phosphatidylation of a number of beta-L- and beta-D-nucleosides was investigated. The first reaction, catalyzed by nucleoside phosphotransferase (NPT) from Erwinia herbicola, consisted of the transfer of the phosphate residue from p-nitrophenylphosphate (p-NPP) to the 5'-hydroxyl group of nucleoside; the second was the phospholipase D (PLD)-catalyzed transphosphatidylation of L-alpha-lecithin with a series of beta-L- and beta-D-nucleosides as the phosphatidyl acceptor resulted in the formation of the respective phospholipid-nucleoside conjugates. Some beta-L-nucleosides displayed similar or even higher substrate activity compared to the beta-D-enantiomers. PMID:17206374

  11. Uptake of Hydrocarbons in Aqueous Solution by Encapsulation in Acyclic Cucurbit[n]uril-Type Molecular Containers.

    Science.gov (United States)

    Lu, Xiaoyong; Isaacs, Lyle

    2016-07-01

    The ability of two water-soluble acyclic cucurbit[n]uril (CB[n]) type containers, whose hydrophobic cavity is defined by a glycoluril tetramer backbone and terminal aromatic (benzene, naphthalene) sidewalls, to act as solubilizing agents for hydrocarbons in water is described. (1) H NMR spectroscopy studies and phase-solubility diagrams establish that the naphthalene-walled container performs as well as, or better than, CB[7] and CB[8] in promoting the uptake of poorly soluble hydrocarbons into aqueous solution through formation of host-hydrocarbon complexes. The naphthalene-walled acyclic CB[n] container is able to extract large hydrocarbons from crude oil into aqueous solution. PMID:27169688

  12. ABC Transporters and their Role in Nucleoside and Nucleotide Drug Resistance

    OpenAIRE

    Fukuda, Yu; Schuetz, John D.

    2012-01-01

    ATP-binding cassette (ABC) transporters confer drug resistance against a wide range of chemotherapeutic agents, including nucleoside and nucleotide based drugs. While nucleoside based drugs have been used for many years in the treatment of solid and hematological malignancies as well as viral and autoimmune diseases, the potential contribution of ABC transporters has only recently been recognized. This neglect is likely because activation of nucleoside derivatives require an initial carrier-m...

  13. Energies for cyclic and acyclic aggregations of adamantane and diamantane units sharing vertices, edges, or six-membered rings

    CERN Document Server

    Balaban, Alexandru T; Klein, Douglas J; Ortiz, Yenni P

    2015-01-01

    Diamondoids are hydrocarbons having a carbon scaffold comprised from polymer-like composites of adamantane cages. The present paper describes computed total energies and "SWB-tension" energies (often referred to as "strain" energies) for species having $n$ adamantane or diamantane units sharing pairwise: one carbon atom (spiro-[n]adamantane or spiro-[$n$]diamantane); one C-C bond (one-bond-sharing-[$n$]adamantane or one-bond-sharing-[$n$]diamantane); or one chair-shaped hexagon of carbon atoms (1234-helical-cata-[$n$]diamantanes). Each of the five investigated polymer-like types is considered either as an acyclic or a cyclic chain of adamantane- or diamantane-unit cages. With increasing $n$ values, SWB-tension energies for acyclic aggregates are found to increase linearly, while the net SWB-tension energies of cyclic aggregates often go thru a minimum at a suitable value of $n$. In all five cases, a limiting common energy per unit ($E/n$ ) is found to be approached by both cyclic and acyclic chains as $n\\to \\...

  14. Synthesis of modified cyclic and acyclic dextrins and comparison of their complexation ability

    Directory of Open Access Journals (Sweden)

    Kata Tuza

    2014-12-01

    Full Text Available We compared the complex forming ability of α-, β- and γ-cyclodextrins (α-CD, β-CD and γ-CD with their open ring analogs. In addition to the native cyclodextrins also modified cyclodextrins and the corresponding maltooligomers, functionalized with neutral 2-hydroxypropyl moieties, were synthesized. A new synthetic route was worked out via bromination, benzylation, deacetylation and debenzylation to obtain the 2-hydroxypropyl maltooligomer counterparts. The complexation properties of non-modified and modified cyclic and acyclic dextrins were studied and compared by photon correlation spectroscopy (PCS and capillary electrophoresis (CE using model guest compounds. In some cases cyclodextrins and their open-ring analogs (acyclodextrins show similar complexation abilities, while with other guests considerably different behavior was observed depending on the molecular dimensions and chemical characteristics of the guests. This was explained by the enhanced flexibility of the non-closed rings. Even the signs of enantiorecognition were observed for the chloropheniramine/hydroxypropyl maltohexaose system. Further studies are planned to help the deeper understanding of the interactions.

  15. Computing the SKT Reliability of Acyclic Directed Networks Using Factoring Method

    Institute of Scientific and Technical Information of China (English)

    KONG Fanjia; WANG Guangxing

    1999-01-01

    This paper presents a factoringalgorithm for computing source-to-K terminal (SKT) reliability, the probability that a source s can send message to a specified set of terminals K, in acyclic directed networks (AD-networks) in which bothnodes and edges can fail. Based on Pivotal decomposition theorem, a newformula is derived for computing the SKT reliability of AD-networks. By establishing a topological property of AD-networks, it is shown that the SKT reliability of AD-networks can be computed by recursively applying this formula. Two new Reliability-Preserving Reductions are alsointroduced. The recursion tree generated by the presented algorithm hasat most 2(|V| - |K|- |C|) leaf nodes, where |V| and |K| are the numbers of nodes and terminals, respectively, while |C| is the number of the nodes satisfying some specified conditions. The computation complexity of the new algorithm is O (|E||V|2(|V| -|K| -|C|)) in the worst case, where |E| is the number of edges. Forsource-to-all-terminal (SAT) reliability, its computation complexity is O (|E|). Comparison of the new algorithm with the existing ones indicates that the new algorithm is more efficient for computing the SKT reliability of AD-networks.

  16. Executive Summary of Ares V: Lunar Capabilities Concept Review Through Phase A-Cycle 3

    Science.gov (United States)

    Holladay, J. B.; Baggett, K. E.; Feldman, S. M.

    2011-01-01

    This Technical Memorandum (TM) was generated as an overall Ares V summary from the Lunar Capabilities Concept Review (LCCR) through Phase A-Cycle 3 (PA-C3) with the intent that it may be coupled with separately published appendices for a more detailed, integrated narrative. The Ares V has evolved from the initial point of departure (POD) 51.00.48 LCCR configuration to the current candidate POD, PA-C3D, and the family of vehicles concept that contains vehicles PA-C3A through H. The logical progression from concept to POD vehicles is summarized in this TM and captures the trade space and performance of each. The family-of-vehicles concept was assessed during PA-C3 and offered flexibility in the path forward with the ability to add options deemed appropriate. A description of each trade space is given in addition to a summary of each Ares V element. The Ares V contributions to a Mars campaign are also highlighted with the goal of introducing Ares V capabilities within the trade space. The assessment of the Ares V vehicle as it pertains to Mars missions remained locked to the architecture presented in Mars Design Reference Authorization 5.0 using the PA-C3D vehicle configuration to assess Mars transfer vehicle options, in-space EDS capabilities, docking adaptor and propellant transfer assessments, and lunar and Mars synergistic potential.

  17. Highly stable acyclic bifunctional chelator for {sup 64}Cu PET imaging

    Energy Technology Data Exchange (ETDEWEB)

    Abada, S.; Lecointre, A.; Christine, C.; Charbonniere, L. [CNRS/UDS, EPCM, Strasbourg (France). Lab. d' Ingenierie Appliquee a l' Analyse; Dechamps-Olivier, I. [Univ. de Reims Champagne Ardenne, Reims (France). Group Chimie de Coordination; Platas-Iglesias, C. [Univ. da Coruna (Spain). Dept. de Quimica Fundamental; Elhabiri, M. [CNRS/UDS, EPCM, Strasbourg (France). Lab. de Physico-Chimie Bioinorganique

    2011-07-01

    Ligand L{sup 1}, based on a pyridine scaffold, functionalized by two bis(methane phosphonate)aminomethyl groups, was shown to display a very high affinity towards Cu(II) (log K{sub CuL}=22.7) and selectivity over Ni(II), Co(II), Zn(II) and Ga(III) ({delta} log K{sub ML}>4) as shown by the values of the stability constants obtained from potentiometric measurements. Insights into the coordination mode of the ligand around Cu(II) cation were obtained by UV-Vis absorption and EPR spectroscopies as well as density functional theory (DFT) calculations (B3LYP model) performed in aqueous solution. The results point to a pentacoordination pattern of the metal ion in the fully deprotonated [CuL{sup 1}]{sup 6-} species. Considering the beneficial thermodynamic parameters of this ligand, kinetic experiments were run to follow the formation of the copper(II) complexes, indicating a very rapid formation of the complex, appropriate for {sup 64}Cu complexation. As L{sup 1} represents a particularly interesting target within the frame of {sup 64}Cu PET imaging, a synthetic protocol was developed to introduce a labeling function on the pyridyl moiety of L{sup 1}, thereby affording L{sup 2}, a potential bifunctional chelator (BFC) for PET imaging.

  18. Synthesis and characterization of tin(IV) phenyl phosphonate in nano form

    Indian Academy of Sciences (India)

    Chitra Sumej; Beena Raveendran

    2008-08-01

    An inorgano–organic ion exchanger, Sn(IV) phenyl phosphonate, has been synthesized in amorphous form. Further, an attempt has been made to synthesize Sn(IV) phenyl phosphonate in the nano form. The materials have been characterized for elemental analysis (ICP–AES), thermal analysis (TGA), X-ray analysis and FTIR spectroscopy. Chemical resistivity of these materials has been accessed in acidic, basic and organic solvent media. Catalytic activity has been studied and compared by using esterification of ethylene glycol as a model reaction wherein glycoldiacetate has been prepared. The transport properties of these materials have been explored by measuring specific proton conduction at different temperatures using SOLARTRON DATASET impedance analyser over a frequency range 1 Hz–1 MHz. It has been observed that Sn(IV) phenyl phosphate in the nano form behaves as a better Bronsted catalyst and proton conductor as compared to the amorphous form.

  19. Two purine nucleoside phosphorylases in Bacillus subtilis. Purification and some properties of the adenosine-specific phosphorylase

    DEFF Research Database (Denmark)

    Jensen, Kaj Frank

    1978-01-01

    Two purine nucleoside phosphorylases (purine-nucleoside:orthophosphate ribosyltransferase, EC 2.4.2.1) were purified from vegetative Bacillus subtilis cells. One enzyme, inosine-guanosine phosphorylase, showed great similarity to the homologous enzyme of Bacillus cereus. It appeared...

  20. Polysulfone Functionalized With Phosphonated Poly(pentafluorostyrene) Grafts for Potential Fuel Cell Applications

    DEFF Research Database (Denmark)

    Dimitrov, Ivaylo; Takamuku, Shogo; Jankova Atanasova, Katja;

    2012-01-01

    of PFS onto PSU backbone is performed via the “click”‐chemistry approach. In a final step, the PFS‐grafts are subjected to the post phosphonation. The copolymers are evaluated as membranes for potential fuel cell applications through thermal analyses, water uptake, and conductivity measurements. The...... proposed synthetic route opens the possibility to tune copolymers’ hydrophilic–hydrophobic balance to obtain membranes with an optimal balance between proton conductivity and mechanical properties....

  1. Binding of nucleotides to nucleoside diphosphate kinase: a calorimetric study.

    Science.gov (United States)

    Cervoni, L; Lascu, I; Xu, Y; Gonin, P; Morr, M; Merouani, M; Janin, J; Giartosio, A

    2001-04-17

    The source of affinity for substrates of human nucleoside diphosphate (NDP) kinases is particularly important in that its knowledge could be used to design more effective antiviral nucleoside drugs (e.g., AZT). We carried out a microcalorimetric study of the binding of enzymes from two organisms to various nucleotides. Isothermal titration calorimetry has been used to characterize the binding in terms of Delta G degrees, Delta H degrees and Delta S degrees. Thermodynamic parameters of the interaction of ADP with the hexameric NDP kinase from Dictyostelium discoideum and with the tetrameric enzyme from Myxococcus xanthus, at 20 degrees C, were similar and, in both cases, binding was enthalpy-driven. The interactions of ADP, 2'deoxyADP, GDP, and IDP with the eukaryotic enzyme differed in enthalpic and entropic terms, whereas the Delta G degrees values obtained were similar due to enthalpy--entropy compensation. The binding of the enzyme to nonphysiological nucleotides, such as AMP--PNP, 3'deoxyADP, and 3'-deoxy-3'-amino-ADP, appears to differ in several respects. Crystallography of the protein bound to 3'-deoxy-3'-amino-ADP showed that the drug was in a distorted position, and was unable to interact correctly with active site side chains. The interaction of pyrimidine nucleoside diphosphates with the hexameric enzyme is characterized by a lower affinity than that with purine nucleotides. Titration showed the stoichiometry of the interaction to be abnormal, with 9--12 binding sites/hexamer. The presence of supplementary binding sites might have physiological implications. PMID:11294625

  2. Nucleoside Inhibitors of Tick-Borne Encephalitis Virus

    Science.gov (United States)

    Eyer, Luděk; Valdés, James J.; Gil, Victor A.; Nencka, Radim; Hřebabecký, Hubert; Šála, Michal; Salát, Jiří; Černý, Jiří; Palus, Martin; De Clercq, Erik

    2015-01-01

    Tick-borne encephalitis virus (TBEV) is a leading cause of human neuroinfections in Europe and Northeast Asia. There are no antiviral therapies for treating TBEV infection. A series of nucleoside analogues was tested for the ability to inhibit the replication of TBEV in porcine kidney cells and human neuroblastoma cells. The interactions of three nucleoside analogues with viral polymerase were simulated using advanced computational methods. The nucleoside analogues 7-deaza-2′-C-methyladenosine (7-deaza-2′-CMA), 2′-C-methyladenosine (2′-CMA), and 2′-C-methylcytidine (2′-CMC) inhibited TBEV replication. These compounds showed dose-dependent inhibition of TBEV-induced cytopathic effects, TBEV replication (50% effective concentrations [EC50]of 5.1 ± 0.4 μM for 7-deaza-2′-CMA, 7.1 ± 1.2 μM for 2′-CMA, and 14.2 ± 1.9 μM for 2′-CMC) and viral antigen production. Notably, 2′-CMC was relatively cytotoxic to porcine kidney cells (50% cytotoxic concentration [CC50] of ∼50 μM). The anti-TBEV effect of 2′-CMA in cell culture diminished gradually after day 3 posttreatment. 7-Deaza-2′-CMA showed no detectable cellular toxicity (CC50 > 50 μM), and the antiviral effect in culture was stable for >6 days posttreatment. Computational molecular analyses revealed that compared to the other two compounds, 7-deaza-2′-CMA formed a large cluster near the active site of the TBEV polymerase. High antiviral activity and low cytotoxicity suggest that 7-deaza-2′-CMA is a promising candidate for further investigation as a potential therapeutic agent in treating TBEV infection. PMID:26124166

  3. Understanding the Mechanism of Action of Triazine-Phosphonate Derivatives as Flame Retardants for Cotton Fabric

    Directory of Open Access Journals (Sweden)

    Monique M. Nguyen

    2015-06-01

    Full Text Available Countless hours of research and studies on triazine, phosphonate, and their combination have provided insightful information into their flame retardant properties on polymeric systems. However, a limited number of studies shed light on the mechanism of flame retardancy of their combination on cotton fabrics. The purpose of this research is to gain an understanding of the thermal degradation process of two triazine-phosphonate derivatives on cotton fabric. The investigation included the preparation of diethyl 4,6-dichloro-1,3,5-triazin-2-ylphosphonate (TPN1 and dimethyl (4,6-dichloro-1,3,5-triazin-2-yloxy methyl phosphonate (TPN3, their application on fabric materials, and the studies of their thermal degradation mechanism. The studies examined chemical components in both solid and gas phases by using attenuated total reflection infrared (ATR-IR spectroscopy, thermogravimetric analysis coupled with Fourier transform infrared (TGA-FTIR spectroscopy, and 31P solid state nuclear magnetic resonance (31P solid state NMR, in addition to the computational studies of bond dissociation energy (BDE. Despite a few differences in their decomposition, TPN1 and TPN3 produce one common major product that is believed to help reduce the flammability of the fabric.

  4. Structure and Order of Phosphonic Acid-Based Self-Assembled Based Self-Assembled

    Energy Technology Data Exchange (ETDEWEB)

    Dubey, M.; Weidner, T; Gamble, L; Castner, D

    2010-01-01

    Organophosphonic acid self-assembled monolayers (SAMs) on oxide surfaces have recently seen increased use in electrical and biological sensor applications. The reliability and reproducibility of these sensors require good molecular organization in these SAMs. In this regard, packing, order, and alignment in the SAMs is important, as it influences the electron transport measurements. In this study, we examine the order of hydroxyl- and methyl-terminated phosphonate films deposited onto silicon oxide surfaces by the tethering by aggregation and growth method using complementary, state-of-art surface characterization tools. Near-edge X-ray absorption fine structure (NEXAFS) spectroscopy and in situ sum frequency generation (SFG) spectroscopy are used to study the order of the phosphonate SAMs in vacuum and under aqueous conditions, respectively. X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry results show that these samples form chemically intact monolayer phosphonate films. NEXAFS and SFG spectroscopy showed that molecular order exists in the octadecylphosphonic acid and 11-hydroxyundecylphosphonic acid SAMs. The chain tilt angles in these SAMs were approximately 37{sup o} and 45{sup o}, respectively.

  5. SYNTHESIS, CHARACTERIZATION AND RING-OPENING POLYMERIZATION OF CYCLIC (ARYLENE PHOSPHONATE) OLIGOMERS

    Institute of Scientific and Technical Information of China (English)

    Hong-ming Zhang; Qing-zhong Guo; Tian-lu Chen

    2004-01-01

    A series of cyclic (arylene phosphonate) oligomers were prepared by reaction of phenylphosphonic dichloride (PPD) with various bisphenols under pseudo-high dilution conditions via interfacial polycondensation. The yield of cyclic (arylenc phosphonate) oligomers is over 85% by using hexadecyltrimethylammonium bromide as phase transfer catalyst (PTC) at 0 ℃. The structures of the cyclic oligomers were confirmed by a combination of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and IR analysis. These cyclic oligomers undergo facile ring-opening polymerization in the melt by using potassium 4,4'-biphenoxide as the initiator to give linear polyphosphonate. Free-radical ring-opening polymerization of cyclic(arylene phosphonate) oligomers containing sulfur linkages was also performed in the melt using 2,2'-dithiobis(benzothiazole) (DTB) as the initiator at 270℃ and the resulting polymer had a Mw of 8 × 103 with a molecular weight distribution of 4. Ring-opening copolymerization of these cyclic oligomers with cyclic carbonate oligomers was also achieved. The average molecular weight of the resulting copolymer is higher than the corresponding homopolymer and the thermal stability of the copolymer is better than the corresponding homopolymer.

  6. Incorporation of oxygen-18 into nucleosides and bases.

    Science.gov (United States)

    Puzo, G; Schram, K H; McCloskey, J A

    1977-06-01

    Extensive incorporation of oxygen-18 at position O4 of the pyrimidine nucleus results from exchange between H218O and nucleosides or bases in 1N HC1 at 100 degrees. The reaction is hindered by substitution at C-5 with the greatest effect shown in pseudouridine (R = ribosy1) and the least in uridine (R = H). Maximum incorporation in the latter compound was 94%, and in uricil was 98%. The method is experimentally simple and the incorporation is readily monitored by mass spectrometry. PMID:896486

  7. A procedure for the preparation and isolation of nucleoside-5’-diphosphates

    Directory of Open Access Journals (Sweden)

    Heidi J. Korhonen

    2015-04-01

    Full Text Available Tris[bis(triphenylphosphoranylideneammonium] pyrophosphate (PPN pyrophosphate was used in the SN2 displacements of the tosylate ion from 5’-tosylnucleosides to afford nucleoside-5’-diphosphates. Selective precipitation permitted the direct isolation of nucleoside-5’-diphosphates from crude reaction mixtures.

  8. Synthesis of carbocyclic nucleoside analogs with five-membered heterocyclic nucleobases

    Science.gov (United States)

    Cho, Jong hyun; Coats, Steven J.; Schinazi, Raymond F.

    2015-01-01

    New carbocyclic nucleoside analogs with five-membered heterocyclic nucleobases were synthesized and evaluated as potential anti-HIV and anti-HCV agents. Among the synthesized carbocyclic nucleoside analogs, the pyrazole amide 15f exhibited modest selective anti-HIV-1 activity (EC50 = 24 µM). PMID:26028788

  9. A procedure for the preparation and isolation of nucleoside-5’-diphosphates

    Science.gov (United States)

    Korhonen, Heidi J; Bolt, Hannah L

    2015-01-01

    Summary Tris[bis(triphenylphosphoranylidene)ammonium] pyrophosphate (PPN pyrophosphate) was used in the SN2 displacements of the tosylate ion from 5’-tosylnucleosides to afford nucleoside-5’-diphosphates. Selective precipitation permitted the direct isolation of nucleoside-5’-diphosphates from crude reaction mixtures. PMID:25977720

  10. Alteration in substrate specificity of horse liver alcohol dehydrogenase by an acyclic nicotinamide analog of NAD(+).

    Science.gov (United States)

    Malver, Olaf; Sebastian, Mina J; Oppenheimer, Norman J

    2014-11-01

    A new, acyclic NAD-analog, acycloNAD(+) has been synthesized where the nicotinamide ribosyl moiety has been replaced by the nicotinamide (2-hydroxyethoxy)methyl moiety. The chemical properties of this analog are comparable to those of β-NAD(+) with a redox potential of -324mV and a 341nm λmax for the reduced form. Both yeast alcohol dehydrogenase (YADH) and horse liver alcohol dehydrogenase (HLADH) catalyze the reduction of acycloNAD(+) by primary alcohols. With HLADH 1-butanol has the highest Vmax at 49% that of β-NAD(+). The primary deuterium kinetic isotope effect is greater than 3 indicating a significant contribution to the rate limiting step from cleavage of the carbon-hydrogen bond. The stereochemistry of the hydride transfer in the oxidation of stereospecifically deuterium labeled n-butanol is identical to that for the reaction with β-NAD(+). In contrast to the activity toward primary alcohols there is no detectable reduction of acycloNAD(+) by secondary alcohols with HLADH although these alcohols serve as competitive inhibitors. The net effect is that acycloNAD(+) has converted horse liver ADH from a broad spectrum alcohol dehydrogenase, capable of utilizing either primary or secondary alcohols, into an exclusively primary alcohol dehydrogenase. This is the first example of an NAD analog that alters the substrate specificity of a dehydrogenase and, like site-directed mutagenesis of proteins, establishes that modifications of the coenzyme distance from the active site can be used to alter enzyme function and substrate specificity. These and other results, including the activity with α-NADH, clearly demonstrate the promiscuity of the binding interactions between dehydrogenases and the riboside phosphate of the nicotinamide moiety, thus greatly expanding the possibilities for the design of analogs and inhibitors of specific dehydrogenases.

  11. A high-yielding, strictly regioselective prebiotic purine nucleoside formation pathway.

    Science.gov (United States)

    Becker, Sidney; Thoma, Ines; Deutsch, Amrei; Gehrke, Tim; Mayer, Peter; Zipse, Hendrik; Carell, Thomas

    2016-05-13

    The origin of life is believed to have started with prebiotic molecules reacting along unidentified pathways to produce key molecules such as nucleosides. To date, a single prebiotic pathway to purine nucleosides had been proposed. It is considered to be inefficient due to missing regioselectivity and low yields. We report that the condensation of formamidopyrimidines (FaPys) with sugars provides the natural N-9 nucleosides with extreme regioselectivity and in good yields (60%). The FaPys are available from formic acid and aminopyrimidines, which are in turn available from prebiotic molecules that were also detected during the Rosetta comet mission. This nucleoside formation pathway can be fused to sugar-forming reactions to produce pentosides, providing a plausible scenario of how purine nucleosides may have formed under prebiotic conditions. PMID:27174989

  12. Mechanistic understanding of calcium-phosphonate solid dissolution and scale inhibitor return behavior in oilfield reservoir: formation of middle phase.

    Science.gov (United States)

    Zhang, Ping; Shen, Dong; Ruan, Gedeng; Kan, Amy T; Tomson, Mason B

    2016-08-01

    Phosphonates are an important class of mineral scale inhibitors used for oilfield scale control. By injecting the phosphonate into an oilfield reservoir, calcium-phosphonate precipitate will form and subsequently release the phosphonate into produced water for scale control. In this study, a systematic procedure is developed to mechanistically characterize an acidic calcium-phosphonate amorphous material that is later developed into a middle phase and eventually a crystalline phase. The phosphonate used in this study is diethylenetriamine pentakis (methylene phosphonic acid) (DTPMP). An amorphous calcium-DTPMP solid is precipitated by mixing a calcium-containing solution with a DTPMP solution. The stoichiometry of this initially formed solid can be experimentally confirmed via a static dissolution test. Following another dynamic development test, two additional Ca-DTPMP solid phases, i.e., a middle phase and a crystalline phase have been observed. Electron microscopy and X-ray diffraction were employed to characterize the morphology and crystallinity of different Ca-DTPMP solids of interest. Evidently, the dynamic brine flushing of the Ca-DTPMP solid developed the initially amorphous material into a middle phase solid with an amorphous/microcrystalline structure and eventually into a crystalline material. Furthermore, a dissolution characterization study was carried out to determine the solubility product of the middle phase solid at different conditions. The obtained mechanistic understanding of the Ca-DTPMP solid related to precipitation chemistry, dissolution behavior and phase transition is critical to elucidate oilfield DTPMP return data and more importantly, can optimize the oilfield scale squeeze design to achieve an extended squeeze lifetime.

  13. Lights and shadows in the challenge of binding acyclovir, a synthetic purine-like nucleoside with antiviral activity, at an apical-distal coordination site in copper(II)-polyamine chelates.

    Science.gov (United States)

    Pérez-Toro, Inmaculada; Domínguez-Martín, Alicia; Choquesillo-Lazarte, Duane; Vílchez-Rodríguez, Esther; González-Pérez, Josefa María; Castiñeiras, Alfonso; Niclós-Gutiérrez, Juan

    2015-07-01

    Several nucleic acid components and their metal complexes are known to be involved in crucial metabolic steps. Therefore the study of metal-nucleic acid interactions becomes essential to understand these biological processes. In this work, the synthetic purine-like nucleoside acyclovir (acv) has been used as a model of guanosine recognition with copper(II)-polyamine chelates. The chemical stability of the N9-acyclic arm in acv offers the possibility to use this antiviral drug to deepen the knowledge of metal-nucleoside interactions. Cu(II) chelates with cyclam, cyclen and trien were used as suitable receptors. All these copper(II) tetraamine chelates have in common the potential ability to yield a Cu-N7(apical) bond assisted by an appropriate (amine)N-H⋯O6(acv) intra-molecular interligand interaction. A series of synthesis afforded the following compounds: [Cu(cyclam)(ClO4)2] (1), {[Cu(cyclam)(μ2-NO3)](NO3)}n (2), {[Cu(cyclam)(μ2-SO4)]·MeOH}n (3), {[Cu(cyclam)(μ2-SO4)]·5H2O}n (4), [Cu(cyclen)(H2O)]SO4·2H2O (5), [Cu(cyclen)(H2O)]SO4·3H2O (6), [Cu(trien)(acv)](NO3)2·acv (7) and [Cu(trien)(acv)]SO4·0.71H2O (8). All these compounds have been characterized by X-ray crystallography and FT-IR spectroscopy. Our results reveal that the macrochelates Cu(cyclen)(2+) and Cu(cyclam)(2+) are unable to bind acv at an apical site. In contrast, the Cu(trien)(2+) complex has proved to be an efficient receptor for acv in compounds (7) and (8). In the ternary complex [Cu(trien)(acv)](2+), the metal binding pattern of acv consists of an apical Cu-N7 bond assisted by an intra-molecular (primary amino)N-H⋯O6(acv) interligand interaction. Structural comparisons reveal that this unprecedented apical role of acv is due to the acyclic nature of trien together with the ability of the Cu(trien)(2+) chelate to generate five-coordinated (type 4+1) copper(II) complexes.

  14. Properties of mammalian nuclear-envelope nucleoside triphosphatase.

    Science.gov (United States)

    Agutter, P S; Cockrill, J B; Lavine, J E; McCaldin, B; Sim, R B

    1979-09-01

    The nucleoside triphosphatase activities of the nuclear envelopes from rat liver, pig liver and simian-virus-40-transformed mouse-embryo 3T3 cells were shown to exhibit similar parperties. All three preparations hydrolyse ATP, 2'-dATP, 3'-dATP, GTP, CTP and UTP in the presence of Mg2+, Ca2+, Mn2+ and Co2+ with a pH optimum of 8.0, are sensitive to inhibition by mercurials, arsenicals, quercetin, proflavin and adenosine 5'-[gamma-thio]triphosphate and are partially inactivated by exposure to high ionic strength. The kinetic behaviour is similar for all substrates irrespective of the source of material. The typical Eadie-Hofstee plot, which is concave upwards at pH 8.0 when the ionic strength is 20mM, becomes linear when the pH is increased to 8.5 or the ionic strength to 160mM. The overall evidence, particularly the labelling of only one polypeptide by [gamma-32P]ATP, suggests that under the conditions of preparation and assay used only one class of nucleoside triphosphatase active sites is detectable in nuclear envelopes. The importance of these results for an understanding of the role of the enzyme in vivo is discussed.

  15. Radiolabeled nucleoside analogs in cancer diagnosis and therapy.

    Science.gov (United States)

    Kassis, A I; Adelstein, S J; Mariani, G

    1996-09-01

    Radiolabeled nucleosides, specifically 5-iodo-2'-deoxyuridine (IUdR) radioiodinated with the Auger-electronemitting 123I or 125I, have been shown to produce extensive DNA damage in mammalian cell systems in vitro. Such nucleosides are cycle-dependent agents that are taken up by mitotically dividing cells in the S phase of the cell cycle. The degree of damage that occurs is related to the fact that these nucleosides bind covalently to DNA bringing the decaying Augerelectron-emitting radionuclide in close proximity to the genome. The use of these radiohalogenated nucleosides in vivo is associated with several problems. The first relates to their extremely short biologic half-life in blood (T1/2 of minutes in humans). The second involves achieving therapeutic ratios in tumor cells in the face of efficient hepatic dehalogenation. The third concerns the uptake of these radiopharmaceuticals by actively proliferating normal cell renewal systems, thus potentially causing toxic side effects. The fourth, one shared with other cycle-dependent drugs, relates to the matter of labeling the whole tumor cell population. To facilitate targeting to tumors, investigators have been examining the direct introduction of these agents into the targeted area or into an arterial blood supply that immediately precedes the target. For example, radiopharmaceutical administration could be intracavitary (bladder, spinal fluid, peritoneum), intralesional (brain tumor, breast mass) or intra-arterial (liver, pancreas). In all these situations, the following conditions must be met: (a) once within the vicinity of the tumor the agent can freely diffuse through the tissues and is selectively taken up by cancerous cells; (b) once the agent has left the target area it is converted quickly into a nontoxic form and/or excreted from the body; and finally, (c) the biologic behavior of the agent is not altered by repeated injections. We report herein our experience and that of others with [123I/125I/131I

  16. Cationic lipids bearing succinic-based, acyclic and macrocyclic hydrophobic domains: synthetic studies and in vitro gene transfer

    DEFF Research Database (Denmark)

    Jubeli, Emile; Maginty, A. B.; Khalique, N. A.;

    2016-01-01

    a dimethylamine or trimethylamine headgroup, and a macrocyclic or an acyclic hydrophobic domain composed of, or derived from two 16-atom, succinic-based acyl chains. The synthesized lipids and a co-lipid of neutral charge, either cholesterol or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), were formulated...... within the hydrophobic domain of the cationic lipids was found to improve lipid hydration. The transfection assays revealed a general trend in which mismatched formulations that employed a rigid lipid combined with a non-rigid (or flexible) lipid, outperformed the matched formulations. The results from...

  17. Synthesis and structures of acyclic monoanionic tetradentate aza beta-diketiminate complexes of magnesium, zinc, and cadmium.

    Science.gov (United States)

    Fritsch, Joseph M; Thoreson, Kristen A; McNeill, Kristopher

    2006-10-28

    An acyclic monoanionic tetradentate nitrogen ligand was prepared through the condensation of 2-(4-tolyl)-malondialdehyde and 8-aminoquinoline to give (BDI(QQ))H where (BDI(QQ))H = (8-quinolyl)-NCHC(4-tolyl)CHNH-(8-quinolyl). Metal complexes, (BDI(QQ))MX, were prepared where MX = MgBr 2, ZnCl 3, and CdOAc 4. The spectroscopic and crystallographic properties of compounds 2, 3, and 4 were explored. Structures of complexes 2, 3, 4, and the tridentate ligand, (BDI(Q))OH, 5, are reported. PMID:17033706

  18. Applying the Directed Acyclic Graph to Examine the Factors Related to the Adoption of E-Learning

    OpenAIRE

    Quang Linh Huynh; Thuy Lan Le Thi

    2014-01-01

    This research explores the causal relationships among the attitude toward using e-learning, the perception on the usefulness of e-learning and the adoption of e-learning as well as the mediating role of the attitude toward using e-learning and the moderating role of the perceived usefulness of e-learning. We use an advanced method known as the directed acyclic graph to investigate the causal associations. Then we use Sobel’s technique and hierarchical regressions to examine the mediating and ...

  19. Catalytic phosphonation of high performance polymers and POSS. Novel components for polymer blend and nanocomposite fuel cell membranes

    Energy Technology Data Exchange (ETDEWEB)

    Bock, T.R.

    2006-10-15

    Aim of this thesis was the preparation and evaluation of phosphonated high performance (HP) polyelectrolytes and polyhedral oligomeric silsesquioxanes (POSS) for polyelectrolyte membrane fuel cell (PEMFC) application. Brominated derivatives of the commercial high performance (HP) polymers poly(ethersulfone) (PES), poly(etheretherketone) (PEEK), poly(phenylsulfone) (PPSu), poly(sulfone) (PSU) and of octaphenyl-POSS of own production were phosphonated by Ni-catalysed Arbuzov reaction. Phosphonated PSU was cast into pure and blend films with sulfonated PEEK (s-PEEK) to investigate H+-conductivity, water uptake and film morphology. Blend films' properties were referenced to films containing unmodified blend partners. Solution-compounding of phosphonated octaphenyl-POSS and s-PEEK was used to produce novel nanocomposite films. An in-situ zirconisation method was assessed as convenient strategy for novel ionically crosslinked membranes of enhanced swelling resistance. Dibromo isocyanuric acid (DBI) and N-bromo succinimide (NBS) as brominating agents allowed polymer analogous preparation of the novel brominated PES and PEEK with precise reaction control. A random distribution of functional groups, i.e. polyelectrolytes' microstructural homogeneity was revealed as decisive factor concerning solubility of phosphonated PSU. Brominated phT8 was prepared with Br2 by a high temperature approach in tetrachloroethane (TCE). Brominated polymers were phosphonated by Ni-catalysis in non-coordinating high temperature solvents, such as diphenylether, benzophenone and diphenylsulfone without notable solvent influence. The lack of solvent - catalyst complexes and high reaction temperatures of 180-200 C led to halogen-free phosphonates with unprecedented high functionalities. Polymer analogous application of P(OSiMe3)3 offered a novel direct access to easily cleavable disilyl ester derivatives. These were obtained from PEEK and PSU in near quantitative yields at NiCl2-loads as

  20. Hydrothermal synthesis, crystal structure and properties of a novel chain coordination polymer constructed by tetrafunctional phosphonate anions and cobalt ions

    International Nuclear Information System (INIS)

    A novel cobalt phosphonate, [Co(HL)(H2O)3]n (1) (L=N(CH2PO3H)33−) has been synthesized by hydrothermal reaction at 150 °C and structurally characterized by X-ray diffraction, infrared spectroscopy, elemental and thermogravimetric analysis. Complex 1 features a 1D chain structure with double-channel built from CoO6 octahedra bridged together by the phosphonate groups. Each cobalt ion is octahedrally coordinated by three phosphonate oxygen atoms and three water molecules. The coordinated water molecules can form the hydrogen bonds with the phosphonate oxygen atoms to link the 1D chains, building a 2D layered structure, further resulting in a 3D network. The luminescence spectrum indicates an emission maximum at 435 nm. The magnetic susceptibility curve exhibits a dominant antiferromagnetic behavior with a weakly ferromagnetic component at low temperatures. - Graphical abstract: The connectivity between cobalt ions and the ligands results in a chain structure with a 1D double-channel structure, which is constructed by A-type subrings and B-type subrings. - Highlights: • The tetrafunctional phosphonate ligand was used as the ligand. • A novel chain structure can be formed by A-type rings and B-type rings. • Two types of rings can form a 1D double-channel structure, along the c-axis

  1. Synthesis of N-(alkoxycarbonyl or alkoxycarbonyl-methyl-alkoxyphosphonyl)-α-amino-O,O-diphenyl phosphonates and their bioactivities

    Institute of Scientific and Technical Information of China (English)

    李慧英; 陈茹玉; 任康太

    1997-01-01

    With phosphoric formic acid (PFA) and its analog,phosphonoacetic acid (PAA),as the lead compounds,α-amino phosphonates were introduced into PFA and PAA.The derivatives oi N-( alkoxycarbonyl-aikoxyphosphonyl)-α-arnino phosphonates (Ⅰ) and N-(alkoxycarbonyl-methyt-alkoxyphosphonyl)-α-amino phosphonates (Ⅱ) with the N-terminal of amino phosphonates bonding to phosphorus atom of PFA and PAA were synthesized via the reaction of the corresponding phosphonyl chloride with a-amino phosphonates in the presence of a base.The 31P NMK spectra of Ⅰ and Ⅱwere determined.It is found that the coupling constants 3Jpp with R3 being alkyl group were lower than those with R3 being (substituted) phenyl,and this result was discussed.The preliminary bioassay showed that some of the compounds Ⅰ and Ⅱhave better activities against tobacco mosaic virus (TMV).The inhibitory was higher than that of DHT (2,4-dioxyhexahydro-1,3,5-triazine).In addition,some of the compounds showed the activity against cancer cells.

  2. The effect of acyclic retinoid on the metabolomic profiles of hepatocytes and hepatocellular carcinoma cells.

    Directory of Open Access Journals (Sweden)

    Xian-Yang Qin

    Full Text Available BACKGROUND/PURPOSE: Acyclic retinoid (ACR is a promising chemopreventive agent for hepatocellular carcinoma (HCC that selectively inhibits the growth of HCC cells (JHH7 but not normal hepatic cells (Hc. To better understand the molecular basis of the selective anti-cancer effect of ACR, we performed nuclear magnetic resonance (NMR-based and capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS-based metabolome analyses in JHH7 and Hc cells after treatment with ACR. METHODOLOGY/PRINCIPAL FINDINGS: NMR-based metabolomics revealed a distinct metabolomic profile of JHH7 cells at 18 h after ACR treatment but not at 4 h after ACR treatment. CE-TOFMS analysis identified 88 principal metabolites in JHH7 and Hc cells after 24 h of treatment with ethanol (EtOH or ACR. The abundance of 71 of these metabolites was significantly different between EtOH-treated control JHH7 and Hc cells, and 49 of these metabolites were significantly down-regulated in the ACR-treated JHH7 cells compared to the EtOH-treated JHH7 cells. Of particular interest, the increase in adenosine-5'-triphosphate (ATP, the main cellular energy source, that was observed in the EtOH-treated control JHH7 cells was almost completely suppressed in the ACR-treated JHH7 cells; treatment with ACR restored ATP to the basal levels observed in both EtOH-control and ACR-treated Hc cells (0.72-fold compared to the EtOH control-treated JHH7 cells. Moreover, real-time PCR analyses revealed that ACR significantly increased the expression of pyruvate dehydrogenase kinases 4 (PDK4, a key regulator of ATP production, in JHH7 cells but not in Hc cells (3.06-fold and 1.20-fold compared to the EtOH control, respectively. CONCLUSIONS/SIGNIFICANCE: The results of the present study suggest that ACR may suppress the enhanced energy metabolism of JHH7 cells but not Hc cells; this occurs at least in part via the cancer-selective enhancement of PDK4 expression. The cancer-selective metabolic pathways

  3. Glucose-lowering Activity of Amino Acid-N-phosphonic Acid Oxovanadium Complexes and Its Interaction with DNA

    Institute of Scientific and Technical Information of China (English)

    LIU, Ju-Tao; FAN, Sheng-Di; LI, Chuan-Bi; LI, De-Qian

    2006-01-01

    Vanadium has well-documented lowering glucose properties both in vitro and in vivo. The design of new oxovanadium(Ⅳ) coordination compounds, intended for use as insulin-enhancing agents in the treatment of diabetes mellitus, can potentially benefit from a synergistic approach, in which the whole complex has more than an additive effect from its component parts. Biological testing with oxovanadium(Ⅳ) organic phosphonic acid, for insulin-enhancing potential included acute administration, by oral gavage in streptozotocin (STZ) diabetic rats. The complexes of oxovanadium(Ⅳ) amino acid-N-phosphonic acid exhibit higher lowering glucose activity in vivo. The interaction of the complexes of oxovanadium(Ⅳ) amino acid-N-phosphonic acid with DNA was investigated by agarose gel electrophoresis. The results indicated that these complexes have strong interaction with DNA.

  4. Bis-phosphonate sequestering agents. Synthesis and preliminary evaluation for in vitro and in vivo uranium(VI) chelation

    Energy Technology Data Exchange (ETDEWEB)

    Sawicki, M.; Lecercle, D.; Taran, F. [CEA Saclay, IBiTecS, Serv Chim Bioorgan et Marquage, F-91191 Gif Sur Yvette (France); Grillon, G.; Le Gall, B.; Serandour, A.L.; Poncy, J.L. [CEA, DSV, DRR, Lab Radiotoxicol, F-91680 Bruyeres Le Chatel (France); Bailly, T.; Burgada, R.; Lecouvey, M.; Challeix, V. [CNRS, Lab Chim Struct Biomol, UMR 7033, F-93017 Bobigny (France); Leydier, A.; Pellet-Rostaing, S. [Univ Lyon 1, ICBMS, UMR 5246, Lab Catalyse et Synth Organ, F-69622 Villeurbanne (France); Ansoborlo, E. [CEA, DEN, DRCP, CETAMA, VRH Marcoule, F-30207 Bagnols Sur Ceze (France)

    2008-07-01

    A library of bis-phosphonate-based ligands was prepared using solution-phase parallel synthesis and tested for its uranium-binding properties. With the help of a screening method, based on a chromo-phoric complex displacement procedure, 23 dipodal and tripodal chelates bearing bis-phosphonate chelating functions were found to display very high affinity for the uranyl ion and were selected for evaluation of their in vivo uranyl-removal efficacy. Among them, 11 ligands induced a huge modification of the uranyl biodistribution by deviating the metal from kidney and bones to liver. Among the other ligands, the most potent was the dipodal bis-phosphonate 3C which reduced the retention of uranyl and increased its excretion by around 10% of the injected metal. (authors)

  5. Interaction between N-Phospho-Amino Acids and Nucleoside in Aqueous Medium

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Nucleosides were phosphorylated with different N- (O, O-diisopropyl) phosphoryl amino acids to give nucleoside mono phosphates in aqueous solution. 2', 3', and 5'-isomers had been confirmed by comparison with authentic samples on the basis of HPLC analysis. The conversion percentage of nucleoside indicated that N- (O, O-diisopropyl) phosphoryl aspartic acid reacted with adenosine and guanosine at a much higher rate than other kinds of N- phosphoryl amino acids, while phosphorylation of cytidine and uridine was relatively easy by using N- (O, O-diisopropyl) phosphoryl threonine. The result could give some clue to the prebiotic code origin of nucleic acid and protein.

  6. Studies on yeast nucleoside triphosphate-nucleoside diphosphate transphosphorylase (nucleoside diphosphokinase). IV. Steady-state kinetic properties with thymidine nucleotides (including 3'-azido-3'-deoxythymidine analogues).

    Science.gov (United States)

    Kuby, S A; Fleming, G; Alber, T; Richardson, D; Takenaka, H; Hamada, M

    1991-01-01

    A study of the steady-state kinetics of the crystalline brewer's yeast (Saccharomyces carlsbergensis) nucleoside diphosphokinase, with the magnesium complexes of the adenine and thymidine nucleotides as reactants, has led to a postulated kinetic mechanism which proceeds through a substituted enzyme. This agrees with the earlier conclusions of Garces and Cleland [Biochemistry 1969; 8:633-640] who characterized a reaction between the magnesium complexes of the adenine and uridine nucleotides. An advantage of using thymidine nucleotides as reactants is that they permit accurate, rapid and continuous assays of the enzymatic activity in coupled-enzymatic tests. Through measurements of the initial velocities and product inhibition studies, the Michaelis constants, maximum velocities, and inhibition constants could be evaluated for the individual substrates. Competitive substrate inhibition was encountered at relatively high substrate concentrations, which also permitted an evaluation of their ability to act as 'dead-end' inhibitors. The Michaelis constants for the 3'-azido-3'-deoxythymidine (AzT) analogues were also evaluated and, although these values were only somewhat higher than those of their natural substrates, the Km's for the adenine nucleotides as paired substrates were lower and the Vmax's were drastically reduced. The pharmacological implications of these observations are touched upon and extrapolated to the cases where therapeutic doses of AzT may be employed.

  7. Streospecific substitution of oxygen-18 for sulfur in nucleoside phosphorothioates.

    Science.gov (United States)

    Connolly, B A; Eckstein, F; Füldner, H H

    1982-04-10

    Reaction of nucleoside phosphorothioates with N-bromosuccinimide in dioxane and H218O leads to the exchange of sulfur for oxygen-18. Using the Sp-isomers of adenosine 5'-O-(1-thiodiphosphate) and adenosine 3',5'-cyclic phosphorothioate, it can be shown by 31P NMR spectroscopy that this reaction proceeds with inversion of configuration yielding the Rp-isomers of [alpha-18O]ADP and [18O]cAMP, respectively. Adenosine 5'-O-(2-thiotriphosphate) and adenosine 5'-O-(3-thiotriphosphate) are likewise converted to [beta-18O]ATP and [gamma-18O]ATP although the stereochemistry of the former reaction has yet to be evaluated. With very slight modifications this reaction is applicable to all the common bases. PMID:6277935

  8. Synthesis of New Lipophilic Phosphonate and Phosphonamidate Analogues of N-Acetylmuramyl-L-alanyl-D-isoglutamine Related to LK 423

    Directory of Open Access Journals (Sweden)

    Uroš Urleb

    2002-05-01

    Full Text Available A syntheses of three new muramyl dipeptide (MDP analogues related to LK 423 as potential immunomodulators are presented. The dipeptide part of the lead compound was modified by introducing a phosphonamide isostere instead of the amide bond between Lalanine and D-glutamic acid (or D-isoglutamine, yielding new MDP analogues 5 and 9. Furthermore, the amide bond between L-Ala and D-Glu was replaced by a phosphonate isostere, giving peptidyl phosphonate 14. The scope and limitations of the synthetic strategies employed are discussed.

  9. Hydrothermal synthesis for new multifunctional materials: A few examples of phosphates and phosphonate-based hybrid materials

    Science.gov (United States)

    Rueff, Jean-Michel; Poienar, Maria; Guesdon, Anne; Martin, Christine; Maignan, Antoine; Jaffrès, Paul-Alain

    2016-04-01

    Novel physical or chemical properties are expected in a great variety of materials, in connection with the dimensionality of their structures and/or with their nanostructures, hierarchical superstructures etc. In the search of new advanced materials, the hydrothermal technique plays a crucial role, mimicking the nature able to produce fractal, hyperbranched, urchin-like or snow flake structures. In this short review including new results, this will be illustrated by examples selected in two types of materials, phosphates and phosphonates, prepared by this method. The importance of the synthesis parameters will be highlighted for a magnetic iron based phosphates and for hybrids containing phosphonates organic building units crystallizing in different structural types.

  10. A Sustainable and Efficient Synthesis of Benzyl Phosphonates Using PEG/KI Catalytic System.

    Science.gov (United States)

    Disale, Shamrao; Kale, Sandip; Abraham, George; Kahandal, Sandeep; Sawarkar, Ashish N; Gawande, Manoj B

    2016-01-01

    An efficient and expedient protocol for the synthesis of benzyl phosphonates using KI/K2CO3 as a catalytic system and PEG-400 as benign solvent has been developed. The reaction proceeds smoothly at room temperature achieving excellent selectivity and yield of the corresponding products. The combination of PEG-400, KI, and K2CO3 in this reaction avoids the need of volatile/toxic organic solvents and reactive alkali metals or metal nanoparticles/hydrides. We believe that this benign combination (PEG-400 and KI) could be used for other related organic transformations. PMID:27579301

  11. Zirconium phosphonate/1,4,5,8-naphthalenediimides self-assembled films

    Directory of Open Access Journals (Sweden)

    MAGALI A. RODRIGUES

    2000-03-01

    Full Text Available The formation and characterization of self-assembled films of zirconium phosphonate / N,N'-di(2-phosphonoethyl-1,4,5,8-naphthalenediimide (DPN is presented. The films were produced on glass substrates by deposition of alternating layers of Zr+4 and DPN. Films containing up to 16 layers on each side of the substrate were obtained and monitored by absorption spectroscopy and ellipsometry. When irradiated, the initially colorless films turned to a persistent pinky color reminiscent of that of DPN anion radical. These films are a promising material to the development of photovoltaic devices.

  12. A sustainable and efficient synthesis of benzyl phosphonates using PEG/KI catalytic system

    Science.gov (United States)

    Gawande, Manoj; Disale, Shamrao; Kale, Sandip; Abraham, George; Kahandal, Sandeep; Sawarkar, Ashish

    2016-08-01

    An efficient and expedient protocol for the synthesis of benzyl phosphonates using KI/K2CO3 as a catalytic system and PEG-400 as benign solvent has been developed. The reaction proceeds smoothly at room temperature achieving excellent selectivity and yield of the corresponding products. The combination of PEG-400, KI and K2CO3 in this reaction avoids the need of volatile/toxic organic solvents and reactive alkali metals or metal nanoparticles/hydrides. We believe that this benign combination (PEG-400 and KI) could be used for other related organic transformations.

  13. Stannoxanes and phosphonates: New approaches in organometallic and transition metal assemblies

    Indian Academy of Sciences (India)

    Vadapalli Chandrasekhar; Kandasamy Gopal; Loganathan Nagarajan; Palani Sasikumar; Pakkirisamy Thilagar

    2006-11-01

    Phosphonate ligands, [RPO3]2-, are extremely versatile in the assembly of multi-tin and multi-copper architectures. We have used organostannoxane cores for supporting multi-ferrocene and multi-porphyrin peripheries. The copper-metalated multi-porphyrin compound is an excellent reagent for facile cleavage of DNA, even in the absence of a co-oxidant. Reaction of -BuPO3H2 with Cu(ClO4)2. 6H2O in the presence of 2-pyridylpyrazole (2-Pypz) leads to the synthesis of a decanuclear copper (II) assembly.

  14. 1-Ammonio-1-phosphono-pentane-1-phospho-nic acid.

    Science.gov (United States)

    Bon, V V; Dudko, A V; Kozachkova, A N; Pekhnyo, V I

    2008-11-26

    The title compound, C(5)H(15)NO(6)P(2), was obtained by the reaction of penta-nenitrile with PCl(3) followed by the dropwise addition of water. The asymmetric unit contains one mol-ecule, which exists as a zwitterion with a positive charge on the -NH(3) group and a negative charge on one of the phospho-nic O atoms. The crystal structure displays N-H⋯O and O-H⋯O hydrogen bonding, which creates a three-dimensional network.

  15. The lipid moiety of brincidofovir is required for in vitro antiviral activity against Ebola virus.

    Science.gov (United States)

    McMullan, Laura K; Flint, Mike; Dyall, Julie; Albariño, César; Olinger, Gene G; Foster, Scott; Sethna, Phiroze; Hensley, Lisa E; Nichol, Stuart T; Lanier, E Randall; Spiropoulou, Christina F

    2016-01-01

    Brincidofovir (BCV) is the 3-hexadecyloxy-1-propanol (HDP) lipid conjugate of the acyclic nucleoside phosphonate cidofovir (CDV). BCV has established broad-spectrum activity against double-stranded DNA (dsDNA) viruses; however, its activity against RNA viruses has been less thoroughly evaluated. Here, we report that BCV inhibited infection of Ebola virus in multiple human cell lines. Unlike the mechanism of action for BCV against cytomegalovirus and other dsDNA viruses, phosphorylation of CDV to the diphosphate form appeared unnecessary. Instead, antiviral activity required the lipid moiety and in vitro activity against EBOV was observed for several HDP-nucleotide conjugates.

  16. Importance of mammalian nuclear-envelope nucleoside triphosphatase in nucleo-cytoplasmic transport of ribonucleoproteins.

    Science.gov (United States)

    Agutter, P S; McCaldin, B; McArdle, H J

    1979-09-15

    The nucleoside triphosphate-stimulated efflux of RNA from isolated nuclei was studied under a range of conditions, and the effects of these conditions on the process were compared with the properties of the nucleoside triphosphatase located in the pore complex. A marked similarity between the rate of efflux and the rate of nucleoside triphosphate hydrolysis was apparent, in terms of substrate specificity, sensitivity to treatment with insolubilized trypsin, kinetics and the effects of increased ionic strength and of many inhibitors. These results are taken, in view of earlier evidence, to suggest that the activity of the nucleoside triphosphatase is a prerequisite for nucleo-cytoplasmic RNA transport in vivo. There are some indications that the nuclear-envelope lipid is also involved in regulating the efflux process.

  17. Modification of Purine and Pyrimidine Nucleosides by Direct C-H Bond Activation

    Directory of Open Access Journals (Sweden)

    Yong Liang

    2015-03-01

    Full Text Available Transition metal-catalyzed modifications of the activated heterocyclic bases of nucleosides as well as DNA or RNA fragments employing traditional cross-coupling methods have been well-established in nucleic acid chemistry. This review covers advances in the area of cross-coupling reactions in which nucleosides are functionalized via direct activation of the C8-H bond in purine and the C5-H or C6-H bond in uracil bases. The review focuses on Pd/Cu-catalyzed couplings between unactivated nucleoside bases with aryl halides. It also discusses cross-dehydrogenative arylations and alkenylations as well as other reactions used for modification of nucleoside bases that avoid the use of organometallic precursors and involve direct C-H bond activation in at least one substrate. The scope and efficiency of these coupling reactions along with some mechanistic considerations are discussed.

  18. Metabolic engineering of an industrial polyoxin producer for the targeted overproduction of designer nucleoside antibiotics.

    Science.gov (United States)

    Qi, Jianzhao; Liu, Jin; Wan, Dan; Cai, You-Sheng; Wang, Yinghu; Li, Shunying; Wu, Pan; Feng, Xuan; Qiu, Guofu; Yang, Sheng-Ping; Chen, Wenqing; Deng, Zixin

    2015-09-01

    Polyoxin and nikkomycin are naturally occurring peptidyl nucleoside antibiotics with potent antifungal bioactivity. Both exhibit similar structural features, having a nucleoside skeleton and one or two peptidyl moieties. Combining the refactoring of the polyoxin producer Streptomyces aureochromogenes with import of the hydroxypyridylhomothreonine pathway of nikkomycin allows the targeted production of three designer nucleoside antibiotics designated as nikkoxin E, F, and G. These structures were determined by NMR and/or high resolution mass spectrometry. Remarkably, the introduction of an extra copy of the nikS gene encoding an ATP-dependent ligase significantly enhanced the production of the designer antibiotics. Moreover, all three nikkoxins displayed improved bioactivity against several pathogenic fungi as compared with the naturally-occurring antibiotics. These data provide a feasible model for high efficiency generation of nucleoside antibiotics related to polyoxins and nikkomycins in a polyoxin cell factory via synthetic biology strategy.

  19. Novel indole-3-sulfonamides as potent HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs)

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Zhijian; Wolkenberg, Scott E.; Lu, Meiqing; Munshi, Vandna; Moyer, Gregory; Feng, Meizhen; Carella, Anthony V.; Ecto, Linda T.; Gabryelski, Lori J.; Lai, Ming-Tain; Prasad, Sridar G.; Yan, Youwei; McGaughey, Georgia B.; Miller, Michael D.; Lindsley, Craig W.; Hartman, George D.; Vacca, Joseph P.; Williams, Theresa M. (Merck)

    2008-09-29

    This Letter describes the design, synthesis, and biological evaluation of novel 3-indole sulfonamides as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) with balanced profiles against common HIV RT mutants K103N and Y181C.

  20. Nucleoside, nucleotide and oligonucleotide based amphiphiles: a successful marriage of nucleic acids with lipids.

    Science.gov (United States)

    Gissot, Arnaud; Camplo, Michel; Grinstaff, Mark W; Barthélémy, Philippe

    2008-04-21

    Amphiphilic molecules based on nucleosides, nucleotides and oligonucleotides are finding more and more biotechnological applications. This Perspective highlights their synthesis, supramolecular organization as well as their applications in the field of biotechnology.

  1. Synthesis of nucleoside tetraphosphates and dinucleoside pentaphosphates via activation of cyclic trimetaphosphate.

    Science.gov (United States)

    Mohamady, Samy; Taylor, Scott D

    2013-06-01

    A procedure for the synthesis of dinucleoside 5'-pentaphosphates (Np5N) and nucleoside 5'-tetraphosphates (Np4) is described. The procedure relies on the activation of cyclic trimetaphosphate followed by a reaction with a nucleoside 5'-monophosphate (NMP) to give intermediates of type 3. Reaction of 3 with water or an NMP gives the desired products in yields ranging from 77 to 86%. PMID:23668391

  2. Cytotoxic purine nucleoside analogues bind to A1, A2A and A3 adenosine receptors

    OpenAIRE

    Jensen, Kyle; Johnson, L’Aurelle A.; Jacobson, Pamala A.; Kachler, Sonja; Kirstein, Mark N.; Lamba, Jatinder; Klotz, Karl-Norbert

    2012-01-01

    Fludarabine, clofarabine and cladribine are anti-cancer agents which are analogues of the purine nucleoside adenosine. These agents have been associated with cardiac and neurological toxicities. Because these agents are analogues of adenosine, they may act through adenosine receptors to elicit their toxic effects. The objective of this study was to evaluate the ability of cytotoxic nucleoside analogues to bind and activate adenosine receptor subtypes (A1, A2A, A2B, and A3). Radioligand bindin...

  3. Nucleoside-nucleotide free diet protects rat colonic mucosa from damage induced by trinitrobenzene sulphonic acid.

    OpenAIRE

    Adjei, A A; Morioka, T.; Ameho, C K; Yamauchi, K.; Kulkarni, A. D.; Al-Mansouri, H M; Kawajiri, A; Yamamoto, S.

    1996-01-01

    BACKGROUND: Growing evidence suggests that intestinal recovery from injury induced by radiation, endotoxin, and protein deficiency is improved by the ingestion of nucleosides and nucleotides. AIM: This study examined the effect of dietary nucleosides and nucleotides supplementation on trinitrobenzene sulphonic acid induced colonic damage in experimental colitis. METHODS: Sprague-Dawley rats were randomised into two groups and fed nucleic acid free 20% casein diet (control) or this diet supple...

  4. Sequencing, functional expression and characterization of rat NTPDase6, a nucleoside diphosphatase and novel member of the ecto-nucleoside triphosphate diphosphohydrolase family.

    Science.gov (United States)

    Braun, N; Fengler, S; Ebeling, C; Servos, J; Zimmermann, H

    2000-11-01

    We have isolated and characterized the cDNA encoding nucleoside triphosphate diphosphohydrolase 6 (NTPDase6), a novel member of the ecto-nucleoside triphosphate diphosphohydrolase family. The rat-brain-derived cDNA has an open reading frame of 1365 bp encoding a protein of 455 amino acid residues, a calculated molecular mass of 49971 Da and a predicted N-terminal hydrophobic sequence. It shares 86% sequence identity with the human CD39L2 sequence and 48% and 51% identity respectively with sequences of the two related human and murine nucleoside diphosphatases (CD39L4, NTPDase5/ER-UDPase). The mRNA was expressed in all tissues investigated, revealing two major transcripts with differing abundances. PCR analysis suggests a single open reading frame. A Myc-His-tagged NTPDase6 was expressed in Chinese hamster ovary (CHO) and PC12 cells for immunological analysis and protein isolation. The protein was contained in membrane fractions of transfected CHO cells and occurred in a soluble form in the cell culture supernatants. NTPDase6 preferentially hydrolysed nucleoside 5'-diphosphates. With different substrates the order of activity was GDP>IDP>UDP,CDP>ADP. Nucleoside 5'-triphosphates were hydrolysed only to a minor extent and no hydrolysis of nucleoside 5'-monophosphates was observed. The enzyme was strongly and equally activated by Ca(2+) and Mg(2+) and had a K(m) for GDP of 211 microM. The immunohistochemical analysis of transfected CHO and PC12 cells suggests that NTPDase6 is associated with the Golgi apparatus and to a small extent also with the plasma membrane. The enzyme might support glycosylation reactions in the Golgi apparatus and, when released from cells, might catalyse the hydrolysis of extracellular nucleotides. PMID:11042118

  5. Cloning, expression, and functional characterization of a Ca(2+)-dependent endoplasmic reticulum nucleoside diphosphatase.

    Science.gov (United States)

    Failer, Bernd U; Braun, Norbert; Zimmermann, Herbert

    2002-10-01

    We have isolated and characterized the cDNA encoding a Ca(2+)-dependent nucleoside diphosphatase (EC ) related to two secreted ATP- and ADP-hydrolyzing apyrases of the bloodsucking insects, Cimex lectularius and Phlebotomus papatasi. The rat brain-derived cDNA has an open reading frame of 1209 bp encoding a protein of 403 amino acids and a calculated molecular mass of 45.7 kDa. The mRNA was expressed in all tissues investigated, revealing two major transcripts with varying preponderance. The immunohistochemical analysis of the Myc-His-tagged enzyme expressed in Chinese hamster ovary cells revealed its association with the endoplasmic reticulum and also with pre-Golgi intermediates. Ca(2+)-dependent nucleoside diphosphatase is a membrane protein with its catalytic site facing the organelle lumen. It hydrolyzes nucleoside 5'-diphosphates in the order UDP >GDP = IDP >CDP but not ADP. Nucleoside 5'-triphosphates were hydrolyzed to a minor extent, and no hydrolysis of nucleoside 5'-monophosphates was observed. The enzyme was strongly activated by Ca(2+), insensitive to Mg(2+), and had a K(m) for UDP of 216 microm. Ca(2+)-dependent nucleoside diphosphatase may support glycosylation reactions related to quality control in the endoplasmic reticulum. PMID:12167635

  6. Lipases in green chemistry: acylation and alcoholysis on steroids and nucleosides.

    Science.gov (United States)

    Baldessari, Alicia; Iglesias, Luis E

    2012-01-01

    In this article, we describe the application of lipases in acylation and alcoholysis reactions on steroids and nucleosides. In the field of steroids, a variety of acetyl and fatty acid derivatives of androstanes, pregnanes, and cholestanes have been prepared through lipase-catalyzed acylation and alcoholysis reactions taking advantage of the high regio- and stereoselectivity of these enzymes. The substrates as well as the products show a high degree of biological activity as neurosteroids, hormones, and glucocorticoids. The regioselective preparation of diacylated nucleosides by means of an enzymatic alcoholysis allowed the synthesis of nucleosides prodrugs or modified nucleosides. The quantitative full deacylation and dealkoxycarbonylation of nucleosides and steroids is a mild synthetic method for the deprotection of these labile compounds. Some of the reported steroid and nucleoside products are novel, and it is not possible to obtain them satisfactorily by following traditional synthetic procedures. The advantages presented by this methodology, such as selectivity, mild reaction conditions, and low environmental impact, make the lipases an important tool in the application of the principles of Green Chemistry, offering a convenient way to prepare derivatives of natural compounds with a great potential in the pharmaceutical industry.

  7. Lipases in green chemistry: acylation and alcoholysis on steroids and nucleosides.

    Science.gov (United States)

    Baldessari, Alicia; Iglesias, Luis E

    2012-01-01

    In this article, we describe the application of lipases in acylation and alcoholysis reactions on steroids and nucleosides. In the field of steroids, a variety of acetyl and fatty acid derivatives of androstanes, pregnanes, and cholestanes have been prepared through lipase-catalyzed acylation and alcoholysis reactions taking advantage of the high regio- and stereoselectivity of these enzymes. The substrates as well as the products show a high degree of biological activity as neurosteroids, hormones, and glucocorticoids. The regioselective preparation of diacylated nucleosides by means of an enzymatic alcoholysis allowed the synthesis of nucleosides prodrugs or modified nucleosides. The quantitative full deacylation and dealkoxycarbonylation of nucleosides and steroids is a mild synthetic method for the deprotection of these labile compounds. Some of the reported steroid and nucleoside products are novel, and it is not possible to obtain them satisfactorily by following traditional synthetic procedures. The advantages presented by this methodology, such as selectivity, mild reaction conditions, and low environmental impact, make the lipases an important tool in the application of the principles of Green Chemistry, offering a convenient way to prepare derivatives of natural compounds with a great potential in the pharmaceutical industry. PMID:22426734

  8. Formation of phosphonates and pyrophosphates in the reactions of chlorophosphate esters with strong organic bases

    Indian Academy of Sciences (India)

    K V P Pavan Kumar; K Praveen Kumar; M Vijjulatha; K C Kumara Swamy

    2004-11-01

    The compounds S(6--Bu-4-Me-C6H2O)2P(O)Cl (1), CH2(6--Bu-4-Me-C6H2O)2P(O)Cl (2) and (2,2'-C20H12O2)P(O)Cl (3) react with diazabicycloundecene (DBU) to give rise to, predominantly, the phosphonate compounds [S(6--Bu-4-Me-C6H2O)2P(O)(DBU)]+[Cl]- (4), [CH2(6--Bu-4-Me-C6H2O)2P(O) (DBU)]+[Cl]- (5) and [(2,2'-C20H12O2)P(O)(DBU)]+[Cl]- (6). The first two compounds could be isolated in the pure state. In analogous reactions of 1 and 2 with diazabicyclononene (DBN) or N-methyl imidazole, only the pyrophosphates [S(6--Bu-4-Me-C6H2O)2P(O)]2O (7) and [CH2(6--Bu-4-Me-C6H2O)2P(O)]2O (8) could be isolated, although the reaction mixture showed several other compounds in the phosphorus NMR. A possible pathway for the formation of phosphonate salts is proposed. The X-ray crystal structures of 4, 7 and 8 are also discussed.

  9. Enhancing the Imaging and Biosafety of Upconversion Nanoparticles through Phosphonate Coating

    Science.gov (United States)

    Li, Ruibin; Ji, Zhaoxia; Dong, Juyao; Chang, Chong Hyun; Wang, Xiang; Sun, Bingbing; Wang, Meiying; Liao, Yu-Pei; Zink, Jeffrey I.; Nel, Andre E.; Xia, Tian

    2015-01-01

    Upconversion nanoparticles (UCNPs), which are generated by doping with rare earth (RE) metals, are increasingly used for bio-imaging because of the advantages they hold over conventional fluorophores. However, because pristine RE nanoparticles (NPs) are unstable in acidic physiological fluids (e.g., lysosomes), leading to intracellular phosphate complexation with the possibility of the lysosomal injury, it is important to ensure that UCNPs are safe designed. In this study, we used commercially available NaYF4: Er/Yb UCNPs to study their stability in lysosomes and simulated lysosomal fluid. We demonstrate that phosphate complexation leads to REPO4 deposition on the particle surfaces and morphological transformation. This leads to a decline in upconversion fluorescence efficiency as well as inducing pro-inflammatory effects at cellular level and in the intact lung. In order to preserve the imaging properties of the UCNPs as well as improve their safety, we experimented with a series of phosphonate chemical moieties to passivate particle surfaces through the strong coordination of the organophosphates with RE atoms. Particle screening and physicochemical characterization revealed that ethylenediaminetetra methylenephosphonic acid (EDTMP) surface coating provides the most stable UCNPs, which maintain their imaging intensity and do not induce pro-inflammatory effects in vitro and in vivo. In summary, phosphonate coating presents a safer design method that preserves and improves the bio-imaging properties of UCNPs, thereby enhancing their biological use. PMID:25727446

  10. Facile Synthesis and Adsorption Properties of Phosphonated Cellulose Beads for Selective Removal of Low-density Lipoprotein

    Institute of Scientific and Technical Information of China (English)

    Hao Feng YU; Guo Qi FU; Li LIU; Bing Lin HE

    2006-01-01

    A novel low-density lipoprotein adsorbent was prepared simply by directly phosphonating porous cellulose beads. Tests in vitro demonstrated that this adsorbent showed quite good adsorption performance for selective removal of low-density lipoprotein from human plasma. The effects of preparation conditions on the lipoprotein sorption properties of the resulted adsorbent were investigated. The adsorption dynamics was also examined.

  11. Characterizing mixed phosphonic acid ligand capping on CdSe/ZnS quantum dots using ligand exchange and NMR spectroscopy.

    Science.gov (United States)

    Davidowski, Stephen K; Lisowski, Carmen E; Yarger, Jeffery L

    2016-03-01

    The ligand capping of phosphonic acid functionalized CdSe/ZnS core-shell quantum dots (QDs) was investigated with a combination of solution and solid-state (31) P nuclear magnetic resonance (NMR) spectroscopy. Two phosphonic acid ligands were used in the synthesis of the QDs, tetradecylphosphonic acid and ethylphosphonic acid. Both alkyl phosphonic acids showed broad liquid and solid-state (31) P NMR resonances for the bound ligands, indicative of heterogeneous binding to the QD surface. In order to quantify the two ligand populations on the surface, ligand exchange facilitated by phenylphosphonic acid resulted in the displacement of the ethylphosphonic acid and tetradecylphosphonic acid and allowed for quantification of the free ligands using (31) P liquid-state NMR. After washing away the free ligand, two broad resonances were observed in the liquids' (31) P NMR corresponding to the alkyl and aromatic phosphonic acids. The washed samples were analyzed via solid-state (31) P NMR, which confirmed the ligand populations on the surface following the ligand exchange process. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26639792

  12. [Enzymatic activity of thymidine kinase of herpes simlex virus strain resistant to H-phosphonates of Acv].

    Science.gov (United States)

    Gus'kova, A A; Skoblov, M Iu; Andronova, V L; Galegov, G A; Kochetkov, S N; Skoblov, Iu S

    2011-01-01

    Cloned laboratory mutants of herpes simplex virus type I resistant to acycloguanosine H-phosphonate have been investigated. For all clones were shown that mutations resulted to increasing of sensitivity to acting of sidofovir. Thymidine kinase of mutant viruses partially preserves the ability to phosphorilate thymidine, but loses the ability to phosphorilate BVDU.

  13. Synthesis of base-substituted uridine 5'-phosphonate analogues as potential P2Y2 receptor ligands

    OpenAIRE

    Van Poecke, Sara; Barrett, Matt; Jacobson, Kenneth A.; Harden, T. Kendall; Van Calenbergh, Serge

    2011-01-01

    A series of 5-modified 5’-phosphonate derivatives of UMP has been prepared in 6 steps from uridine. The analogs were evaluated for their affinity at the P2Y2 receptor. Several derivatives showed partial agonistic activity at the P2Y2 receptor.

  14. Highly stable triple helix formation by homopyrimidine (l)-acyclic threoninol nucleic acids with single stranded DNA and RNA

    DEFF Research Database (Denmark)

    Kumar, Vipin; Kesavan, Venkitasamy; Gothelf, Kurt Vesterager

    2015-01-01

    Acyclic (l)-threoninol nucleic acid (aTNA) containing thymine, cytosine and adenine nucleobases were synthesized and shown to form surprisingly stable triplexes with complementary single stranded homopurine DNA or RNA targets. The triplex structures consist of two (l)-aTNA strands and one DNA or...... RNA, and these triplexes are significantly stronger than the corresponding DNA or RNA duplexes as shown in competition experiments. As a unique property the (l)-aTNAs exclusively form triplex structures with DNA and RNA and no duplex structures are observed by gel electrophoresis. The results were...... compared to the known enantiomer (d)-aTNA, which forms much weaker triplexes depending upon temperature and time. It was demonstrated that (l)-aTNA triplexes are able to stop primer extension on a DNA template, showing the potential of (l)-aTNA for antisense applications....

  15. Acyclic Diene Metathesis (ADMET Polymerization for Precise Synthesis of Defect-Free Conjugated Polymers with Well-Defined Chain Ends

    Directory of Open Access Journals (Sweden)

    Tahmina Haque

    2015-03-01

    Full Text Available This accounts introduces unique characteristics by adopting the acyclic diene metathesis (ADMET polymerization for synthesis of conjugated polymers, poly(arylene vinylenes, known as promising molecular electronics. The method is more suitable than the other methods in terms of atom efficiency affording defect-free, stereo-regular (exclusive trans polymers with well-defined chain ends; the resultant polymers possess better property than those prepared by the conventional methods. The chain ends (vinyl group in the resultant polymer prepared by ruthenium-carbene catalyst(s can be modified by treating with molybdenum-alkylidene complex (olefin metathesis followed by addition of various aldehyde (Wittig type cleavage, affording the end-functionalized polymers exclusively. An introduction of initiating fragment, the other conjugated segment, and one-pot synthesis of end-functionalized block copolymers, star shape polymers can be achieved by adopting this methodology.

  16. Synthesis, spectroscopic characterization and crystal structure of novel NNNN-donor μ-bis(bidentate) tetraaza acyclic Schiff base ligands

    Science.gov (United States)

    Habibi, Mohammad Hossein; Shojaee, Elahe; Nichol, Gary S.

    2012-12-01

    Novel NNNN-donor μ-bis(bidentate) tetraaza acyclic Schiff base ligands with different substituents (CF3, N(CH3)2 or OH groups) were synthesized by the condensation reaction of triethylenetetramine with 4-substituted benzaldehydes. Triethylenetetramine tris(4-trifluoromethylbenzylidene) (TTFMB), triethylenetetramine tris(4-dimethylaminobenzylidene) (TTDMB) and triethylenetetramine tris(2,4-dihydroxybenzylidene) (TTDHB) were formed as N4 donor ligands. The formation of a five-membered imidazolidine ring from the ethylenediamine backbone as a spacer-cumbridging unit gives rise to a new type of imidazolidine ligand. The structure of the TTFMB and TTDMB were determined by single crystal X-ray crystallography. The synthesized ligands have been characterized on the basis of the results of cyclic voltammetry (CV) and spectroscopic studies viz. FT-IR spectroscopy (FT-IR), mass spectroscopy (MS) and UV-Vis spectroscopy (UV-Vis).

  17. Heterologous expression, purification, and enzymatic characterization of the acyclic carotenoid 1,2-hydratase from Rubrivivax gelatinosus.

    Science.gov (United States)

    Steiger, Sabine; Mazet, Andreas; Sandmann, Gerhard

    2003-06-01

    The carotenoid 1,2-hydratase CrtC from Rubrivivax gelatinosus has been expressed in Escherichia coli in an active form and purified by affinity chromatography. The enzyme catalyzes the conversion of various acyclic carotenes including 1-hydroxy derivatives. This broad substrate specificity reflects the participation of CrtC in 1'-HO-spheroidene and in spirilloxanthin biosynthesis. Enzyme kinetic studies including the determination of substrate specificity constants indicate that among the alternative biosynthetic routes to 1'-HO-spheroidene the one via spheroidene is the dominating pathway. In contrast to CrtC from Rvi. gelatinosus, the equivalent enzyme from Rhodobacter capsulatus, a closely related bacterium which lacks the biosynthetic branch to spirilloxanthin and accumulates spheroidene instead of substantial amounts of 1'-HO-spheroidene, is extremely poor in converting 1-HO-carotenoids. The individual catalytic properties of both carotenoid 1,2-hydratases reflect the in situ carotenogenic pathways in both purple photosynthetic bacteria.

  18. PM-IRRAS Determination of Molecular Orientation of Phosphonic Acid Self-Assembled Monolayers on Indium Zinc Oxide.

    Science.gov (United States)

    Sang, Lingzi; Mudalige, Anoma; Sigdel, Ajaya K; Giordano, Anthony J; Marder, Seth R; Berry, Joseph J; Pemberton, Jeanne E

    2015-05-26

    Self-assembled monolayers (SAMs) of phosphonic acids (PAs) on transparent conductive oxide (TCO) surfaces can facilitate improvement in TCO/organic semiconductor interface properties. When ordered PA SAMs are formed on oxide substrates, interface dipole and electronic structure are affected by the functional group properties, orientation, and binding modes of the modifiers. Choosing octylphosphonic acid (OPA), F13-octylphosphonic acid (F13OPA), pentafluorophenyl phosphonic acid (F5PPA), benzyl phosphonic acid (BnPA), and pentafluorobenzyl phosphonic acid (F5BnPA) as a representative group of modifiers, we report polarization modulation-infrared reflection-absorption spectroscopy (PM-IRRAS) of binding and molecular orientation on indium-doped zinc oxide (IZO) substrates. Considerable variability in molecular orientation and binding type is observed with changes in PA functional group. OPA exhibits partially disordered alkyl chains but on average the chain axis is tilted ∼57° from the surface normal. F13OPA tilts 26° with mostly tridentate binding. The F5PPA ring is tilted 23° from the surface normal with a mixture of bidentate and tridentate binding; the BnPA ring tilts 31° from normal with a mixture of bidentate and tridentate binding, and the F5BnPA ring tilts 58° from normal with a majority of bidentate with some tridenate binding. These trends are consistent with what has been observed previously for the effects of fluorination on orientation of phosphonic acid modifiers. These results from PM-IRRAS are correlated with recent results on similar systems from near-edge X-ray absorption fine structure (NEXAFS) and density functional theory (DFT) calculations. Overall, these results indicate that both surface binding geometry and intermolecular interactions play important roles in dictating the orientation of PA modifiers on TCO surfaces. This work also establishes PM-IRRAS as a routine method for SAM orientation determination on complex oxide substrates

  19. Human concentrative nucleoside transporter 3 transfection with ultrasound and microbubbles in nucleoside transport deficient HEK293 cells greatly increases gemcitabine uptake.

    Science.gov (United States)

    Paproski, Robert J; Yao, Sylvia Y M; Favis, Nicole; Evans, David; Young, James D; Cass, Carol E; Zemp, Roger J

    2013-01-01

    Gemcitabine is a hydrophilic clinical anticancer drug that requires nucleoside transporters to cross plasma membranes and enter cells. Pancreatic adenocarcinomas with low levels of nucleoside transporters are generally resistant to gemcitabine and are currently a clinical problem. We tested whether transfection of human concentrative nucleoside transporter 3 (hCNT3) using ultrasound and lipid stabilized microbubbles could increase gemcitabine uptake and sensitivity in HEK293 cells made nucleoside transport deficient by pharmacologic treatment with dilazep. To our knowledge, no published data exists regarding the utility of using hCNT3 as a therapeutic gene to reverse gemcitabine resistance. Our ultrasound transfection system--capable of transfection of cell cultures, mouse muscle and xenograft CEM/araC tumors--increased hCNT3 mRNA and (3)H-gemcitabine uptake by >2,000- and 3,400-fold, respectively, in dilazep-treated HEK293 cells. Interestingly, HEK293 cells with both functional human equilibrative nucleoside transporters and hCNT3 displayed 5% of (3)H-gemcitabine uptake observed in cells with only functional hCNT3, suggesting that equilibrative nucleoside transporters caused significant efflux of (3)H-gemcitabine. Efflux assays confirmed that dilazep could inhibit the majority of (3)H-gemcitabine efflux from HEK293 cells, suggesting that hENTs were responsible for the majority of efflux from the tested cells. Oocyte uptake transport assays were also performed and provided support for our hypothesis. Gemcitabine uptake and efflux assays were also performed on pancreatic cancer AsPC-1 and MIA PaCa-2 cells with similar results to that of HEK293 cells. Using the MTS proliferation assay, dilazep-treated HEK293 cells demonstrated 13-fold greater resistance to gemcitabine compared to dilazep-untreated HEK293 cells and this resistance could be reversed by transfection of hCNT3 cDNA. We propose that transfection of hCNT3 cDNA using ultrasound and microbubbles may be a

  20. Binding Strength of Nucleobases and Nucleosides on Silver Nanoparticles Probed by a Colorimetric Method.

    Science.gov (United States)

    Yu, Lu; Li, Na

    2016-06-01

    Because of their unique and tunable properties, oligonucleotide-functionalized noble metal nanoparticles have provided a versatile platform for various engineering and biomedical applications. The vast majority of such applications were demonstrated with gold nanoparticles (AuNPs) while only a few were demonstrated with sliver nanoparticles (AgNPs). This is largely due to the lack of robust protocols to functionalize AgNPs with thiol-modified oligonucleotides. Previous studies have revealed strong interactions between nucleobases and AgNPs. This could enable an alternative way to functionalize AgNPs with non-thiolated oligonucleotides. However, there is no quantitative study on the interaction strengths between AgNPs and oligonucleotides. Several methods have been used for quantitative evaluation of the interaction strengths between AuNPs and oligonucleotides. These methods often require specialized equipment that might not be widely accessible or rely on labor-intensive procedures to obtain the adsorption isotherms. Herein, we developed a colorimetric method, as a simple and high-throughput alternative of existing methods, to quantify the binding strength between AgNPs and nucleobases/nucleosides. In this colorimetric method, concentration-dependent destabilizing effects of nucleobase/nucleoside adsorption on AgNPs are utilized to indirectly quantify the amount of nucleobases/nucleosides adsorbed on AgNPs, thus deriving the binding strength between AgNPs and nucleobases/nucleosides. First, the concentration-dependent AgNP aggregation kinetics in the presence of nucleobases/nucleosides were systematically investigated. Then, this colorimetric method was used to determine the binding strengths between AgNPs and various DNA/RNA nucleobases/nucleosides. It was found that the ranking of interaction strengths between AgNPs and DNA/RNA nucleosides (dC < dT < dA, rC < rU < rA) is generally agreed with that between AgNPs and corresponding nucleobases (C < T < U < A). This

  1. Proton transport properties of tin phosphate, chromotropic acid anchored onto tin phosphate and tin phenyl phosphonate

    Indian Academy of Sciences (India)

    Chithra Sumej; P P Sharmila; Nisha J Tharayil; S Suma

    2013-02-01

    Tin (IV) phosphates of the class of tetravalent metal acid (TMA) salts have been synthesized by sol–gel method. The functionalized materials of tin (IV) phosphate (SnP) like chromotropic acid anchored tin phosphate (SnPCA) and tin phenyl phosphonate (SnPP) were also synthesized. These materials have been characterized for elemental analysis (ICP–AES), thermal analysis, X-ray analysis and FTIR spectroscopy. Chemical resistivity of these materials has been accessed in acidic, basic and organic solvent media. The proton present in the structural hydroxyl groups indicates good potential for TMA salts to exhibit solid-state proton conduction. The transport properties of these materials have been explored by measuring specific proton conductance at different temperatures. Based on the specific conduction data and Arrhenius plots, a suitable mechanism has been proposed.

  2. Apoplastic Nucleoside Accumulation in Arabidopsis Leads to Reduced Photosynthetic Performance and Increased Susceptibility Against Botrytis cinerea.

    Science.gov (United States)

    Daumann, Manuel; Fischer, Marietta; Niopek-Witz, Sandra; Girke, Christopher; Möhlmann, Torsten

    2015-01-01

    Interactions between plant and pathogen often occur in the extracellular space and especially nucleotides like ATP and NAD have been identified as key players in this scenario. Arabidopsis mutants accumulating nucleosides in the extracellular space were generated and studied with respect to susceptibility against Botrytis cinerea infection and general plant fitness determined as photosynthetic performance. The mutants used are deficient in the main nucleoside uptake system ENT3 and the extracellular nucleoside hydrolase NSH3. When grown on soil but not in hydroponic culture, these plants markedly accumulate adenosine and uridine in leaves. This nucleoside accumulation was accompanied by reduced photosystem II efficiency and altered expression of photosynthesis related genes. Moreover, a higher susceptibility toward Botrytis cinerea infection and a reduced induction of pathogen related genes PR1 and WRKY33 was observed. All these effects did not occur in hydroponically grown plants substantiating a contribution of extracellular nucleosides to these effects. Whether reduced general plant fitness, altered pathogen response capability or more direct interactions with the pathogen are responsible for these observations is discussed.

  3. Apoplastic nucleoside accumulation in Arabidopsis leads to reduced photosynthetic performance and increased susceptibility against Botrytis cinerea

    Directory of Open Access Journals (Sweden)

    Manuel eDaumann

    2015-12-01

    Full Text Available ABSTRACT Interactions between plant and pathogen often occur in the extracellular space and especially nucleotides like ATP and NAD have been identified as key players in this scenario. Arabidopsis mutants accumulating nucleosides in the extracellular space were generated and studied with respect to susceptibility against Botrytis cinerea infection and general plant fitness determined as photosynthetic performance. The mutants used are deficient in the main nucleoside uptake system ENT3 and the extracellular nucleoside hydrolase NSH3. When grown on soil but not in hydroponic culture, these plants markedly accumulate adenosine and uridine in leaves. This nucleoside accumulation was accpmpanied by reduced photosystem II efficiency and altered expression of photosynthesis related genes. Moreover, a higher susceptibility towards Botrytis cinerea infection and a reduced induction of pathogen related genes PR1 and WRKY33 was observed. All these effects did not occur in hydroponically grown plants substantiating a contribution of extracellular nucleosides to these effects. Whether reduced general plant fitness, altered pathogen response capability or more direct interactions with the pathogen are responsible for these observations is discussed.

  4. Pharmaceutical and clinical development of phosphonate-based radiopharmaceuticals for the targeted treatment of bone metastases.

    Science.gov (United States)

    Lange, Rogier; Ter Heine, Rob; Knapp, Russ Ff; de Klerk, John M H; Bloemendal, Haiko J; Hendrikse, N Harry

    2016-10-01

    Therapeutic phosphonate-based radiopharmaceuticals radiolabeled with beta, alpha and conversion electron emitting radioisotopes have been investigated for the targeted treatment of painful bone metastases for >35years. We performed a systematic literature search and focused on the pharmaceutical development, preclinical research and early human studies of these radiopharmaceuticals. The characteristics of an ideal bone-targeting therapeutic radiopharmaceutical are presented and compliance with these criteria by the compounds discussed is verified. The importance of both composition and preparation conditions for the stability and biodistribution of several agents is discussed. Very few studies have described the characterization of these products, although knowledge on the molecular structure is important with respect to in vivo behavior. This review discusses a total of 91 phosphonate-based therapeutic radiopharmaceuticals, of which only six agents have progressed to clinical use. Extensive clinical studies have only been described for (186)Re-HEDP, (188)Re-HEDP and (153)Sm-EDTMP. Of these, (153)Sm-EDTMP represents the only compound with worldwide marketing authorization. (177)Lu-EDTMP has recently received approval for clinical use in India. This review illustrates that a thorough understanding of the radiochemistry of these agents is required to design simple and robust preparation and quality control methods, which are needed to fully exploit the potential benefits of these theranostic radiopharmaceuticals. Extensive biodistribution and dosimetry studies are indispensable to provide the portfolios that are required for assessment before human administration is possible. Use of the existing knowledge collected in this review should guide future research efforts and may lead to the approval of new promising agents. PMID:27496068

  5. Resistance issues with new nucleoside/nucleotide backbone options.

    Science.gov (United States)

    Wainberg, Mark A; Turner, Dan

    2004-09-01

    The nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) remain an enduring feature of combination therapy. As NRTI/NtRTI options continue to expand, questions arise about how best to combine these agents to create effective dual NRTI/NtRTI backbones in antiretroviral regimens while avoiding treatment-emergent drug resistance. Clinicians must consider how NRTIs/NtRTIs such as tenofovir DF (TDF), abacavir (ABC), and emtricitabine (FTC), as well as new once-daily and coformulated NRTIs/NtRTIs, interact with older agents when combined in novel regimens and how sequencing the new NRTIs can preserve future treatment options. Resistance data from clinical trials have revealed important information on the patterns, prevalence, and effects of resistance seen among patients experiencing virologic failure. In recent years, the prevalence of some mutations such as M184V and Q151M has remained relatively constant, while the L74V mutation, the 69 insertions, and thymidine analogue mutations have decreased in prevalence. Other mutations such as K65R and Y115F, while still relatively uncommon, are increasing in prevalence. This increase may be due to the use of new treatment combinations that select for these mutations at a higher rate. Clinical trials suggest that new regimens containing TDF or ABC select for K65R and that this mutation is observed more frequently with TDF; in contrast, L74V is observed more frequently in ABC-containing regimens but is not commonly selected by TDF-containing regimens. Several lines of evidence are converging to suggest that the presence of zidovudine may decrease the risk of L74V and K65R in ABC- or TDF-containing regimens. This review summarizes the clinical implications of resistance profiles associated with new NRTI/NtRTI regimens in current use and in advanced clinical studies. PMID:15319668

  6. Gas chromatographic-mass spectrometric characterization of all acyclic C5-C7 alkenes from fluid catalytic cracked gasoline using polydimethylsiloxane and squalane stationary phases.

    Science.gov (United States)

    Soják, Ladislav; Addová, Gabriela; Kubinec, Róbert; Kraus, Angelika; Hu, Gengyuan

    2002-02-15

    Published retention indices of acyclic alkenes C5-C7 on squalane and polydimethylsiloxane as stationary phases were investigated, and reliable retention indices of alkenes from various sources were converted to separation systems used in a laboratory. Retention indices measured on available authentic commercial alkenes and on alkenic fraction of gasoline, published retention indices as well as means of GC-MS were used for verification of calculated retention indices. Retention of some gas chromatographic unseparated isomer pairs was obtained by mass spectrometric deconvolution using a specific single-ion monitoring. On the basis of these retention data, C5-C7 alkenes were identified and analyzed in the gasoline from fluid catalytic cracking. In the gasoline all 59 acyclic C5-C7 isomeric alkenes were determined at significantly different concentration levels.

  7. Anti-EGFRvIII monoclonal antibody armed with {sup 177}Lu: in vivo comparison of macrocyclic and acyclic ligands

    Energy Technology Data Exchange (ETDEWEB)

    Hens, Marc; Vaidyanathan, Ganesan; Zhao Xiaoguang [Department of Radiology, Duke University Medical Center, Durham, NC 27710 (United States); Bigner, Darell D. [Department of Pathology, Duke University Medical Center, Durham, NC 27710 (United States); Zalutsky, Michael R., E-mail: zalut001@mc.duke.ed [Department of Radiology, Duke University Medical Center, Durham, NC 27710 (United States)

    2010-10-15

    Introduction: Monoclonal antibody (mAb) L8A4 binds specifically to the epidermal growth factor receptor variant III (EGFRvIII) that is present on gliomas but not on normal tissues, and is internalized rapidly after receptor binding. Because of the short range of its {beta}-emissions, labeling this mAb with {sup 177}Lu would be an attractive approach for the treatment of residual tumor margins remaining after surgical debulking of brain tumors. Materials and Methods: L8A4 mAb was labeled with {sup 177}Lu using the acyclic ligands [(R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1, 2-diamine-pentaacetic acid (CHX-A''-DTPA) and 2-(4-isothiocyanatobenzyl)-6-methyldiethylene-triaminepentaacetic acid (1B4M-DTPA), and the macrocyclic ligands S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (C-DOTA) and {alpha}-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7, 10-tetraacetic acid (MeO-DOTA). Paired-label tissue distribution experiments were performed in athymic mice bearing subcutaneous EGFRvIII-expressing U87.{Delta}EGFR glioma xenografts over a period of 1 to 8 days to directly compare {sup 177}Lu-labeled L8A4 to L8A4 labeled with {sup 125}I using N-succinimidyl 4-guanidinomethyl-3-[{sup 125}I]iodobenzoate ([{sup 125}I]SGMIB). Results: Except with C-DOTA, tumor uptake for the {sup 177}Lu-labeled mAb was significantly higher than the co-administered radioiodinated preparation; however, this was also the case for spleen, liver, bone and kidneys. Tumor/normal tissue ratios for {sup 177}Lu-1B4M-DTPA-L8A4 and, to an even greater extent, {sup 177}Lu-MeO-DOTA-L8A4 were higher than those for [{sup 125}I]SGMIB-L8A4 in most other tissues. Conclusions: Tumor and normal tissue distribution patterns for this anti-EGFRvIII mAb were dependent on the nature of the bifunctional chelate used for {sup 177}Lu labeling. Optimal results were obtained with 1B4M-DTPA and MeO-DOTA, suggesting no clear advantage

  8. Structure of purine nucleoside phosphorylase (DeoD) from Bacillus anthracis

    International Nuclear Information System (INIS)

    The crystal structure of purine nucleoside phosphorylase (DeoD) from B. anthracis was solved by X-ray crystallography using molecular replacement and refined at a resolution of 2.24 Å. Protein structures from the causative agent of anthrax (Bacillus anthracis) are being determined as part of a structural genomics programme. Amongst initial candidates for crystallographic analysis are enzymes involved in nucleotide biosynthesis, since these are recognized as potential targets in antibacterial therapy. Purine nucleoside phosphorylase is a key enzyme in the purine-salvage pathway. The crystal structure of purine nucleoside phosphorylase (DeoD) from B. anthracis has been solved by molecular replacement at 2.24 Å resolution and refined to an R factor of 18.4%. This is the first report of a DeoD structure from a Gram-positive bacterium

  9. Synthesis of 4'α-C Phenyl-Branched Carbocyclic Nucleoside Using Ring-Closing Metathesis

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Joon Hee; Ko, Ok Hyun [Chosun University, Gwangju(Korea, Republic of)

    2003-09-15

    An efficient synthetic route for preparing novel 4'α-C phenyl branched carbocyclic nucleoside is described. The installation of phenyl group at the 4'-position of carbocyclic nucleoside was successfully accomplished via a sequential [3,3]-sigmatropic rearrangement and ring-closing metathesis (RCM) beginning from simple ketone such as 2-hydroxy acetophenone.

  10. Apoptosis induced by nucleosides in the human hepatoma HepG2

    Institute of Scientific and Technical Information of China (English)

    Suh-Ching Yang; Che-Lin Chiu; Chi-Chang Huang; Jiun-Rong Chen

    2005-01-01

    AIM: To investigate the apoptotic effects of nucleosides on the human hepatoma HepG2.METHODS: The nucleosides included inosine (I), cytidine(C), uridine (U), thymidine (T), adenosine (A), and guanosine (G). Cells were incubated by the mediums with or without nucleosides at 37 ℃ in a 50 mL/L CO2 humidified atmosphere.RESULTS: It was found that the cell viabilities were significantly decreased, when cells were treated with 30 mmol/L I, 30 mmol/L C, 30 mmol/L U, 30 mmol/L T,0.5 mmol/L A, and 0.5 mmol/L G after 12 h incubation (P<0.05). About the apoptotic phenomenon, the cell percentages of sub-G1 cells were significantly increased in the mediums containing nucleosides such as C, U, T,A, and G (P<0.05). Furthermore, the caspase-3 activity was increased, when the cells were incubated with T(P<0.05). The protein expressions of p53 and p21 showed no difference in each group. To investigate the mechanism of apoptosis induced by nucleosides, it was found that the contents of soluble Fas ligand contents were increased in HepG2 cells following I, U, T, and A treatment (P<0.05).But, TNF-α and cytochrome c were undetectable.CONCLUSION: Thymidine may induce the apoptosis in HepG2, but the effective dosages and reactive time must be investigated in the future study. However, the apoptosis-inducing abilities of other nucleosides were still unclear in this study.

  11. Synthesis of Novel Homo-N-Nucleoside Analogs Composed of a Homo-1,4-Dioxane Sugar Analog and Substituted 1,3,5-Triazine Base Equivalents

    Directory of Open Access Journals (Sweden)

    Qiang Yu

    2008-12-01

    Full Text Available Enantioselective syntheses from dimethyl tartrate of 1,3,5-triazine homo-N-nucleoside analogs, containing a 1,4-dioxane moiety replacing the sugar unit in natural nucleosides, were accomplished. The triazine heterocycle in the nucleoside analogs was further substituted with combinations of NH2, OH and Cl in the 2,4-triazine positions.

  12. Phenylalanine Ammonia-Lyase-Catalyzed Deamination of an Acyclic Amino Acid: Enzyme Mechanistic Studies Aided by a Novel Microreactor Filled with Magnetic Nanoparticles.

    Science.gov (United States)

    Weiser, Diána; Bencze, László Csaba; Bánóczi, Gergely; Ender, Ferenc; Kiss, Róbert; Kókai, Eszter; Szilágyi, András; Vértessy, Beáta G; Farkas, Ödön; Paizs, Csaba; Poppe, László

    2015-11-01

    Phenylalanine ammonia-lyase (PAL), found in many organisms, catalyzes the deamination of l-phenylalanine (Phe) to (E)-cinnamate by the aid of its MIO prosthetic group. By using PAL immobilized on magnetic nanoparticles and fixed in a microfluidic reactor with an in-line UV detector, we demonstrated that PAL can catalyze ammonia elimination from the acyclic propargylglycine (PG) to yield (E)-pent-2-ene-4-ynoate. This highlights new opportunities to extend MIO enzymes towards acyclic substrates. As PG is acyclic, its deamination cannot involve a Friedel-Crafts-type attack at an aromatic ring. The reversibility of the PAL reaction, demonstrated by the ammonia addition to (E)-pent-2-ene-4-ynoate yielding enantiopure l-PG, contradicts the proposed highly exothermic single-step mechanism. Computations with the QM/MM models of the N-MIO intermediates from L-PG and L-Phe in PAL show similar arrangements within the active site, thus supporting a mechanism via the N-MIO intermediate.

  13. Phenylalanine Ammonia-Lyase-Catalyzed Deamination of an Acyclic Amino Acid: Enzyme Mechanistic Studies Aided by a Novel Microreactor Filled with Magnetic Nanoparticles.

    Science.gov (United States)

    Weiser, Diána; Bencze, László Csaba; Bánóczi, Gergely; Ender, Ferenc; Kiss, Róbert; Kókai, Eszter; Szilágyi, András; Vértessy, Beáta G; Farkas, Ödön; Paizs, Csaba; Poppe, László

    2015-11-01

    Phenylalanine ammonia-lyase (PAL), found in many organisms, catalyzes the deamination of l-phenylalanine (Phe) to (E)-cinnamate by the aid of its MIO prosthetic group. By using PAL immobilized on magnetic nanoparticles and fixed in a microfluidic reactor with an in-line UV detector, we demonstrated that PAL can catalyze ammonia elimination from the acyclic propargylglycine (PG) to yield (E)-pent-2-ene-4-ynoate. This highlights new opportunities to extend MIO enzymes towards acyclic substrates. As PG is acyclic, its deamination cannot involve a Friedel-Crafts-type attack at an aromatic ring. The reversibility of the PAL reaction, demonstrated by the ammonia addition to (E)-pent-2-ene-4-ynoate yielding enantiopure l-PG, contradicts the proposed highly exothermic single-step mechanism. Computations with the QM/MM models of the N-MIO intermediates from L-PG and L-Phe in PAL show similar arrangements within the active site, thus supporting a mechanism via the N-MIO intermediate. PMID:26345352

  14. SBA-15 mesoporous silica free-standing thin films containing copper ions bounded via propyl phosphonate units - preparation and characterization

    Science.gov (United States)

    Laskowski, Lukasz; Laskowska, Magdalena; Jelonkiewicz, Jerzy; Dulski, Mateusz; Wojtyniak, Marcin; Fitta, Magdalena; Balanda, Maria

    2016-09-01

    The SBA-15 silica thin films containing copper ions anchored inside channels via propyl phosphonate groups are investigated. Such materials were prepared in the form of thin films, with hexagonally arranged pores, laying rectilinear to the substrate surface. However, in the case of our thin films, their free standing form allowed for additional research possibilities, that are not obtainable for typical thin films on a substrate. The structural properties of the samples were investigated by X-ray reflectometry, atomic force microscopy (AFM) and transmission electron microscopy (TEM). The molecular structure was examined by Raman spectroscopy supported by numerical simulations. Magnetic measurements (SQUID magnetometry and EPR spectroscopy) showed weak antiferromagnetic interactions between active units inside silica channels. Consequently, the pores arrangement was determined and the process of copper ions anchoring by propyl phosphonate groups was verified in unambiguous way. Moreover, the type of interactions between magnetic atoms was determined.

  15. Versatile synthesis of amino acid functionalized nucleosides via a domino carboxamidation reaction

    Directory of Open Access Journals (Sweden)

    Vicky Gheerardijn

    2014-11-01

    Full Text Available Functionalized oligonucleotides have recently gained increased attention for incorporation in modified nucleic acid structures both for the design of aptamers with enhanced binding properties as well as the construction of catalytic DNA and RNA. As a shortcut alternative to the incorporation of multiple modified residues, each bearing one extra functional group, we present here a straightforward method for direct linking of functionalized amino acids to the nucleoside base, thus equipping the nucleoside with two extra functionalities at once. As a proof of principle, we have introduced three amino acids with functional groups frequently used as key-intermediates in DNA- and RNAzymes via an efficient and straightforward domino carboxamidation reaction.

  16. Rh-Catalyzed Asymmetric Hydrogenation of a-Enol Ester Phosphonates with 1-Phenylethylamine-Derived Phosphine- Phosphoramidite Ligands

    Institute of Scientific and Technical Information of China (English)

    2012-01-01

    HU Juan, WANG Dao-yong, ZHENG Zhuo, HU Xiang-ping J. Mol. Catal. (China) 2012, 26(6), 487 ~492 Chiral phosphine-phosphoramidite ligand, ( So, S,, )-2b, was found to be highly efficient in the Rh-catalyzed asymmetric hydrogenation of various α-enol ester phosphonates, in which excellent enantioselectivities (up to 〉99% ee) and high catalyticactivity ( S/C up to 5000) were achieved.

  17. Acyclic retinoid in chemoprevention of hepatocellular carcinoma: Targeting phosphorylated retinoid X receptor-α for prevention of liver carcinogenesis

    Directory of Open Access Journals (Sweden)

    Masahito Shimizu

    2012-01-01

    Full Text Available One of the key features of hepatocellular carcinoma (HCC is the high rate of intrahepatic recurrence that correlates with poor prognosis. Therefore, in order to improve the clinical outcome for patients with HCC, development of a chemopreventive agent that can decrease or delay the incidence of recurrence is a critical issue for urgent investigation. Acyclic retinoid (ACR, a synthetic retinoid, successfully improves HCC patient survival by preventing recurrence and the formation of secondary tumors. A malfunction of the retinoid X receptor-α (RXRα due to phosphorylation by the Ras-MAPK signaling pathway plays a critical role in liver carcinogenesis, and ACR exerts chemopreventive effects on HCC development by inhibiting RXRα phosphorylation. Here, we review the relationship between retinoid signaling abnormalities and liver disease, the mechanisms of how RXRα phosphorylation contributes to liver carcinogenesis, and the detailed effects of ACR on preventing HCC development, especially based on the results of our basic and clinical research. We also outline the concept of "clonal deletion and inhibition" therapy, which is defined as the removal and inhibition of latent malignant clones from the liver before they expand into clinically detectable HCC, because ACR prevents the development of HCC by implementing this concept. Looking toward the future, we discuss "combination chemoprevention" using ACR as a key drug since it can generate a synergistic effect, and may thus be an effective new strategy for the prevention of HCC.

  18. Intramolecular OH⋅⋅⋅Fluorine Hydrogen Bonding in Saturated, Acyclic Fluorohydrins: The γ-Fluoropropanol Motif

    Science.gov (United States)

    Linclau, Bruno; Peron, Florent; Bogdan, Elena; Wells, Neil; Wang, Zhong; Compain, Guillaume; Fontenelle, Clement Q; Galland, Nicolas; LeQuestel, Jean-Yves; Graton, Jérôme

    2015-01-01

    Fluorination is commonly exercised in compound property optimization. However, the influence of fluorination on hydrogen-bond (HB) properties of adjacent functional groups, as well as the HB-accepting capacity of fluorine itself, is still not completely understood. Although the formation of OH⋅⋅⋅F intramolecular HBs (IMHBs) has been established for conformationally restricted fluorohydrins, such interaction in flexible compounds remained questionable. Herein is demonstrated for the first time—and in contrast to earlier reports—the occurrence of OH⋅⋅⋅F IMHBs in acyclic saturated γ-fluorohydrins, even for the parent 3-fluoropropan-1-ol. The relative stereochemistry is shown to have a crucial influence on the corresponding h1JOH⋅⋅⋅F values, as illustrated by syn- and anti-4-fluoropentan-2-ol (6.6 and 1.9Hz). The magnitude of OH⋅⋅⋅F IMHBs and their strong dependence on the overall molecular conformational profile, fluorination motif, and alkyl substitution level, is rationalized by quantum chemical calculations. For a given alkyl chain, the “rule of shielding” applies to OH⋅⋅⋅F IMHB energies. Surprisingly, the predicted OH⋅⋅⋅F IMHB energies are only moderately weaker than these of the corresponding OH⋅⋅⋅OMe. These results provide new insights of the impact of fluorination of aliphatic alcohols, with attractive perspectives for rational drug design. PMID:26494542

  19. Anopheles gambiae Purine Nucleoside Phosphorylase: Catalysis, Structure, and Inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Taylor,E.; Rinaldo-Matthis, A.; Li, L.; Ghanem, M.; Hazleton, K.; Cassera, M.; Almo, S.; Schramm, V.

    2007-01-01

    The purine salvage pathway of Anopheles gambiae, a mosquito that transmits malaria, has been identified in genome searches on the basis of sequence homology with characterized enzymes. Purine nucleoside phosphorylase (PNP) is a target for the development of therapeutic agents in humans and purine auxotrophs, including malarial parasites. The PNP from Anopheles gambiae (AgPNP) was expressed in Escherichia coli and compared to the PNPs from Homo sapiens (HsPNP) and Plasmodium falciparum (PfPNP). AgPNP has kcat values of 54 and 41 s-1 for 2'-deoxyinosine and inosine, its preferred substrates, and 1.0 s-1 for guanosine. However, the chemical step is fast for AgPNP at 226 s-1 for guanosine in pre-steady-state studies. 5'-Deaza-1'-aza-2'-deoxy-1'-(9-methylene)-Immucillin-H (DADMe-ImmH) is a transition-state mimic for a 2'-deoxyinosine ribocation with a fully dissociated N-ribosidic bond and is a slow-onset, tight-binding inhibitor with a dissociation constant of 3.5 pM. This is the tightest-binding inhibitor known for any PNP, with a remarkable Km/Ki* of 5.4 x 107, and is consistent with enzymatic transition state predictions of enhanced transition-state analogue binding in enzymes with enhanced catalytic efficiency. Deoxyguanosine is a weaker substrate than deoxyinosine, and DADMe-Immucillin-G is less tightly bound than DADMe-ImmH, with a dissociation constant of 23 pM for AgPNP as compared to 7 pM for HsPNP. The crystal structure of AgPNP was determined in complex with DADMe-ImmH and phosphate to a resolution of 2.2 Angstroms to reveal the differences in substrate and inhibitor specificity. The distance from the N1' cation to the phosphate O4 anion is shorter in the AgPNP{center_dot}DADMe-ImmH{center_dot}PO4 complex than in HsPNP{center_dot}DADMe-ImmH{center_dot}SO4, offering one explanation for the stronger inhibitory effect of DADMe-ImmH for AgPNP.

  20. Role of Citrate Ions in the Phosphonate-based Inhibitor System for Mild Steel in Aqueous Chloride Media

    Directory of Open Access Journals (Sweden)

    G. Gunasekaran

    2005-01-01

    Full Text Available The corrosion inhibition efficiency of phosphonic acid and its derivatives for the inhibition of corrosion of mild steel in neutral chloride media is decided by its ability to form protectivefilm over the surface. In this context, the effect of addition of metal cations and certain organic compounds, such as citrate in conjugation with phosphonic acid to impart synergistic corrosion inhibition has been explored. The experiments were carried out using various concentrations of trisodium citrate and zinc ions in an aqueous solution of 2-carboxyethyl phosphonic acid (2CEPA at 25 ppm. The corrosion characteristics have been determined using electrochemical impedance spectroscopy together with determination of corrosion rate by weight-loss method. It has been observed that a combination of inhibitive ions, namely citrate, ZCEPA, and zinc ions at 25 ppm gives 96 per cent inhibition efficiency and this corrosion inhibition is due to the formation of a protective film. By increasing the concentration of citrate beyond 25 ppm, the corrosion inhibition efficiency decreases. This paper discusses the role of citrate and zinc ions in imparting added corrosion inhibition ability using 2CEPA on the basis of experimental results.

  1. Aminopropanedinitrile (aminomalononitrile, AMN) in the synthesis of C-nucleosides and exocyclic amino thiazole N-nucleosides. Formation and reactions of 2-substituted-5-amino-4-oxazolecarbonitriles

    Energy Technology Data Exchange (ETDEWEB)

    Scheuerman, R.A.

    1992-01-01

    Aminopropanedinitrile (aminomalononitrile, AMN) reacts with a wide variety of alkyl, aryl, or heteroaryl acid chlorides in the presence of 1-methyl-2-pyrrolidinone to give N-(dicyanomethyl)carboxamides which are easily cyclized in situ or after isolation to 2-substituted-5-amino-4-oxazolecarbonitriles in good to excellent yields. Electron attracting or electron releasing groups on the phenyl rings do not appear to greatly influence the yields of oxazoles and steric factors do not appear to be important in the aliphatic series. The reaction of 2, 5-anhydro-3, 4, 6-tri-O-benzoyl-[beta]-D-allonyl chloride with aminopropane-dinitrile gives 2, 5-anhydro-N-(dicyanomethyl)-[beta]-D-allonamide-3, 4, 6-tribenzoate which is converted to 5-amino-2-(2, 3, 5-tri-O-benzoyl-[beta]-D-ribofuranosyl)-4-oxazolecarbonitrile, which is used to prepare other C-nucleosides including 2-([beta]-D-ribofuranosyl)oxazole-4-carboxamide (oxazofurin), an analogue of the antitumor and antiviral C-nucleoside tiazofurin. Attempted deblocking of several benzoyl protected C-nucleosides with sodium methoxide led to double elimination reactions and the formation of furan derivatives. The 2-substituted-5-amino-4-oxazolecarbonitriles react with ortho esters to give imidates which are cyclized to axazolo[5,4-d]pyrimidines. Reactions of 2-substituted-5-amino-4-oxazolecarbonitriles include acylation of the 5-amino group, dediazotization of the 5-amino group, nucleophilic attack and ring opening of the oxazole, and acid catalyzed ring opening of the oxazole. Sugar isothiocyanates are prepared and react with aminopropane-dinitrile (aminomalononitrile, AMN) in the presence of 1-methyl-2-pyrrolidinone to afford exocyclic amino thiazole N-nucleosides.

  2. A functionalized phosphonate-rich organosilica layered hybrid material (PSLM) fabricated through a mild process for heavy metal uptake

    Energy Technology Data Exchange (ETDEWEB)

    Daikopoulos, Chris [Department of Materials Science and Engineering, University of Ioannina, Ioannina 45110 (Greece); Bourlinos, Athanasios B. [Institute of Materials Science, NCSR “Demokritos”, Ag. Paraskevi Attikis, Athens 15310 (Greece); Georgiou, Yiannis [Laboratory of Physical Chemistry, Department of Environmental and Natural Resources Management, University of Patras, Seferi 2, Agrinio 30100 (Greece); Deligiannakis, Yiannis, E-mail: ideligia@cc.uoi.gr [Laboratory of Physical Chemistry, Department of Environmental and Natural Resources Management, University of Patras, Seferi 2, Agrinio 30100 (Greece); Zboril, Radek [Regional Centre of Advanced Technologies and Materials, Faculty of Science, Department of Physical Chemistry and Experimental Physics, Palacky University, Olomouc 77146 (Czech Republic); Karakassides, Michael A. [Department of Materials Science and Engineering, University of Ioannina, Ioannina 45110 (Greece)

    2014-04-01

    Highlights: • Novel phosphonate-rich organosilica layered hybrid material (PSLM) fabricated through a mild xerogel process. • Surface Complexation Modeling reveals that PSLM bears 2 types of functional groups able to bind heavy metal. • Maximum metal uptake capacities were found 2.72 mmol g{sup −1} for Cu{sup 2+}, 1.67 mmol g{sup −1} for Pb{sup 2+} and 1.00 mmol g{sup −1} for Cd{sup 2+} at pH 7. • EPR spectroscopy reveals local coordination environment for Cu{sup 2+} ions. - Abstract: A phosphonate-rich organosilica layered hybrid material (PSLM) made of 3-(trihydroxysilyl)propyl methylphosphonate, monosodium salt, as the single silica source, has been obtained from its aqueous solution through a xerogel process and mild thermal aging. The method is simple, affording bulk quantities of powdered PSLM in a single-step. The hybrid is stable in water and possesses a high content of phosphonate groups fixed on the solid matrix. In addition, PSLM shows good thermal stability, which exceeds 300 °C in air. The material was characterized using SEM, TEM, XRD, FT-IR and TGA techniques. Potentiometric titrations show that PSLM bears high-surface density of phosphonate groups (3 mmol g{sup −1}). As a result, the material displays high metal uptake capacity for heavy metal ions such as Cu{sup 2+} (2.72 mmol g{sup −1}), Pb{sup 2+} (1.67 mmol g{sup −1}) and Cd{sup 2+} (1.00 mmol g{sup −1}) at neutral pH values e.g. the pH of natural waters. Detailed theoretical modeling using a Surface Complexation Model combined with Electron Paramagnetic Resonance (EPR) spectroscopy shows that the surface distribution of surface bound Cu{sup 2+} ions is rather homogeneous e.g. copper-binding phosphonate sites are arranged in average distances 5–8 Å.

  3. Antiproliferative activity of bicyclic benzimidazole nucleosides: synthesis, DNA-binding and cell cycle analysis.

    Science.gov (United States)

    Sontakke, Vyankat A; Lawande, Pravin P; Kate, Anup N; Khan, Ayesha; Joshi, Rakesh; Kumbhar, Anupa A; Shinde, Vaishali S

    2016-04-26

    An efficient route was developed for synthesis of bicyclic benzimidazole nucleosides from readily available d-glucose. The key reactions were Vörbruggen glycosylation and ring closing metathesis (RCM). Primarily, to understand the mode of DNA binding, we performed a molecular docking study and the binding was found to be in the minor groove region. Based on the proposed binding model, UV-visible and fluorescence spectroscopic techniques using calf thymus DNA (CT-DNA) demonstrated a non-intercalative mode of binding. Antiproliferative activity of nucleosides was tested against MCF-7 and MDA-MB-231 breast cancer cell lines and found to be active at low micromolar concentrations. Compounds and displayed significant antiproliferative activity as compared to and with the reference anticancer drug, doxorubicin. Cell cycle analysis showed that nucleoside induced cell cycle arrest at the S-phase. Confocal microscopy has been performed to validate the induction of cellular apoptosis. Based on these findings, such modified bicyclic benzimidazole nucleosides will make a significant contribution to the development of anticancer drugs. PMID:27074628

  4. Activities of adenine nucleotide and nucleoside degradation enzymes in platelets of rats infected by Trypanosoma evansi.

    Science.gov (United States)

    Oliveira, Camila B; Da Silva, Aleksandro S; Vargas, Lara B; Bitencourt, Paula E R; Souza, Viviane C G; Costa, Marcio M; Leal, Claudio A M; Moretto, Maria B; Leal, Daniela B R; Lopes, Sonia T A; Monteiro, Silvia G

    2011-05-31

    Nucleotide and nucleoside-degrading enzymes, such as nucleoside triphosphate diphosphohydrose (NTPDase), 5'-nucleotidase and adenosine deaminase (ADA) are present in the surface membranes of platelets, involved in clotting disturbances of Trypanosoma evansi-infected animals. Thus, this study was aimed at evaluating the activities of these enzymes in platelets of rats experimentally infected with T. evansi. Animals were divided into four groups, according to the level of parasitemia. Blood samples were collected on days 3 (group A: at the beginning of parasitemia), 5 (group B: high parasitemia) and 15 (group C: chronic infection), post-infection. Group D (control group) was composed of non-infected animals for platelet count, separation and enzymatic assays. Animals from groups A and B showed marked thrombocytopenia, but platelet count was not affected in chronically infected rats. NTPDase, 5'-nucleotidase and ADA activities decreased (pplatelets from rats of groups A and B, when compared to the control group. In group C, only NTPDase and 5'-nucleoside activities decreased (pplatelet count and nucleotide/nucleoside hydrolysis were positive and statistically significant (pPlatelet aggregation was decreased in all infected groups, in comparison to the control group (pplatelets of T. evansi-infected animals might be related to thrombocytopenia, that by reducing the number of platelets, there was less release of ATP and ADP. Another possibility being suggested is that changes have occurred in the membrane of these cells, decreasing the expression of these enzymes in the cell membrane.

  5. Synthesis of Novel Uracil Non-Nucleoside Derivatives as Potential Reverse Transcriptase Inhibitors of HIV-1

    DEFF Research Database (Denmark)

    El-Brollosy, Nasser R.; Al-Deeb, Omar. A.; El-Emam, Ali A.;

    2009-01-01

    Novel emivirine and TNK-651 analogues 5a-d were synthesized by reaction of chloromethyl ethyl ether and / or benzyl chloromethyl ether, respectively, with uracils having 5-ethyl and 6-(4-methylbenzyl) or 6-(3,4-dimethoxybenzyl) substituents. A series of new uracil non-nucleosides substituted at N...

  6. Structural studies of nucleoside analog and feedback inhibitor binding to Drosophila melanogaster multisubstrate deoxyribonucleoside kinase

    DEFF Research Database (Denmark)

    Mikkelsen, Niels Egil; Munch-Petersen, Birgitte; Eklund, Hans

    2008-01-01

    relate them to the binding of substrate and feedback inhibitors. dCTP and dGTP binds similarly as the feedback inhibitor dTTP with the base in the substrate site. All investigated nucleoside analogs bind similarly as the pyrimidine substrates with many interactions in common. In contrast, the base of d...

  7. Determination of the nucleosidic structural parameters by means of DNA vibrational markers

    Science.gov (United States)

    Ghomi, M.; Letellier, R.; Taillandier, E.

    1990-10-01

    Normal mode calculations based on the GF-Wilson method and a reliable force field allow the vibrational markers arising from the deoxyadenosine (dA) and deoxyguanosine (dG) residues in DNA double helical chains (right- and left-handed conformations) to be reproduced. To do this, a fast, optimized code running on a CRAY-2 computer has been performed. The normal modes of these nucleosides have been calculated as a function of their structural parameters, on the basis of a non-redundant set of internal coordinates. This study permits a better understanding of the behaviour of the main nucleosidic markers used experimentally to determine the conformation of an oligonucleotide or polynucleotide in the crystalline phase and in solution. Taking account of the calculated data, we propose a reliable set of values for the nucleosidic structural parameters which are in good agreement with those estimated by other techniques such as X-ray diffraction or nuclear magnetic resonance (NMR) spectroscopy. We have extended this study to follow the evolution of the nucleosidic vibrational markers as a function of the sugar conformation and the glycosidic torsion angle.

  8. Pd0-Catalyzed Methyl Transfer on Nucleosides and Oligonucleotides, Envisaged as a PET Tracer

    Directory of Open Access Journals (Sweden)

    Eric Fouquet

    2013-11-01

    Full Text Available The methyl transfer reaction from activated monomethyltin, via a modified Stille coupling reaction, was studied under “ligandless” conditions on fully deprotected 5'-modified nucleosides and one dinucleotide. The reaction was optimized to proceed in a few minutes and quantitative yield, even under dilute conditions, thus affording a rapid and efficient new method for oligonucleotide labelling with carbon-11.

  9. Phosphorylation of nm23/nucleoside diphosphate kinase by casein kinase 2 in vitro

    DEFF Research Database (Denmark)

    Engel, M; Issinger, O G; Lascu, I;

    1994-01-01

    We have investigated phosphorylation of human nucleoside diphosphate kinase (NDPK) and of homologous NDPK from different species by human casein kinase 2 (CK-2). The human NDPK isotypes A and B were phosphorylated by CK-2 in vitro both when the purified proteins and total lysate of HL-60 leukemia...

  10. Use of nucleoside (tide) analogues in patients with hepatitis B-related acute liver failure

    DEFF Research Database (Denmark)

    Dao, Doan Y; Seremba, Emmanuel; Ajmera, Veeral;

    2012-01-01

    The efficacy of nucleoside(tide) analogues (NA) in the treatment of acute liver failure due to hepatitis B virus (HBV-ALF) remains controversial. We determined retrospectively the impact of NAs in a large cohort of patients with HBV-ALF....

  11. Dietary nucleotide and nucleoside exposure in infancy and atopic dermatitis, recurrent wheeze, and allergic sensitization

    NARCIS (Netherlands)

    Timmermans, M.J.C.; Dagnelie, P.C.; Theunisz, E.H.; Ewalds, D.; Thijs, C.; Mommers, M.; Arts, I.C.

    2015-01-01

    We hypothesized that early life exposure to nucleotides and nucleosides lowers the risk of recurrent wheeze, atopic dermatitis, and allergic sensitization among n = 429 children. Concentrations in breast milk were established by high-performance liquid chromatography; concentrations in formula milks

  12. Investigation of proton affinities and gas phase vibrational spectra of protonated nucleosides, deoxynucleosides, and their analogs

    NARCIS (Netherlands)

    H.U. Ung; K.T. Huynh; J.C. Poutsma; J. Oomens; G. Berden; T.H. Morton

    2015-01-01

    DNA nucleobases make use of hydrogen bonding, whether in associating to form the Watson-Crick double-helix or in producing alternative structures such as the G-quadruplex or the i-motif. Nucleoside proton-bound dimers provide an avenue for investigating characteristics that they possess within the i

  13. Etching of Crystalline ZnO Surfaces upon Phosphonic Acid Adsorption: Guidelines for the Realization of Well-Engineered Functional Self-Assembled Monolayers.

    Science.gov (United States)

    Ostapenko, Alexandra; Klöffel, Tobias; Eußner, Jens; Harms, Klaus; Dehnen, Stefanie; Meyer, Bernd; Witte, Gregor

    2016-06-01

    Functionalization of metal oxides by means of covalently bound self-assembled monolayers (SAMs) offers a tailoring of surface electronic properties such as their work function and, in combination with its large charge carrier mobility, renders ZnO a promising conductive oxide for use as transparent electrode material in optoelectronic devices. In this study, we show that the formation of phosphonic acid-anchored SAMs on ZnO competes with an unwanted chemical side reaction, leading to the formation of surface precipitates and severe surface damage at prolonged immersion times of several days. Combining atomic force microscopy (AFM), X-ray diffraction (XRD), and thermal desorption spectroscopy (TDS), the stability and structure of the aggregates formed upon immersion of ZnO single crystal surfaces of different orientations [(0001̅), (0001), and (101̅0)] in phenylphosphonic acid (PPA) solution were studied. By intentionally increasing the immersion time to more than 1 week, large crystalline precipitates are formed, which are identified as zinc phosphonate. Moreover, the energetics and the reaction pathway of this transformation have been evaluated using density functional theory (DFT), showing that zinc phosphonate is thermodynamically more favorable than phosphonic acid SAMs on ZnO. Precipitation is also found for phosphonic acids with fluorinated aromatic backbones, while less precipitation occurs upon formation of SAMs with phenylphosphinic anchoring units. By contrast, no precipitates are formed when PPA monolayer films are prepared by sublimation under vacuum conditions, yielding smooth surfaces without noticeable etching. PMID:27159837

  14. Adsorbed States of phosphonate derivatives of N-heterocyclic aromatic compounds, imidazole, thiazole, and pyridine on colloidal silver: comparison with a silver electrode.

    Science.gov (United States)

    Podstawka, Edyta; Olszewski, Tomasz K; Boduszek, Bogdan; Proniewicz, Leonard M

    2009-09-01

    Here, we report a systematic surface-enhanced Raman spectroscopy (SERS) study of the structures of phosphonate derivatives of the N-heterocyclic aromatic compounds imidazole (ImMeP ([hydroxy(1H-imidazol-5-yl)methyl]phosphonic acid) and (ImMe)(2)P (bis[hydroxy-(1H-imidazol-4-yl)-methyl]phosphinic acid)), thiazole (BAThMeP (butylaminothiazol-2-yl-methyl)phosphonic acid) and BzAThMeP (benzylaminothiazol-2-yl-methyl)phosphonic acid)), and pyridine ((PyMe)(2)P (bis[(hydroxypyridin-3-yl-methyl)]phosphinic acid)) adsorbed on nanometer-sized colloidal particles. We compared these structures to those on a roughened silver electrode surface to determine the relationship between the adsorption strength and the geometry. For example, we showed that all of these biomolecules interact with the colloidal surface through aromatic rings. However, for BzAThMeP, a preferential interaction between the benzene ring and the colloidal silver surface is observed more so than that between the thiazole ring and this substrate. The PC(OH)C fragment does not take part in the adsorption process, and the phosphonate moiety of ImMeP and (ImMe)(2)P, being removed from the surface, only assists in this process.

  15. New acyclic bis phenylpropanoid and neolignans, from Myristica fragrans Houtt., exhibiting PARP-1 and NF-κB inhibitory effects.

    Science.gov (United States)

    Muñoz Acuña, Ulyana; Carcache, Peter J Blanco; Matthew, Susan; Carcache de Blanco, Esperanza J

    2016-07-01

    The bioassay-guided fractionation of the aril of Myristica fragrans (mace spice) yielded five phenolic compounds, one new acyclic bis phenylpropanoid (1) and four previously known phenolic compounds: compounds (1) (S) 1-(3,4,5-trimethoxyphenyl)-2-(3-methoxy-5-(prop-1-yl) phenyl)-propan-1-ol, (2) benzenemethanol; α-[1-[2,6-dimethoxy-4-(2-propen-1-yl)phenoxy]ethyl]-3,4-dimethoxy-1-acetate, (3) odoratisol A, phenol, 4-[(2S,3S)-2,3-dihydro-7-methoxy-3-methyl-5-(1E)-1-propenyl-2-benzofuranyl]-2,6-dimethoxy, (4) 1,3-benzodioxate-5-methanol,α-[1-[2,6-dimethoxy-4-(2-propenyl)phenoxy]ethyl]-acetate, (5) licarin C; benzofuran,2,3-dihydro-7-methoxy-3-methyl-5-(1E)-1-yl-2-(3,4,5-trimethoxyphenyl). An NMR tube Mosher ester reaction was used in an approach to characterize and determine the assignment of the absolute configuration of the new isolated chiral alcohol (1). The PARP-1 inhibitory activity was evaluated for compound (1) (IC50=3.04μM), compound (2) (IC50=0.001μM), compound (4) (IC50=22.07μM) and compound (5) (IC50=3.11μM). Furthermore, the isolated secondary metabolites were tested for NF-κB and K-Ras inhibitory activities. When tested in the p65 assay, compounds (2) and (4) displayed potent NF-κB inhibition (IC50=1.5 nM and 3.4nM, respectively). PMID:26920294

  16. Acyclic identification of aptamers for human alpha-thrombin using over-represented libraries and deep sequencing.

    Directory of Open Access Journals (Sweden)

    Gillian V Kupakuwana

    Full Text Available BACKGROUND: Aptamers are oligonucleotides that bind proteins and other targets with high affinity and selectivity. Twenty years ago elements of natural selection were adapted to in vitro selection in order to distinguish aptamers among randomized sequence libraries. The primary bottleneck in traditional aptamer discovery is multiple cycles of in vitro evolution. METHODOLOGY/PRINCIPAL FINDINGS: We show that over-representation of sequences in aptamer libraries and deep sequencing enables acyclic identification of aptamers. We demonstrated this by isolating a known family of aptamers for human α-thrombin. Aptamers were found within a library containing an average of 56,000 copies of each possible randomized 15mer segment. The high affinity sequences were counted many times above the background in 2-6 million reads. Clustering analysis of sequences with more than 10 counts distinguished two sequence motifs with candidates at high abundance. Motif I contained the previously observed consensus 15mer, Thb1 (46,000 counts, and related variants with mostly G/T substitutions; secondary analysis showed that affinity for thrombin correlated with abundance (K(d = 12 nM for Thb1. The signal-to-noise ratio for this experiment was roughly 10,000∶1 for Thb1. Motif II was unrelated to Thb1 with the leading candidate (29,000 counts being a novel aptamer against hexose sugars in the storage and elution buffers for Concanavilin A (K(d = 0.5 µM for α-methyl-mannoside; ConA was used to immobilize α-thrombin. CONCLUSIONS/SIGNIFICANCE: Over-representation together with deep sequencing can dramatically shorten the discovery process, distinguish aptamers having a wide range of affinity for the target, allow an exhaustive search of the sequence space within a simplified library, reduce the quantity of the target required, eliminate cycling artifacts, and should allow multiplexing of sequencing experiments and targets.

  17. Peretinoin, an acyclic retinoid, improves the hepatic gene signature of chronic hepatitis C following curative therapy of hepatocellular carcinoma

    International Nuclear Information System (INIS)

    The acyclic retinoid, peretinoin, has been shown to be effective for suppressing hepatocellular carcinoma (HCC) recurrence after definitive treatment in a small-scale randomized clinical trial. However, little has been documented about the mechanism by which peretinoin exerts its inhibitory effects against recurrent HCC in humans in vivo. Twelve hepatitis C virus-positive patients whose HCC had been eradicated through curative resection or ablation underwent liver biopsy at baseline and week 8 of treatment with either a daily dose of 300 or 600 mg peretinoin. RNA isolated from biopsy samples was subjected to gene expression profile analysis. Peretinoin treatment elevated the expression levels of IGFBP6, RBP1, PRB4, CEBPA, G0S2, TGM2, GPRC5A, CYP26B1, and many other retinoid target genes. Elevated expression was also observed for interferon-, Wnt-, and tumor suppressor-related genes. By contrast, decreased expression levels were found for mTOR- and tumor progression-related genes. Interestingly, gene expression profiles for week 8 of peretinoin treatment could be classified into two groups of recurrence and non-recurrence with a prediction accuracy rate of 79.6% (P<0.05). In the liver of patients with non-recurrence, expression of PDGFC and other angiogenesis genes, cancer stem cell marker genes, and genes related to tumor progression was down-regulated, while expression of genes related to hepatocyte differentiation, tumor suppression genes, and other genes related to apoptosis induction was up-regulated. Gene expression profiling at week 8 of peretinoin treatment could successfully predict HCC recurrence within 2 years. This study is the first to show the effect of peretinoin in suppressing HCC recurrence in vivo based on gene expression profiles and provides a molecular basis for understanding the efficacy of peretinoin

  18. Acyclic Cucurbit[n]uril-Type Molecular Containers: Influence of Linker Length on Their Function as Solubilizing Agents.

    Science.gov (United States)

    Sigwalt, David; Moncelet, Damien; Falcinelli, Shane; Mandadapu, Vijaybabu; Zavalij, Peter Y; Day, Anthony; Briken, Volker; Isaacs, Lyle

    2016-05-01

    Two acyclic cucurbit[n]uril (CB[n])-type molecular containers that differ in the length of the (CH2 )n linker (M2C2: n=2, M2C4: n=4) between their aromatic sidewalls and sulfonate solubilizing groups were prepared and studied. The inherent solubilities of M2C2 (68 mm) and M2C4 (196 mm) are higher than the analogue with a (CH2 )3 linker (M2, 14 mm) studied previously. (1) H NMR dilution experiments show that M2C2 and M2C4 do not self-associate in water, which enables their use as solubilizing excipients. We used phase solubility diagrams (PSDs) to compare the solubilizing capacities of M2, M2C2, M2C4, hydroxypropyl-β-cyclodextrin (HP-β-CD), and sulfobutylether-β-cyclodextrin (SBE-β-CD) toward 15 insoluble drugs. We found that M2C2 and M2C4-as gauged by the slope of their PSDs-are less potent solubilizing agents than M2. However, the higher inherent solubility of M2C2 allows higher concentrations of drug to be formulated using M2C2 than with M2 in several cases. The solubilizing ability of M2C2 and SBE-β-CD were similar in many cases, with Krel values averaging 23 and 12, respectively, relative to HP-β-CD. In vitro cytotoxicity and in vivo maximum tolerated dose studies document the biocompatibility of M2C2. PMID:26990780

  19. Assembly of phosphonic acids on GaN and AlGaN

    Energy Technology Data Exchange (ETDEWEB)

    Simpkins, B S; Stine, R; Theodore, N D; Pehrsson, P E [Chemistry Division, Naval Research Laboratory, Washington DC (United States); Hong, S [Thomas Jefferson High School, McClean, VA (United States); Maekinen, A J [Optical Sciences Division, Naval Research Laboratory, Washington, DC (United States); Mastro, M A; Eddy, C R Jr [Electronics Science and Technology Division, Naval Research Laboratory, Washington, DC (United States)

    2010-01-13

    Self-assembled monolayers of octadecylphosphonic acid and 16-phosphonohexadecanoic acid (PHDA) were formed on the semiconductor substrates gallium nitride (GaN) and aluminium gallium nitride (AlGaN). The presence of the molecular layers was verified through x-ray photoelectron spectroscopy and ultraviolet photoelectron spectroscopy. Structural information was acquired with infrared spectroscopy which verified the bonding orientation of the carboxyl-containing PHDA. The impact of the molecular layers on the channel conductivity and the surface electronic structure of an AlGaN/GaN heterostructure was measured. Our results indicate that pinning of the surface Fermi level prohibits modification of the channel conductivity by the layer. However, a surface dipole of {approx}0.8 eV is present and associated with both phosphonic acid layers. These results are of direct relevance to field-effect-based biochemical sensors and metal-semiconductor contact formation for this system and provide a fundamental basis for further applications of GaN and AlGaN technology in the fields of biosensing and microelectronics.

  20. Thermal and Dielectric Behavior Studies of Poly(Arylene Ether Sulfones with Sulfonated and Phosphonated Pendants

    Directory of Open Access Journals (Sweden)

    Shimoga D. Ganesh

    2016-01-01

    Full Text Available The present paper discusses the aspects of the synthesizing valeric acid based poly(ether sulfones with active carboxylic acid pendants (VALPSU from solution polymerization technique via nucleophilic displacement polycondensation reaction among 4,4′-dichlorodiphenyl sulfone (DCDPS and 4,4′-bis(4-hydroxyphenyl valeric acid (BHPA. The conditions necessary to synthesize and purify the polymer were investigated in some detail. The synthesized poly(ether sulfones comprise sulfone and ether linkages in addition to reactive carboxylic acid functionality; these active carboxylic acid functional groups were exploited to hold the phenyl sulphonic acid and phenyl phosphonic acid pendants. The phenyl sulphonic acid pendants in VALPSU were easily constructed by altering active carboxylic acid moieties by sulfanilic acid using N,N′-dicyclohexylcarbodiimide (DCC mediated mild synthetic route, whereas the latter one was built in two steps. Initially, polyphosphoric acid condensation with VALPSU by 4-bromoaniline and next straightforward palladium catalyzed synthetic route, in both of which acidic pendants are clenched by polymer backbone via amide linkage. Without impairing the primary polymeric backbone modified polymers were prepared by varying the stoichiometric ratios of respective combinations. All the polymers were physicochemically characterized and pressed into tablets; electrical contacts were established to study the dielectric properties. Finally, the influence of the acidic pendants on the dielectric properties was examined.

  1. Adsorption Behaviors and Mechanism of Macroporous Phosphonic Acid Resin for Gadolinium

    Institute of Scientific and Technical Information of China (English)

    吴香梅; 熊春华; 姚彩萍

    2004-01-01

    The adsorption behaviors and mechanism of a novel chelate resin, macroporous phosphonic acid resin(PAR)for Gd(Ⅲ)were investigated. The statically and dynamically saturated adsorption capacity is respectively 308 mg·g-1resin and 296 mg·g-1resin at 298 K in Hac-NaAc medium at pH 5.6. Gd(Ⅲ)adsorbed on PAR can be reductively eluted by 0.5~5.0 mol·L-1 HCl used as eluant and the elution percentage is up to 94.7% in 1.0 mol·L-1 HCl. The resin can be regenerated and reused without apparent decrease in adsorption capacity. The apparent adsorption rate constant is k298=3.96×10-5 s-1. The adsorption behavior of PAR for Gd(Ⅲ) conforms to the Freundlich isotherm. The thermodynamic adsorption parameter, enthalpy change △H of PAR for Gd(Ⅲ)is 22.6kJ·mol-1. The apparent adsorption activation energy(Ea)of PAR for Gd(Ⅲ)is 5.0 kJ·mol-1. The molar coordination ratio of the functional group of PAR to Gd(Ⅲ)is about 3∶1. The adsorption mechanism of PAR for Gd(Ⅲ)was examined by using chemical method and IR spectrometry.

  2. Adsorption Behavior and Mechanism of Macroporous Phosphonic Acid Resin for Lu3+

    Institute of Scientific and Technical Information of China (English)

    WANG Hui-jun; XIONG Chun-hua

    2006-01-01

    The article is based on a research on the adsorption behavior and adsorption mechanism of macroporous phosphonic acid resin (PAR) for Lu3+ and the influence of the medium's pH, adsorption temperature, adsorption time, etc on adsorbing Lu3 + . The best value of medium's pH to the adsorption of PAR for Lu3 + was found to be 4.92. The static adsorption maximum capacity of PAR for Lu3 + is 220 mg· g-1. The thermodynamic adsorption parameters are respectively △H= 11.3 kJ·mol-1, △S =46.3 J·mol-1 ·K-1, △G = - 2.50 kJ·mol-1 and the apparent activity energy is Ea= 31.4 kJ· mol- 1. The adsorption behavior of PAR for Lu3 + obeys the Freundlich isotherm. The apparent adsorption rate constant is k298 = 4.68 × 10-5 s-1. The coordinate ratio of the functional radical to Lu3 + is approximately 4: 1. The best eluant is 1.0 mol· L- 1 HCl. The adsorption mechanism of PAR for Lu3 + was separately confirmed by chemical analysis and IR spectra.

  3. Adsorption of strontium (II) metal ions using phosphonate-functionalized polymer

    Indian Academy of Sciences (India)

    S M BHOSLE; S PONRATHNAM; S S TAMBE; N N CHAVAN

    2016-10-01

    Diethyl[3-(methoxydimethylsilyl)propyl]phosphonate (DMPP) polymer was synthesized for the strontium (II) metal ion recovery using diethylallylphosphonate as staring material. Diethylallylphosphonate was reactedwith poly(methylhydro)siloxane (MW 1900–2000 g mol$^{−1}$) in the presence of Speier’s catalyst. The synthesized monomer was characterized by IR, ${}^1$H NMR, ${}^{13}$C NMR and FT-IR spectroscopy techniques, and the synthesizedpolymers were characterized by IR and NMR spectroscopy, differential scanning calorimetry, thermogravimetric analysis and solubility. The synthesized polymer was used for sequestering strontium metal from the aqueous solution. The metal binding was examined by the energy dispersive spectroscopy and scanning electron microscopy for the adsorbed Sr(II). Batch adsorption studies were performed by varying three parameters, namely initial pH, adsorbentdose and the contact time. The reaction kinetics was determined by the Langmuir, Freundlich, and pseudo-firstand second-order models. Results of this study indicate that the synthesized polymer DMPP has been effective inremoving Sr(II) from the aqueous solution.

  4. Improving lanthanide nanocrystal colloidal stability in competitive aqueous buffer solutions using multivalent PEG-phosphonate ligands.

    Science.gov (United States)

    Cao, Pengpeng; Tong, Lemuel; Hou, Yi; Zhao, Guangyao; Guerin, Gerald; Winnik, Mitchell A; Nitz, Mark

    2012-09-01

    The range of properties available in the lanthanide series has inspired research into the use of lanthanide nanoparticles for numerous applications. We aim to use NaLnF(4) nanoparticles for isotopic tags in mass cytometry. This application requires nanoparticles of narrow size distribution, diameters preferably less than 15 nm, and robust surface chemistry to avoid nonspecific interactions and to facilitate bioconjugation. Nanoparticles (NaHoF(4), NaEuF(4), NaGdF(4), and NaTbF(4)) were synthesized with diameters from 9 to 11 nm with oleic acid surface stabilization. The surface ligands were replaced by a series of mono-, di-, and tetraphosphonate PEG ligands, whose synthesis is reported here. The colloidal stability of the resulting particles was monitored over a range of pH values and in phosphate containing solutions. All of the PEG-phosphonate ligands were found to produce non-aggregated colloidally stable suspensions of the nanoparticles in water as judged by DLS and TEM measurements. However, in more aggressive solutions, at high pH and in phosphate buffers, the mono- and diphosphonate PEG ligands did not stabilize the particles and aggregation as well as flocculation was observed. However, the tetraphosphonate ligand was able to stabilize the particles at high pH and in phosphate buffers for extended periods of time.

  5. Synthesis of nucleoside and nucleotide conjugates of bile acids, and polymerase construction of bile acid-functionalized DNA.

    Science.gov (United States)

    Ikonen, Satu; Macícková-Cahová, Hana; Pohl, Radek; Sanda, Miloslav; Hocek, Michal

    2010-03-01

    Aqueous Sonogashira cross-coupling reactions of 5-iodopyrimidine or 7-iodo-7-deazaadenine nucleosides with bile acid-derived terminal acetylenes linked via an ester or amide tether gave the corresponding bile acid-nucleoside conjugates. Analogous reactions of halogenated nucleoside triphosphates gave directly bile acid-modified dNTPs. Enzymatic incorporation of these modified nucleotides to DNA was successfully performed using Phusion polymerase for primer extension. One of the dNTPs (dCTP bearing cholic acid) was also efficient for PCR amplification. PMID:20165813

  6. Analysis of the Nucleoside Content of Cordyceps sinensis Using the Stepwise Gradient Elution Technique of Thin-Layer Chromatography

    Institute of Scientific and Technical Information of China (English)

    MA,King-Wah(马敬桦); CHAU,Foo-Tim(周福添); WU,Jian-Yong(吴建勇)

    2004-01-01

    Nucleoside is the main class of active components in Cordyceps sinensis. Thin-layer chromatography (TLC) is one of the most commonly used methods in pharmacopoeias for analyzing chemical components of herbal medicine. Since the isocratic elution method cannot be applied successfully in TLC analysis for separating all the nucleoside components, the stepwise gradient elution has been developed in this work to separate eight nucleoside standards with success. In this way, quantitative analyses of the samples of Cordyceps sinensis were achieved via the proposed TLC procedure coupled with the scanning densitometric techniques of CAMAG and TLCQA methods for qualitative and quantitative analysis.

  7. Delayed hepatic uptake of multi-phosphonic acid poly(ethylene glycol) coated iron oxide measured by real-time Magnetic Resonance Imaging

    CERN Document Server

    Ramniceanu, G; Vezignol, C; Graillot, A; Loubat, C; Mignet, N; Berret, J -F

    2016-01-01

    We report on the synthesis, characterization, stability and pharmacokinetics of novel iron based contrast agents for magnetic resonance imaging (MRI). Statistical copolymers combining multiple phosphonic acid groups and poly(ethylene glycol) (PEG) were synthesized and used as coating agents for 10 nm iron oxide nanocrystals. In vitro, protein corona and stability assays show that phosphonic acid PEG copolymers outperform all other coating types examined, including low molecular weight anionic ligands and polymers. In vivo, the particle pharmacokinetics is investigated by monitoring the MRI signal intensity from mouse liver, spleen and arteries as a function of the time, between one minute and seven days after injection. Iron oxide particles coated with multi-phosphonic acid PEG polymers are shown to have a blood circulation lifetime of 250 minutes, i.e. 10 to 50 times greater than that of recently published PEGylated probes and benchmarks. The clearance from the liver takes in average 2 to 3 days and is indep...

  8. Selective electrochemical discrimination between dopamine and phenethylamine-derived psychotropic drugs using electrodes modified with an acyclic receptor containing two terminal 3-alkoxy-5-nitroindazole rings.

    Science.gov (United States)

    Doménech, Antonio; Navarro, Pilar; Arán, Vicente J; Muro, Beatriz; Montoya, Noemí; García-España, Enrique

    2010-06-01

    Electrochemical discrimination between dopamine and psychotropic drugs which have in common a skeletal structure of phenethylamine, can be obtained using acyclic receptors L(1) and L(2), containing two terminal 3-alkoxy-5-nitroindazole rings. Upon attachment to graphite electrodes, L(1) and L(2) exhibit a well-defined, essentially reversible solid state electrochemistry in contact with aqueous media, based on electrolyte-assisted reduction processes involving successive cation and anion insertion/binding. As a result, a distinctive, essentially Nernstian electrochemical response is obtained for phenethylammonium ions of methamphetamine (METH), p-methoxyamphetamine (PMA), amphetamine (AMPH), mescaline (MES), homoveratrylamine (HOM), phenethylamine (PEA) and dopamine (DA) in aqueous media.

  9. The chemoenzymatic synthesis of clofarabine and related 2′-deoxyfluoroarabinosyl nucleosides: the electronic and stereochemical factors determining substrate recognition by E. coli nucleoside phosphorylases

    OpenAIRE

    Fateev, Ilja V; Konstantin V. Antonov; Konstantinova, Irina D; Tatyana I. Muravyova; Seela, Frank; Esipov, Roman S; Anatoly I. Miroshnikov; Mikhailopulo, Igor A.

    2014-01-01

    Two approaches to the synthesis of 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine (1, clofarabine) were studied. The first approach consists in the chemical synthesis of 2-deoxy-2-fluoro-α-D-arabinofuranose-1-phosphate (12a, 2FAra-1P) via three step conversion of 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranose (9) into the phosphate 12a without isolation of intermediary products. Condensation of 12a with 2-chloroadenine catalyzed by the recombinant E. coli purine nucleosid...

  10. Effect of Time and Deposition Method on Quality of Phosphonic Acid Modifier Self-Assembled Monolayers on Indium Zinc Oxide

    Energy Technology Data Exchange (ETDEWEB)

    Sang, Lingzi; Knesting, Kristina M.; Bulusu, Anuradha; Sigdel, Ajaya K.; Giordano, Anthony J.; Marder, Seth R.; Berry, Joseph J.; Graham, Samuel; Ginger, David S.; Pemberton, Jeanne E.

    2016-12-15

    Phosphonic acid (PA) self-assembled monolayers (SAMs) are utilized at critical interfaces between transparent conductive oxides (TCO) and organic active layers in organic photovoltaic devices (OPVs). The effects of PA deposition method and time on the formation of close-packed, high-quality monolayers is investigated here for SAMs fabricated by solution deposition, micro-contact printing, and spray coating. The solution deposition isotherm for pentafluorinated benzylphosphonic acid (F5BnPA) on indium-doped zinc oxide (IZO) is studied using polarization modulation-infrared reflection-absorption spectroscopy (PM-IRRAS) at room temperature as a model PA/IZO system. Fast surface adsorption occurs within the first min; however, well-oriented high-quality SAMs are reached only after -48 h, presumably through a continual process of molecular adsorption/desorption and monolayer filling accompanied by molecular reorientation. Two other rapid, soak-free deposition techniques, micro-contact printing and spray coating, are also explored. SAM quality is compared for deposition of phenyl phosphonic acid (PPA), F13-octylphosphonic acid (F13OPA), and pentafluorinated benzyl phosphonic acid (F5BnPA) by solution deposition, micro-contact printing and spray coating using PM-IRRAS. In contrast to micro-contact printing and spray coating techniques, 48-168 h solution deposition at both room temperature and 70 degrees C result in contamination- and surface etch-free close-packed monolayers with good reproducibility. SAMs fabricated by micro-contact printing and spray coating are much less well ordered.

  11. Carbazole dye with phosphonic acid anchoring groups for long-term heat stability of dye-sensitized solar cells

    International Nuclear Information System (INIS)

    In dye-sensitized solar cells (DSSCs), the binding strength between the dye and TiO2 surface may affect the heat stability of the DSSCs. Carboxylic acids have generally been used as the anchoring groups for the adsorption of dyes on TiO2 surfaces. However, a phosphonic acid anchor is expected to effect more stable bonding to a TiO2 surface because of its tridentate binding capability. In this study, we developed a new carbazole dye that employed a phosphonic acid anchor, MK-94. We studied the effect of the dye anchoring group on the heat stability of DSSCs by comparing MK-94, MK-2 (a carbazole dye with a carboxylic acid anchoring group), and Z-907 (a well-known, robust Ru complex dye with a carboxylic acid anchoring group). In the initial performance assessment, the DSSC with MK-94 exhibited a lower short circuit current (jsc) but a higher open circuit voltage (ΔVoc) than MK-2. With respect to heat stability, decreases in jsc and ΔVoc were suppressed with MK-94, and the drop of the power conversion efficiency (PCE) was kept within 6% after 504 h of heating. In addition, MK-94 demonstrated the longest electron lifetime and largest charge transfer resistance than the other dyes during the stability test. In contrast, the PCE decreased 27% from the initial value in the DSSC with MK-2. Thus, the phosphonic acid anchor was effective in extending the long-term heat stability of the DSSCs

  12. Amalgamation of Nucleosides and Amino Acids in Antibiotic Biosynthesis: Discovery of an L-Threonine:Uridine-5'-Aldehyde Transaldolase

    OpenAIRE

    Barnard-Britson, Sandra; Chi, Xiuling; Nonaka, Koichi; Spork, Anatol P.; Tibrewal, Nidhi; Goswami, Anwesha; Pahari, Pallab; Ducho, Christian; Rohr, Jurgen; Van Lanen, Steven G

    2012-01-01

    The lipopeptidyl nucleoside antibiotics reperesented by A-90289, caprazamycin, and muraymycin, are structurally highlighted by a nucleoside core that contains a nonproteinogenic β-hydroxy-α-amino acid named 5′-C-glycyluridine (GlyU). Bioinformatic analysis of the biosynthetic gene clusters revealed a shared open reading frame encoding a protein with sequence similarity to serine hydroxymethyltransferases, resulting in the proposal that this shared enzyme catalyzes an aldol-type condensation w...

  13. Corrosion inhibition of low phosphonic multipolymer water treatment agent of industry circulating on brass in aqueous solution

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    In response to environmental guidelines, a low phosphonic multipolymer was synthesized and its corrosion inhibition efficiency to brass in synthetic water was investigated through weight loss measurements and electrochemical tests.It showed that the synthesized inhibitor decreased corrosion under the conditions tested.Potentiodynamic polarization curves indicated that the new inhibitor acted as an anodic inhibitor, reducing metal dissolution.The composition of protective films formed on the brass was studied by energy-dispersive X-ray analysis (EDX).The inhibition effects were due to the formation of a protective film of the multipolymer inhibitor on the metal surface.

  14. Flexible Acyclic Polyol-Chloride Anion Complexes and Their Characterization by Photoelectron Spectroscopy and Variable Temperature Binding Constant Determinations.

    Science.gov (United States)

    Shokri, Alireza; Wang, Xue-Bin; Wang, Yanping; O'Doherty, George A; Kass, Steven R

    2016-03-17

    Flexible acyclic alcohols with one to five hydroxyl groups were bound to a chloride anion and these complexes were interrogated by negative ion photoelectron spectroscopy and companion density functional theory computations. The resulting vertical detachment energies are reproduced on average to 0.10 eV by M06-2X/aug-cc-pVTZ predictions and range from 4.45-5.96 eV. These values are 0.84-2.35 eV larger than the adiabatic detachment energy of Cl(-) as a result of the larger hydrogen bond networks in the bigger polyols. Adiabatic detachment energies of the alcohol-Cl(-) clusters are more difficult to determine both experimentally and computationally. This is due to the large geometry changes that occur upon photodetachment and the large bond dissociation energy of H-Cl which enables the resulting chlorine atom to abstract a hydrogen from any of the methylene (CH2) or methine (CH) positions. Both ionic and nonionic hydrogen bonds (i.e., OH···Cl(-) and OH···OH···Cl(-)) form in the larger polyols complexes and are found to be energetically comparable. Subtle structural differences, consequently can lead to the formation of different types of hydrogen bonds, and maximizing the ionic ones is not always preferred. Solution equilibrium binding constants between the alcohols and tetrabutylammonium chloride (TBACl) in acetonitrile at -24.2, +22.0, and +53.6 °C were also determined. The free energies of association are nearly identical for all of the substrates (i.e., ΔG° = -2.8 ± 0.7 kcal mol(-1)). Compensating enthalpy and entropy values reveal, contrary to expectation and the intrinsic gas-phase preferences, that the bigger systems with more hydroxyl groups are entropically favored and enthalpically disfavored relative to the smaller species. This suggests that more solvent molecules are released upon binding TBACl to alcohols with more hydroxyl groups and is consistent with the measured negative heat capacities. These quantities increase with molecular

  15. Flexible Acyclic Polyol-Chloride Anion Complexes and Their Characterization by Photoelectron Spectroscopy and Variable Temperature Binding Constant Determinations

    Energy Technology Data Exchange (ETDEWEB)

    Shokri, Alireza; Wang, Xue B.; Wang, Yangping; O' Doherty, George A.; Kass, Steven R.

    2016-03-17

    Flexible acyclic alcohols with 1–5 hydroxyl groups were bound to chloride anion and these complexes were interrogated by negative ion photoelectron spectroscopy and companion density functional theory computations. The resulting vertical detachment energies are reproduced on average to 0.10 eV by M06-2X/aug-cc-pVTZ predictions and range from 4.45 – 5.96 eV. These values are 0.84 – 2.35 eV larger than the adiabatic detachment energy of Cl– as a result of the larger hydrogen bond networks in the bigger polyols. Adiabatic detachment energies of the alcohol–Cl– clusters are more difficult to determine both experimentally and computationally. This is due to the large geometry changes that occur upon photodetachment and the large bond dissociation energy of H–Cl which enables the resulting chlorine atom to abstract a hydrogen from any of the methylene (CH2) or methine (CH) positions. Both ionic and non-ionic hydrogen bonds (i.e., OH•••Cl– and OH•••OH•••Cl–) form in the larger polyols complexes, and are found to be energetically comparable. Subtle structural differences, consequently can lead to the formation of different types of hydrogen bonds and maximizing the ionic ones is not always preferred. Solution equilibrium binding constants between the alcohols and tetrrabuylammonium chloride (TBACl) in acetonitrile at -24.2, 22.0, and 53.6 °C were also determined. The free energies of association are nearly identical for all of the substrates (i.e., ΔG° = -2.8 ± 0.7 kcal mol–1). Compensating enthalpy and entropy values reveal, contrary to expectation and the intrinsic gas-phase preferences, that the bigger systems with more hydroxyl groups are entropically favored and enthalpically disfavored relative to the smaller species. This suggests that more solvent molecules are released upon binding TBACl to alcohols with more hydroxyl groups and is consistent with the measured negative heat capacities. These quantities increase with

  16. Transcriptional and cellular responses of the green alga Chlamydomonas reinhardtii to perfluoroalkyl phosphonic acids.

    Science.gov (United States)

    Sanchez, David; Houde, Magali; Douville, Mélanie; De Silva, Amila O; Spencer, Christine; Verreault, Jonathan

    2015-03-01

    Perfluoroalkyl phosphonic acids (PFPAs), a new class of perfluoroalkyl substances used primarily in the industrial sector as surfactants, were recently detected in surface water and wastewater treatment plant effluents. Toxicological effects of PFPAs have as yet not been investigated in aquatic organisms. The objective of the present study was to evaluate the effects of perfluorooctylphosphonic acid (C8-PFPA) and perfluorodecylphosphonic acid (C10-PFPA) exposure (31-250μg/L) on Chlamydomonas reinhardtii using genomic (qRT-PCR), biochemical (reactive oxygen species production (ROS) and lipid peroxidation), and physiological (cellular viability) indicators. After 72h of exposure, no differences were observed in cellular viability for any of the two perfluorochemicals. However, increase in ROS concentrations (36% and 25.6% at 125 and 250μg/L, respectively) and lipid peroxidation (35.5% and 35.7% at 125 and 250μg/L, respectively) was observed following exposure to C10-PFPA. C8-PFPA exposure did not impact ROS production and lipid peroxidation in algae. To get insights into the molecular response and modes of action of PFPA toxicity, qRT-PCR-based assays were performed to analyze the transcription of genes related to antioxidant responses including superoxide dismutase (SOD-1), glutathione peroxidase (GPX), catalase (CAT), glutathione S-transferase (GST), and ascorbate peroxidase (APX I). Genomic analyses revealed that the transcription of CAT and APX I was up-regulated for all the C10-PFPA concentrations. In addition, PFPAs were quantified in St. Lawrence River surface water samples and detected at concentrations ranging from 250 to 850pg/L for C8-PFPA and 380 to 650pg/L for C10-PFPA. This study supports the prevalence of PFPAs in the aquatic environment and suggests potential impacts of PFPA exposure on the antioxidant defensive system in C. reinhardtii. PMID:25621396

  17. Synthesis and herbicidal activity evaluation of novel α-amino phosphonate derivatives containing a uracil moiety.

    Science.gov (United States)

    Che, Jian-yi; Xu, Xiao-yun; Tang, Zi-long; Gu, Yu-cheng; Shi, De-qing

    2016-02-15

    A series of novel α-amino phosphonate derivatives containing a uracil moiety 3a-3l were designed and synthesized by a Lewis acid (magnesium perchlorate) catalyzed the Kabachnik-Fields reaction. The bioassays {in vitro, in vivo [Glass House 1 (GH1) and Glass House 2 (GH2)]} showed that most of compounds 3 exhibited excellent and selective herbicidal activities; for example, in GH1 test, compounds 3b, 3d, 3f, 3h and 3j showed excellent and wide spectrum herbicidal activities at the dose of 1000 g/ha, and compounds 3b and 3j exhibited 100% inhibition activities against the four plants in both post- and pre-emergence treatments. Moreover, most of compounds 3 showed higher inhibition against Amaranthus retroflexus and Digitaria sanguinalis than Glyphosate did in pre-emergence treatment. In GH2 test, the four compounds (3b, 3d, 3h and 3j) exhibited 100% inhibition against Solanum nigrum, Amaranthus retroflexus and Ipomoea hederacea in post-emergence treatment and displayed 100% inhibition against Solanum nigrum, Amaranthus retroflexus in pre-emergence treatment at the rate of 250 g/ha, and compound 3b showed the best and broad spectrum herbicidal activities against the six test plants. However, the four compounds displayed weaker herbicidal activities against Lolium perenne and Echinochloa crus-galli than the other four plants at the rate of 250 g/ha in both pre- and post-emergence treatments. So, compounds 3 can be used as a lead compound for further structure optimization for developing potential selective herbicidal agent. Their preliminary structure-activity relationships were also investigated. PMID:26786699

  18. Properties of poly(lactic acid nanocomposites based on montmorillonite, sepiolite and zirconium phosphonate

    Directory of Open Access Journals (Sweden)

    K. Fukushima

    2012-11-01

    Full Text Available Poly(lactic acid (PLA based nanocomposites based on 5 wt.% of an organically modified montmorillonite (CLO, unmodified sepiolite (SEP and organically modified zirconium phosphonate (ZrP were obtained by melt blending. Wide angle X-ray scattering (WAXS and scanning electron microscopy (SEM analysis showed a different dispersion level depending on the type and functionalisation of nanoparticles. Differenctial scanning calorimetric (DSC analysis showed that PLA was able to crystallize on heating, and that the addition of ZrP could promote extent of PLA crystallization, whereas the presence of CLO and SEP did not significantly affect the crystallization on heating and melting behaviour of PLA matrix. Dynamic Mechanical Thermoanalysis (DMTA results showed that addition of all nanoparticles brought considerable improvements in E' of PLA, resulting in a remarkable increase of elastic properties for PLA nanocomposites. The melt viscosity and dynamic shear moduli (G',G" of PLA nanocomposites were also enhanced significantly by the presence of CLO and SEP, and attributed to the formation of a PLA/nanoparticle interconnected structure within the polymer matrix. The oxygen permeability of PLA did not significantly vary upon addition of SEP and ZrP nanoparticles. Only addition of CLO led to about 30% decrease compared to PLA permeability, due to the good clay dispersion and clay platelet-like morphology. The characteristic high transparency of PLA in the visible region was kept upon addition of the nanoparticles. Based on these achievements, a high potential of these PLA nanocomposites in sustainable packaging applications could be envisaged.

  19. Rapid Synthesis and Antiviral Activity of (Quinazolin-4-YlaminoMethyl-Phosphonates Through Microwave Irradiation

    Directory of Open Access Journals (Sweden)

    Baoan Song

    2012-06-01

    Full Text Available This study describes the simple synthesis of new (quinazolin-4-ylamino methylphosphonates via microwave irradiation. Substituted-2-aminobenzonitrile reacted with 1,1-dimethoxy-N,N-dimethylmethanamine at a reflux condition to obtain N'-(substituted-2-cyanophenyl-N,N-dimethylformamidine (1. The subsequent reaction of this intermediate product with α-aminophosphonate (2 in a solution containing glacial acetic acid in 2-propanol through microwave irradiation resulted in the formation of (quinazolin-4-ylaminomethyl-phosphonate derivatives 3a to 3x, which were unequivocally characterized by the spectral data and elemental analysis. The influence of the reaction conditions on the yield of 3a was investigated to optimize the synthetic conditions. The relative optimal conditions for the synthesis of 3a include a 1:1 molar ratio of N’-(2-cyanophenyl-N,N-dimethylformamidine to diethyl amino(phenylmethylphosphonate and a 4:1 volume ratio of isopropanol to HOAc in the solvent mixture, at a reaction temperature of 150 °C, with a microwave power of 100 W and a corresponding pressure of 150 psi for 20 min in the microwave synthesizer. The yield of 3a was approximately 79%, whereas those of 3b to 3x were approximately 77% to 86%. Some of the synthesized compounds displayed weak to good anti-Tobacco mosaic virus (TMV activity.

  20. Samarium-153 ethylenediamine tetramethylene phosphonate therapy for bone pain palliation in skeletal metastases

    Directory of Open Access Journals (Sweden)

    Tripathi Madhavi

    2006-01-01

    Full Text Available BACKGROUND: Systemic therapy with radionuclides may be used for the treatment of patients with painful skeletal metastases owing to its efficacy, low cost and low toxicity. Imported radionuclides for pain palliation, like Strontium-89 are expensive; particularly for developing countries. In the Indian scenario, Samarium-153 (Sm-153 is produced in our own reactors and as a result, it is readily available and economical. AIM: We undertook this study to determine the efficacy and toxicity of single-dose Sm-153 ethylenediamine tetramethylene phosphonate as a palliative treatment for painful skeletal metastases. MATERIALS AND METHODS: Eightysix patients with painful skeletal metastases from various primaries, were treated with Sm-153 EDTMP at a dose of 37 MBq/kg. The effects were evaluated according to change in visual analogue pain score, analgesic consumption, Karnofsky performance score, mobility score and blood count tests, conducted regularly for 16 weeks. STATISTICS: Repeated measures analysis. RESULTS: The overall response rates were 73%, while complete response was seen in 12.4%. Reduction in analgesic consumption with improvement in Karnofsky performance score and mobility score, was seen in all responders. Response rates were 80.3 and 80.5% in breast and prostate cancer, respectively. One case, each of Wilms tumor, ovarian cancer, germ cell tumor testis, multiple myeloma, primitive neuroectodermal tumor and oesophageal cancer, did not respond to therapy. No serious side-effects were noted, except for fall in white blood cell, platelet and haemoglobin counts, which gradually returned to normal levels by six-eight weeks. CONCLUSION: Sm-153 EDTMP provided effective palliation in 73% patients with painful bone metastases: the major toxicity was temporary myelosuppression.

  1. Rapid and liquid-based selection of genetic switches using nucleoside kinase fused with aminoglycoside phosphotransferase.

    Directory of Open Access Journals (Sweden)

    Masahiro Tominaga

    Full Text Available The evolutionary design of genetic switches and circuits requires iterative rounds of positive (ON- and negative (OFF- selection. We previously reported a rapid OFF selection system based on the kinase activity of herpes simplex virus thymidine kinase (hsvTK on the artificial mutator nucleoside dP. By fusing hsvTK with the kanamycin resistance marker aminoglycoside-(3'-phosphotransferase (APH, we established a novel selector system for genetic switches. Due to the bactericidal nature of kanamycin and nucleoside-based lethal mutagenesis, both positive and negative selection could be completed within several hours. Using this new selector system, we isolated a series of homoserine lactone-inducible genetic switches with different expression efficiencies from libraries of the Vibrio fischeri lux promoter in two days, using only liquid handling.

  2. Electronic Signatures of all Four DNA Nucleosides in a Tunneling Gap

    Science.gov (United States)

    Chang, Shuai

    2011-03-01

    New approaches to DNA sequencing are required to reduce costs and increase the availability of personalized genomics. Using Scanning Tunneling Microscope as a tool, we report measurements of the current signals generated as free nucleosides diffuse into a tunnel junction in which both electrodes are functionalized with a reagent that presents a hydrogen bond donor and acceptor to the nucleosides. This functionalization serves to both limit the range of molecular orientations in the tunnel gap and reduce the contact resistance, increasing the selectivity of the tunneling signal, so that a direct readout may be possible with a few repeated reads. This work was supported by a grant from the Sequencing Technology Program of the National Human Genome Research Institute (HG004378).

  3. Nucleoside analogues are activated by bacterial deoxyribonucleoside kinases in a species-specific manner

    DEFF Research Database (Denmark)

    Sandrini, Michael; Clausen, Anders; On, Stephen L. W.;

    2007-01-01

    . The tested Gram-negative bacteria were susceptible to 3"-azido-3"-deoxythymidine (AZT) in the concentration range 0.032-31.6 µM except for a single E. coli isolate and two Pseudomonas aeruginosa isolates which were resistant to the tested AZT concentrations. Purified recombinant S. enterica thymidine kinase......To investigate the bactericidal activity of antiviral and anticancer nucleoside analogues against a variety of pathogenic bacteria and characterize the activating enzymes, deoxyribonucleoside kinases (dNKs). Several FDA-approved nucleoside analogue drugs were screened for their potential...... and Listeria monocytogenes. These genes were tested for their ability to increase the susceptibility of a dNK-deficient E. coli strain to various analogues. We overexpressed, purified and characterized the substrate specificity and kinetic properties of the recombinant enzymes from S. enterica and B. cereus...

  4. Induction of nucleoside phosphorylase in Enterobacter aerogenes and enzymatic synthesis of adenine arabinoside

    Institute of Scientific and Technical Information of China (English)

    Xiao-kun WEI; Qing-bao DING; Lu ZHANG; Yong-li GUO; Lin OU; Chang-lu WANG

    2008-01-01

    Nucleoside phosphorylases (NPases) were found to be induced in Enterobacter aerogenes DGO-04, and cytidine and cytidine 5'-monophosphate (CMP) were the best inducers. Five mmol/L to fifteen mmol/L cytidine or CMP could distinctly increase the activities of purine nucleoside phosphorylase (PNPase), uridine phosphorylase (UPase) and thymidine phosphorylase (TPase) when they were added into medium from 0 to 8 h. In the process of enzymatic synthesis of adenine arabinoside from adenine and uracil arabinoside with wet cells ofEnterobacter aerogenes DCJO-04 induced by cytidine or CMP, the reaction time could be shortened from 36 to 6 h. After enzymatic reaction the activity of NPase in the cells induced remained higher than that in the cells uninduced.

  5. Purification, crystallization, and preliminary X-ray diffraction study of purine nucleoside phosphorylase from E. coli

    Energy Technology Data Exchange (ETDEWEB)

    Abramchik, Yu. A., E-mail: inna@ns.crys.ras.ru; Timofeev, V. I., E-mail: espiov@ibch.ru; Zhukhlistova, N. E., E-mail: tostars@mail.ru [Russian Academy of Sciences, Shubnikov Institute of Crystallography (Russian Federation); Muravieva, T. I.; Esipov, R. S. [Russian Academy of Sciences, Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry (Russian Federation); Kuranova, I. P. [Russian Academy of Sciences, Shubnikov Institute of Crystallography (Russian Federation)

    2015-07-15

    Crystals of E. coli purine nucleoside phosphorylase were grown in microgravity by the capillary counter-diffusion method through a gel layer. The X-ray diffraction data set suitable for the determination of the three-dimensional structure at atomic resolution was collected from one crystal at the Spring-8 synchrotron facility to 0.99 Å resolution. The crystals belong to sp. gr. P2{sub 1} and have the following unit-cell parameters: a = 74.1 Å, b = 110.2 Å, c = 88.2 Å, α = γ = 90°, β = 111.08°. The crystal contains six subunits of the enzyme comprising a hexamer per asymmetric unit. The hexamer is the biological active form of E. coli. purine nucleoside phosphorylase.

  6. Purification, crystallization, and preliminary X-ray diffraction study of purine nucleoside phosphorylase from E. coli

    International Nuclear Information System (INIS)

    Crystals of E. coli purine nucleoside phosphorylase were grown in microgravity by the capillary counter-diffusion method through a gel layer. The X-ray diffraction data set suitable for the determination of the three-dimensional structure at atomic resolution was collected from one crystal at the Spring-8 synchrotron facility to 0.99 Å resolution. The crystals belong to sp. gr. P21 and have the following unit-cell parameters: a = 74.1 Å, b = 110.2 Å, c = 88.2 Å, α = γ = 90°, β = 111.08°. The crystal contains six subunits of the enzyme comprising a hexamer per asymmetric unit. The hexamer is the biological active form of E. coli. purine nucleoside phosphorylase

  7. Interaction between N-phosphoryl-α-, β- and γ-amino acids and nucleosides

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The reactions of four different N-(O,O'-diisopropyl) phosphoamino acids (DIPP-aa), such as N-phosphoryl-L-α-alanine (DIPPL-α-Ala), N-phosphoryl-D-α-alanine (DIPP-D-α-Ala), N-phosphoryl-β-alanine (DIPP-β-Ala) and N-phosphoryl-γ-amino butyric acid (DIPP-γ-Aba), and four nucleosides, adenosine (A), guanosine (G), cytdine (C) and uridine (U), were studied by electrospray ionization tandem mass spectrometry (ESI-MS/MS) and HPLC/ESI-MS. DIPP-L-α-Ala and D1PP-D-α-Ala produced the same phosphorylated nucleosides, dinucleotides and phosphoroligopeptide. However, DIPP-β-Ala and DIPP-γ-Aba gave no relevant products.

  8. Using conformationally locked nucleosides to calibrate the anomeric effect: Implications for glycosyl bond stability

    Science.gov (United States)

    Moon, Hyung Ryong; Siddiqui, Maqbool A.; Sun, Guangyu; Filippov, Igor V.; Landsman, Nicholas A.; Lee, Yi-Chien; Adams, Kristie M.; Barchi, Joseph J.; Deschamps, Jeffrey R.; Nicklaus, Marc C.; Kelley, James A.

    2010-01-01

    Steric and electronic parameters such as the anomeric effect (AE) and gauche effect play significant roles in steering the North ⇆ South equilibrium of nucleosides in solution. Two isomeric oxa-bicyclo[3.1.0]hexane nucleosides that are conformationally locked in either the North or the South conformation of the pseudorotational cycle were designed to study the consequences of having the AE operational or not, independent of other parameters. The rigidity of the system allowed the orientation of the orbitals involved to be set in “fixed” relationships, either antiperiplanar where the AE is permanently “on”, or gauche where the AE is impaired. The consequences of these two alternatives were subject to high-level calculations and measured experimentally by x-ray crystallography, hydrolytic stability of the glycosyl bond, and pKa values. PMID:21052524

  9. Comparison of Clostridium difficile detection by monolayer and by inhibition of nucleoside uptake

    International Nuclear Information System (INIS)

    Detection and identification of Clostridium difficile toxin by traditional monolayer assay were compared with results obtained by a new procedure based on toxin-dependent inhibition of target cell uptake of a radioactive nucleoside. A high degree of correlation was noted between the two determinations. Although the new procedure was quantitative and objective, its value is seen at present as a rapid screen that may support results obtained in monolayers and as a potential assay for other, currently unidentified, toxins

  10. Sinefungin, a Natural Nucleoside Analogue of S-Adenosylmethionine, Inhibits Streptococcus pneumoniae Biofilm Growth

    OpenAIRE

    Mukesh Kumar Yadav; Seok-Won Park; Sung-Won Chae; Jae-Jun Song

    2014-01-01

    Pneumococcal colonization and disease is often associated with biofilm formation, in which the bacteria exhibit elevated resistance both to antibiotics and to host defense systems, often resulting in infections that are persistent and difficult to treat. We evaluated the effect of sinefungin, a nucleoside analogue of S-adenosylmethionine, on pneumococcal in vitro biofilm formation and in vivo colonization. Sinefungin is bacteriostatic to pneumococci and significantly decreased biofilm growth ...

  11. Modification of guanine bases by nucleoside phosphoramidite reagents during the solid phase synthesis of oligonucleotides.

    OpenAIRE

    Pon, R T; Damha, M J; Ogilvie, K K

    1985-01-01

    Nucleoside 3'-phosphoramidite and chlorophosphite reagents have been found to react with the lactam function of guanine. This reaction caused unsatisfactory results when oligodeoxyribonucleotides containing a large number of guanine bases were prepared in an automated solid phase synthesizer. The guanine modification is unstable, and leads to depurination and chain cleavage. This side reaction can be eliminated by protecting the O6-position. A new O6-p-nitrophenylethyldeoxyguanosine phosphora...

  12. Altered Enthalpy-Entropy Compensation in Picomolar Transition State Analogues of Human Purine Nucleoside Phosphorylase†

    OpenAIRE

    Edwards, Achelle A.; Mason, Jennifer M.; Clinch, Keith; Tyler, Peter C.; Evans, Gary B.; Schramm, Vern L.

    2009-01-01

    Human purine nucleoside phosphorylase (PNP) belongs to the trimeric class of PNPs and is essential for catabolism of deoxyguanosine. Genetic deficiency of PNP in humans causes a specific T-cell immune deficiency and transition state analogue inhibitors of PNP are in development for treatment of T-cell cancers and autoimmune disorders. Four generations of Immucillins have been developed, each of which contains inhibitors binding with picomolar affinity to human PNP. Full inhibition of PNP occu...

  13. Detergent inhibited, heat labile nucleoside triphosphatase in cores of avian myeloblastosis virus

    DEFF Research Database (Denmark)

    Jensen, Kaj Frank

    1978-01-01

    Endogenous DNA synthesis was studied in isolated core particles of avian myeloblastosis virus. It was found that cores contained an enzymatic activity which rapidly converted the added nucleoside triphosphates to diphosphates (but not further) at 0 degrees C, thus inhibiting DNA synthesis. This t...... triphosphatase probably originates from the viral membranes. In the cores the enzyme is completely inactivated by low concentrations (0.02%) of Nonident P-40. Also, the enzyme is very thermolabile and denatures rapidly at 38 degrees C....

  14. Inhibitory Effect of Bridged Nucleosides on Thermus aquaticus DNA Polymerase and Insight into the Binding Interactions.

    Directory of Open Access Journals (Sweden)

    Sung-Kun Kim

    Full Text Available Modified nucleosides have the potential to inhibit DNA polymerases for the treatment of viral infections and cancer. With the hope of developing potent drug candidates by the modification of the 2',4'-position of the ribose with the inclusion of a bridge, efforts were focused on the inhibition of Taq DNA polymerase using quantitative real time PCR, and the results revealed the significant inhibitory effects of 2',4'-bridged thymidine nucleoside on the polymerase. Study on the mode of inhibition revealed the competitive mechanism with which the 2',4'-bridged thymidine operates. With a Ki value of 9.7 ± 1.1 μM, the 2',4'-bridged thymidine proved to be a very promising inhibitor. Additionally, docking analysis showed that all the nucleosides including 2',4'-bridged thymidine were able to dock in the active site, indicating that the substrate analogs reflect a structural complementarity to the enzyme active site. The analysis also provided evidence that Asp610 was a key binding site for 2',4'-bridged thymidine. Molecular dynamics (MD simulations were performed to further understand the conformational variations of the binding. The root-mean-square deviation (RMSD values for the peptide backbone of the enzyme and the nitrogenous base of the inhibitor stabilized within 0.8 and 0.2 ns, respectively. Furthermore, the MD analysis indicates substantial conformational change in the ligand (inhibitor as the nitrogenous base rotated anticlockwise with respect to the sugar moiety, complemented by the formation of several new hydrogen bonds where Arg587 served as a pivot axis for binding formation. In conclusion, the active site inhibition of Taq DNA polymerase by 2',4'-bridged thymidine suggests the potential of bridged nucleosides as drug candidates.

  15. Current Status of Older and New Purine Nucleoside Analogues in the Treatment of Lymphoproliferative Diseases

    OpenAIRE

    Pawel Robak; Ewa Lech-Maranda; Tadeusz Robak; Anna Korycka

    2009-01-01

    For the past few years more and more new cytotoxic agents active in the treatment of hematological malignancies have been synthesized and become available for either in vitro studies or clinical trials. Among them the class of antineoplastic drugs belonging to the purine nucleoside analogues group (PNAs) plays an important role. Three of them: pentostatin (DCF), cladribine (2-CdA) and fludarabine (FA) were approved by Food and Drug Administration (FDA) for the treatment of hematological malig...

  16. Synergistic cytotoxicity of the DNA alkylating agent busulfan, nucleoside analogs and SAHA in lymphoma cell lines

    OpenAIRE

    Valdez, Benigno C.; Murray, David; Nieto, Yago; Li, Yang; Wang, Guiyun; Champlin, Richard E.; Andersson, Borje S.

    2011-01-01

    Hematopoietic stem cell transplantation (HSCT) is a promising treatment for lymphomas. Its success depends on effective pre-transplant conditioning regimens. We previously reported on the efficacy of DNA alkylating agent-nucleoside analog (NA) combinations for conditioning in AML. We hypothesized that a similar combinatory approach can be used for lymphomas. A combination of busulfan (Bu) with two NAs – clofarabine (Clo), fludarabine (Flu) or gemcitabine (Gem) – resulted in synergistic cytoto...

  17. Comparison of Clostridium difficile detection by monolayer and by inhibition of nucleoside uptake

    Energy Technology Data Exchange (ETDEWEB)

    Fuhr, J.E.; Trent, D.J.; Collmann, I.R.

    1987-02-01

    Detection and identification of Clostridium difficile toxin by traditional monolayer assay were compared with results obtained by a new procedure based on toxin-dependent inhibition of target cell uptake of a radioactive nucleoside. A high degree of correlation was noted between the two determinations. Although the new procedure was quantitative and objective, its value is seen at present as a rapid screen that may support results obtained in monolayers and as a potential assay for other, currently unidentified, toxins.

  18. Synthesis and properties of triplex-forming oligonucleotides containing 2'-modified nucleoside analogues

    OpenAIRE

    Lou, Chenguang

    2011-01-01

    Triplex-forming oligonucleotides (TFOs) bind to the major groove of the DNA duplex via the Hoogsteen interactions to generate triple helices. Potential applications of triplex technology are in regulation of gene expression, site-directed gene-knockout, mutation correction and as tools in molecular biotechnology. The presence of 2’-modified nucleosides in therapeutic oligonucleotides inhibits enzymatic degradation in vivo. Therefore such sugar modifications have the potential to improve the b...

  19. The antiretroviral nucleoside analogue Abacavir reduces cell growth and promotes differentiation of human medulloblastoma cells

    OpenAIRE

    De Rossi, Alessandra; Russo, Giuseppe; Puca, Andrew; La Montagna, Raffaele; Caputo, Mariella; Mattioli, Eliseo; Lopez, Massimo; Giordano, Antonio; Pentimalli, Francesca

    2009-01-01

    Abacavir is one of the most efficacious nucleoside analogues, with a well-characterized inhibitory activity on reverse transcriptase enzymes of retroviral origin, and has been clinically approved for the treatment of AIDS. Recently, Abacavir has been shown to inhibit also the human telomerase activity. Telomerase activity seems to be required in essentially all tumours for the immortalization of a subset of cells, including cancer stem cells. In fact, many cancer cells are dependent on telome...

  20. Synthesis of some nucleosides derivatives from L- rhamnose with expected biological activity

    OpenAIRE

    Ghoneim Amira

    2011-01-01

    Abstract Practical procedures for production of variously blocked compounds from L-rhamnose have been developed. These compounds are highly useful as indirect β-L-rhamnosyl donors. This approach represents a new method for the synthesis of aromatic nucleoside analogues and the synthesis of (3S, 4S, 5S, 6R) 3, 4, 5-triacetoxy-2-methyl-7,9-diaza-1-oxa-spiro [4,5]decane-10-one-8-thione (7).

  1. Nuclear quadrupole resonance of 14N and 2H in pyrimidines, purines, and their nucleosides

    Science.gov (United States)

    Rabbani, S. R.; Edmonds, D. T.; Gosling, P.

    Using nuclear quadrupole double-resonance techniques, nitrogen-14 and deuterium nuclear quadrupole coupling constants and asymmetry parameters have been measured in uracil, 5-bromouracil, cytosine, adenine, xanthine, hypoxanthine, their nucleosides, 2-aminopyrimidine, and benzimidazole. Zeeman studies and the detection of the simultaneous transitions of neighboring nuclei allowed in many cases a complete assignment of the observed spectral lines to particular 14N and 2D sites.

  2. Toxicity of nucleoside analogues used to treat AIDS and the selectivity of the mitochondrial DNA polymerase.

    Science.gov (United States)

    Lee, Harold; Hanes, Jeremiah; Johnson, Kenneth A

    2003-12-23

    Incorporation of nucleoside analogues by the mitochondrial DNA polymerase has been implicated as the primary cause underlying many of the toxic side effects of these drugs in HIV therapy. Recent success in reconstituting recombinant human enzyme has afforded a detailed mechanistic analysis of the reactions governing nucleotide selectivity of the polymerase and the proofreading exonuclease. The toxic side effects of nucleoside analogues are correlated with the kinetics of incorporation by the mitochondrial DNA polymerase, varying over 6 orders of magnitude in the sequence zalcitabine (ddC) > didanosine (ddI metabolized to ddA) > stavudine (d4T) > lamivudine (3TC) > tenofovir (PMPA) > zidovudine (AZT) > abacavir (metabolized to carbovir, CBV). In this review, we summarize our current efforts to examine the mechanistic basis for nucleotide selectivity by the mitochondrial DNA polymerase and its role in mitochondrial toxicity of nucleoside analogues used to treat AIDS and other viral infections. We will also discuss the promise and underlying challenges for the development of new analogues with lower toxicity.

  3. The search for and identification of amino acids, nucleobases and nucleosides in samples returned from Mars

    Science.gov (United States)

    Gehrke, Charles W.; Ponnamperuma, Cyril; Kuo, Kenneth C.; Stalling, David L.; Zumwalt, Robert W.

    1989-01-01

    An investigation of the returned Mars samples for biologically important organic compounds, with emphasis on amino acid, the puring and pyrimidine bases, and nucleosides is proposed. These studies would be conducted on subsurface samples obtained by drilling past the surface oxidizing layer with emphasis on samples containing the larges quantities of organic carbon as determined by the rover gas chromatographic mass spectrometer (GCMS). Extraction of these molecules from the returned samples will be performed using the hydrothermal extraction technique described by Cheng and Ponnamperuma. More rigorous extraction methods will be developed and evaluated. For analysis of the extract for free amino acids or amino acids present in a bound or peptidic form, aliquots will be analyzed by capillary GCMS both before and after hydrolysis with 6N hydrochloric acid. Establishment of the presence of amino acids would then lead to the next logical step which would be the use of chiral stationary gas chromatography phases to determine the enatiomeic composition of the amino acids present, and thus potentially establish their biotic or abiotic origin. Confirmational analyses for amino acids would include ion-exchange and reversed-phase liquid chromatographic analysis. For analyses of the returned Mars samples for nucleobases and nucleosides, affinity and reversed-phase liquid chromatography would be utilized. This technology coupled with scanning UV detection for identification, presents a powerful tool for nucleobase and nucleoside analysis. Mass spectrometric analysis of these compounds would confirm their presence in samples returned form Mars.

  4. Cytokinin Nucleosides - Natural Compounds with a Unique Spectrum of Biological Activities.

    Science.gov (United States)

    Drenichev, Mikhail S; Oslovsky, Vladimir E; Mikhailov, Sergey N

    2016-01-01

    Cytokinin nucleosides exhibit antitumor, antiviral, antiprotozoal, blood pressure reducing, anti-inflammatory, and antipsychotic activity. These compounds also influence platelet aggregation and exhibit some other biological activities. Cytokinins are N6-substituted adenines and represent an important group of phytohormones with diverse biochemical functions in plants, stimulating cell division and plant growth. The main structural feature of cytokinin nucleosides is the presence of a hydrophobic hydrocarbon moiety at the N6-position of adenosine. This moiety is responsible for a difference in physicochemical and biological properties as compared to adenosine. 1-N-Tuberculosinyladenosine and N6-tuberculosinyladenosine are specifically produced by Mycobacterium tuberculosis as components of the plasmatic membrane, thus making them attractive targets for clinical test development. Structurally related compounds were found in marine organisms. It has been shown also that tRNA contains N6-isoprenyladenosine and some other related compounds. This review summarizes the structural features, biological activity, and the synthesis of cytokinin nucleosides and some of their closely related derivatives such as cytokinins and terpene derivatives of adenine. PMID:27086793

  5. Design, synthesis and biological evaluation of phosphorodiamidate prodrugs of antiviral and anticancer nucleosides

    Science.gov (United States)

    McGuigan, Christopher; Bourdin, Claire; Derudas, Marco; Hamon, Nadège; Hinsinger, Karen; Kandil, Sahar; Madela, Karolina; Meneghesso, Silvia; Pertusati, Fabrizio; Serpi, Michaela; Slusarczyk, Magdalena; Chamberlain, Stanley; Kolykhalov, Alexander; Vernachio, John; Vanpouille, Christophe; Introini, Andrea; Margolis, Leonid; Balzarini, Jan

    2014-01-01

    We herein report the application of the phosphorodiamidate phosphate prodrug approach to a series of thirteen nucleoside analogs with antiviral or anticancer activity. Twenty-five symmetrical phosphorodiamidates were synthesized, bearing esterified l-Alanine (and in one case d-alanine) in the prodrug moiety, each as single stereoisomer. The presence of an achiral phosphorus represents a potential advantage over the phosphoramidate ProTide approach, where diastereoisomeric mixtures are routinely obtained, and different biological profiles may be expected from the diastereoisomers. Optimization of the synthetic pathway allowed us to identify two general methods depending on the particular nucleoside analogs. All the compounds were biologically evaluated in antiviral and anticancer assays and several showed improvement of activity compared to their parent nucleosides, as in the case of ddA, d4T, abacavir and acyclovir against HIV-1 and/or HIV-2. The biological results were supported by metabolism studies with carboxypeptidase Y monitored by 31P NMR to investigate their bioactivation. This work further validates the phosphorodiamidate approach as a monophosphate prodrug motif with broad application in the antiviral and anticancer fields. PMID:24177359

  6. Conformational analysis of an acyclic tetrapeptide: ab-initio structure determination from X-ray powder diffraction, Hirshfeld surface analysis and electronic structure.

    Science.gov (United States)

    Das, Uday; Naskar, Jishu; Mukherjee, Alok Kumar

    2015-12-01

    A terminally protected acyclic tetrapeptide has been synthesized, and the crystal structure of its hydrated form, Boc-Tyr-Aib-Tyr-Ile-OMe·2H2O (1), has been determined directly from powder X-ray diffraction data. The backbone conformation of tetrapeptide (1) exhibiting two consecutive β-turns is stabilized by two 4 → 1 intramolecular N-H · · · O hydrogen bonds. In the crystalline state, the tetrapeptide molecules are assembled through water-mediated O-H · · · O hydrogen bonds to form two-dimensional molecular sheets, which are further linked by intermolecular C-H · · · O hydrogen bonds into a three-dimensional supramolecular framework. The molecular electrostatic potential (MEP) surface of (1) has been used to supplement the crystallographic observations. The nature of intermolecular interactions in (1) has been analyzed quantitatively through the Hirshfeld surface and two-dimensional fingerprint plot. The DFT optimized molecular geometry of (1) agrees closely with that obtained from the X-ray structure analysis. The present structure analysis of Boc-Tyr-Aib-Tyr-Ile-OMe·2H2 O (1) represents a case where ab-initio crystal structure of an acyclic tetrapeptide with considerable molecular flexibility has been accomplished from laboratory X-ray powder diffraction data.

  7. Counting acyclic hypergraphs

    Institute of Scientific and Technical Information of China (English)

    WANG; Jianfang

    2001-01-01

    [1]Harker, P. T., Pang, J. S., Finite-dimensional variational inequality and nonlinear complementarity problems: A survey of theory, algorithm, and applications, Mathematical Programming, 1990, 48(2): 161.[2]Eaves, B. C., The linear complementarity problem, Management Science, 1971, 17(3): 612.[3]Eaves, B. C., On the basic theorem of complementarity problem, Math. Programming, 1971, 1(1): 68.[4]Karamardian, S., Generalized complementarity problem, J. Optim. Theory Appl., 1971, 8(1): 161.[5]Kojima, M., A unification of the existence theorems of the nonlinear complementarity problem, Math. Programming, 1975, 9(2): 257.[6]Moré, J. J., Classes of functions and feasibility conditions in nonlinear complementarity problems, Math. Programming, 1974, 6(2): 327.[7]Moré, J. J., Coercivity conditions in nonlinear complementarity problems, SIAM Rev., 1974, 16(1): 1.[8]Smith, T. E., A solution condition for complementarity problems, with an application to spatial price equilibrium, Appl. Math. Computation, 1984, 15(1): 61.[9]Isac, G., Bulavaski, V., Kalashnikov, V., Exceptional families, topological degree and complementarity problems, J. Global Optim., 1997, 10(2): 207.[10]Zhao, Y. B., Han, J. Y., Qi, H. D., Exceptional families and existence theorems for variational inequality problems, J. Optim. Theory Appl., 1999, 101(2): 475.[11]Zhao, Y. B., Han, J. Y., Exceptional family of elements for a variational inequality problem and its applications, Journal of Global Optimization, 1999, 14(2): 313.[12]Zhao, Y. B., Exceptional families and finite dimensional variational inequalities over polyhedral convex sets, Appl. Math. Computation, 1997, 87(1): 111.[13]Lloyd, N. Q., Degree Theory, Cambridge: Cambridge University Press, 1978, 6—54.[14]Ortega, J. M., Rheinholdt, W. C., Iterative Solution of Nonlinear Equations in Several Variables, New York: Academic Press, 1970, 30—45.[15]Isac, G., Obuchowska, W. T., Functions without exceptional family of elements and complementarity problems, J. Optim. Theory Appl., 1998, 99(1): 147.[16]Hartman, P., Stampacchia, G., On some nonlinear elliptic differentiable functional equation, Acta Math., 1966, 115(2): 271.

  8. Self-assembled monolayer and multilayer formation using redox-active Ru complex with phosphonic acids on silicon oxide surface

    International Nuclear Information System (INIS)

    The formation of self-assembled monolayer and multilayer using redox-active Ru complex molecules with phosphonic acids on SiO2 surface has been examined using X-ray photoelectron spectroscopy (XPS), ellipsometry, and time of flight secondary mass-ion spectroscopy (TOF-SIMS). We found that an introduction of a Zr adlayer leads to higher surface molecular density of Ru complex SAMs on the SiO2 surface, compared to that of obtained from the direct adsorption of Ru complex monolayer on the SiO2 surface. We further tried to fabricate a multilayer film using this molecule with Zr(IV) ion acting as a chemical glue by a successive immersion process. The XPS data revealed that the molecular densities of the multilayers were also higher for the immobilization with Zr adlayer between Ru complex and SiO2 surface than those without the Zr adlayer, suggesting that Zr adlayer is effective in forming highly packed molecular layer of phosphonic acids on SiO2 surface. We found the film growth reached a saturation point after 6 layers on the SiO2 surface. The film growth saturation can be explained by a molecular domain boundary effect encountered due to the large tilt angle of the molecular layer.

  9. A novel glucose biosensor based on phosphonic acid-functionalized silica nanoparticles for sensitive detection of glucose in real samples

    International Nuclear Information System (INIS)

    An effective strategy for preparation amperometric biosensor by using the phosphonic acid-functionalized silica nanoparticles (PFSi NPs) as special modified materials is proposed. In such a strategy, glucose oxidase (GOD) was selected as model protein to fabricate glucose biosensor in the presence of phosphonic acid-functionalized silica nanoparticles (PFSi NPs). The PFSi NPs were first modified on the surface of glassy carbon (GC) electrode, then, GOD was adsorbed onto the PFSi NPs film by drop-coating. The PFSi NPs were characterized by transmission electron microscopy (TEM) and nuclear magnetic resonance (NMR) spectra. The interaction of PFSi NPs with GOD was investigated by the circular dicroism spectroscopy (CD). The results showed PFSi NPs could essentially maintain the native conformation of GOD. The direct electron transfer of GOD on (PFSi NPs)/GCE electrode exhibited excellent electrocatalytic activity for the oxidation of glucose. The proposed biosensor modified with PFSi NPs displayed a fast amperometric response (5 s) to glucose, a good linear current–time relation over a wide range of glucose concentrations from 5.00 × 10−4 to 1.87 × 10−1 M, and a low detection limit of 2.44 × 10−5 M (S/N = 3). Moreover, the biosensor can be used for assessment of the concentration of glucose in many real samples (relative error < 3%). The GOD biosensor modified with PFSi NPs will have essential meaning and practical application in future that attributed to the simple method of fabrication and good performance

  10. A Multifunctional Mn(II) Phosphonate for Rapid Separation of Methyl Orange and Electron-Transfer Photochromism.

    Science.gov (United States)

    Gao, Chao-Ying; Yang, Yang; Ai, Jing; Tian, Hong-Rui; Li, Lei-Jiao; Yang, Weiting; Dang, Song; Sun, Zhong-Ming

    2016-08-01

    A Mn(II) phosphonate of the general formula [Mn(H2 L)2 (H2 O)2 (H2 bibp)] adopts a layered motif with protonated H2 bibp(2+) cations embedded in the channels (H4 L=thiophene-2-phosphonic acid; bibp=4,4'-bis(1-imidazolyl)biphenyl). The title compound exhibits excellent adsorptive removal of methyl orange (MO) dye from aqueous solution. Its advantageous features include fast adsorption, high uptake capacity, selective removal, and reusability, which are of great significance for practical application in wastewater treatment. Meanwhile, the compound displays rapid photochromism upon irradiation with visible light at room temperature. Extensive research has demonstrated that such behavior is based on a ligand-to-ligand charge-transfer (LLCT) mechanism. The irradiated sample possesses an ultra-long-lived charge-separated state. Moreover, not only is the compound the first Mn-based photochromic MOF, but it is also one of the very few examples showing LLCT with non-photochromic components. PMID:27374008

  11. The effect of complexing agent on the extraction of Ce(III) and Nd(III) by 2-ethylhexyl phosphonic acid mono-2-ethylhexyl ester

    International Nuclear Information System (INIS)

    Liquid-liquid extraction of Ce(III) and Nd(III) has been studied using 2-ethylhexyl phosphonic acid mono-2-ethylhexyl ester (EHEHPA) in kerosene as the extractant. An improvement in separation factor between these elements has been observed in the presence of the complexing agent, glycine. (author). 6 refs., 1 tab

  12. Novel sulfonated poly (ether ether ketone)/phosphonic acid-functionalized titania nanohybrid membrane by an in situ method for direct methanol fuel cells

    Science.gov (United States)

    Wu, Hong; Cao, Ying; Li, Zhen; He, Guangwei; Jiang, Zhongyi

    2015-01-01

    Sulfonated poly (ether ether ketone)/phosphonic acid-functionalized titania nanohybrid membranes are prepared by an in situ method using titanium tetrachloride (TiCl4) as inorganic precursor and amino trimethylene phosphonic acid (ATMP) as modifier. Phosphonic acid-functionalized titania nanoparticles with a uniform particle size of ∼50 nm are formed and dispersed homogeneously in the SPEEK matrix with good interfacial compatibility. Accordingly, the nanohybrid membranes display remarkably enhanced proton conduction property due to the incorporation of additional sites for proton transport and the formation of well-connected channels by bridging the hydrophilic domains in SPEEK matrix. The nanohybrid membrane with 6 wt. % of phosphonic acid-functionalized titania nanoparticles exhibits the highest proton conductivity of 0.334 S cm-1 at 65 °C and 100% RH, which is 63.7% higher than that of pristine SPEEK membrane. Furthermore, the as-prepared nanohybrid membranes also show elevated thermal and mechanical stabilities as well as decreased methanol permeability.

  13. In vivo inhibition of dipeptidyl peptidase IV activity by pro-pro-diphenyl-phosphonate (Prodipine).

    Science.gov (United States)

    De Meester, I; Belyaev, A; Lambeir, A M; De Meyer, G R; Van Osselaer, N; Haemers, A; Scharpé, S

    1997-07-01

    Dipeptidyl peptidase IV (DPP IV, EC 3.4.14.5), also known as CD26, is a membrane-bound serine protease that cleaves off aminoterminal dipeptides from peptides with a penultimate proline (or, at a much slower rate, a penultimate alanine). Recently, we synthesized and characterized a number of dipeptide-derived diphenylphosphonates. Out of the resulting series of slow-binding irreversible inhibitors of DPP IV, diphenyl 1-(S)-prolylpyrrolidine-2(R,S)-phosphonate hydrochloride (Pro-Pro-diphenylphosphonate or Prodipine) was selected for further study. We investigated the in vivo applicability of Prodipine. Male rabbits weighing 3-4 kg received a single intravenous injection with 10 mg Prodipine or saline. After 1 hr, plasma DPP IV activity had decreased to less than 20% of the preinjection value and remained unchanged during a 24-hr observation period. In a next step, we aimed to study (i) the dose dependency and (ii) the duration of the effect after a single intravenous dose of Prodipine. A profound and long-lasting inhibition of plasma DPP IV activity was observed in the treated animals (1, 5 or 10 mg). It took 5 to 8 days to reach half of the pretreatment DPP IV activity and generally more than 20 days for a complete recovery. Systemic treatment with Prodipine not only led to inhibition of plasma DPP IV activity but also decreased tissue DPP IV activity in circulating mononuclear cells, kidney cortex, thymus, spleen, lung, and liver. No differences in activities of the related peptidases aminopeptidase P (APP, EC 3.4.11.9), prolyl oligopeptidase (PO, EC 3.4.21.26), or aminopeptidase M (mAAP, EC 3.4.11.2) were detected between Prodipine-treated and control rabbits. The in vivo applicability of this chemically stable, irreversible inhibitor of DPP IV opens new possibilities, not only to further unravel the biological functions of this intriguing ectopeptidase, but also to explore this enzyme as a new target in various fields of pharmacological research.

  14. The chemoenzymatic synthesis of clofarabine and related 2'-deoxyfluoroarabinosyl nucleosides: the electronic and stereochemical factors determining substrate recognition by E. coli nucleoside phosphorylases.

    Science.gov (United States)

    Fateev, Ilja V; Antonov, Konstantin V; Konstantinova, Irina D; Muravyova, Tatyana I; Seela, Frank; Esipov, Roman S; Miroshnikov, Anatoly I; Mikhailopulo, Igor A

    2014-01-01

    Two approaches to the synthesis of 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine (1, clofarabine) were studied. The first approach consists in the chemical synthesis of 2-deoxy-2-fluoro-α-D-arabinofuranose-1-phosphate (12a, (2F)Ara-1P) via three step conversion of 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranose (9) into the phosphate 12a without isolation of intermediary products. Condensation of 12a with 2-chloroadenine catalyzed by the recombinant E. coli purine nucleoside phosphorylase (PNP) resulted in the formation of clofarabine in 67% yield. The reaction was also studied with a number of purine bases (2-aminoadenine and hypoxanthine), their analogues (5-aza-7-deazaguanine and 8-aza-7-deazahypoxanthine) and thymine. The results were compared with those of a similar reaction with α-D-arabinofuranose-1-phosphate (13a, Ara-1P). Differences of the reactivity of various substrates were analyzed by ab initio calculations in terms of the electronic structure (natural purines vs analogues) and stereochemical features ((2F)Ara-1P vs Ara-1P) of the studied compounds to determine the substrate recognition by E. coli nucleoside phosphorylases. The second approach starts with the cascade one-pot enzymatic transformation of 2-deoxy-2-fluoro-D-arabinose into the phosphate 12a, followed by its condensation with 2-chloroadenine thereby affording clofarabine in ca. 48% yield in 24 h. The following recombinant E. coli enzymes catalyze the sequential conversion of 2-deoxy-2-fluoro-D-arabinose into the phosphate 12a: ribokinase (2-deoxy-2-fluoro-D-arabinofuranose-5-phosphate), phosphopentomutase (PPN; no 1,6-diphosphates of D-hexoses as co-factors required) (12a), and finally PNP. The substrate activities of D-arabinose, D-ribose and D-xylose in the similar cascade syntheses of the relevant 2-chloroadenine nucleosides were studied and compared with the activities of 2-deoxy-2-fluoro-D-arabinose. As expected, D-ribose exhibited the best substrate activity

  15. The chemoenzymatic synthesis of clofarabine and related 2′-deoxyfluoroarabinosyl nucleosides: the electronic and stereochemical factors determining substrate recognition by E. coli nucleoside phosphorylases

    Directory of Open Access Journals (Sweden)

    Ilja V. Fateev

    2014-07-01

    Full Text Available Two approaches to the synthesis of 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyladenine (1, clofarabine were studied. The first approach consists in the chemical synthesis of 2-deoxy-2-fluoro-α-D-arabinofuranose-1-phosphate (12a, 2FAra-1P via three step conversion of 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranose (9 into the phosphate 12a without isolation of intermediary products. Condensation of 12a with 2-chloroadenine catalyzed by the recombinant E. coli purine nucleoside phosphorylase (PNP resulted in the formation of clofarabine in 67% yield. The reaction was also studied with a number of purine bases (2-aminoadenine and hypoxanthine, their analogues (5-aza-7-deazaguanine and 8-aza-7-deazahypoxanthine and thymine. The results were compared with those of a similar reaction with α-D-arabinofuranose-1-phosphate (13a, Ara-1P. Differences of the reactivity of various substrates were analyzed by ab initio calculations in terms of the electronic structure (natural purines vs analogues and stereochemical features (2FAra-1P vs Ara-1P of the studied compounds to determine the substrate recognition by E. coli nucleoside phosphorylases. The second approach starts with the cascade one-pot enzymatic transformation of 2-deoxy-2-fluoro-D-arabinose into the phosphate 12a, followed by its condensation with 2-chloroadenine thereby affording clofarabine in ca. 48% yield in 24 h. The following recombinant E. coli enzymes catalyze the sequential conversion of 2-deoxy-2-fluoro-D-arabinose into the phosphate 12a: ribokinase (2-deoxy-2-fluoro-D-arabinofuranose-5-phosphate, phosphopentomutase (PPN; no 1,6-diphosphates of D-hexoses as co-factors required (12a, and finally PNP. The substrate activities of D-arabinose, D-ribose and D-xylose in the similar cascade syntheses of the relevant 2-chloroadenine nucleosides were studied and compared with the activities of 2-deoxy-2-fluoro-D-arabinose. As expected, D-ribose exhibited the best substrate

  16. A novel nucleoside kinase from Burkholderia thailandensis: a member of the phosphofructokinase B-type family of enzymes.

    Science.gov (United States)

    Ota, Hiroko; Sakasegawa, Shin-Ichi; Yasuda, Yuko; Imamura, Shigeyuki; Tamura, Tomohiro

    2008-12-01

    The genome of the mesophilic Gram-negative bacterium Burkholderia thailandensis contains an open reading frame (i.e. the Bth_I1158 gene) that has been annotated as a putative ribokinase and PFK-B family member. Notably, although the deduced amino acid sequence of the gene showed only 29% similarity to the recently identified nucleoside kinase from hyperthermophilic archaea Methanocaldococcus jannaschii, 15 of 17 residues reportedly involved in the catalytic activity of M. jannaschii nucleoside kinase were conserved. The gene was cloned and functionally overexpressed in Rhodococcus erythropolis, and the purified enzyme was characterized biochemically. The substrate specificity of the enzyme was unusually broad for a bacterial PFK-B protein, and the specificity extended not only to purine and purine-analog nucleosides but also to uridine. Inosine was the most effective phosphoryl acceptor, with the highest k(cat)/K(m) value (80 s(-1).mm(-1)) being achieved when ATP served as the phosphoryl donor. By contrast, this enzyme exhibited no activity toward ribose, indicating that the recombinant enzyme was a nucleoside kinase rather than a ribokinase. To our knowledge, this is the first detailed analysis of a bacterial nucleoside kinase in the PFK-B family.

  17. Three-dimensional topographic index applied to the prediction of acyclic C5-C8 alkenes Kováts retention indices on polydimethylsiloxane and squalane columns.

    Science.gov (United States)

    Ren, Yueying; Liu, Huanxiang; Yao, Xiaojun; Liu, Mancang

    2007-06-29

    A novel approach is described for the prediction of gas chromatographic Kováts retention indices of 150 acyclic C5-C8 alkenes on two stationary phases (polydimethylsiloxane, PDMS, and squalane, SQ). The heuristic method was used to build multiple linear regression models using descriptors calculated by MODLESLAB software and CODESSA program. The resulting quantitative structure-retention relationship (QSRR) models were well-correlated, with predictive R2 values of 0.970 and 0.958 for retention indices on PDMS and SQ columns, respectively. 1Omegap, a three-dimensional (3D) topographic index, was found to play the most important role in the description of the chromatographic retention behavior of the alkenes in these two stationary phases. Moreover, this index could completely distinguish different isomers of alkene. Therefore, it can also be extended to distinguish different isomers of other compounds so that can well describe their quantitative structure-retention relationships.

  18. Synthesis and olfactory characterization of silicon-containing derivatives of the acyclic lily-of-the-valley odorant 5,7,7-trimethyl-4-methylideneoctanal.

    Science.gov (United States)

    Dörrich, Steffen; Mahler, Christoph; Tacke, Reinhold; Kraft, Philip

    2014-11-01

    5-Methyl-4-methylidene-6-(trimethylsilyl)hexanal (1b), a sila analog of the acyclic lily-of-the-valley odorant 5,7,7-trimethyl-4-methylideneoctanal (1a), and the Si-containing derivatives 2-6 were prepared in multistep syntheses, starting from Cl3 SiH and Cl2 SiMe2 , respectively. Compounds 1b, 2-6, and their new precursors were characterized by elemental analyses (C, H, N) and NMR spectroscopic studies ((1) H, (13) C, (15) N, and (29) Si). To gain more information about the structureodor correlation in the family of lily-of-the-valley or 'muguet' odorants, C/Si analogs 1a/1b and derivatives 2-6 were evaluated for their olfactory properties.

  19. An intersubunit disulfide bridge stabilizes the tetrameric nucleoside diphosphate kinase of Aquifex aeolicus.

    Science.gov (United States)

    Boissier, Fanny; Georgescauld, Florian; Moynié, Lucile; Dupuy, Jean-William; Sarger, Claude; Podar, Mircea; Lascu, Ioan; Giraud, Marie-France; Dautant, Alain

    2012-06-01

    The nucleoside diphosphate kinase (Ndk) catalyzes the reversible transfer of the γ-phosphate from nucleoside triphosphate to nucleoside diphosphate. Ndks form hexamers or two types of tetramers made of the same building block, namely, the common dimer. The secondary interfaces of the Type I tetramer found in Myxococcus xanthus Ndk and of the Type II found in Escherichia coli Ndk involve the opposite sides of subunits. Up to now, the few available structures of Ndk from thermophiles were hexameric. Here, we determined the X-ray structures of four crystal forms of the Ndk from the hyperthermophilic bacterium Aquifex aeolicus (Aa-Ndk). Aa-Ndk displays numerous features of thermostable proteins and is made of the common dimer but it is a tetramer of Type I. Indeed, the insertion of three residues in a surface-exposed spiral loop, named the Kpn-loop, leads to the formation of a two-turn α-helix that prevents both hexamer and Type II tetramer assembly. Moreover, the side chain of the cysteine at position 133, which is not present in other Ndk sequences, adopts two alternate conformations. Through the secondary interface, each one forms a disulfide bridge with the equivalent Cys133 from the neighboring subunit. This disulfide bridge was progressively broken during X-ray data collection by radiation damage. Such crosslinks counterbalance the weakness of the common-dimer interface. A 40% decrease of the kinase activity at 60°C after reduction and alkylation of the protein corroborates the structural relevance of the disulfide bridge on the tetramer assembly and enzymatic function. PMID:22467275

  20. Analysis of the Main Nucleosides in Cordyceps Sinensis by LC/ESI-MS

    Directory of Open Access Journals (Sweden)

    Yun-Biao He

    2010-01-01

    Full Text Available A sensitive, selective and reliable liquid chromatography-mass spectrometry coupled with electrospray ionization interface method for simultaneous separation and determination of thymine, adenine, adenosine and cordycepin in Cordyceps sinensis has been established. The optimum separation for these analytes was achieved using a gradient elution system and a 2.0 × 150 mm Shimadzu VP-ODS column. 2-Chloroadenosine was used as internal standard for this assay. [M+H]+ions at m/z 127, 136, 268, 252 and 302 were chosen and selective ion monitoring (SIM mode was used for quantitative analysis of the four main nucleosides. The regression equations were linear in the range of 1.0–117.5 μg·mL-1 for thymine, 1.8-127.0 μg·mL-1 for adenine, 0.6-114.0 μg·mL-1 for adenosine and 0.5-107.5 μg·mL-1 for cordycepin. The limits of quantitation (LOQ and detection (LOD were 1.0 and 0.2 μg·mL-1 for thymine, 1.8 and 0.6 μg·mL-1 for adenine, 0.6 and 0.1 μg·mL-1 for adenosine and 0.5 and 0.1 μg·mL-1 for cordycepin, respectively. The recoveries of the four nucleosides ranged from 98.47 to 99.32%. The developed method was successfully used to determine nucleosides in Cordyceps sinensis from different sources.

  1. Simultaneous quantification and splenocyte-proliferating activities of nucleosides and bases in Cervi cornu Pantotrichum

    Directory of Open Access Journals (Sweden)

    Ying Zong

    2014-01-01

    Full Text Available Background: Cervi Cornu Pantotrichum has been a well known traditional Chinese medicine, which is young horn of Cervus Nippon Temminck (Hualurong: HLR. At present, the methods used for the quality control of Cervi Cornu Pantotrichum show low specificity. Objective: To describe a holistic method based on chemical characteristics and splenocyte-proliferating activities to evaluate the quality of HLR. Materials and Methods: The nucleosides and bases from HLR were identified by high performance liquid chromatography electrospray ionization mass spectrometry (HPLC-ESI-MS, and six of them were chosen to be used for simultaneous HPLC quantification according to the results of proliferation of mouse splenocytes in vitro. Results: In this study, eight nucleosides and bases have been identified. In addition, uracil, hypoxanthine, uridine, inosine, guanosine, and adenosine were chosen to be used for simultaneous HPLC quantification. Simultaneous quantification of these six substances was performed on ten groups of HLR under the condition of a TIANHE Kromasil C 18 column (5 μm, 4.6 mm × 250 mm i.d. and a gradient elution of water and acetonitrile. Of the ten groups, HLR displayed the highest total nucleoside contents (TNC, sum of adenosine and uracil, 0.412 mg/g with the strongest splenocyte-proliferating activities. Conclusion: These results suggest that TNC (such as particularly highly contained adenosine and uracil in HLR has a certain correlation with the activity of splenocyte-proliferating, and it may be used as a quality control for HLR. This comprehensive method could be applied to other traditional Chinese medicines to ameliorate their quality control.

  2. Thermodynamics and kinetics of inhibitor binding to human equilibrative nucleoside transporter subtype-1.

    Science.gov (United States)

    Rehan, Shahid; Ashok, Yashwanth; Nanekar, Rahul; Jaakola, Veli-Pekka

    2015-12-15

    Many nucleoside transport inhibitors are in clinical use as anti-cancer, vasodilator and cardioprotective drugs. However, little is known about the binding energetics of these inhibitors to nucleoside transporters (NTs) due to their low endogenous expression levels and difficulties in the biophysical characterization of purified protein with ligands. Here, we present kinetics and thermodynamic analyses of inhibitor binding to the human equilibrative nucleoside transporter-1 (hENT1), also known as SLC29A1. Using a radioligand binding assay, we obtained equilibrium binding and kinetic rate constants of well-known NT inhibitors--[(3)H]nitrobenzylmercaptopurine ribonucleoside ([(3)H]NBMPR), dilazep, and dipyridamole--and the native permeant, adenosine, to hENT1. We observed that the equilibrium binding affinities for all inhibitors decreased whereas, the kinetic rate constants increased with increasing temperature. Furthermore, we found that binding is enthalpy driven and thus, an exothermic reaction, implying that the transporter does not discriminate between its inhibitors and substrates thermodynamically. This predominantly enthalpy-driven binding by four chemically distinct ligands suggests that the transporter may not tolerate diversity in the type of interactions that lead to high affinity binding. Consistent with this, the measured activation energy of [(3)H]NBMPR association was relatively large (20 kcal mol(-1)) suggesting a conformational change upon inhibitor binding. For all three inhibitors the enthalpy (ΔH°) and entropy (ΔS°) contributions to the reaction energetics were determined by van't Hoff analysis to be roughly similar (25-75% ΔG°). Gains in enthalpy with increasing polar surface area of inhibitors suggest that the binding is favored by electrostatic or polar interactions between the ligands and the transporter.

  3. The Crystal Structure of Streptococcus pyogenes Uridine Phosphorylase Reveals a Distinct Subfamily of Nucleoside Phosphorylases

    Energy Technology Data Exchange (ETDEWEB)

    Tran, Timothy H.; Christoffersen, S.; Allan, Paula W.; Parker, William B.; Piskur, Jure; Serra, I.; Terreni, M.; Ealick, Steven E. (Cornell); (Pavia); (Lund); (Southern Research)

    2011-09-20

    Uridine phosphorylase (UP), a key enzyme in the pyrimidine salvage pathway, catalyzes the reversible phosphorolysis of uridine or 2'-deoxyuridine to uracil and ribose 1-phosphate or 2'-deoxyribose 1-phosphate. This enzyme belongs to the nucleoside phosphorylase I superfamily whose members show diverse specificity for nucleoside substrates. Phylogenetic analysis shows Streptococcus pyogenes uridine phosphorylase (SpUP) is found in a distinct branch of the pyrimidine subfamily of nucleoside phosphorylases. To further characterize SpUP, we determined the crystal structure in complex with the products, ribose 1-phosphate and uracil, at 1.8 {angstrom} resolution. Like Escherichia coli UP (EcUP), the biological unit of SpUP is a hexamer with an ?/? monomeric fold. A novel feature of the active site is the presence of His169, which structurally aligns with Arg168 of the EcUP structure. A second active site residue, Lys162, is not present in previously determined UP structures and interacts with O2 of uracil. Biochemical studies of wild-type SpUP showed that its substrate specificity is similar to that of EcUP, while EcUP is {approx}7-fold more efficient than SpUP. Biochemical studies of SpUP mutants showed that mutations of His169 reduced activity, while mutation of Lys162 abolished all activity, suggesting that the negative charge in the transition state resides mostly on uracil O2. This is in contrast to EcUP for which transition state stabilization occurs mostly at O4.

  4. Simultaneous quantification and splenocyte-proliferating activities of nucleosides and bases in Cervi cornu Pantotrichum

    Science.gov (United States)

    Zong, Ying; Wang, Yu; Li, Hang; Li, Na; Zhang, Hui; Sun, Jiaming; Niu, Xiaohui; Gao, Xiaochen

    2014-01-01

    Background: Cervi Cornu Pantotrichum has been a well known traditional Chinese medicine, which is young horn of Cervus Nippon Temminck (Hualurong: HLR). At present, the methods used for the quality control of Cervi Cornu Pantotrichum show low specificity. Objective: To describe a holistic method based on chemical characteristics and splenocyte-proliferating activities to evaluate the quality of HLR. Materials and Methods: The nucleosides and bases from HLR were identified by high performance liquid chromatography electrospray ionization mass spectrometry (HPLC-ESI-MS), and six of them were chosen to be used for simultaneous HPLC quantification according to the results of proliferation of mouse splenocytes in vitro. Results: In this study, eight nucleosides and bases have been identified. In addition, uracil, hypoxanthine, uridine, inosine, guanosine, and adenosine were chosen to be used for simultaneous HPLC quantification. Simultaneous quantification of these six substances was performed on ten groups of HLR under the condition of a TIANHE Kromasil C18 column (5 μm, 4.6 mm × 250 mm i.d.) and a gradient elution of water and acetonitrile. Of the ten groups, HLR displayed the highest total nucleoside contents (TNC, sum of adenosine and uracil, 0.412 mg/g) with the strongest splenocyte-proliferating activities. Conclusion: These results suggest that TNC (such as particularly highly contained adenosine and uracil) in HLR has a certain correlation with the activity of splenocyte-proliferating, and it may be used as a quality control for HLR. This comprehensive method could be applied to other traditional Chinese medicines to ameliorate their quality control. PMID:25422536

  5. Enhancement of Peripheral Nerve Regrowth by the Purine Nucleoside Analog and Cell Cycle Inhibitor, Roscovitine

    Science.gov (United States)

    Law, Vincent; Dong, Sophie; Rosales, Jesusa L.; Jeong, Myung-Yung; Zochodne, Douglas; Lee, Ki-Young

    2016-01-01

    Peripheral nerve regeneration is a slow process that can be associated with limited outcomes and thus a search for novel and effective therapy for peripheral nerve injury and disease is crucial. Here, we found that roscovitine, a synthetic purine nucleoside analog, enhances neurite outgrowth in neuronal-like PC12 cells. Furthermore, ex vivo analysis of pre-injured adult rat dorsal root ganglion (DRG) neurons showed that roscovitine enhances neurite regrowth in these cells. Likewise, in vivo transected sciatic nerves in rats locally perfused with roscovitine had augmented repopulation of new myelinated axons beyond the transection zone. By mass spectrometry, we found that roscovitine interacts with tubulin and actin. It interacts directly with tubulin and causes a dose-dependent induction of tubulin polymerization as well as enhances Guanosine-5′-triphosphate (GTP)-dependent tubulin polymerization. Conversely, roscovitine interacts indirectly with actin and counteracts the inhibitory effect of cyclin-dependent kinases 5 (Cdk5) on Actin-Related Proteins 2/3 (Arp2/3)-dependent actin polymerization, and thus, causes actin polymerization. Moreover, in the presence of neurotrophic factors such as nerve growth factor (NGF), roscovitine-enhanced neurite outgrowth is mediated by increased activation of the extracellular signal-regulated kinases 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) pathways. Since microtubule and F-actin dynamics are critical for axonal regrowth, the ability of roscovitine to activate the ERK1/2 and p38 MAPK pathways and support polymerization of tubulin and actin indicate a major role for this purine nucleoside analog in the promotion of axonal regeneration. Together, our findings demonstrate a therapeutic potential for the purine nucleoside analog, roscovitine, in peripheral nerve injury.

  6. Nucleoside drugs induce cellular differentiation by caspase-dependent degradation of stem cell factors.

    Directory of Open Access Journals (Sweden)

    Tanja Musch

    Full Text Available BACKGROUND: Stem cell characteristics are an important feature of human cancer cells and play a major role in the therapy resistance of tumours. Strategies to target cancer stem cells are thus of major importance for cancer therapy. Differentiation therapy by nucleoside drugs represents an attractive approach for the elimination of cancer stem cells. However, even if it is generally assumed that the activity of these drugs is mediated by their ability to modulate epigenetic pathways, their precise mode of action remains to be established. We therefore analysed the potential of three nucleoside analogues to induce differentiation of the embryonic cancer stem cell line NTERA 2 D1 and compared their effect to the natural ligand retinoic acid. METHODOLOGY/PRINCIPAL FINDINGS: All nucleoside analogues analyzed, but not retinoic acid, triggered proteolytic degradation of the Polycomb group protein EZH2. Two of them, 3-Deazaneplanocin A (DZNep and 2'-deoxy-5-azacytidine (decitabine, also induced a decrease in global DNA methylation. Nevertheless, only decitabine and 1beta-arabinofuranosylcytosine (cytarabine effectively triggered neuronal differentiation of NT2 cells. We show that drug-induced differentiation, in contrast to retinoic acid induction, is caused by caspase activation, which mediates depletion of the stem cell factors NANOG and OCT4. Consistent with this observation, protein degradation and differentiation could be counteracted by co-treatment with caspase inhibitors or by depletion of CASPASE-3 and CASPASE-7 through dsRNA interference. In agreement with this, OCT4 was found to be a direct in-vitro-target of CASPASE-7. CONCLUSIONS/SIGNIFICANCE: We show that drug-induced differentiation is not a consequence of pharmacologic epigenetic modulation, but is induced by the degradation of stem-cell-specific proteins by caspases. Our results thus uncover a novel pathway that induces differentiation of embryonic cancer stem cells and is triggered by

  7. An integrated QSAR-PBK/D modelling approach for predicting detoxification and DNA adduct formation of 18 acyclic food-borne α,β-unsaturated aldehydes

    International Nuclear Information System (INIS)

    Acyclic α,β-unsaturated aldehydes present in food raise a concern because the α,β-unsaturated aldehyde moiety is considered a structural alert for genotoxicity. However, controversy remains on whether in vivo at realistic dietary exposure DNA adduct formation is significant. The aim of the present study was to develop physiologically based kinetic/dynamic (PBK/D) models to examine dose-dependent detoxification and DNA adduct formation of a group of 18 food-borne acyclic α,β-unsaturated aldehydes without 2- or 3-alkylation, and with no more than one conjugated double bond. Parameters for the PBK/D models were obtained using quantitative structure–activity relationships (QSARs) defined with a training set of six selected aldehydes. Using the QSARs, PBK/D models for the other 12 aldehydes were defined. Results revealed that DNA adduct formation in the liver increases with decreasing bulkiness of the molecule especially due to less efficient detoxification. 2-Propenal (acrolein) was identified to induce the highest DNA adduct levels. At realistic dietary intake, the predicted DNA adduct levels for all aldehydes were two orders of magnitude lower than endogenous background levels observed in disease free human liver, suggesting that for all 18 aldehydes DNA adduct formation is negligible at the relevant levels of dietary intake. The present study provides a proof of principle for the use of QSAR-based PBK/D modelling to facilitate group evaluations and read-across in risk assessment. - Highlights: • Physiologically based in silico models were made for 18 α,β-unsaturated aldehydes. • Kinetic parameters were determined by in vitro incubations and a QSAR approach. • DNA adduct formation was negligible at levels relevant for dietary intake. • The use of QSAR-based PBK/D modelling facilitates group evaluations and read-across

  8. An integrated QSAR-PBK/D modelling approach for predicting detoxification and DNA adduct formation of 18 acyclic food-borne α,β-unsaturated aldehydes

    Energy Technology Data Exchange (ETDEWEB)

    Kiwamoto, R., E-mail: reiko.kiwamoto@wur.nl; Spenkelink, A.; Rietjens, I.M.C.M.; Punt, A.

    2015-01-01

    Acyclic α,β-unsaturated aldehydes present in food raise a concern because the α,β-unsaturated aldehyde moiety is considered a structural alert for genotoxicity. However, controversy remains on whether in vivo at realistic dietary exposure DNA adduct formation is significant. The aim of the present study was to develop physiologically based kinetic/dynamic (PBK/D) models to examine dose-dependent detoxification and DNA adduct formation of a group of 18 food-borne acyclic α,β-unsaturated aldehydes without 2- or 3-alkylation, and with no more than one conjugated double bond. Parameters for the PBK/D models were obtained using quantitative structure–activity relationships (QSARs) defined with a training set of six selected aldehydes. Using the QSARs, PBK/D models for the other 12 aldehydes were defined. Results revealed that DNA adduct formation in the liver increases with decreasing bulkiness of the molecule especially due to less efficient detoxification. 2-Propenal (acrolein) was identified to induce the highest DNA adduct levels. At realistic dietary intake, the predicted DNA adduct levels for all aldehydes were two orders of magnitude lower than endogenous background levels observed in disease free human liver, suggesting that for all 18 aldehydes DNA adduct formation is negligible at the relevant levels of dietary intake. The present study provides a proof of principle for the use of QSAR-based PBK/D modelling to facilitate group evaluations and read-across in risk assessment. - Highlights: • Physiologically based in silico models were made for 18 α,β-unsaturated aldehydes. • Kinetic parameters were determined by in vitro incubations and a QSAR approach. • DNA adduct formation was negligible at levels relevant for dietary intake. • The use of QSAR-based PBK/D modelling facilitates group evaluations and read-across.

  9. Synthesis of nucleoside 5'-tetraphosphates containing terminal fluorescent labels via activated cyclic trimetaphosphate.

    Science.gov (United States)

    Mohamady, Samy; Taylor, Scott D

    2014-03-01

    2'-Deoxynucleotide 5'-tetraphosphates in which a fluorescent label is attached to the terminal phosphate are used as key reagents in high-throughput DNA sequencing techniques and in single nucleotide polymorphism typing assays. We demonstrate that this class of compounds can be prepared by reacting fluorophores such as 7-hydroxy-4-methylcoumarin, methylfluorescein, fluorescein and resorufin with an activated form of cyclic trimetaphosphate to give intermediate 11. Reaction of 11 with 2'-deoxynucleoside 5'-monophosphates or a nucleoside 5'-monophosphate gave the target compounds in good yield. PMID:24552623

  10. Focus on Chirality of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

    Directory of Open Access Journals (Sweden)

    Valeria Famiglini

    2016-02-01

    Full Text Available Chiral HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs are of great interest since one enantiomer is often more potent than the corresponding counterpart against the HIV-1 wild type (WT and the HIV-1 drug resistant mutant strains. This review exemplifies the various studies made to investigate the effect of chirality on the antiretroviral activity of top HIV-1 NNRTI compounds, such as nevirapine (NVP, efavirenz (EFV, alkynyl- and alkenylquinazolinone DuPont compounds (DPC, diarylpyrimidine (DAPY, dihydroalkyloxybenzyloxopyrimidine (DABO, phenethylthiazolylthiourea (PETT, indolylarylsulfone (IAS, arylphosphoindole (API and trifluoromethylated indole (TFMI The chiral separation, the enantiosynthesis, along with the biological properties of these HIV-1 NNRTIs, are discussed.

  11. Biophysical Insights into the Inhibitory Mechanism of Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors

    Directory of Open Access Journals (Sweden)

    Nicolas Sluis-Cremer

    2013-11-01

    Full Text Available HIV-1 reverse transcriptase (RT plays a central role in HIV infection. Current United States Federal Drug Administration (USFDA-approved antiretroviral therapies can include one of five approved non-nucleoside RT inhibitors (NNRTIs, which are potent inhibitors of RT activity. Despite their crucial clinical role in treating and preventing HIV-1 infection, their mechanism of action remains elusive. In this review, we introduce RT and highlight major advances from experimental and computational biophysical experiments toward an understanding of RT function and the inhibitory mechanism(s of NNRTIs.

  12. Metabolic Abnormalities Associated with the Use of Protease Inhibitors and Non-nucleoside Reverse Transcriptase Inhibitors

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    Madhu N. Rao

    2006-01-01

    Full Text Available The use of protease inhibitors and non-nucleoside reverse transcriptase inhibitors for the treatment of HIV infection and AIDS has been associated with multiple abnormalities in glucose and lipid metabolism. Specifically, these abnormalities include insulin resistance, increased triglycerides and increased LDL cholesterol levels. The metabolic disturbances are due to a combination of factors, including the direct effect of medications, restoration to health and HIV disease, as well as individual genetic predisposition. Of the available anti-retroviral medications, indinavir has been associated with causing the most insulin resistance and ritonavir with causing the most hypertriglyceridemia.

  13. Anti-flavivirus Activity of Different Tritylated Pyrimidine and Purine Nucleoside Analogues.

    Science.gov (United States)

    McGuigan, Christopher; Serpi, Michaela; Slusarczyk, Magdalena; Ferrari, Valentina; Pertusati, Fabrizio; Meneghesso, Silvia; Derudas, Marco; Farleigh, Laura; Zanetta, Paola; Bugert, Joachim

    2016-06-01

    A series of tritylated and dimethoxytritylated analogues of selected pyrimidine and purine nucleosides were synthesized and evaluated for their in vitro inhibitory activity against two important members of the genus Flavivirus in the Flaviviridae family, the yellow fever (YFV) and dengue viruses (DENV). Among all compounds tested, the 5'-O-tritylated and the 5'-O-dimethoxytritylated 5-fluorouridine derivatives exerted potency against YFV. Interestingly in the series of purine analogues, the 5'O, N-bis-tritylated fludarabine derivative revealed strong inhibitory activity against DENV at μm concentrations, however significantly weaker potency against YFV. PMID:27551659

  14. Ethenoguanines undergo glycosylation by nucleoside 2'-deoxyribosyltransferases at non-natural sites.

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    Wenjie Ye

    Full Text Available Deoxyribosyl transferases and functionally related purine nucleoside phosphorylases are used extensively for synthesis of non-natural deoxynucleosides as pharmaceuticals or standards for characterizing and quantitating DNA adducts. Hence exploring the conformational tolerance of the active sites of these enzymes is of considerable practical interest. We have determined the crystal structure at 2.1 Å resolution of Lactobacillus helveticus purine deoxyribosyl transferase (PDT with the tricyclic purine 8,9-dihydro-9-oxoimidazo[2,1-b]purine (N2,3-ethenoguanine at the active site. The active site electron density map was compatible with four orientations, two consistent with sites for deoxyribosylation and two appearing to be unproductive. In accord with the crystal structure, Lactobacillus helveticus PDT glycosylates the 8,9-dihydro-9-oxoimidazo[2,1-b]purine at N7 and N1, with a marked preference for N7. The activity of Lactobacillus helveticus PDT was compared with that of the nucleoside 2'-deoxyribosyltransferase enzymes (DRT Type II from Lactobacillus leichmannii and Lactobacillus fermentum, which were somewhat more effective in the deoxyribosylation than Lactobacillus helveticus PDT, glycosylating the substrate with product profiles dependent on the pH of the incubation. The purine nucleoside phosphorylase of Escherichia coli, also commonly used in ribosylation of non-natural bases, was an order of magnitude less efficient than the transferase enzymes. Modeling based on published active-site structures as templates suggests that in all cases, an active site Phe is critical in orienting the molecular plane of the purine derivative. Adventitious hydrogen bonding with additional active site residues appears to result in presentation of multiple nucleophilic sites on the periphery of the acceptor base for ribosylation to give a distribution of nucleosides. Chemical glycosylation of O9-benzylated 8,9-dihydro-9-oxoimidazo[2,1-b]purine also resulted

  15. Screening of new non-nucleoside reverse transcriptase inhibitors of HIV-1 based on traditional Chinese medicines database

    Institute of Scientific and Technical Information of China (English)

    Tao Liu; Ai Xiu Li; You Pan Miao; Ke Zhu Wu; Yi Ma

    2009-01-01

    HIV-1 RT is an important target for the treatment of AIDS. There are two major classes of antiviral agents that inhibit HIV-1 RT have been identified, nucleoside RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). In this report, a noval class of non-nucleoside compound with potential RT inhibitory activity were found from the traditional Chinese medicines database (TCMD) using a combination of virtual screening, docking, molecular dynamic simulations, where results were ranked by scoring function of the docking tool. The result indicates that M4753 (a compound derived from TCMD) has not only the lowest bonding energy but also the best match in geometric conformation with the forthcoming NNRTIs. Accordingly M4753 might possibly become a promising lead compound of NNRTIs for AIDS therapy.

  16. CORROSION BEHAVIOR OF A ZIRCONIUM-TITANIUM BASED PHOSPHONIC ACID CONVERSION COATING ON AA6061 ALUMINIUM ALLOY

    Institute of Scientific and Technical Information of China (English)

    S.H.Wang; C.S.Liu; F.J.Shan

    2008-01-01

    The conversion coating was formed by dipping AA6061 in a fluorotitanate/zirconate acid and amino trimethylene phosphonic acid (ATMP) solution at room temperature. The formation process and the anti-corrosion performance of the conversion coating were investigated using electrochemical test and salt spray test (SST),respectively. The electrochemical test shows that the Zr/Ti and ATMP coating improves the cor-rosion resistance of AA6061 as good as the chromate (Ⅵ) coating.But the results of SST show that the corrosion resistance of Zr/Ti and ATMP coating is not as good as the chromate (Ⅵ) coating.The corrosion area is less than 2% after 72 h.

  17. Designable architectures on nanoparticle surfaces: zirconium phosphate nanoplatelets as a platform for tetravalent metal and phosphonic acid assemblies.

    Science.gov (United States)

    Mosby, Brian M; Goloby, Mark; Díaz, Agustín; Bakhmutov, Vladimir; Clearfield, Abraham

    2014-03-11

    Surface-functionalized zirconium phosphate (ZrP) nanoparticles were synthesized using a combination of ion exchange and self-assembly techniques. The surface of ZrP was used as a platform to deposit tetravalent metal ions by direct ion exchange with the protons of the surface phosphate groups. Subsequently, phosphonic acids were attached to the metal ion layer, effectively functionalizing the ZrP nanoparticles. Use of axially oriented bisphosphonic acids led to the ability to build layer-by-layer assemblies from the nanoparticle surface. Varying the metal ion and ligand used allowed designable architectures to be synthesized on the nanoparticle surface. X-ray powder diffraction, XPS, electron microprobe, solid-state NMR, FTIR, and TGA were used to characterize the synthesized materials.

  18. Synthesis and biological characterization of new amino-phosphonates for mitochondrial pH determination by 31P NMR spectroscopy

    International Nuclear Information System (INIS)

    A series of mitochondria targeted α-amino-phosphonates combining a diethoxy-phosphoryl group and an alkyl chain-connected triphenylphosphonium bromide tail were designed and synthesized, and their pH-sensitive 31P NMR properties and biological activities in vitro and in vivo were evaluated. The results showed a number of these mitoaminophosphonates exhibiting pKa values fitting the mitochondrial pH range, short relaxation, and chemical shift parameters compatible with sensitive 31P NMR detection, and low cytotoxicity on green algae and murine fibroblasts cell cultures. Of these, two selected compounds demonstrated to distribute at NMR detectable levels within the cytosolic and mitochondrial sites following their perfusion to isolated rat livers, with no detrimental effects on cell energetics and aerobic respiration. This study provided a new molecular scaffold for further development of in situ spectroscopic real-time monitoring of mitochondrion/cytosol pH gradients. (authors)

  19. Preparation, characterization and application of N-methylene phosphonic acid chitosan grafted magnesia–zirconia stationary phase

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Qing; Chen, Jie; Huang, Kun; Zhang, Xin; Xu, Li [Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030 (China); Shi, Zhi-guo, E-mail: shizg@whu.edu.cn [Department of Chemistry, Wuhan University, Wuhan 430072 (China)

    2015-01-07

    Highlights: • N-methylene phosphonic acid chitosan grafted MgO–ZrO{sub 2} was prepared. • It exhibited superior HILIC chromatographic performance to the bare MgO–ZrO{sub 2}. • Monosaccharides, phospholipids and peptides were successfully separated. • It was a promising HILIC stationary phase. - Abstract: A hydrophilic stationary phase (SP) was prepared through grafting N-methylene phosphonic acid chitosan on magnesia–zirconia particles (P-CTS-MgO–ZrO{sub 2}) via Lewis acid–base interaction. The resulting material was characterized by thermogravimetric analysis, Fourier transform infrared spectroscopy, scanning electron microscope and nitrogen adsorption analysis. The chromatographic performance of P-CTS-MgO–ZrO{sub 2} was systemically evaluated by studying effect of acetonitrile content, pH and buffer concentration in the mobile phase. The results demonstrated that the novel SP provided hydrophilic, electrostatic-repulsion and ion-exchange interactions. Compared to the bare MgO–ZrO{sub 2}, P-CTS-MgO–ZrO{sub 2} exhibited superior peak shape, reasonable resolution and reduced analysis time in separation of basic analytes. Besides, remarkable resolving power of acids, i.e. six non-steroidal anti-inflammatory drugs which failed to be eluted from the bare MgO–ZrO{sub 2}, was obtained with the theoretical plate number (N/m) of 4653–31313, asymmetry factor <1.21 and the resolution of 1.6–3.4. Finally, P-CTS-MgO–ZrO{sub 2} SP was applied to separate monosaccharides, phospholipids and peptides. P-CTS-MgO–ZrO{sub 2} was a promising hydrophilic SP for wide applications.

  20. N2-(1-Methoxycarbonylethyl)guanosine, a new nucleoside coupled with an amino acid derivative from Amanita exitialis

    Institute of Scientific and Technical Information of China (English)

    Yu Lang Chi; Hui Ye Zhang; Jing Hua Xue; Jing Hao; Mei Fang Liu; Xiao Yi Wei

    2009-01-01

    A new purine nucleoside coupled with an amino acid derivative, N2-(1-methoxycarbonylethyl)guanosine 1, along with βearboline and russulaceramide was isolated from the fruiting bodies ofAmanita exitialis, a newly described poisonous mushroom. Its structure was elucidated by spectroscopic methods. This is the first report of naturally occurring nucleosides in which an α-amino acid derivative is bonded through its a-amino nitrogen to a nucleobase aglycone by a C-N bond. The new compound was found to be toxic in brine shrimp lethality test (BST).

  1. Non-nucleoside reverse transcriptase inhibitors: a review on pharmacokinetics, pharmacodynamics, safety and tolerability

    Directory of Open Access Journals (Sweden)

    Iris Usach

    2013-09-01

    Full Text Available Introduction: Human immunodeficiency virus (HIV type-1 non-nucleoside and nucleoside reverse transcriptase inhibitors (NNRTIs are key drugs of highly active antiretroviral therapy (HAART in the clinical management of acquired immune deficiency syndrome (AIDS/HIV infection. Discussion: First-generation NNRTIs, nevirapine (NVP, delavirdine (DLV and efavirenz (EFV are drugs with a low genetic barrier and poor resistance profile, which has led to the development of new generations of NNRTIs. Second-generation NNRTIs, etravirine (ETR and rilpivirine (RPV have been approved by the Food and Drug Administration and European Union, and the next generation of drugs is currently being clinically developed. This review describes recent clinical data, pharmacokinetics, metabolism, pharmacodynamics, safety and tolerability of commercialized NNRTIs, including the effects of sex, race and age differences on pharmacokinetics and safety. Moreover, it summarizes the characteristics of next-generation NNRTIs: lersivirine, GSK 2248761, RDEA806, BILR 355 BS, calanolide A, MK-4965, MK-1439 and MK-6186. Conclusions: This review presents a wide description of NNRTIs, providing useful information for researchers interested in this field, both in clinical use and in research.

  2. Cloning, expression and characterization of a nucleoside diphosphate kinase (NDPK) gene from tobacco

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Nucleoside diphosphate kinase (NDPK) is a housekeeping enzyme that maintains the intracellular levels of all (d)NTPs used in biosynthesis except ATP. Here we report that a full-length cDNA encoding nucleoside diphosphate kinase (NDPK) was cloned using yeast two-hybrid approach. A tobacco NDPK gene was obtained and designated as NtNDPK1 . NtNDPK1 is 704 bp in length and encodes a putative 16.2 kD protein of 148 amino acids. Phylogenic analysis showed that NtNDPK1 is highly homologous to other plant NDPK genes and identified as type Ⅰ (NDPK1). RNA-gel blot analysis showed that there was no significant difference of NtNDPK1 expression in roots, stems, leaves and buds. And expression of NtNDPK1 was induced by ABA and PEG and repressed by NaCl, but not significantly affected by Paraquat, wounding and low temperature (4℃) treatments, indicating that NtNDPK1 may play a certain role in response to abiotic stress. In vitro phosphorylation assay demonstrated that NtNDPK1 had autophosphorylation activity.

  3. Proteomic of the nucleoside diphosphate kinase from T. cruzi: preliminary structural studies, expression and purification

    International Nuclear Information System (INIS)

    Full text: The enzyme nucleoside diphosphate kinase (NDPK) is a major component of the pathway for the synthesis of nucleosides triphosphates other than ATP. The mechanism of reaction involves the formation of a phospho-histidine intermediate. All known NDPK are oligomers made of small polypeptides of about 150 residues (17kDa) with a high degree of sequence similarity. T. cruzi NDPK (TcNDPK) has been characterized and could be involved in flagellar movement and therefore in the pathology of the parasite. T. cruzi NDPK (TcNDPK) has been cloned in E. coli DH5α strain. The gene has been cloned into a pRSET A plasmid and expressed in E. coli BL21-DE3 strain as a fusion protein containing TcNDPK preceded by an hexa-His-tag. The fusion protein has been purified with a HiTrap chelating column loaded with 0,1M NiSO4 in different buffer conditions and its purification level visualized in SDS-PAGE. The conformational state of the purified TcNDPK has been observed by different methods such as native PAGE. We have obtained large quantities of TcNDPK to be used for crystallization and interaction assays. The objective of this work is the resolution of the three-dimensional structure of TcNDPK by X-ray crystallography as a first step for rational drug design based on the structure. (author)

  4. Nucleoside analogue reverse transcriptase inhibitors differentially inhibit human LINE-1 retrotransposition.

    Directory of Open Access Journals (Sweden)

    R Brad Jones

    Full Text Available BACKGROUND: Intact LINE-1 elements are the only retrotransposons encoded by the human genome known to be capable of autonomous replication. Numerous cases of genetic disease have been traced to gene disruptions caused by LINE-1 retrotransposition events in germ-line cells. In addition, genomic instability resulting from LINE-1 retrotransposition in somatic cells has been proposed as a contributing factor to oncogenesis and to cancer progression. LINE-1 element activity may also play a role in normal physiology. METHODS AND PRINCIPAL FINDINGS: Using an in vitro LINE-1 retrotransposition reporter assay, we evaluated the abilities of several antiretroviral compounds to inhibit LINE-1 retrotransposition. The nucleoside analogue reverse transcriptase inhibitors (nRTIs: stavudine, zidovudine, tenofovir disoproxil fumarate, and lamivudine all inhibited LINE-1 retrotransposition with varying degrees of potencies, while the non-nucleoside HIV-1 reverse transcriptase inhibitor nevirapine showed no effect. CONCLUSIONS/SIGNIFICANCE: Our data demonstrates the ability for nRTIs to suppress LINE-1 retrotransposition. This is immediately applicable to studies aimed at examining potential roles for LINE-1 retrotransposition in physiological processes. In addition, our data raises novel safety considerations for nRTIs based on their potential to disrupt physiological processes involving LINE-1 retrotransposition.

  5. Methylated nucleosides in tRNA and tRNA methyltransferases

    Directory of Open Access Journals (Sweden)

    Hiroyuki eHori

    2014-05-01

    Full Text Available To date, more than 90 modified nucleosides have been found in tRNA and the biosynthetic pathways of the majority of tRNA modifications include a methylation step(s. Recent studies of the biosynthetic pathways have demonstrated that the availability of methyl group donors for the methylation in tRNA is important for correct and efficient protein synthesis. In this review, I focus on the methylated nucleosides and tRNA methyltransferases. The primary functions of tRNA methylations are linked to the different steps of protein synthesis, such as the stabilization of tRNA structure, reinforcement of the codon–anticodon interaction, regulation of wobble base pairing, and prevention of frameshift errors. However, beyond these basic functions, recent studies have demonstrated that tRNA methylations are also involved in the RNA quality control system and regulation of tRNA localization in the cell. In a thermophilic eubacterium, tRNA modifications and the modification enzymes form a network that responses to temperature changes. Furthermore, several modifications are involved in genetic diseases, infections, and the immune response. Moreover, structural, biochemical, and bioinformatics studies of tRNA methyltransferases have been clarifying the details of tRNA methyltransferases and have enabled these enzymes to be classified. In the final section, the evolution of modification enzymes is discussed.

  6. Synthesis and Biological Evaluation of Triazolyl 13α-Estrone–Nucleoside Bioconjugates

    Directory of Open Access Journals (Sweden)

    Brigitta Bodnár

    2016-09-01

    Full Text Available 2′-Deoxynucleoside conjugates of 13α-estrone were synthesized by applying the copper-catalyzed alkyne–azide click reaction (CuAAC. For the introduction of the azido group the 5′-position of the nucleosides and a propargyl ether functional group on the 3-hydroxy group of 13α-estrone were chosen. The best yields were realized in our hands when the 3′-hydroxy groups of the nucleosides were protected by acetyl groups and the 5′-hydroxy groups were modified by the tosyl–azide exchange method. The commonly used conditions for click reaction between the protected-5′-azidonucleosides and the steroid alkyne was slightly modified by using 1.5 equivalent of Cu(I catalyst. All the prepared conjugates were evaluated in vitro by means of MTT assays for antiproliferative activity against a panel of human adherent cell lines (HeLa, MCF-7 and A2780 and the potential inhibitory activity of the new conjugates on human 17β-hydroxysteroid dehydrogenase 1 (17β-HSD1 was investigated via in vitro radiosubstrate incubation. Some protected conjugates displayed moderate antiproliferative properties against a panel of human adherent cancer cell lines (the protected cytidine conjugate proved to be the most potent with IC50 value of 9 μM. The thymidine conjugate displayed considerable 17β-HSD1 inhibitory activity (IC50 = 19 μM.

  7. Parameterization of AZT-A widely used nucleoside inhibitor of HIV-1 reverse transcriptase

    Science.gov (United States)

    Carvalho, Alexandra T. P.; Fernandes, Pedro A.; Ramos, Maria J.

    Seven nucleoside reverse transcriptase (RT) inhibitors are currently used in the clinical treatment of acquired immunodeficiency syndrome (AIDS). These substrate analogues block DNA synthesis by the viral enzyme RT. However, the emergence of resistant variants of RT allied to their long-term toxicity requires the design of new and better RT inhibitors, with long-term in vivo efficacy. In this work we used density functional theory (DFT) calculations to develop a set of molecular mechanics (MM) parameters committed to the AMBER force field for one of the most used in the clinic nucleoside reverse transcriptase inhibitors (NRTIs): zidovudine (AZT). These parameters were tested by comparing the optimized geometries of AZT at both the DFT and MM levels of theory. The ability of the new parameters to reproduce the torsional energy of the azide group was also verified by scanning the surface in MM with the new parameters and comparing the results with the same potential energy surface (PES) at the DFT level. Finally, the parameters were validated through classical MD simulations of AZT in aqueous environment.

  8. Acanthamoeba polyphaga mimivirus NDK: preliminary crystallographic analysis of the first viral nucleoside diphosphate kinase

    Energy Technology Data Exchange (ETDEWEB)

    Jeudy, Sandra [Information Génomique et Structurale, CNRS UPR 2589, 31 Chemin Joseph Aiguier, 13402 Marseille CEDEX 20 (France); Coutard, Bruno [Architecture et Fonction des Macromolecules Biologiques, CNRS UMR 6098, 31 Chemin Joseph Aiguier, 13402 Marseille CEDEX 20 (France); Lebrun, Régine [IBSM, 31 Chemin Joseph Aiguier, 13402 Marseille CEDEX 20 (France); Abergel, Chantal, E-mail: chantal.abergel@igs.cnrs-mrs.fr [Information Génomique et Structurale, CNRS UPR 2589, 31 Chemin Joseph Aiguier, 13402 Marseille CEDEX 20 (France)

    2005-06-01

    A. polyphaga mimivirus, the largest known double-stranded DNA virus, is the first virus to exhibit a nucleoside diphosphate kinase gene. The expression and crystallization of the viral NDK are reported. The complete sequence of the largest known double-stranded DNA virus, Acanthamoeba polyphaga mimivirus, has recently been determined [Raoult et al. (2004 ▶), Science, 306, 1344–1350] and revealed numerous genes not expected to be found in a virus. A comprehensive structural and functional study of these gene products was initiated [Abergel et al. (2005 ▶), Acta Cryst. F61, 212–215] both to better understand their role in the virus physiology and to obtain some clues to the origin of DNA viruses. Here, the preliminary crystallographic analysis of the viral nucleoside diphosphate kinase protein is reported. The crystal belongs to the cubic space group P2{sub 1}3, with unit-cell parameter 99.425 Å. The self-rotation function confirms that there are two monomers per asymmetric unit related by a twofold non-crystallographic axis and that the unit cell thus contains four biological entities.

  9. Detection of RNA nucleoside modifications with the uridine-specific ribonuclease MC1 from Momordica charantia.

    Science.gov (United States)

    Addepalli, Balasubrahmanym; Lesner, Nicholas P; Limbach, Patrick A

    2015-10-01

    A codon-optimized recombinant ribonuclease, MC1 is characterized for its uridine-specific cleavage ability to map nucleoside modifications in RNA. The published MC1 amino acid sequence, as noted in a previous study, was used as a template to construct a synthetic gene with a natural codon bias favoring expression in Escherichia coli. Following optimization of various expression conditions, the active recombinant ribonuclease was successfully purified as a C-terminal His-tag fusion protein from E. coli [Rosetta 2(DE3)] cells. The isolated protein was tested for its ribonuclease activity against oligoribonucleotides and commercially available E. coli tRNA(Tyr I). Analysis of MC1 digestion products by ion-pairing reverse phase liquid-chromatography coupled with mass spectrometry (IP-RP-LC-MS) revealed enzymatic cleavage of RNA at the 5'-termini of uridine and pseudouridine, but cleavage was absent if the uridine was chemically modified or preceded by a nucleoside with a bulky modification. Furthermore, the utility of this enzyme to generate complementary digestion products to other common endonucleases, such as RNase T1, which enables the unambiguous mapping of modified residues in RNA is demonstrated. PMID:26221047

  10. Crystallization and preliminary X ray analysis of nucleoside diphosphate kinase 1 from T. cruzi

    International Nuclear Information System (INIS)

    Introduction: Trypanosoma cruzi is the etiologic agent of Chagas disease. The Nucleoside diphosphate kinases (NDPKs) are enzymes involved in energy management and nucleoside balance in the cell. T. cruzi TcNDPK1, a canonical isoform. The objective of this work is obtaining protein's crystals, diffract and process the data for tridimensional structure resolution. Materials and Methods: TcNDPK1 was expressed in E. coli as a fusion protein with Nterminal His-tag. TcNDPK1 was overexpressed and purified by FPLC. Crystallization was assayed by sitting drop and hanging drop vapor diffusion method. Crystals was frozen and diffracted on synchrotron x-ray radiation in Campinas (Brasil). The data set collected was reduced and merged using MOSFLM and SCALA programs. Results and Discussion: His-TcNDPK was overexpressed, purified and crystallized. The crystals are diffracted and collected the data to 3.5A. The crystals belong to the trigonal space group P3, with unit cell parameters a=127.94, b=127.84, c=275.49. Structure determination is under way. These results will provide relevant information that could be the first step in rational drug design for treating Chagas disease.(authors)

  11. Expression and functional activity of nucleoside transporters in human choroid plexus

    Directory of Open Access Journals (Sweden)

    Grujicic Danica

    2010-01-01

    Full Text Available Abstract Background Human equilibrative nucleoside transporters (hENTs 1-3 and human concentrative nucleoside transporters (hCNTs 1-3 in the human choroid plexus (hCP play a role in the homeostasis of adenosine and other naturally occurring nucleosides in the brain; in addition, hENT1, hENT2 and hCNT3 mediate membrane transport of nucleoside reverse transcriptase inhibitors that could be used to treat HIV infection, 3'-azido-3'-deoxythymidine, 2'3'-dideoxycytidine and 2'3'-dideoxyinosine. This study aimed to explore the expression levels and functional activities of hENTs 1-3 and hCNTs 1-3 in human choroid plexus. Methods Freshly-isolated pieces of lateral ventricle hCP, removed for various clinical reasons during neurosurgery, were obtained under Local Ethics Committee approval. Quantification of mRNAs that encoded hENTs and hCNTs was performed by the hydrolysis probes-based reverse transcription real time-polymerase chain reaction (RT-qPCR; for each gene of interest and for 18 S ribosomal RNA, which was an endogenous control, the efficiency of PCR reaction (E and the quantification cycle (Cq were calculated. The uptake of [3H]inosine by the choroid plexus pieces was investigated to explore the functional activity of hENTs and hCNTs in the hCP. Results RT-qPCR revealed that the mRNA encoding the intracellularly located transporter hENT3 was the most abundant, with E-Cq value being only about 40 fold less that the E-Cq value for 18 S ribosomal RNA; mRNAs encoding hENT1, hENT2 and hCNT3 were much less abundant than mRNA for the hENT3, while mRNAs encoding hCNT1 and hCNT2 were of very low abundance and not detectable. Uptake of [3H]inosine by the CP samples was linear and consisted of an Na+-dependent component, which was probably mediated by hCNT3, and Na+-independent component, mediated by hENTs. The latter component was not sensitive to inhibition by S-(4-nitrobenzyl-6-thioinosine (NBMPR, when used at a concentration of 0.5 μM, a finding that

  12. 5’-Phosphate and 5’-Phosphonate Ester Derivatives of (N)-Methanocarba Adenosine with in Vivo Cardioprotective Activity

    OpenAIRE

    Kumar, T. Santhosh; Yang, Tiehong; Mishra, Shilpi; Cronin, Chunxia; Charkaborty, Saibal; Shen, Jian-Bing; Liang, Bruce T.; Jacobson, Kenneth A.

    2013-01-01

    Activation of a cardiac myocyte P2X4 receptor protects in heart failure. 5’-Phosphonate and 5’-phosphate analogues of AMP containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system could protect from heart failure by potentially activating this cardioprotective channel. Phosphoesters and phosphonodiesters were synthesized and administered in vivo via a mini-osmotic pump in a mouse ischemic heart failure model; most significantly increased intact heart contractile function (echocardiography) ...

  13. Structure Activity Relationship of (N)-Methanocarba Phosphonate Analogues of 5’-AMP as Cardioprotective Agents Acting Through a Cardiac P2X Receptor

    OpenAIRE

    Kumar, T. Santhosh; Zhou, Si-yuan; Joshi, Bhalchandra V.; Balasubramanian, Ramachandran; Yang, Tiehong; Liang, Bruce T.; Jacobson, Kenneth A.

    2010-01-01

    P2X receptor activation protects in heart failure models. MRS2339 3, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system, activates this cardioprotective channel. Michaelis–Arbuzov and Wittig reactions provided phosphonate analogues of 3, expected to be stable in vivo due to the C-P bond. After chronic administration via a mini-osmotic pump (Alzet), some analogues significantly increased intact heart contractile function in calsequestrin-overexpressing mice (...

  14. p-Phosphonic acid calix[8]arene assisted dispersion and stabilisation of pea-pod C60@multi-walled carbon nanotubes in water.

    Science.gov (United States)

    Chen, Xianjue; Gibson, Christopher T; Britton, Joshua; Eggers, Paul K; Wahid, M Haniff; Raston, Colin L

    2015-02-11

    A facile approach has been developed for non-covalently stabilising pristine C60 and multi-walled carbon nanotubes (MWCNTs) in water in the presence of p-phosphonic acid calix[8]arene, along with the formation of a 'pea-pod' encapsulation of the fullerene inside the MWCNTs. Aqueous dispersions of the different carbon nano-materials are readily decorated with palladium nanoparticles.

  15. Synthesis and evaluation of thymidine kinase 1-targeting carboranyl pyrimidine nucleoside analogs for boron neutron capture therapy of cancer.

    Science.gov (United States)

    Agarwal, Hitesh K; Khalil, Ahmed; Ishita, Keisuke; Yang, Weilian; Nakkula, Robin J; Wu, Lai-Chu; Ali, Tehane; Tiwari, Rohit; Byun, Youngjoo; Barth, Rolf F; Tjarks, Werner

    2015-07-15

    A library of sixteen 2nd generation amino- and amido-substituted carboranyl pyrimidine nucleoside analogs, designed as substrates and inhibitors of thymidine kinase 1 (TK1) for potential use in boron neutron capture therapy (BNCT) of cancer, was synthesized and evaluated in enzyme kinetic-, enzyme inhibition-, metabolomic-, and biodistribution studies. One of these 2nd generation carboranyl pyrimidine nucleoside analogs (YB18A [3]), having an amino group directly attached to a meta-carborane cage tethered via ethylene spacer to the 3-position of thymidine, was approximately 3-4 times superior as a substrate and inhibitor of hTK1 than N5-2OH (2), a 1st generation carboranyl pyrimidine nucleoside analog. Both 2 and 3 appeared to be 5'-monophosphorylated in TK1(+) RG2 cells, both in vitro and in vivo. Biodistribution studies in rats bearing intracerebral RG2 glioma resulted in selective tumor uptake of 3 with an intratumoral concentration that was approximately 4 times higher than that of 2. The obtained results significantly advance the understanding of the binding interactions between TK1 and carboranyl pyrimidine nucleoside analogs and will profoundly impact future design strategies for these agents. PMID:26087030

  16. Characterization of enhanced-fluidity liquid hydrophilic interaction chromatography for the separation of nucleosides and nucleotides.

    Science.gov (United States)

    Philibert, Gwenaëlle S; Olesik, Susan V

    2011-11-11

    Hydrophilic interaction chromatography (HILIC) is a liquid chromatographic separation mechanism commonly used for polar biological molecules. The use of enhanced-fluidity liquid chromatography (EFLC) with mixtures of methanol/water/carbon dioxide is compared to acetonitrile/water mobile phases for the separation of nucleosides and nucleotides under HILIC conditions. Enhanced-fluidity liquid chromatography involves using common mobile phases with the addition of substantial proportions of a dissolved gas which provides greater mobile phase diffusivity and lower viscosity. The impact of varying several experimental parameters, including temperature, addition of base, salt, and CO₂ was studied to provide optimized HILIC separations. Each of these parameters plays a key role in the retention of the analytes, which demonstrates the complexity of the retention mechanism in HILIC. The tailing of phosphorylated compounds was overcome with the use of phosphate salts and the addition of a strong base; efficiency and peak asymmetry were compared with the addition of either triethylamine (TEA), 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,5-diazabicyclo [4.3.0] non-5-ene (DBN). DBN and DABCO both led to increased efficiency and lower peak asymmetry; DBN provided the best results. Sodium chloride and carbon dioxide were added to enhance the selectivity between the analytes, giving a successful isocratic separation of nucleosides and nucleotides within 8 min. The retention mechanism involved in EFL-HILIC was explored by varying the temperature and the mole fraction of CO₂. These studies showed that partitioning was the dominant mechanism. The thermodynamics study confirmed that the solvent strength is maintained in EFLC and that a change in entropy was mainly responsible for the improved selectivity. The selectivity using methanol/water/carbon dioxide varied greatly compared to that obtained with acetonitrile/water. Finally while this study highlights the optimization of EFL

  17. Early Cellular Responses of Purine Nucleoside-mediated Protection of Hypoxia-induced Injuries of Neuronal PC12 Cells

    Directory of Open Access Journals (Sweden)

    Bettina Tomaselli

    2005-01-01

    Full Text Available Hypoxia in brain may lead to cell death by apoptosis and necrosis. In parallel adenosine, a powerful endogenous neuroprotectant is formed. We wanted to investigate the effect of adenosine and its purine nucleoside relatives, inosine and guanosine on early cellular responses to hypoxia. O2-sensitive neuronal PC12-cells were subjected to chemical hypoxia induced with rotenone, an inhibitor of mitochondrial complex I. Loss of viability after hypoxic insult was impressively rescued by adenosine, guanosine and inosine. PC12-cells mainly express the A2A adenosine receptor. Its inhibition with a specific antagonist (CSC induced cell death of PC12-cells, which could be salvaged by adenosine but not with guanosine or inosine. We have previously demonstrated the important role of mitogen activated protein kinases 1/2 (p42/44 MAPK in purine-mediated rescue. In this study we were interested in the involvement of protein kinases whose activities mediate these processes, including protein kinase A (PKA, phosphoinositide 3-kinase (PI3-K and protein kinase C-related kinases (PRK 1/2. Pharmacological inhibition of PKA and PI3-K increased hypoxia-induced toxicity and likewise also affected the rescue by purine nucleosides. Nerve growth factor (NGF and purine nucleosides induced an activation of PRK 1/2, which to our knowledge indicates for the first time that these kinases are potentially involved in purine nucleoside-mediated rescue of hypoxic neuronal cells. Results suggest that A2A receptor expressing cells are mainly dependent on the purine nucleoside adenosine for their rescue after hypoxic insult. In addition to PKA, PI3-K is an important effector molecule in A2A-mediated signaling and for the rescue of PC12-cells after hypoxic insult.

  18. Assays To Detect the Formation of Triphosphates of Unnatural Nucleotides: Application to Escherichia coli Nucleoside Diphosphate Kinase.

    Science.gov (United States)

    Matsuura, Mariko F; Shaw, Ryan W; Moses, Jennifer D; Kim, Hyo-Joong; Kim, Myong-Jung; Kim, Myong-Sang; Hoshika, Shuichi; Karalkar, Nilesh; Benner, Steven A

    2016-03-18

    One frontier in synthetic biology seeks to move artificially expanded genetic information systems (AEGIS) into natural living cells and to arrange the metabolism of those cells to allow them to replicate plasmids built from these unnatural genetic systems. In addition to requiring polymerases that replicate AEGIS oligonucleotides, such cells require metabolic pathways that biosynthesize the triphosphates of AEGIS nucleosides, the substrates for those polymerases. Such pathways generally require nucleoside and nucleotide kinases to phosphorylate AEGIS nucleosides and nucleotides on the path to these triphosphates. Thus, constructing such pathways focuses on engineering natural nucleoside and nucleotide kinases, which often do not accept the unnatural AEGIS biosynthetic intermediates. This, in turn, requires assays that allow the enzyme engineer to follow the kinase reaction, assays that are easily confused by ATPase and other spurious activities that might arise through "site-directed damage" of the natural kinases being engineered. This article introduces three assays that can detect the formation of both natural and unnatural deoxyribonucleoside triphosphates, assessing their value as polymerase substrates at the same time as monitoring the progress of kinase engineering. Here, we focus on two complementary AEGIS nucleoside diphosphates, 6-amino-5-nitro-3-(1'-β-D-2'-deoxyribofuranosyl)-2(1H)-pyridone and 2-amino-8-(1'-β-D-2'-deoxyribofuranosyl)-imidazo[1,2-a]-1,3,5-triazin-4(8H)-one. These assays provide new ways to detect the formation of unnatural deoxyribonucleoside triphosphates in vitro and to confirm their incorporation into DNA. Thus, these assays can be used with other unnatural nucleotides. PMID:26829203

  19. Surface-enhanced Raman scattering studies on the interaction of phosphonate derivatives of imidazole, thiazole, and pyridine with a silver electrode in aqueous solution.

    Science.gov (United States)

    Podstawka, Edyta; Kudelski, Andrzej; Olszewski, Tomasz K; Boduszek, Bogdan

    2009-07-23

    Surface-enhanced Raman scattering (SERS) spectra from phosphonate derivatives of N-heterocyclic aromatic compounds immobilized on an electrochemically roughened silver electrode surface are reported and compared to Raman spectra of the corresponding solid species. The tested compounds contain imidazole [ImMeP ([hydroxy-(1H-imidazol-5-yl)-methyl]-phosphonic acid) and (ImMe)2P (bis[hydroxy-(1H-imidazol-4-yl)-methyl]-phosphinic acid)]; thiazole [BAThMeP ((butylamino-thiazol-2-yl-methyl)-phosphonic acid) and BzAThMeP ((benzylamino-thiazol-2-yl-methyl)-phosphonic acid)]; and pyridine ((PyMe)2P (bis[(hydroxy-pyridin-3-yl-methyl)]-phosphinic acid) aromatic rings. Changes in wavenumber, broadness, and the enhancement of N-heterocyclic aromatic ring bands upon adsorption are consistent with the adsorption primarily occurring through the N lone pair of electrons with the ring arranged in a largely edge-on manner for ImMeP and BzAThMeP or in a slightly inclined orientation to the silver electrode surface at an intermediate angle from the surface normal for (ImMe)2P, BAThMeP, and (PyMe)2P. A strong enhancement of a roughly 1500 cm(-1) SERS signal for ImMeP and (PyMe)2P is also observed. This phenomenon is attributed to the formation of a localized C=C bond, which is accompanied by a decrease in the ring-surface pi-electrons' overlap. In addition, more intense SERS bands due to the benzene ring in BzAThMeP are observed than those observed for the thiazole ring, which suggests a preferential adsorption of benzene. Some interaction of a phosphonate unit is also suggested but with moderate strength between biomolecules. The strength of the P=O coordination to the silver electrode is highest for ImMeP but lowest for BzAThMeP. For all studied biomolecules, the contribution of the structural components to their ability to interact with their receptors was correlated with the SERS patterns.

  20. Evaluation of capillary chromatographic supports for immobilized human purine nucleoside phosphorylase in frontal affinity chromatography studies.

    Science.gov (United States)

    de Moraes, Marcela Cristina; Temporini, Caterina; Calleri, Enrica; Bruni, Giovanna; Ducati, Rodrigo Gay; Santos, Diógenes Santiago; Cardoso, Carmen Lucia; Cass, Quezia Bezerra; Massolini, Gabriella

    2014-04-18

    The aim of this work was to optimize the preparation of a capillary human purine nucleoside phosphorylase (HsPNP) immobilized enzyme reactor (IMER) for characterization and affinity screening studies of new inhibitors by frontal affinity chromatography coupled to mass spectrometry (FAC-MS). For this purpose two monolithic supports, a Chromolith Speed Rod (0.1mm I.D.×5cm) and a methacrylate-based monolithic epoxy polymeric capillary column (0.25mm I.D.×5cm) with epoxy reactive groups were considered and compared to an IMER previously developed using an open fused silica capillary. Each HsPNP-IMER was characterized in terms of catalytic activity using Inosine as standard substrate. Furthermore, they were also explored for affinity ranking experiments. Kd determination was carried out with the based fused silica HsPNP-IMER and the results are herein discussed.

  1. Simple and rapid synthesis of some nucleoside derivatives: structural and spectral characterization

    Directory of Open Access Journals (Sweden)

    Shagir A. Chowdhury

    2016-03-01

    Full Text Available In our present investigation a new series of nucleoside derivatives (2-13 were synthesized from uridine (1 via only two step reactions by direct acylation method. Firstly, uridine (1 was treated with 4-t-butylbenzoyl chloride in pyridine at -5ºC and afforded the 5´-O-(4-t-butylbenzoyluridine derivative (2 in an excellent yield. In order to obtain newer products, the 5´-O-uridine derivative was further transformed to a series of 2´,3´-di-O-acyl derivatives (2-13 containing a wide variety of functionalities in a single molecular framework. The yields of the compounds were more than 80%. The synthesized titled compounds were characterized by their physical properties, FTIR (Fourier transform infrared spectroscopy, 1H-NMR (Nuclear magnetic resonance spectroscopy and elemental analysis.

  2. New nucleoside/nucleotide backbone options: a review of recent studies.

    Science.gov (United States)

    Ruane, Peter J; DeJesus, Edwin

    2004-09-01

    The nucleoside/nucleotide reverse transcriptase inhibitor (NRTI/NtRTI) class continues to serve as an important component of the standard of care for HIV infection. Combinations of dual NRTIs/NtRTIs with protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs) remain the most commonly used regimens in clinical practice. In recent years, clinical outcomes data on previously novel NRTI/NtRTI backbone combinations have provided clinicians with new options to address potency, tolerability, and convenience of antiretroviral therapy. However, the tolerability, drug-drug interactions, and resistance profiles of specific regimens using new NRTI/NtRTI combinations must be weighed against the needs and preferences of individual patients. This review summarizes recent efficacy and safety data on emerging NRTI/NtRTI combination backbones, including tenofovir DF (TDF) with lamivudine (3TC), abacavir with 3TC, didanosine (ddI) with 3TC, ddI with emtricitabine (FTC), and TDF with FTC. PMID:15319666

  3. Synthesis of 5'-3H-2-Amino-6-cyclopropylaminopurine Nucleosides

    Institute of Scientific and Technical Information of China (English)

    YANG Zhen-Jun; Chung K. Chu; ZHANG Li-He

    2003-01-01

    @@ We have described a novel use of the D4G prodrug (Cyclo-D4G) approach to stabilize the nucleoside and maintain the anti-HIV activity. β-D-Dioxolanyl-2-amino-6-cyclopropylaminopurine (10, DACP) was synthesized as a prodrug of β-D-dioxolanyl guanine (DXG) and showed potent anti-HIV activity in vitro (EC50=0.18 μmol·L-1 The pharmacokinetics of Cyclo-D4G and DACP following intravenous and oral administration of DACP to rhesusmonkeys and rats did not give D4G and DXG as detectable metabolic products by HPLC. Therefore the radio labeled Cyclo-D4G and DACP are necessary for the pharmacokinetics studies in detail.

  4. Interaction of bis-aryl functionalized molecules with nucleosides and nucleic acids

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    A series of novel molecules with a cyclen(1,4,7,10-tetraazacyclododecane) moiety appended on and bearing different aromatic fragments in the structures were synthesized and characterized.The binding activities of these compounds towards DNA were systematically studied by spectroscopic,viscometric and gel electrophoresis methods.The results suggest that the stacking interaction plays an important role in improving the DNA binding ability of the compounds.The binding modes of the compounds towards DNA are also affected by the sizes of the aromatic rings.The binding interaction between binaphthyl compound 1b and several nucleosides was studied by fluorescence titration.Stacking interaction and hydrophobic interaction play the key role in such non-selective binding process.

  5. Discovery, characterization, and lead optimization of 7-azaindole non-nucleoside HIV-1 reverse transcriptase inhibitors.

    Science.gov (United States)

    Stanton, Richard A; Lu, Xiao; Detorio, Mervi; Montero, Catherine; Hammond, Emily T; Ehteshami, Maryam; Domaoal, Robert A; Nettles, James H; Feraud, Michel; Schinazi, Raymond F

    2016-08-15

    A library of 585 compounds built off a 7-azaindole core was evaluated for anti-HIV-1 activity, and ten hits emerged with submicromolar potency and therapeutic index >100. Of these, three were identified as non-nucleoside reverse transcriptase (RT) inhibitors and were assayed against relevant resistant mutants. Lead compound 8 inhibited RT with submicromolar potency (IC50=0.73μM) and also maintained some activity against the clinically important RT mutants K103N and Y181C (IC50=9.2, 3.5μM) in cell-free assays. Free energy perturbation guided lead optimization resulted in the development of a compound with a two-fold increase in potency against RT (IC50=0.36μM). These data highlight the discovery of a unique scaffold with the potential to move forward as next-generation anti-HIV-1 agents. PMID:27390064

  6. Synthesis and HIV-1 Reverse Transcriptase Inhibitory Activity of Non-Nucleoside Phthalimide Derivatives

    Institute of Scientific and Technical Information of China (English)

    UNGWITAYATORN Jiraporn; WIWAT Chanpen; MATAYATSUK Chutima; PIMTHON Jutarat; PIYAVIRIYAKUL Suratsawadee

    2008-01-01

    A new type of non-nucleoside HIV-1 reverse transcriptase inhibitors in phthalimide series has been synthesized from either the reaction of N-carboethoxyphthalimide with amines or phthalimide with appropriate alkyl halides.The in vitro inhibitory activity of the synthesized compounds was studied by a radiometric assay at a concentration of 200 μg/mL using poly(rA)-oligo(dT) as a template-primer and methyl-[3H]dTTP as a substrate.The three most potent compounds, N-(m,p-dihydroxybenzyl)phthalimide (11), N-[2-(a-furyl)ethyl]phthalimide (29) and N-(5-methylpyrazin-2-ylmethyl)phthalimide (25) exhibited IC50 values of 60.90, 98.10 and 120.75 μg/mL, respecas a substrate).

  7. Intersubunit ionic interactions stabilize the nucleoside diphosphate kinase of Mycobacterium tuberculosis

    DEFF Research Database (Denmark)

    Georgescauld, Florian; Moynie, Lucile; Habersetzer, Johann;

    2013-01-01

    thermal stability. The mutation also decreased stability to denaturation by urea and guanidinium. The D93N mutant was still hexameric and retained full activity. When exposed to low concentrations of urea it dissociated into folded monomers followed by unfolding while dissociation and unfolding...... of the wild type simultaneously occur at higher urea concentrations. The dissociation step was not observed in guanidine hydrochloride, suggesting that low concentration of salt may stabilize the hexamer. Indeed, guanidinium and many other salts stabilized the hexamer with a half maximum effect of about 0.1 M......Most nucleoside diphosphate kinases (NDPKs) are hexamers. The C-terminal tail interacting with the neighboring subunits is crucial for hexamer stability. In the NDPK from Mycobacterium tuberculosis (Mt) this tail is missing. The quaternary structure of Mt-NDPK is essential for full enzymatic...

  8. Aquaporin 3 (AQP3 participates in the cytotoxic response to nucleoside-derived drugs

    Directory of Open Access Journals (Sweden)

    Trigueros-Motos Laia

    2012-09-01

    Full Text Available Abstract Background Nucleoside analogs used in the chemotherapy of solid tumors, such as the capecitabine catabolite 5′-deoxy-5-fluorouridine (5′-DFUR trigger a transcriptomic response that involves the aquaglyceroporin aquaporin 3 along with other p53-dependent genes. Here, we examined whether up-regulation of aquaporin 3 (AQP3 mRNA in cancer cells treated with 5′-DFUR represents a collateral transcriptomic effect of the drug, or conversely, AQP3 participates in the activity of genotoxic agents. Methods The role of AQP3 in cell volume increase, cytotoxicity and cell cycle arrest was analyzed using loss-of-function approaches. Results 5′-DFUR and gemcitabine, but not cisplatin, stimulated AQP3 expression and cell volume, which was partially and significantly blocked by knockdown of AQP3. Moreover, AQP3 siRNA significantly blocked other effects of nucleoside analogs, including G1/S cell cycle arrest, p21 and FAS up-regulation, and cell growth inhibition. Short incubations with 5-fluorouracil (5-FU also induced AQP3 expression and increased cell volume, and the inhibition of AQP3 expression significantly blocked growth inhibition triggered by this drug. To further establish whether AQP3 induction is related to cell cycle arrest and apoptosis, cells were exposed to long incubations with escalating doses of 5-FU. AQP3 was highly up-regulated at doses associated with cell cycle arrest, whereas at doses promoting apoptosis induction of AQP3 mRNA expression was reduced. Conclusions Based on the results, we propose that the aquaglyceroporin AQP3 is required for cytotoxic activity of 5’-DFUR and gemcitabine in the breast cancer cell line MCF7 and the colon adenocarcinoma cell line HT29, and is implicated in cell volume increase and cell cycle arrest.

  9. Aquaporin 3 (AQP3) participates in the cytotoxic response to nucleoside-derived drugs

    International Nuclear Information System (INIS)

    Nucleoside analogs used in the chemotherapy of solid tumors, such as the capecitabine catabolite 5′-deoxy-5-fluorouridine (5′-DFUR) trigger a transcriptomic response that involves the aquaglyceroporin aquaporin 3 along with other p53-dependent genes. Here, we examined whether up-regulation of aquaporin 3 (AQP3) mRNA in cancer cells treated with 5′-DFUR represents a collateral transcriptomic effect of the drug, or conversely, AQP3 participates in the activity of genotoxic agents. The role of AQP3 in cell volume increase, cytotoxicity and cell cycle arrest was analyzed using loss-of-function approaches. 5′-DFUR and gemcitabine, but not cisplatin, stimulated AQP3 expression and cell volume, which was partially and significantly blocked by knockdown of AQP3. Moreover, AQP3 siRNA significantly blocked other effects of nucleoside analogs, including G1/S cell cycle arrest, p21 and FAS up-regulation, and cell growth inhibition. Short incubations with 5-fluorouracil (5-FU) also induced AQP3 expression and increased cell volume, and the inhibition of AQP3 expression significantly blocked growth inhibition triggered by this drug. To further establish whether AQP3 induction is related to cell cycle arrest and apoptosis, cells were exposed to long incubations with escalating doses of 5-FU. AQP3 was highly up-regulated at doses associated with cell cycle arrest, whereas at doses promoting apoptosis induction of AQP3 mRNA expression was reduced. Based on the results, we propose that the aquaglyceroporin AQP3 is required for cytotoxic activity of 5’-DFUR and gemcitabine in the breast cancer cell line MCF7 and the colon adenocarcinoma cell line HT29, and is implicated in cell volume increase and cell cycle arrest

  10. In vivo phenotypic characterisation of nucleoside label-retaining cells in mouse periosteum

    Directory of Open Access Journals (Sweden)

    HM Cherry

    2014-03-01

    Full Text Available Periosteum is known to contain cells that, after isolation and culture-expansion, display properties of mesenchymal stromal/stem cells (MSCs. However, the equivalent cells have not been identified in situ mainly due to the lack of specific markers. Postnatally, stem cells are slow-cycling, long-term nucleoside-label-retaining cells. This study aimed to identify and characterise label-retaining cells in mouse periosteum in vivo. Mice received iodo-deoxy-uridine (IdU via the drinking water for 30 days, followed by a 40-day washout period. IdU+ cells were identified by immunostaining in conjunction with MSC and lineage markers. IdU-labelled cells were detected throughout the periosteum with no apparent focal concentration, and were negative for the endothelial marker von Willebrand factor and the pan-haematopoietic marker CD45. Subsets of IdU+ cells were positive for the mesenchymal/stromal markers vimentin and cadherin-11. IdU+ cells expressed stem cell antigen-1, CD44, CD73, CD105, platelet-derived growth factor receptor-α and p75, thereby displaying an MSC-like phonotype. Co-localisation was not detectable between IdU and the pericyte markers CD146, alpha smooth muscle actin or NG2, nor did IdU co-localise with β-galactosidase in a transgenic mouse expressing this reporter gene in pericytes and smooth muscle cells. Subsets of IdU+ cells expressed the osteoblast-lineage markers Runx2 and osteocalcin. The IdU+ cells expressing osteocalcin were lining the bone and were negative for the MSC marker p75. In conclusion, mouse periosteum contains nucleoside-label-retaining cells with a phenotype compatible with MSCs that are distinct from pericytes and osteoblasts. Future studies characterising the MSC niche in vivo could reveal novel therapeutic targets for promoting bone regeneration/repair.

  11. Ab Initio Inverstagation of the Excited States of Nucleobases and Nucleosides

    Science.gov (United States)

    Szalay, Péter G.; Fogarasi, Géza; Watson, Thomas; Perera, Ajith; Lotrich, Victor; Bartlett, Rod J.

    2011-06-01

    Most living bodies are exposed to sunlight, essential life sustaining processes are using this natural radiation. Sunlight has, however, several components (has a broad "spectrum") and in particular the invisible component (UV, ultraviolet) is harmful for living organisms. Scientists around the word are busy to understand what happens in the cell when it is exposed to light: it seems that the building blocks of cells and in particular those carrying the genetic information (DNA and RNA) are highly protected against this exposition. Our research focuses on the spectral properties of the building blocks of DNA and RNA, the so called nucleobases and nucleosides, in order to understand this mechanism. Due to improvement in computer technology both at hardware and software side we are now able to use the most accurate methods of ab initio quantum chemistry to investigate the spectroscopic properties of these building blocks. These calculations provide direct information on the properties of these molecules but also provide important benchmarks for cheaper methods which can be used for even larger systems. We have calculated the excited state properties for the nucleobases (cytosine, guanine and adenine), their complexes with water and with each other (Watson-Crick base pairs and stacks) as well as corresponding nucleosides at the EOM-CCSD(T)/aug-cc-pVDZ level of theory and try to answer the following questions: (1) how the order of excited states varies in different nucleobases; (2) how hydration influences the excitation energy and order of excited states; (3) is there any effect of the sugar substituent; (4) how do close lying other bases change the spectrum. The calculations involve over hundred correlated electrons and up to thousand basis functions. Such calculations are now routinely available with the recently developed ACESIII code and can make use of hundreds or even several thousand of processors. V. Lotrich, N. Flocke, M. Ponton, A. Yau, A. Perera, E. Deumens

  12. Purification, crystallization and preliminary structural analysis of nucleoside diphosphate kinase from Bacillus anthracis

    Energy Technology Data Exchange (ETDEWEB)

    Misra, Gauri [Molecular and Structural Biology Division, Central Drug Research Institute, PO Box 173, Chattar Manzil, Mahatma Gandhi Marg, Lucknow 226 001 (India); Aggarwal, Anita [Institute of Genomics and Integrative Biology, Mall Road, Delhi 110 007 (India); Mittal, Sonia [Molecular and Structural Biology Division, Central Drug Research Institute, PO Box 173, Chattar Manzil, Mahatma Gandhi Marg, Lucknow 226 001 (India); Singh, Yogendra [Institute of Genomics and Integrative Biology, Mall Road, Delhi 110 007 (India); Ramachandran, Ravishankar, E-mail: r-ravishankar@cdri.res.in [Molecular and Structural Biology Division, Central Drug Research Institute, PO Box 173, Chattar Manzil, Mahatma Gandhi Marg, Lucknow 226 001 (India)

    2007-12-01

    Nucleoside diphosphate kinase from B. anthracis has been crystallized. Preliminary crystallographic analysis shows that there is one monomer in the asymmetric unit of the crystal. Bacillus anthracis nucleoside diphosphate kinase (BaNdk) is an enzyme whose primary function is to maintain deoxynucleotide triphosphate (dNTP) pools by converting deoxynucleotide diphosphates to triphosphates using ATP as the major phosphate donor. Although the structures of Ndks from a variety of organisms have been elucidated, the enzyme from sporulating bacteria has not been structurally characterized to date. Crystals of the B. anthracis enzyme were grown using the vapour-diffusion method from a hanging drop consisting of 2 µl 10 mg ml{sup −1} protein in 50 mM Tris–HCl pH 8.0, 50 mM NaCl, 5 mM EDTA equilibrated against 500 µl reservoir solution consisting of 2.25 M ammonium formate and 0.1 M HEPES buffer pH 7.25. Diffraction data extending to 2.0 Å were collected at room temperature from a single crystal with unit-cell parameters a = b = 107.53, c = 52.3 Å. The crystals are hexagonal in shape and belong to space group P6{sub 3}22. The crystals contain a monomer in the asymmetric unit, which corresponds to a Matthews coefficient (V{sub M}) of 2.1 Å{sup 3} Da{sup −1} and a solvent content of about 36.9%.

  13. Synthetic incorporation of Nile Blue into DNA using 2′-deoxyriboside substitutes: Representative comparison of (R- and (S-aminopropanediol as an acyclic linker

    Directory of Open Access Journals (Sweden)

    Daniel Lachmann

    2010-02-01

    Full Text Available The Nile Blue chromophore was incorporated into oligonucleotides using “click” chemistry for the postsynthetic modification of oligonucleotides. These were synthesized using DNA building block 3 bearing an alkyne group and reacted with the azide 4. (R-3-amino-1,2-propanediol was applied as the linker between the phosphodiester bridges. Two sets of DNA duplexes were prepared. One set carried the chromophore in an A-T environment, the second set in a G-C environment. Both were characterized by optical spectroscopy. Sequence-dependent fluorescence quenching was applied as a sensitive tool to compare the stacking interactions with respect to the chirality of the acyclic linker attachment. The results were compared to recent results from duplexes that carried the Nile Blue label in a sequentially and structurally identical context, except for the opposite chirality of the linker ((S-3-amino-1,2-propandiol. Only minor, negligible differences were observed. Melting temperatures, UV–vis absorption spectra together with fluorescence quenching data indicate that Nile Blue stacks perfectly between the adjacent base pairs regardless of whether it has been attached via an S- or R-configured linker. This result was supported by geometrically optimized DNA models.

  14. Synthesis, spectroscopic studies and inhibitory activity against bactria and fungi of acyclic and macrocyclic transition metal complexes containing a triamine coumarine Schiff base ligand

    Science.gov (United States)

    Abou-Hussein, A. A.; Linert, Wolfgang

    2015-04-01

    Two series of new mono and binuclear complexes with a Schiff base ligand derived from the condensation of 3-acetylcoumarine and diethylenetriamine, in the molar ratio 2:1 have been prepared. The ligand was characterized by elemental analysis, IR, UV-visible, 1H-NMR and mass spectra. The reaction of the Schiff base ligand with cobalt(II), nickel(II), copper(II), zinc(II) and oxovanadium(IV) lead to mono or binuclear species of cyclic or macrocyclic complexes, depending on the mole ratio of metal to ligand and as well as on the method of preparation. The Schiff base ligand behaves as a cyclic bidentate, tetradendate or pentaentadentae ligand. The formation of macrocyclic complexes depends significantly on the dimension of the internal cavity, the rigidity of the macrocycles, the nature of its donor atoms and on the complexing properties of the anion involved in the coordination. Electronic spectra and magnetic moments of the complexes indicate that the geometries of the metal centers are either square pyramidal or octahedral for acyclic or macro-cyclic complexes. The structures are consistent with the IR, UV-visible, ESR, 1H-NMR, mass spectra as well as conductivity and magnetic moment measurements. The Schiff base ligand and its metal complexes were tested against two pathogenic bacteria as Gram-positive and Gram-negative bacteria as well as one kind of fungi. Most of the complexes exhibit mild antibacterial and antifungal activities against these organisms.

  15. Inhibition of visna virus replication and cytopathic effect in sheep choroid plexus cell cultures by selected anti-HIV agents.

    Science.gov (United States)

    Thormar, H; Balzarini, J; Debyser, Z; Witvrouw, M; Desmyter, J; De Clercq, E

    1995-05-01

    Several anti-HIV agents were tested against visna virus replication and cytopathic effect (CPE) in sheep choroid plexus cell cultures. Sulphated polysaccharides (i.e., dextran sulphate, pentosan polysulphate and heparin) and plant lectins, which inhibit viral adsorption and fusion, were found to be 10- to 40-fold less active against visna virus than against HIV. Bicyclam derivatives were at least 250-fold less active against visna virus and the highly HIV-1 specific TIBO derivatives were without a significant inhibitory effect on visna virus at subtoxic concentrations. In contrast, several 2',3'-dideoxynucleosides and acyclic nucleoside phosphonate analogues, which inhibit reverse transcription, were found to be very effective inhibitors of visna virus replication and viral CPE in cell culture. PMID:7486958

  16. 6-Methylpurine derived sugar modified nucleosides: Synthesis and in vivo antitumor activity in D54 tumor expressing M64V-Escherichia coli purine nucleoside phosphorylase.

    Science.gov (United States)

    Hassan, Abdalla E A; Abou-Elkhair, Reham A I; Parker, William B; Allan, Paula W; Secrist, John A

    2016-01-27

    Impressive antitumor activity has been observed with fludarabine phosphate against tumors that express Escherichia coli purine nucleoside phosphorylase (PNP) due to the liberation of 2-fluoroadenine in the tumor tissue. 6-Methylpurine (MeP) is another cytotoxic adenine analog that does not exhibit selectivity when administered systemically, and could be very useful in a gene therapy approach to cancer treatment involving E. coli PNP. The prototype MeP releasing prodrug 9-(2-deoxy-β-d-ribofuranosyl)-6-methylpurine (1) [MeP-dR] has demonstrated good activity against tumors expressing E. coli PNP, but its antitumor activity is limited due to toxicity resulting from the generation of MeP from gut bacteria. Therefore, we have embarked on a medicinal chemistry program to identify a combination of non-toxic MeP prodrugs and non-human adenosine glycosidic bond cleaving enzymes. The two best MeP-based substrates with M64V-E coli PNP, a mutant which was engineered to tolerate modification at the 5'-position of adenosine and its analogs, were 9-(6-deoxy-α-l-talofuranosyl)-6-methylpurine (3) [methyl(talo)-MeP-R] and 9-(α-l-lyxofuranosyl)6-methylpurine (4) [lyxo-MeP-R]. The detailed synthesis methyl(talo)-MeP-R and lyxo-MeP-R, and the evaluation of their substrate activity with 4 enzymes not normally associated with cancer patients is described. In addition, we have determined the intraperitoneal pharmacokinetic (ip-PK) properties of methyl(talo)-MeP-R and have determined its in vivo bystander activity in mice bearing D54 tumors that express M64V PNP. The observed good in vivo bystander activity of [methyl(talo)-MeP-R/M64V-E coli PNP combination suggests that these agents could be useful for the treatment of cancer.

  17. Phosphonate self-assembled monolayers as organic linkers in solid-state quantum dot sensetized solar cells

    KAUST Repository

    Ardalan, Pendar

    2010-06-01

    We have employed X-ray photoelectron spectroscopy (XPS), ultraviolet-visible (UV-vis) spectroscopy, infrared (IR) spectroscopy, water contact angle (WCA) measurements, ellipsometry, and electrical measurements to study the effects of self-assembled monolayers (SAMs) with phosphonic acid headgroups on the bonding and performance of cadmium sulfide (CdS) solid-state quantum dot sensitized solar cells (QDSSCs). ∼2 to ∼6 nm size CdS quantum dots (QDs) were grown on the SAM-passivated TiO2 surfaces by successive ionic layer adsorption and reaction (SILAR). Our results show differences in the bonding of the CdS QDs at the TiO2 surfaces with a SAM linker. Moreover, our data indicate that presence of a SAM increases the CdS uptake on TiO2 as well as the performance of the resulting devices. Importantly, we observe ∼2 times higher power conversion efficiencies in the devices with a SAM compared to those that lack a SAM. © 2010 IEEE.

  18. Effects of increasing doses of samarium-153-ethylenediaminetetramethylene phosphonate on axial and appendicular skeletal growth in juvenile rabbits

    International Nuclear Information System (INIS)

    Introduction: Targeted radiotherapy using samarium-153-ethylenediaminetetramethylene phosphonate (153Sm-EDTMP) is currently under investigation for treatment of osteosarcoma. Osteosarcoma often occurs in children, and previous studies on a juvenile rabbit model demonstrated that clinically significant damage to developing physeal cartilage may occur as a result of systemic 153Sm-EDTMP therapy. The aim of this study was to evaluate the late effects of 153Sm-EDTMP on skeletal structures during growth to maturity and to determine if there is a dose response of 153Sm-EDTMP on growth of long bones. Methods: Female 8-week-old New Zealand white rabbits were divided into three treatment groups plus controls. Each rabbit was intravenously administered a predetermined dose of 153Sm-EDTMP. Multiple bones of each rabbit were radiographed every 2 months until physeal closure, with subsequent measurements made to assess for abbreviated bone growth. Statistical analyses were performed to determine the differences in bone length between groups, with significance set at P153Sm-EDTMP. Further investigation regarding the effects of bone-seeking radiopharmaceuticals on bone growth and physeal cartilage is warranted

  19. Corrosion inhibition behavior of propyl phosphonic acid–Zn2+ system for carbon steel in aqueous solution

    International Nuclear Information System (INIS)

    The effectiveness of propyl phosphonic acid (PPA) as a corrosion inhibitor in association with a bivalent cation like Zn2+ has been studied. An eco-friendly inhibitor in controlling corrosion of carbon steel in neutral aqueous medium in the absence and presence of Zn2+ has been evaluated by gravimetric method. Impedance studies of the metal/solution interface indicated that the surface film is highly protective against the corrosion of carbon steel in the aqueous environment. Potentiodynamic polarization studies showed that the inhibitor is a mixed inhibitor. X-ray photoelectron spectroscopic analysis (XPS) of the protective film exhibited the presence of the elements viz., iron, phosphorus, oxygen, carbon and zinc. The chemical shifts in the binding energies of these elements inferred that the surface film is composed of oxides/hydroxides of iron(III), Zn(OH)2 and [Fe(II)/(III)–Zn(II)–PPA] complex. Further, the surface analysis techniques viz., FT-IR, AFM and SEM studies confirm the formation of an adsorbed protective film on the carbon steel surface. Based on all these results, a plausible mechanism of corrosion inhibition is proposed.

  20. Investigation of vinyl phosphonic acid/hydroxylated α-Al 2O 3( 0 0 0 1 ) reaction enthalpies

    Science.gov (United States)

    Hector, L. G., Jr.; Opalka, S. M.; Nitowski, G. A.; Wieserman, L.; Siegel, D. J.; Yu, H.; Adams, J. B.

    2001-11-01

    The eleven ion vinyl phosphonic acid (VPA) molecule consists of a phosphorus ion that serves as a cationic anchor for two electron-rich functional groups, viz., a tripodal oxygen-rich base and vinyl hydrocarbon tail. Recent inelastic tunneling experiments have implied that VPA binds in a tridentate coordination though its base leaving the vinyl tail free to react with a resin in adhesive bonding applications. Using first-principles total energy calculations, the reaction enthalpies for bonding of a single VPA molecule to selected threefold sites on hydroxylated α-Al 2O 3(0 0 0 1) are investigated. Tridentate, bidentate and unidentate coordinations, both with and without liberated water molecules, are examined to determine if the tridentate coordination is favored over the others and the extent to which the VPA molecule is sensitive to surface site geometry. The electron localization function is used to examine the extent of covalent character between the P-O bonds that anchor the VPA fragment to the oxide surface. Some comments on the entropic contributions of the VPA and H 2O molecules to the binding energetics are offered, along with a discussion of the effects of H 2O placement on the oxide surface and aluminum alloying agents.

  1. Stability of phosphonic self assembled monolayers (SAMs) on cobalt chromium (Co-Cr) alloy under oxidative conditions

    Science.gov (United States)

    Bhure, Rahul; Abdel-Fattah, Tarek M.; Bonner, Carl; Hall, Felicia; Mahapatro, Anil

    2011-04-01

    Cobalt chromium (Co-Cr) alloys have been widely used in the biomedical arena for cardiovascular, orthopedic and dental applications. Surface modification of the alloy allows us to tailor the interfacial properties to address critical challenges of Co-Cr alloy in medical applications. Self assembled monolayers (SAMs) of Octadecylphosphonic acid (ODPA) have been used to form thin films on the oxide layer of the Co-Cr alloy surface by solution deposition technique. The SAMs formed were investigated for their stability to oxidative conditions of ambient laboratory environment over periods of 1, 3, 7 and 14 days. The samples were then characterized for their stability using X-ray Photoelectron Spectroscopy (XPS), Atomic Force Microscopy (AFM) and contact angle measurements. Detailed high energy XPS elemental scans confirmed the presence of the phosphonic monolayer after oxidative exposure which suggested that the SAMs were firmly attached to the oxide layer of Co-Cr alloy. AFM images gave topographical data of the surface and showed islands of SAMs on Co-Cr alloy surface, before and after SAM formation and also over the duration of the oxidative exposure. Contact angle measurements confirmed the hydrophobicity of the surface over 14 days. Thus the SAMs were found to be stable for the duration of the study. These SAMs could be subsequently tailored by modifying the terminal functional groups and could be used for various potential biomedical applications such as drug delivery, biocompatibility and tissue integration.

  2. A (Fluoroalkyl)Guanidine Modulates the Relaxivity of a Phosphonate-Containing T 1-Shortening Contrast Agent.

    Science.gov (United States)

    Wu, Xinping; Dawsey, Anna C; Siriwardena-Mahanama, Buddhima N; Allen, Matthew J; Williams, Travis J

    2014-12-01

    Responsive magnetic resonance imaging (MRI) contrast agents, those that change their relaxivity according to environmental stimuli, have promise as next generation imaging probes in medicine. While several of these are known based on covalent modification of the contrast agents, fewer are known based on controlling non-covalent interactions. We demonstrate here accentuated relaxivity of a T 1-shortening contrast agent, Gd-DOTP(5-) based on non-covalent, hydrogen bonding of Gd-DOTP(5-) with a novel fluorous amphiphile. By contrast to the phosphonate-containing Gd-DOTP(5-) system, the relaxivity of the analogous clinically approved contrast agent, Gd-DOTA(-) is unaffected by the same fluorous amphiphile under similar conditions. Mechanistic studies show that placing the fluorous amphiphile in proximity of the gadolinium center in Gd-DOTP(5-) caused an increase in τ m (bound-water residence lifetime or the inverse of water exchange rate, τ m = 1/k ex) and an increase in τ R (rotational correlation time), with τ R being the factor driving enhanced relaxivity. Further, these effects were not observed when Gd-DOTA(-) was treated with the same fluorous amphiphile. Thus, Gd-DOTP(5-) and Gd-DOTA(-) respond to the fluorous amphiphile differently, presumably because the former binds to the amphiphile with higher affinity. (DOTP = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraphosphonic acid; DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). PMID:25431503

  3. A review of the developments of multi-purpose primers and adhesives comprising novel dithiooctanoate monomers and phosphonic acid monomers.

    Science.gov (United States)

    Ikemura, Kunio; Endo, Takeshi; Kadoma, Yoshinori

    2012-02-01

    This paper reviews the developments of dithiooctanoate monomers and acidic adhesive monomers, and their roles in multi-purpose primers and adhesives in promoting adhesion to multiple substrate materials. Novel dithiooctanoate monomers exhibited excellent bonding to precious metals and alloys when compared against conventional sulfur-containing monomers. Newly developed phosphonic acid monomers, endowed with a water-soluble nature, enabled sufficient demineralization of dental hard tissues and thus improved bonding to both ground enamel and dentin. The optimal combination for bonding to dental hard tissues and precious and non-precious metals and alloys was 5.0 wt% 10-methacryloyloxydecyl 6,8-dithiooctanoate (10-MDDT) and 1.0 wt% 6-methacryloyloxyhexyl phosphonoacetate (6-MHPA). For bonding to dental porcelain, alumina, zirconia, and gold (Au) alloy, a ternary combination of silane coupling agent, acidic adhesive monomers, and dithiooctanoate monomers seemed promising. The latest development was a single-bottle, multi-purpose, self-etching adhesive which contained only acidic adhesive monomers and dithiooctanoate monomers but which produced strong adhesion to ground enamel and dentin, sandblasted zirconia, and Au alloy.

  4. Structure-Property Relationship of Layered Metal Oxide Phosphonate/Chitosan Nanohybrids for Transducer in Biosensing Device

    Science.gov (United States)

    De, Sriparna; Mohanty, Smita; Nayak, Sanjay Kumar

    2015-01-01

    A candid approach to analyze the performance characteristics of phenyl phosphonate-functionalized zirconium oxide and pure zirconium oxide (ZrO2) fillers reinforced chitosan nanocomposites and their suitability as a potential biomaterial for the development of transducer surface in biosensing device has been investigated in this communication. Functionalization of ZrO2 has been carried out using sulfophenylphosphonate which was confirmed using Fourier transform infrared spectrographs. The electrostatic intercalation of chitosan with filler particles was monitored using electrochemical impedance analyzer which exhibits lowest bulk resistance which is highly effective for ionic switching. Incorporation of zirconium sulfophenylphosphonate (ZrSP) the ionic conductivity of the chitosan film attained a value of 1.2 × 10-6 S/cm as compared to the unmodified one which is a prefeasibility work for the fabrication of biosensing platform. Variation in performance characteristics has been evaluated through morphological and thermal characterization. TGA and DSC analysis reveal that the thermal stability and decomposition temperature of the nanocomposites were improved by the addition of reinforcing filler particles. XRD and SEM and TEM results support the above assumption. The continuous alignment of the proton transfer channels of the nanocomposites was thoroughly investigated by AFM analysis which revealed phase morphology for improved enzyme entrapment. Further, surface functionalized nanofillers result considerable increment of mechanical properties in terms of elastic modulus and tensile stress.

  5. The sarin-like organophosphorus agent bis(isopropyl methyl)phosphonate induces ER stress in human astrocytoma cells.

    Science.gov (United States)

    Arima, Yosuke; Shiraishi, Hiroaki; Saito, Atsushi; Yoshimoto, Kanji; Namera, Akira; Makita, Ryosuke; Murata, Kazuhiro; Imaizumi, Kazunori; Nagao, Masataka

    2016-01-01

    Organophosphorus (OP) compounds such as sarin are toxic agents that irreversibly inhibit the enzyme acetylcholinesterase. A recent study showed that OP compounds also have multiple toxicity mechanisms, and another suggested that endoplasmic reticulum (ER) dysfunction contributes to OP toxicity. However, the signaling pathway and mechanisms involved are poorly understood. We examined whether the sarin-like OP agent bis(isopropyl methyl)phosphonate (BIMP), which exhibits toxicity similar to that of sarin, induced ER stress in human astrocytoma CCF-STTG1 cells. Our results demonstrate that BIMP exposure reduced cell viability. Moreover, it induced changes in mitochondrial membrane potential and increased cleavage of caspase 3. Treatment with BIMP increased the mRNA levels of the ER stress marker genes binding immunoglobulin protein (BiP) and the transcription factor C/EBP homologous protein (CHOP). Furthermore, BIMP increased the protein expressions and phosphorylation of BiP, CHOP, and protein kinase RNA-like ER kinase and the phosphorylation of eukaryotic translation initiation factor 2. Compared to BIMP treatment alone, pretreatment with the CHOP siRNA, siCHOP, decreased BIMP-dependent CHOP expression and improved CCF-STTG1 cell viability. Our findings suggest that BIMP induced mitochondrial dysfunction and apoptotic cell death event mediated by ER stress in CCF-STTG1 cells and that treatment targeted at managing ER stress has the potential to attenuate the toxicity of OP nerve agents. PMID:27665771

  6. Structural analysis of a phosphonate hydroxylase with an access tunnel at the back of the active site.

    Science.gov (United States)

    Li, Changqing; Junaid, Muhammad; Almuqri, Eman Abdullah; Hao, Shiguang; Zhang, Houjin

    2016-05-01

    FrbJ is a member of the Fe(2+)/α-ketoglutarate-dependent dioxygenase family which hydroxylates the natural product FR-900098 of Streptomyces rubellomurinus, yielding the phosphonate antibiotic FR-33289. Here, the crystal structure of FrbJ, which shows structural homology to taurine dioxygenase (TauD), a key member of the same family, is reported. Unlike other members of the family, FrbJ has an unusual lid structure which consists of two β-strands with a long loop between them. To investigate the role of this lid motif, a molecular-dynamics simulation was performed with the FrbJ structure. The molecular-dynamics simulation analysis implies that the lid-loop region is highly flexible, which is consistent with the fact that FrbJ has a relatively broad spectrum of substrates with different lengths. Interestingly, an access tunnel is found at the back of the active site which connects the putative binding site of α-ketoglutarate to the solvent outside. PMID:27139827

  7. Synthesis and Crystal Structure of Diethyl 5-Acetoxy-3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl-5-phosphonate

    Institute of Scientific and Technical Information of China (English)

    SHANG Zhi-Qiang; CHEN Ru-Yu; HUANG You

    2006-01-01

    The crystal structure of the title compound, diethyl 5-acetoxy-3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl-5-phosphonate (Ci5H19ClNO6P, Mr = 375.73), has been synthesized by the treatment of nitrile oxides and 1-acetyloxy-vinylphosphonate under very mild conditions in good yields, and determined by single-crystal X-ray diffraction. The crystal belongs to monoclinic, space group C2/c with a = 16.914(10), b = 10.567(7), c = 21.927(13)(A),β = 110.249(11)°, V= 3677(4)(A)3,Z = 8, Dc = 1.358 g/cm3, F(000) = 1568, μ(MoKa) = 0.324 mm-1, S = 1.011, the final R = 0.0661and wR = 0.1556. The X-ray analytic results showed that the dihedral angle between the phenyl group and the isoxazoline ring is 10.7°.

  8. Synthesis and Crystal Structure of Diethyl (4,6-diamino-1,3,5-triazine-2-yl) phosphonate

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The crystal of the title compound diethyl (4,6-diamino-1,3,5-triazine-2-yl) phosphonate, (C14H28N10O6P2, Mr=494.40), has been prepared and determined by X-ray single crystal diffraction. The crystal belongs to the triclinic system, space group P with parameters: a=8.398(1) , b=10.206(1), c=14.538(2), α=75.221(3), β=85.965(3), γ=81.746(3)°, V=1191.6(3)3, S=1.028, Z=2, Dc=1.378Mg/m3, μ=0.233mm-1, F(000)=520, λ(MoKα)=0.71073, T=293(2)K, final R=0.071 and wR=0.1953 for 4177 independent reflections with I≥2σ(I). In the title compound, each molecule is linked to five neighbour molecules by hydrogen bonds forming layers perpendicular to the a axis and molecules in each layer are linked by a two-dimensional network of hydrogen bonds in the bc plane.

  9. New N-Acetyltransferase Fold in the Structure and Mechanism of the Phosphonate Biosynthetic Enzyme FrbF

    Energy Technology Data Exchange (ETDEWEB)

    Bae, Brian; Cobb, Ryan E.; DeSieno, Matthew A.; Zhao, Huimin; Nair, Satish K. (UIUC)

    2015-10-15

    The enzyme FrbF from Streptomyces rubellomurinus has attracted significant attention due to its role in the biosynthesis of the antimalarial phosphonate FR-900098. The enzyme catalyzes acetyl transfer onto the hydroxamate of the FR-900098 precursors cytidine 5'-monophosphate-3-aminopropylphosphonate and cytidine 5'-monophosphate-N-hydroxy-3-aminopropylphosphonate. Despite the established function as a bona fide N-acetyltransferase, FrbF shows no sequence similarity to any member of the GCN5-like N-acetyltransferase (GNAT) superfamily. Here, we present the 2.0 {angstrom} resolution crystal structure of FrbF in complex with acetyl-CoA, which demonstrates a unique architecture that is distinct from those of canonical GNAT-like acetyltransferases. We also utilized the co-crystal structure to guide structure-function studies that identified the roles of putative active site residues in the acetyltransferase mechanism. The combined biochemical and structural analyses of FrbF provide insights into this previously uncharacterized family of N-acetyltransferases and also provide a molecular framework toward the production of novel N-acyl derivatives of FR-900098.

  10. Pigment Changes Associated with Application of Ethephon ((2-Chloroethyl)phosphonic Acid) to Fig (Ficus carica L.) Fruits.

    Science.gov (United States)

    Puech, A A; Rebeiz, C A; Crane, J C

    1976-04-01

    The application of (2-chloroethyl)phosphonic acid (Ethephon) to ;Mission' fig fruits (Ficus carica L.) during late period II of their development stimulated ripening and change in color from green to bluish black within 8 days. Chlorophylls a and b decreased rapidly within 4 days after Ethephon treatment, and degradation continued at a decreasing rate for an additional 4 days, at which time the fruits had attained their maximum diameter and were considered fully ripe. Levels of beta-carotene, lutein, violaxanthin, and neoxanthin decreased in a pattern similar to that of chlorophylls a and b. The rates of beta-carotene and lutein degradation were initially greater than those of the xanthophyll pigments. Degradation rates of the various carotenoids were comparable 4 to 8 days after treatment.There was no measurable anthocyanin synthesis during a 2- to 4-day period following Ethephon treatment. Beyond this lag phase, anthocyanin accumulation was linear, and the amount of pigment synthesized was a function of both light intensity and duration. Although Ethephon promoted the rate of anthocyanin accumulation, it did not increase the total amount of pigment synthesized in treated fruits. Etiolation of fruits from the time of Ethephon treatment until maturity stimulated an increase in growth and completely inhibited anthocyanin production in the skin. Ethephon-treated fruits which ripened while etiolated were larger in diameter and higher in both fresh and dry weights than nonetiolated controls.

  11. Bioavailability and bioconcentration potential of perfluoroalkyl-phosphinic and -phosphonic acids in zebrafish (Danio rerio): Comparison to perfluorocarboxylates and perfluorosulfonates.

    Science.gov (United States)

    Chen, Fangfang; Gong, Zhiyuan; Kelly, Barry C

    2016-10-15

    Currently, information regarding bioavailability and bioconcentration potential of perfluoroalkyl phosphinic acids (PFPiAs) in aquatic organisms does not exist. The main objective of the present study was to assess uptake and elimination kinetics of PFPiAs in zebrafish (Danio rerio) following aqueous exposure. The results showed that PFPiA exposure can result in very high steady-state bioconentration factors (BCFss), compared to perfluorocarboxylates and perfluorosulfonates.C6/C10 PFPiA exhibited the highest BCFss, ranging between 10(7) and 10(10), orders of magnitude higher than those for long-chain perfluorocarboxylates. Strong positive relationships were observed between BCFss versus the membrane-water distribution coefficient (Dmw) and the protein-water partition coefficient (Kpw) of the studied perfluoroalkyl substances. However, BCFss exhibited a substantial drop for the very hydrophobic PFPiAs (C8/C10 and C6/C12 PFPiAs). The reduced BCFss of these long-chain PFPiAs (perfluoroalkyl chain length=18; Dmw=10(9)) is likely the result of reduced bioavailability due to interaction with solute molecules/organic matter present in the water phase and/or reduced gill membrane permeability. While PFPiAs can be metabolized to perfluoroalkyl phosphonic acids, the metabolic transformation rate seems insufficient to counteract the high degree of uptake across gill membranes. These findings help to better understand exposure pathways and bioaccumulation behavior of these important perfluorinated acids in aquatic systems. PMID:27285794

  12. Preparation of a Novel Calcium Phosphate Cement Using N-methylene Phosphonic Chitosan as a Gelling Agent

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    A modified chitosan ( N-methylene phosphonic Chitosan, NMPC ) was synthesized to improve solubility and ability to bind calcium ion. The properties of the raw material chitosan and its derivative NMPC were characterized using FTIR, 1 H-NMR. The aim of this study was to enhance the compressive CPC by reinforcing with NMPC. A formulation consisting of CPC powder, buffer solution and gelling agent was used for preparation of the CPC. CPC powder consisted of tetracalcium phosphate (TTCP) and dicalcium phosphate anhydrous ( DCPA ). NMPC which acted as the gelling agent was dissolved iuto KH2 PO4 -Na2 HPO4 buffer solution. Each specimen in the mold was sandwiched between two fritted glass sides and kept for 24 hours. Compressive strengths were determined, the setting product was identified using X-ray diffraction and scanning electron microscopy was used to investigate the hydroxyapatite particles size and porosity. The experimental results showed that the dominating influence on the compressive strengths of CPC-NMPC was the HA particle size, its uniformity and appropriate porosity.

  13. Cross-linked polymeric nanogel formulations of 5'-triphosphates of nucleoside analogues: role of the cellular membrane in drug release.

    Science.gov (United States)

    Vinogradov, Serguei V; Kohli, Ekta; Zeman, Arin D

    2005-01-01

    Activation of cytotoxic nucleoside analogues in vivo depends primarily on their cell-specific phosphorylation. Anticancer chemotherapy using nucleoside analogues may be significantly enhanced by intracellular administration of active phosphorylated drugs. However, the cellular transport of anionic compounds is very ineffective and restricted by many drug efflux transporters. Recently developed cationic nanogel carriers can encapsulate large amounts of nucleoside 5'-triphosphates that form polyionic complexes with protonated amino groups on the polyethylenimine backbone of the nanogels. In this paper, the 5'-triphosphate of an antiviral nucleoside analogue, 3'-azido-2',3'-dideoxythymidine (AZT), was efficiently synthesized and its complexes with nanogels were obtained and evaluated as potential cytotoxic drug formulations for treatment of human breast carcinoma cells. A selective phosphorylating reagent, tris-imidazolylphosphate, was used to convert AZT into the nucleoside analogue 5'-triphosphate using a one-pot procedure. The corresponding 3'-azido-2',3'-dideoxythymidine 5'-triphosphate (AZTTP) was isolated with high yield (75%). Nanogels encapsulated up to 30% of AZTTP by weight by mixing solutions of the carrier and the drug. The AZTTP/nanogel formulation showed enhanced cytotoxicity in two breast cancer cell lines, MCF-7 and MDA-MB-231, demonstrating IC50 values 130-200 times lower than those values for AZT alone. The exact mechanism of drug release from nanogels remains unclear. One mechanism could involve interaction with negatively charged counterions. A high affinity of nanogels to isolated cellular membranes has been observed, especially for nanogels made of amphiphilic block copolymer, Pluronic P85. Cellular trafficking of nanogel particles, contrasted by polyethylenimine-coordinated copper(II) ions, was studied by transmission electron microscopy (TEM), which revealed membranotropic properties of nanogels. A substantial release of encapsulated drug was

  14. ADME studies of [5‐3H]‐2′‐O‐methyluridine nucleoside in mice: a building block in siRNA therapeutics

    OpenAIRE

    Lozac'h, Frederic; Christensen, Jesper; Faller, Thomas; van de Kerkhof, Esther; Krauser, Joel; Garnier, Maxime; Litherland, Karine; Catoire, Alexandre; Natt, Francois; Hunziker, Jurg; Swart, Piet

    2016-01-01

    Abstract The chemical modification 2′‐O‐methyl of nucleosides is often used to increase siRNA stability towards nuclease activities. However, the metabolic fate of modified nucleosides remains unclear. Therefore, the aim of this study was to determine the mass balance, pharmacokinetic, and absorption, distribution, metabolism, and excretion (ADME)‐properties of tritium‐labeled 2′‐O‐methyluridine, following a single intravenous dose to male CD‐1 mice. The single intravenous administration of [...

  15. L-Aspartic and l-glutamic acid ester-based ProTides of anticancer nucleosides: Synthesis and antitumoral evaluation.

    Science.gov (United States)

    Gao, Ling-Jie; De Jonghe, Steven; Daelemans, Dirk; Herdewijn, Piet

    2016-05-01

    A series of novel aryloxyphosphoramidate nucleoside prodrugs based on l-aspartic acid and l-glutamic acid as amino acid motif has been synthesized and evaluated for antitumoral activity. Depending on the cancer cell line studied and on the nature of the parent nucleoside compound (gemcitabine, 5-iodo-2'-deoxy-uridine, floxuridine or brivudin), the corresponding ProTides are endowed with an improved or decreased cytotoxic activity. PMID:27032331

  16. Comparative effects of dietary nucleoside-nucleotide mixture and its components on endotoxin induced bacterial translocation and small intestinal injury in protein deficient mice.

    OpenAIRE

    Adjei, A A; Yamauchi, K.; Chan, Y. C.; Konishi, M; Yamamoto, S.

    1996-01-01

    BACKGROUND--Nucleoside-nucleotide mixture has been shown to improve gut morphology and reduce the incidence of bacterial translocation in protein deficient mice. AIMS--To compare the reparative effect of nucleoside-nucleotide mixture and their individual components on maintenance of gut integrity and bacterial translocation based on their differential metabolism and utilisation. METHODS--ICR (CD-1) mice were randomised into eight groups of 10 animals each and fed 20% casein diet (control), pr...

  17. Bone mineral density changes in protease inhibitor-sparing vs. nucleoside reverse transcriptase inhibitor-sparing highly active antiretroviral therapy: data from a randomized trial

    DEFF Research Database (Denmark)

    Hansen, Ann-Brit Eg; Obel, N; Nielsen, H;

    2011-01-01

    The aim of the study was to compare changes in bone mineral density (BMD) over 144 weeks in HIV-infected patients initiating nucleoside reverse transcriptase inhibitor (NRTI)-sparing or protease inhibitor-sparing highly active antiretroviral therapy (HAART).......The aim of the study was to compare changes in bone mineral density (BMD) over 144 weeks in HIV-infected patients initiating nucleoside reverse transcriptase inhibitor (NRTI)-sparing or protease inhibitor-sparing highly active antiretroviral therapy (HAART)....

  18. Identification of an Alternative Nucleoside Triphosphate: 5′-Deoxyadenosylcobinamide Phosphate Nucleotidyltransferase in Methanobacterium thermoautotrophicum ΔH

    OpenAIRE

    Michael G Thomas; Escalante-Semerena, Jorge C.

    2000-01-01

    Computer analysis of the archaeal genome databases failed to identify orthologues of all of the bacterial cobamide biosynthetic enzymes. Of particular interest was the lack of an orthologue of the bifunctional nucleoside triphosphate (NTP):5′-deoxyadenosylcobinamide kinase/GTP:adenosylcobinamide-phosphate guanylyltransferase enzyme (CobU in Salmonella enterica). This paper reports the identification of an archaeal gene encoding a new nucleotidyltransferase, which is proposed to be the nonorth...

  19. TDP1 repairs nuclear and mitochondrial DNA damage induced by chain-terminating anticancer and antiviral nucleoside analogs

    OpenAIRE

    Huang, Shar-yin N.; Murai, Junko; Dalla Rosa, Ilaria; Dexheimer, Thomas S.; Naumova, Alena; Gmeiner, William H.; Pommier, Yves

    2013-01-01

    Chain-terminating nucleoside analogs (CTNAs) that cause stalling or premature termination of DNA replication forks are widely used as anticancer and antiviral drugs. However, it is not well understood how cells repair the DNA damage induced by these drugs. Here, we reveal the importance of tyrosyl–DNA phosphodiesterase 1 (TDP1) in the repair of nuclear and mitochondrial DNA damage induced by CTNAs. On investigating the effects of four CTNAs—acyclovir (ACV), cytarabine (Ara-C), zidovudine (AZT...

  20. Standardized comparison of the relative impacts of HIV-1 reverse transcriptase (RT) mutations on nucleoside RT inhibitor susceptibility.

    OpenAIRE

    Melikian, George L.; Rhee, Soo-Yon; Taylor, Jonathan; Fessel, W. Jeffrey; Kaufman, David; Towner, William; Troia-Cancio, Paolo V.; Zolopa, Andrew; Robbins, Gregory K.; Kagan, Ron; Israelski, Dennis; Shafer, Robert W.

    2012-01-01

    Determining the phenotypic impacts of reverse transcriptase (RT) mutations on individual nucleoside RT inhibitors (NRTIs) has remained a statistical challenge because clinical NRTI-resistant HIV-1 isolates usually contain multiple mutations, often in complex patterns, complicating the task of determining the relative contribution of each mutation to HIV drug resistance. Furthermore, the NRTIs have highly variable dynamic susceptibility ranges, making it difficult to determine the relative eff...

  1. The Ex Vivo Human Placental Transfer of the Anti-HIV Nucleoside Inhibitor Abacavir and the Protease Inhibitor Amprenavir

    OpenAIRE

    Bawdon, R E

    1998-01-01

    Objective: The transfer of abacavir, a new nucleoside inhibitor, and amprenavir, a new protease inhibitor, used for the treatment of human immunodeficiency virus, has been studied in the ex vivo human placental model.Methods: The ex vivo human placental model used C14 antipyrine to determine the transport fraction and clearance index of these compounds at both the peak and trough serum concentrations. The clearance index accumulation and tissue concentrations were determined for each drug by ...

  2. The ex vivo human placental transfer of the anti-HIV nucleoside inhibitor abacavir and the protease inhibitor amprenavir.

    OpenAIRE

    Bawdon, R E

    1998-01-01

    OBJECTIVE: The transfer of abacavir, a new nucleoside inhibitor, and amprenavir, a new protease inhibitor, used for the treatment of human immunodeficiency virus, has been studied in the ex vivo human placental model. METHODS: The ex vivo human placental model used C14 antipyrine to determine the transport fraction and clearance index of these compounds at both the peak and trough serum concentrations. The clearance index accumulation and tissue concentrations were determined for each drug by...

  3. Purine metabolic enzymes in lymphocytes. III. Effects of immunosuppressants on adenosine deaminase and purine nucleoside phosphorylase activities

    OpenAIRE

    Kurashige, Satonori; Akuzawa, Yuki; Yoshida, Toshiharu; Kodama, Kazue

    1983-01-01

    Mice were treated with a single injection of 6-mercaptopurine riboside (6MP-R), predonine or cyclophosphamide (CY), and the effects of these immunosuppressants on blastogenic responses to phytohemagglutinin P (PHA-P) or bacterial lipopoly saccharide (LPS) and on adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP) activities were studied with spleen lymphocytes. The retardation of blastogenic responses to both PHA-P and LPS were associated with the retardation of both intracellu...

  4. Involvement of Concentrative Nucleoside Transporter 1 in Intestinal Absorption of Trifluridine Using Human Small Intestinal Epithelial Cells.

    Science.gov (United States)

    Takahashi, Koichi; Yoshisue, Kunihiro; Chiba, Masato; Nakanishi, Takeo; Tamai, Ikumi

    2015-09-01

    TAS-102, which is effective for refractory metastatic colorectal cancer, is a combination drug of anticancer trifluridine (FTD; which is derived from pyrimidine nucleoside) and FTD-metabolizing enzyme inhibitor tipiracil hydrochloride (TPI) at a molecular ratio of 1:0.5. To evaluate the intestinal absorption mechanism of FTD, the uptake and transcellular transport of FTD by human small intestinal epithelial cell (HIEC) monolayer as a model of human intestinal epithelial cells was investigated. The uptake and membrane permeability of FTD by HIEC monolayers were saturable, Na(+) -dependent, and inhibited by nucleosides. These transport characteristics are mostly comparable with those of concentrative nucleoside transporters (CNTs). Moreover, the uptake of FTD by CNT1-expressing Xenopus oocytes was the highest among human CNT transporters. The obtained Km and Vmax values of FTD by CNT1 were 69.0 μM and 516 pmol/oocyte/30 min, respectively. The transcellular transport of FTD by Caco-2 cells, where CNT1 is heterologously expressed, from apical to basolateral side was greater than that by Mock cells. In conclusion, these results demonstrated that FTD exhibits high oral absorption by the contribution of human CNT1.

  5. Testing nucleoside analogues as inhibitors of Bacillus anthracis spore germination in vitro and in macrophage cell culture.

    Science.gov (United States)

    Alvarez, Zadkiel; Lee, Kyungae; Abel-Santos, Ernesto

    2010-12-01

    Bacillus anthracis, the etiological agent of anthrax, has a dormant stage in its life cycle known as the endospore. When conditions become favorable, spores germinate and transform into vegetative bacteria. In inhalational anthrax, the most fatal manifestation of the disease, spores enter the organism through the respiratory tract and germinate in phagosomes of alveolar macrophages. Germinated cells can then produce toxins and establish infection. Thus, germination is a crucial step for the initiation of pathogenesis. B. anthracis spore germination is activated by a wide variety of amino acids and purine nucleosides. Inosine and l-alanine are the two most potent nutrient germinants in vitro. Recent studies have shown that germination can be hindered by isomers or structural analogues of germinants. 6-Thioguanosine (6-TG), a guanosine analogue, is able to inhibit germination and prevent B. anthracis toxin-mediated necrosis in murine macrophages. In this study, we screened 46 different nucleoside analogues as activators or inhibitors of B. anthracis spore germination in vitro. These compounds were also tested for their ability to protect the macrophage cell line J774a.1 from B. anthracis cytotoxicity. Structure-activity relationship analysis of activators and inhibitors clarified the binding mechanisms of nucleosides to B. anthracis spores. In contrast, no structure-activity relationships were apparent for compounds that protected macrophages from B. anthracis-mediated killing. However, multiple inhibitors additively protected macrophages from B. anthracis. PMID:20921305

  6. Increasing conclusiveness of metabonomic studies by chem-informatic preprocessing of capillary electrophoretic data on urinary nucleoside profiles.

    Science.gov (United States)

    Szymańska, E; Markuszewski, M J; Capron, X; van Nederkassel, A-M; Heyden, Y Vander; Markuszewski, M; Krajka, K; Kaliszan, R

    2007-01-17

    Nowadays, bioinformatics offers advanced tools and procedures of data mining aimed at finding consistent patterns or systematic relationships between variables. Numerous metabolites concentrations can readily be determined in a given biological system by high-throughput analytical methods. However, such row analytical data comprise noninformative components due to many disturbances normally occurring in analysis of biological samples. To eliminate those unwanted original analytical data components advanced chemometric data preprocessing methods might be of help. Here, such methods are applied to electrophoretic nucleoside profiles in urine samples of cancer patients and healthy volunteers. The electrophoretic nucleoside profiles were obtained under following conditions: 100 mM borate, 72.5 mM phosphate, 160 mM SDS, pH 6.7; 25 kV voltage, 30 degrees C temperature; untreated fused silica capillary 70 cm effective length, 50 microm I.D. Different most advanced preprocessing tools were applied for baseline correction, denoising and alignment of electrophoretic data. That approach was compared to standard procedure of electrophoretic peak integration. The best results of preprocessing were obtained after application of the so-called correlation optimized warping (COW) to align the data. The principal component analysis (PCA) of preprocessed data provides a clearly better consistency of the nucleoside electrophoretic profiles with health status of subjects than PCA of peak areas of original data (without preprocessing).

  7. Discovery of β-D-2'-deoxy-2'-α-fluoro-4'-α-cyano-5-aza-7,9-dideaza adenosine as a potent nucleoside inhibitor of respiratory syncytial virus with excellent selectivity over mitochondrial RNA and DNA polymerases.

    Science.gov (United States)

    Clarke, Michael O; Mackman, Richard; Byun, Daniel; Hui, Hon; Barauskas, Ona; Birkus, Gabriel; Chun, Byoung-Kwon; Doerffler, Edward; Feng, Joy; Karki, Kapil; Lee, Gary; Perron, Michel; Siegel, Dustin; Swaminathan, Swami; Lee, William

    2015-06-15

    Novel 4'-substituted β-d-2'-deoxy-2'-α-fluoro (2'd2'F) nucleoside inhibitors of respiratory syncytial virus (RSV) are reported. The introduction of 4'-substitution onto 2'd2'F nucleoside analogs resulted in compounds demonstrating potent cell based RSV inhibition, improved inhibition of the RSV polymerase by the nucleoside triphosphate metabolites, and enhanced selectivity over incorporation by mitochondrial RNA and DNA polymerases. Selectivity over the mitochondrial polymerases was found to be extremely sensitive to the specific 4'-substitution and not readily predictable. Combining the most potent and selective 4'-groups from N-nucleoside analogs onto a 2'd2'F C-nucleoside analog resulted in the identification of β-D-2'-deoxy-2'-α-fluoro-4'-α-cyano-5-aza-7,9-dideaza adenosine as a promising nucleoside lead for RSV.

  8. Leishmania donovani Nucleoside Hydrolase terminal domains in cross-protective immunotherapy against Leishmania amazonensis murine infection

    Directory of Open Access Journals (Sweden)

    Dirlei eNico

    2014-06-01

    Full Text Available Nucleoside hydrolases of the Leishmania genus are vital enzymes for the replication of the DNA and conserved phylogenetic markers of the parasites. Leishmania donovani Nucleoside hydrolase (NH36 induced a main CD4+ T cell driven protective response against Leishmania chagasi infection in mice which is directed against its C-terminal domain. In this study, we used the three recombinant domains of NH36: N-terminal domain (F1, amino acids 1-103, central domain (F2 aminoacids 104-198 and C-terminal domain (F3 amino acids 199-314 in combination with saponin and assayed their immunotherapeutic effect on Balb/c mice previously infected with L. amazonensis. We identified that the F1 and F3 peptides determined strong cross-immunotherapeutic effects, reducing the size of footpad lesions to 48% and 64%, and the parasite load in footpads to 82.6% and 81%, respectively. The F3 peptide induced the strongest anti-NH36 antibody response and intradermal response (IDR against L. amazonenis and a high secretion of IFN-γ and TNF-α with reduced levels of IL-10. The F1 vaccine, induced similar increases of IgG2b antibodies and IFN-γ and TNF-α levels, but no IDR and no reduction of IL-10. The multiparameter flow cytometry analysis was used to assess the immune response after immunotherapy and disclosed that the degree of the immunotherapeutic effect is predicted by the frequencies of the CD4+ and CD8+ T cells producing IL-2 or TNF-α or both. Total frequencies and frequencies of double-cytokine CD4 T cell producers were enhanced by F1 and F3 vaccines. Collectively, our multifunctional analysis disclosed that immunotherapeutic protection improved as the CD4 responses progressed from 1+ to 2+, in the case of the F1 and F3 vaccines, and as the CD8 responses changed qualitatively from 1+ to 3+, mainly in the case of the F1 vaccine, providing new correlates of immunotherapeutic protection against cutaneous leishmaniasis in mice based on T-helper TH1 and CD8+ mediated

  9. Determination of nucleosides in Cordyceps sinensis and Ganoderma lucidum by high performance liquid chromatography method

    Directory of Open Access Journals (Sweden)

    Masood Shah Khan

    2015-01-01

    Full Text Available Background: Nucleosides are supportive in the regulation and modulation of various physiological processes in body, they acts as precursors in nucleic acid synthesis, enhance immune response, help in absorption of iron and influence the metabolism of fatty acids. Cordyceps sinensis and Ganoderma lucidum are well-known for its use in traditional medicine of China, Nepal and India. They are rich in nucleosides such as adenine, adenosine, cordycepin, etc. Hence, a simple, economic and accurate high-performance liquid chromatography (HPLC analytical method was proposed for determination of adenine and adenosine for the quality control of plants. Materials and Methods: Chromatographic experiments were conducted on YL9100 HPLC system (South Korea. Reversed-phase chromatography was performed on a C18 column with methanol and dihydrogen phosphate as the mobile phase in isocratic elution method at a flow rate of 1.0 mL/min. Detection was carried out at 254 nm, which gives a sharp peak of adenine and adenosine at a retention time of 6.53 ± 0.02 min and 12.41 ± 0.02, respectively. Results and Discussion: Linear regression analysis data for the calibration plot showed a good linear relationship between response and concentration in the range of 25–200 µg/mL for adenosine and 100–800 µg/mL for adenine with regression coefficient of 0.999 and 0.996, respectively. The adenine was found 0.16% and 0.71% w/w in G. lucidum and in C. sinensis, respectively, and adenosine was found to be 0.14% w/w in G. lucidum whereas absent in C. sinensis. Conclusion: The developed HPLC method for the quantification of adenosine and adenine can be used for the quality control and standardization of crude drug and for the different herbal formulations, in which adenine and adenosine are present as major constituents. The wide linearity range, sensitivity, accuracy, and simple mobile phase imply the method is suitable for routine quantification of adenosine and adenine with

  10. Rigid Adenine Nucleoside Derivatives as Novel Modulators of the Human Sodium Symporters for Dopamine and Norepinephrine.

    Science.gov (United States)

    Janowsky, Aaron; Tosh, Dilip K; Eshleman, Amy J; Jacobson, Kenneth A

    2016-04-01

    Thirty-two congeneric rigid adenine nucleoside derivatives containing a North (N)-methanocarba ribose substitution and a 2-arylethynyl group either enhanced (up to 760% of control) or inhibited [(125)I] methyl (1R,2S,3S)-3-(4-iodophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate (RTI-55) binding at the human dopamine (DA) transporter (DAT) and inhibited DA uptake. Several nucleosides also enhanced [(3)H]mazindol [(±)-5-(4-chlorophenyl)-3,5-dihydro-2H-imidazo[2,1-a]isoindol-5-ol] binding to the DAT. The combination of binding enhancement and functional inhibition suggests possible allosteric interaction with the tropanes. The structure-activity relationship of this novel class of DAT ligands was explored: small N(6)-substition (methyl or ethyl) was favored, while the N1 of the adenine ring was essential. Effective terminal aryl groups include thien-2-yl (compounds 9 and 16), with EC50 values of 35.1 and 9.1 nM, respectively, in [(125)I]RTI-55 binding enhancement, and 3,4-difluorophenyl as in the most potent DA uptake inhibitor (compound 6) with an IC50 value of 92 nM (3-fold more potent than cocaine), but not nitrogen heterocycles. Several compounds inhibited or enhanced binding at the norepinephrine transporter (NET) and serotonin transporter (SERT) and inhibited function in the micromolar range; truncation at the 4'-position in compound 23 allowed for weak inhibition of the SERT. We have not yet eliminated adenosine receptor affinity from this class of DAT modulators, but we identified modifications that remove DAT inhibition as an off-target effect of potent adenosine receptor agonists. Thus, we have identified a new class of allosteric DAT ligands, rigidified adenosine derivatives, and explored their initial structural requirements. They display a very atypical pharmacological profile, i.e., either enhancement by increasing affinity or inhibition of radioligand binding at the DAT, and in some cases the NET and SERT, and inhibition of neurotransmitter

  11. Acyclic Cucurbit[n]uril-Type Molecular Container Enables Systemic Delivery of Effective Doses of Albendazole for Treatment of SK-OV-3 Xenograft Tumors.

    Science.gov (United States)

    Hettiarachchi, Gaya; Samanta, Soumen K; Falcinelli, Shane; Zhang, Ben; Moncelet, Damien; Isaacs, Lyle; Briken, Volker

    2016-03-01

    Approximately, 40-70% of active pharmaceutical ingredients (API) are severely limited by their extremely poor aqueous solubility, and consequently, there is a high demand for excipients that can be used to formulate clinically relevant doses of these drug candidates. Here, proof-of-concept studies demonstrate the potential of our recently discovered acyclic cucurbit[n]uril-type molecular container Motor1 (M1) as a solubilizing agent for insoluble drugs. M1 did not induce significant rates of mutations in various Salmonella typhimurium test strains during the Ames test, suggesting low genotoxicity. M1 also has low risk of causing cardiac toxicity in humans since it did not inhibit the human Ether-à-go-go-Related Gene channel as tested on transfected CHO cell lines via patch clamp analysis. Albendazole (ABZ) is a widely used antihelminthic agent but that has also shown promising efficacy against cancerous cells in vitro. However, due to its low aqueous solubility (2.7 μM) and poor pharmacokinetics, ABZ is clinically limited as an anticancer agent. Here we investigated the potential of M1 as a solubilizing excipient for ABZ formulation. A pharmacokinetic study indicated that ABZ escapes the peritoneal cavity resulting in 78% absolute bioavailability, while its active intermediate metabolite, albendazole sulfoxide, achieved 43% absolute bioavailability. The daily dosing of 681 mg/kg M1 complexed with 3.2 mg/kg of ABZ for 14 days did not result in significant weight loss or pathology in Swiss Webster mice. In vivo efficacy studies using this M1·ABZ inclusion complex showed significant decreases in tumor growth rates and increases in survival of mice bearing SK-OV-3 xenograft tumors. In conclusion, we provide substantial new evidence demonstrating that M1 is a safe and efficient excipient that enables in vivo parenteral delivery of poorly water-soluble APIs.

  12. In Vitro selectivity of an acyclic cucurbit[n]uril molecular container towards neuromuscular blocking agents relative to commonly used drugs.

    Science.gov (United States)

    Ganapati, Shweta; Zavalij, Peter Y; Eikermann, Matthias; Isaacs, Lyle

    2016-01-28

    An acyclic cucurbit[n]uril (CB[n]) based molecular container (2, a.k.a. Calabadion 2) binds to both amino-steroidal and benzylisoquinolinium type neuromuscular blocking agents (NMBAs) in vitro, and reverses the effect of these drugs in vivo displaying faster recovery times than placebo and the γ-cyclodextrin (CD) based and clinically used reversal agent Sugammadex. In this study we have assessed the potential for other drugs commonly used during and after surgery (e.g. antibiotics, antihistamines, and antiarrhythmics) to interfere with the ability of 2 to bind NMBAs rocuronium and cisatracurium in vitro. We measured the binding affinities (Ka, M(-1)) of twenty seven commonly used drugs towards 2 and simulated the equilibrium between 2, NMBA, and drug based on their standard clinical dosages to calculate the equilibrium concentration of 2·NMBA in the presence of the various drugs. We found that none of the 27 drugs studied possess the combination of a high enough binding affinity with 2 and a high enough standard dosage to be able to promote the competitive dissociation (a.k.a. displacement interactions) of the 2·NMBA complex with the formation of the 2·drug complex. Finally, we used the simulations to explore how the potential for displacement interactions is affected by a number of factors including the Ka of the 2·NMBA complex, the Ka of the AChR·NMBA complex, the Ka of the 2·drug complex, and the dosage of the drug.

  13. Acyclic Cucurbit[n]uril-Type Molecular Container Enables Systemic Delivery of Effective Doses of Albendazole for Treatment of SK-OV-3 Xenograft Tumors.

    Science.gov (United States)

    Hettiarachchi, Gaya; Samanta, Soumen K; Falcinelli, Shane; Zhang, Ben; Moncelet, Damien; Isaacs, Lyle; Briken, Volker

    2016-03-01

    Approximately, 40-70% of active pharmaceutical ingredients (API) are severely limited by their extremely poor aqueous solubility, and consequently, there is a high demand for excipients that can be used to formulate clinically relevant doses of these drug candidates. Here, proof-of-concept studies demonstrate the potential of our recently discovered acyclic cucurbit[n]uril-type molecular container Motor1 (M1) as a solubilizing agent for insoluble drugs. M1 did not induce significant rates of mutations in various Salmonella typhimurium test strains during the Ames test, suggesting low genotoxicity. M1 also has low risk of causing cardiac toxicity in humans since it did not inhibit the human Ether-à-go-go-Related Gene channel as tested on transfected CHO cell lines via patch clamp analysis. Albendazole (ABZ) is a widely used antihelminthic agent but that has also shown promising efficacy against cancerous cells in vitro. However, due to its low aqueous solubility (2.7 μM) and poor pharmacokinetics, ABZ is clinically limited as an anticancer agent. Here we investigated the potential of M1 as a solubilizing excipient for ABZ formulation. A pharmacokinetic study indicated that ABZ escapes the peritoneal cavity resulting in 78% absolute bioavailability, while its active intermediate metabolite, albendazole sulfoxide, achieved 43% absolute bioavailability. The daily dosing of 681 mg/kg M1 complexed with 3.2 mg/kg of ABZ for 14 days did not result in significant weight loss or pathology in Swiss Webster mice. In vivo efficacy studies using this M1·ABZ inclusion complex showed significant decreases in tumor growth rates and increases in survival of mice bearing SK-OV-3 xenograft tumors. In conclusion, we provide substantial new evidence demonstrating that M1 is a safe and efficient excipient that enables in vivo parenteral delivery of poorly water-soluble APIs. PMID:26756920

  14. In Vitro selectivity of an acyclic cucurbit[n]uril molecular container towards neuromuscular blocking agents relative to commonly used drugs.

    Science.gov (United States)

    Ganapati, Shweta; Zavalij, Peter Y; Eikermann, Matthias; Isaacs, Lyle

    2016-01-28

    An acyclic cucurbit[n]uril (CB[n]) based molecular container (2, a.k.a. Calabadion 2) binds to both amino-steroidal and benzylisoquinolinium type neuromuscular blocking agents (NMBAs) in vitro, and reverses the effect of these drugs in vivo displaying faster recovery times than placebo and the γ-cyclodextrin (CD) based and clinically used reversal agent Sugammadex. In this study we have assessed the potential for other drugs commonly used during and after surgery (e.g. antibiotics, antihistamines, and antiarrhythmics) to interfere with the ability of 2 to bind NMBAs rocuronium and cisatracurium in vitro. We measured the binding affinities (Ka, M(-1)) of twenty seven commonly used drugs towards 2 and simulated the equilibrium between 2, NMBA, and drug based on their standard clinical dosages to calculate the equilibrium concentration of 2·NMBA in the presence of the various drugs. We found that none of the 27 drugs studied possess the combination of a high enough binding affinity with 2 and a high enough standard dosage to be able to promote the competitive dissociation (a.k.a. displacement interactions) of the 2·NMBA complex with the formation of the 2·drug complex. Finally, we used the simulations to explore how the potential for displacement interactions is affected by a number of factors including the Ka of the 2·NMBA complex, the Ka of the AChR·NMBA complex, the Ka of the 2·drug complex, and the dosage of the drug. PMID:26648135

  15. Proton Conduction in a Phosphonate-Based Metal–Organic Framework Mediated by Intrinsic “Free Diffusion inside a Sphere”

    Science.gov (United States)

    2016-01-01

    Understanding the molecular mechanism of proton conduction is crucial for the design of new materials with improved conductivity. Quasi-elastic neutron scattering (QENS) has been used to probe the mechanism of proton diffusion within a new phosphonate-based metal–organic framework (MOF) material, MFM-500(Ni). QENS suggests that the proton conductivity (4.5 × 10–4 S/cm at 98% relative humidity and 25 °C) of MFM-500(Ni) is mediated by intrinsic “free diffusion inside a sphere”, representing the first example of such a mechanism observed in MOFs. PMID:27182787

  16. The Chemical and Physical Properties of Poly( ε -caprolactone) Scaffolds Functionalised with Poly(vinyl phosphonic acid-co-acrylic acid)

    OpenAIRE

    Bassi, A. K.; Gough, J. E.; Zakikhani, M.; Downes, S

    2011-01-01

    There is a clinical need for a synthetic alternative to bone graft substitute (BGS) derived from demineralised bone matrix. We report the electrospinning of Poly(ε-caprolactone) (PCL) to form a 3-dimensional scaffold for use as a synthetic BGS. Additionally, we have used Poly(vinyl phosphonic acid-co-acrylic acid) (PVPA) to improve bone formation. Fibres were formed using a 10% w/v PCL/acetone solution. Infrared spectroscopy confirmed that the electrospinning process had no effect on the func...

  17. Current Status of Older and New Purine Nucleoside Analogues in the Treatment of Lymphoproliferative Diseases

    Directory of Open Access Journals (Sweden)

    Pawel Robak

    2009-03-01

    Full Text Available For the past few years more and more new cytotoxic agents active in the treatment of hematological malignancies have been synthesized and become available for either in vitro studies or clinical trials. Among them the class of antineoplastic drugs belonging to the purine nucleoside analogues group (PNAs plays an important role. Three of them: pentostatin (DCF, cladribine (2-CdA and fludarabine (FA were approved by Food and Drug Administration (FDA for the treatment of hematological malignancies. Recently three novel PNAs: clofarabine (CAFdA, nelarabine (ara-G and forodesine (immucillin H, BCX-1777 have been synthesized and introduced into preclinical studies and clinical trials. These agents seem to be useful mainly for the treatment of human T-cell proliferative disorders and they are currently undergoing clinical trials in lymphoid malignancies. However, there are also several studies suggesting the role of these drugs in B-cell malignancies. This review will summarize current knowledge concerning the mechanism of action, pharmacologic properties, clinical activity and toxicity of PNAs accepted for use in clinical practice, as well as new agents available for clinical trials.

  18. Five putative nucleoside triphosphate diphosphohydrolase genes are expressed in Trichomonas vaginalis.

    Science.gov (United States)

    Frasson, Amanda Piccoli; Dos Santos, Odelta; Meirelles, Lúcia Collares; Macedo, Alexandre José; Tasca, Tiana

    2016-01-01

    Trichomonas vaginalis is a protozoan that parasitizes the human urogenital tract causing trichomoniasis, the most common non-viral sexually transmitted disease. The parasite has unique genomic characteristics such as a large genome size and expanded gene families. Ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) is an enzyme responsible for hydrolyzing nucleoside tri- and diphosphates and has already been biochemically characterized in T. vaginalis. Considering the important role of this enzyme in the production of extracellular adenosine for parasite uptake, we evaluated the gene expression of five putative NTPDases in T. vaginalis. We showed that all five putative TvNTPDase genes (TvNTPDase1-5) were expressed by both fresh clinical and long-term grown isolates. The amino acid alignment predicted the presence of the five crucial apyrase conserved regions, transmembrane domains, signal peptides, phosphorylation and catalytic sites. Moreover, a phylogenetic analysis showed that TvNTPDase sequences make up a clade with NTPDases intracellularly located. Biochemical NTPDase activity (ATP and ADP hydrolysis) is responsive to the serum-restrictive conditions and the gene expression of TvNTPDases was mostly increased, mainly TvNTPDase2 and TvNTPDase4, although there was not a clear pattern of expression among them. In summary, the present report demonstrates the gene expression patterns of predicted NTPDases in T. vaginalis.

  19. Analogues of uracil nucleosides with intrinsic fluorescence (NIF-analogues): synthesis and photophysical properties.

    Science.gov (United States)

    Segal, Meirav; Fischer, Bilha

    2012-02-28

    Uridine cannot be utilized as fluorescent probe due to its extremely low quantum yield. For improving the uracil fluorescence characteristics we extended the natural chromophore at the C5 position by coupling substituted aromatic rings directly or via an alkenyl or alkynyl linker to create fluorophores. Extension of the uracil base was achieved by treating 5-I-uridine with the appropriate boronic acid under the Suzuki coupling conditions. Analogues containing an alkynyl linker were obtained from 5-I-uridine and the suitable boronic acid in a Sonogashira coupling reaction. The uracil fluorescent analogues proposed here were designed to satisfy the following requirements: a minimal chemical modification at a position not involved in base-pairing, resulting in relatively long absorption and emission wavelengths and high quantum yield. 5-((4-Methoxy-phenyl)-trans-vinyl)-2'-deoxy-uridine, 6b, was found to be a promising fluorescent probe. Probe 6b exhibits a quantum yield that is 3000-fold larger than that of the natural chromophore (Φ 0.12), maximum emission (478 nm) which is 170 nm red shifted as compared to uridine, and a Stokes shift of 143 nm. In addition, since probe 6b adopts the anti conformation and S sugar puckering favored by B-DNA, it makes a promising nucleoside analogue to be incorporated in an oligonucleotide probe for detection of genetic material.

  20. Preliminary characterization of (nucleoside-2′-O-)-methyltransferase crystals from Meaban and Yokose flaviviruses

    Energy Technology Data Exchange (ETDEWEB)

    Mastrangelo, Eloise; Bollati, Michela; Milani, Mario [Department of Biomolecular Sciences and Biotechnology, CNR-INFM, University of Milano, Via Celoria 26, 20133 Milano (Italy); Lamballeire, Xavier de; Brisbare, Nadege [Unité des Virus Emergents, Faculté de Médecine, 27 Boulevard Jean Moulin, 13005 Marseille (France); Dalle, Karen; Lantez, Violaine; Egloff, Marie-Pierre; Coutard, Bruno; Canard, Bruno [Laboratoire Architecture et Fonction des Macromolécules Biologiques, UMR 6098 CNRS ESIL, Case 932, 163 Avenue de Luminy, 13288 Marseille CEDEX 9 (France); Gould, Ernest; Forrester, Naomi [CEH Oxford, Mansfield Road, Oxford OX1 3SR (United Kingdom); Bolognesi, Martino, E-mail: martino.bolognesi@unimi.it [Department of Biomolecular Sciences and Biotechnology, CNR-INFM, University of Milano, Via Celoria 26, 20133 Milano (Italy)

    2006-08-01

    Two methyltransferases from flaviviruses (Meaban and Yokose viruses) have been overexpressed and crystallized. Diffraction data and characterization of the two crystal forms are presented, together with a preliminary molecular-replacement solution for both enzymes. Viral methyltranferases (MTase) are involved in the third step of the mRNA-capping process, transferring a methyl group from S-adenosyl-l-methionine (SAM) to the capped mRNA. MTases are classified into two groups: (guanine-N7)-methyltransferases (N7MTases), which add a methyl group onto the N7 atom of guanine, and (nucleoside-2′-O-)-methyltransferases (2′OMTases), which add a methyl group to a ribose hydroxyl. The MTases of two flaviviruses, Meaban and Yokose viruses, have been overexpressed, purified and crystallized in complex with SAM. Characterization of the crystals together with details of preliminary X-ray diffraction data collection (at 2.8 and 2.7 Å resolution, respectively) are reported here. The sequence homology relative to Dengue virus 2′OMTase and the structural conservation of specific residues in the putative active sites suggest that both enzymes belong to the 2′OMTase subgroup.

  1. Antiviral therapy for chronic hepatitis B: Combination of nucleoside analogs and interferon

    Institute of Scientific and Technical Information of China (English)

    Satoru; Hagiwara; Naoshi; Nishida; Masatoshi; Kudo

    2015-01-01

    The ideal goal of chronic hepatitis B(CHB) treatment should be suppression of emergence of hepatocellular carcinoma through the disappearance of hepatitis B s antigen(HBs Ag) rather than the control of serum hepatitis B virus-DNA level. For this purpose, various types of combination therapies using nucleoside analogs(NAs) and interferon(IFN) have been conducted. The therapeutic effects of combination of two different kinds of agents are better than those of the monotherapy using NAs or IFN alone, probably because different pharmaceutical properties might act in a coordinated manner. Recently, combination therapies with NAs and IFN and sequential therapies with NAs administration followed by IFN therapy have been routinely employed. We previously reported that combination therapy using entecavir(ETV) and pegylated(PEG)-IFN showed antiviral effects in 71% of CHB patients; the effect of this combination was better than that using lamivudine(LAM) and PEG-IFN. This is partially explained by the better antiviral effects of ETV than those of LAM. In our analysis, the cohort of CHB consisted of the patients who showed a flare-up of hepatitis before antiviral therapy, and their baseline HBs Ag levels were relatively low. Therefore, in addition to the combination of the agents, the appropriate selection of patients is critical to achieve a good viral response.

  2. Triple-Nucleoside Analog Antiretroviral Therapy: Is There Still a Role in Clinical Practice? A Review

    Directory of Open Access Journals (Sweden)

    Kessler Harold A

    2005-06-01

    Full Text Available Abstract The development and widespread clinical use of coformulated abacavir/lamivudine/zidovudine (ABC/3TC/ZDV as Trizivir represented an important advance in the management of HIV-infected patients, especially those with adherence challenges. With a low pill burden, no food restrictions, limited drug-drug interactions, and a favorable resistance profile, ABC/3TC/ZDV remains an alternative option in the US Department of Health and Human Services Consensus Panel Guidelines as initial treatment in antiretroviral-naive patients. Recent data have shown ABC/3TC/ZDV to be less efficacious in suppressing and/or maintaining suppression of virologic replication compared with efavirenz-containing antiretroviral therapy. Although triple-nucleoside/nucleotide reverse transcriptase inhibitor (t-NRTI combinations that do not contain a thymidine analog (ZDV or stavudine have recently shown high virologic failure rates in clinical trials and clinical practice, t-NRTI regimens containing a thymidine analog have consistently been shown to be efficacious.

  3. The search for an identification of amino acids, nucleobases and nucleosides in samples returned from Mars

    Science.gov (United States)

    Gehrke, Charles W.; Ponnamperuma, Cyril; Kuo, Kenneth C.; Stalling, David L.; Zumwalt, Robert W.

    1988-01-01

    The Mars Sample Return mission will provide us with a unique source of material from our solar system; material which could advance our knowledge of the processes of chemical evolution. As has been pointed out, Mars geological investigations based on the Viking datasets have shown that primordial Mars was in many biologically important ways similar to the primordial Earth; the presence of surface liquid water, moderate surface temperatures, and atmosphere of carbon dioxide and nitrogen, and high geothermal heat flow. Indeed, it would seem that conditions on Earth and Mars were fundamentally similar during the first one billion years or so. As has been pointed out, Mars may well contain the best preserved record of the events that transpired on the early planets. Examination of that early record will involve searching for many things, from microfossils to isotopic abundance data. We propose an investigation of the returned Mars samples for biologically important organic compounds, with emphases on amino acids, the purine and pyrimidine bases, and nucleosides.

  4. Tunnel conductance of Watson-Crick nucleoside-base pairs from telegraph noise

    Science.gov (United States)

    Chang, Shuai; He, Jin; Lin, Lisha; Zhang, Peiming; Liang, Feng; Young, Michael; Huang, Shuo; Lindsay, Stuart

    2009-05-01

    The use of tunneling signals to sequence DNA is presently hampered by the small tunnel conductance of a junction spanning an entire DNA molecule. The design of a readout system that uses a shorter tunneling path requires knowledge of the absolute conductance across base pairs. We have exploited the stochastic switching of hydrogen-bonded DNA base-nucleoside pairs trapped in a tunnel junction to determine the conductance of individual molecular pairs. This conductance is found to be sensitive to the geometry of the junction, but a subset of the data appears to come from unstrained molecular pairs. The conductances determined from these pairs are within a factor of two of the predictions of density functional calculations. The experimental data reproduces the counterintuitive theoretical prediction that guanine-deoxycytidine pairs (3 H-bonds) have a smaller conductance than adenine-thymine pairs (2 H-bonds). A bimodal distribution of switching lifetimes shows that both H-bonds and molecule-metal contacts break.

  5. Evaluation of serum nucleoside diphosphate kinase A for the detection of colorectal cancer

    Science.gov (United States)

    Otero-Estévez, Olalla; De Chiara, Loretta; Barcia-Castro, Leticia; Páez de la Cadena, María; Rodríguez-Berrocal, Francisco Javier; Cubiella, Joaquín; Hernández, Vicent; Martínez-Zorzano, Vicenta Soledad

    2016-01-01

    We previously described the over-expression of nucleoside diphosphate kinase A (NDKA) in tumours and serum from colorectal cancer (CRC) patients, suggesting its use as biomarker. In this study we evaluated the diagnostic accuracy of serum NDKA to detect advanced neoplasia (CRC or advanced adenomas). Furthermore, the performance of NDKA was compared with the faecal immunochemical test (FIT). The study population included a case-control cohort and a screening cohort (511 asymptomatic first-degree relatives of CRC patients that underwent a colonoscopy and a FIT). Serum NDKA was elevated in CRC patients in the case-control cohort (p = 0.002). In the screening cohort, NDKA levels were higher for advanced adenomas (p = 0.010) and advanced neoplasia (p = 0.006) compared to no neoplasia. Moreover, elevated NDKA was associated with severe characteristics of adenomas (≥3 lesions, size ≥ 1 cm or villous component). Setting specificity to 85%, NDKA showed a sensitivity of 30.19% and 29.82% for advanced adenomas and advanced neoplasia, respectively. NDKA combined with FIT (100 ng/mL cut-off) detected advanced adenomas and advanced neoplasia with 45.28% and 49.12% sensitivity, with specificity close to 90%. The combination of serum NDKA and FIT can improve the detection of advanced neoplasia, mainly for lesions located on the proximal colon, in asymptomatic individuals with CRC family-risk. PMID:27222072

  6. Calculations of the Energetics of Oxidation of Aqueous Nucleosides and the Effects of Prototropic Equilibria.

    Science.gov (United States)

    Close, David M; Wardman, Peter

    2016-06-16

    Recently the calculated standard reduction potentials of the radical-cations of N-methyl substituted DNA bases have been reported that agree fairly well with the experimental results. However, there are issues reflecting the fact that the experimental results usually relate to the couple E(o)(Nuc(•),H(+)/NucH(+)), whereas the calculated results are for the E(o)(Nuc(•+)/Nuc) couple. To calculate the midpoint reduction potential at pH 7 (Em7), it is important to have accurate acid dissociation constants (pKs) for both ground-state bases and their radicals, and the effects of uncertainty in some of these values (e.g., that of the adenosine radical) must be considered. Calculations of the pKs of the radicals of the nucleic acid bases (as nucleosides) have been performed to explore the effects the various pKs have on calculating the values of Em7 and to see what improvements can be made with the accuracy of the calculations.

  7. Effective strand invasion ODN incorporating a new bicyclic nucleoside analogue (WNA).

    Science.gov (United States)

    Aoki, Eriko; Taniguchi, Yosuke; Sasaki, Shigeki

    2007-01-01

    Efficient and specific targeting of DNA sequences by synthetic ligands is a major goal in chemical biology. Triplex-forming oligonucleotides (TFOs) are sequence-specific DNA-binding agents, but are limited to homopurine/homopyrimidine target sequences. We have previously reported two useful analogues (WNA: W-shaped nucleoside analogues), WNA-bT and WNAbC, which recognize a TA and a CG interrupting site forming triplexes with high stability and selectivity, respectively. However, their ability to form triplexes depended on their neighbouring bases in the TFO. Subsequent studies have shown that the sequence-dependency of the WNA analogues, for the formation of triplexes, has been partially solved by use of a WNA analogue bearing a substituted aromatic ring. Investigations into the effects of the substituted aromatic ring of WNA derivatives on the stability of triplexes led to the discovery of strand invasion by the TFO incorporating the new WNA analogue to form a highly stable duplex. PMID:18029683

  8. 75Se-substituted purine nucleoside derivatives as tumor diagnostic agents

    International Nuclear Information System (INIS)

    Eight 75Se-substituted purine nucleoside derivatives were represented for the first time and their synthesis was described. The substances were tested in animal experiments for their suitability for tumor diagnostic agents and the change of organ kinetic distribution in dependence on structural characteristics of the compounds was studied. Whole-body retention was essentially higher for all substances possessing an isopropylidene group. Methylation at position 8 results in a preferable excretation via the liver. The substitution of the amino-group by a hydroxyl group increases the excretion rate which is preferably a renal one. The uptake rates recorded for Ehrlich-ascites cell-suspensions give evidence of a dependence on the number of hydropholic groups. Four of the compounds tested show tendencies to a specific uptake in neoplastic tissue, the tumour-muscle quotients are partly in the same order of magnitude like those of 111In or 57Co bleomycine. The tumour-blood quotients do not reach the values of the commercial comaparative preparations. (author)

  9. Global Conformational Dynamics of HIV-1 Reverse Transcriptase Bound to Non-Nucleoside Inhibitors

    Directory of Open Access Journals (Sweden)

    Peter V. Coveney

    2012-07-01

    Full Text Available HIV-1 Reverse Transcriptase (RT is a multifunctional enzyme responsible for the transcription of the RNA genome of the HIV virus into DNA suitable for incorporation within the DNA of human host cells. Its crucial role in the viral life cycle has made it one of the major targets for antiretroviral drug therapy. The Non-Nucleoside RT Inhibitor (NNRTI class of drugs binds allosterically to the enzyme, affecting many aspects of its activity. We use both coarse grained network models and atomistic molecular dynamics to explore the changes in protein dynamics induced by NNRTI binding. We identify changes in the flexibility and conformation of residue Glu396 in the RNaseH primer grip which could provide an explanation for the acceleration in RNaseH cleavage rate observed experimentally in NNRTI bound HIV-1 RT. We further suggest a plausible path for conformational and dynamic changes to be communicated from the vicinity of the NNRTI binding pocket to the RNaseH at the other end of the enzyme.

  10. Exploring QSAR of Non-Nucleoside Reverse Transcriptase Inhibitors by Neural Networks: TIBO Derivatives

    Directory of Open Access Journals (Sweden)

    Driss Cherqaoui

    2004-01-01

    Full Text Available Abstract: Human Immunodeficiency Virus type 1 (HIV-1 reverse transcriptase is an important target for chemotherapeutic agents against the AIDS disease. 4,5,6,7-Tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H-ones (TIBO derivatives are potent non-nucleoside reverse transcriptase inhibitors (NNRTIs. In the present work, quantitative structure-activity relationship (QSAR analysis for a set of 82 TIBO derivatives has been investigated by means of a three-layered neural network (NN. It has been shown that NN can be a potential tool in the investigation of QSAR analysis compared with the models given in the literature. NN gave good statistical results both in fitting and prediction processes (0.861 ≤ r² ≤ 0.928, 0.839 ≤q² ≤ 0.845. The relevant factors controlling the anti-HIV-1 activity of TIBO derivatives have been identified. The results are along the same lines as those of our previous studies on HEPT derivatives and indicate the importance of the hydrophobic parameter in modeling the QSAR for TIBO derivatives.

  11. Sinefungin, a Natural Nucleoside Analogue of S-Adenosylmethionine, Inhibits Streptococcus pneumoniae Biofilm Growth

    Directory of Open Access Journals (Sweden)

    Mukesh Kumar Yadav

    2014-01-01

    Full Text Available Pneumococcal colonization and disease is often associated with biofilm formation, in which the bacteria exhibit elevated resistance both to antibiotics and to host defense systems, often resulting in infections that are persistent and difficult to treat. We evaluated the effect of sinefungin, a nucleoside analogue of S-adenosylmethionine, on pneumococcal in vitro biofilm formation and in vivo colonization. Sinefungin is bacteriostatic to pneumococci and significantly decreased biofilm growth and inhibited proliferation and structure of actively growing biofilms but did not alter growth or the matrix structure of established biofilms. Sinefungin significantly reduced pneumococcal colonization in rat middle ear. The quorum sensing molecule (autoinducer-2 production was significantly reduced by 92% in sinefungin treated samples. The luxS, pfs, and speE genes were downregulated in biofilms grown in the presence of sinefungin. This study shows that sinefungin inhibits pneumococcal biofilm growth in vitro and colonization in vivo, decreases AI-2 production, and downregulates luxS, pfs, and speE gene expressions. Therefore, the S-adenosylmethionine (SAM inhibitors could be used as lead compounds for the development of novel antibiofilm agents against pneumococci.

  12. Effect of Purine Nucleoside Analogue-Acyclovir on The Sperm Parameters and Testosterone Production in Rats

    Directory of Open Access Journals (Sweden)

    Vahid Nejati

    2013-01-01

    Full Text Available Background: Acyclovir (ACV, a synthetic purine nucleoside analogue derived fromguanosine, is known to be toxic to gonads and the aim of this study was to evaluate theeffect of ACV on the sperm parameters and testosterone production in rat.Materials and Methods: In this experimental study, forty adult male Wistar rats (220± 20 g were randomly divided into five groups (n=8 for each group. One groupserved as control and one group served as sham control [distilled water was intraperitoneally(i.p. injected]. ACV was administered intraperitoneally in the drugtreatment groups (4, 16 and 48 mg/kg/day for 15 days. Eighteen days after the lastinjection, rats were sacrificed by CO2 inhalation. After that, cauda epididymideswere removed surgically. At the end, sperm concentrations in the cauda epididymis,sperm motility, morphology, viability, chromatin quality and DNA integrity wereanalyzed. Serum testosterone concentrations were determined.Results: The results showed that ACV did not affect sperm count, but decreased spermmotility and sperm viability at 16 and 48 mg/kg dose-levels. Sperm abnormalities increasedat 48 mg/kg dose-level of ACV. Further, ACV significantly increases DNA damageat 16 and 48 mg/kg dose-levels and chromatin abnormality at all doses. Besides, asignificant decrease in serum testosterone concentrations was observed at 16 and 48 mg/kg doses.Conclusion: The present results highly support the idea that ACV induces testicular toxicityby adverse effects on the sperm parameters and serum level of testosterone in malerats.

  13. Amphiphilic cationic nanogels as brain-targeted carriers for activated nucleoside reverse transcriptase inhibitors

    Science.gov (United States)

    Warren, G; Makarov, E; Lu, Y; Senanayake, T; Rivera, K; Gorantla, S; Poluektova, LY; Vinogradov, SV

    2015-01-01

    Progress in AIDS treatment shifted emphasis towards limiting adverse effects of antiviral drugs while improving the treatment of hard-to-reach viral reservoirs. Many therapeutic nucleoside reverse transcriptase inhibitors (NRTI) have a limited access to the central nervous system (CNS). Increased NRTI levels induced various complications during the therapy, including neurotoxicity, due to the NRTI toxicity to mitochondria. Here, we describe an innovative design of biodegradable cationic cholesterol-ε-polylysine nanogel carriers for delivery of triphosphorylated NRTIs that demonstrated high anti-HIV activity along with low neurotoxicity, warranting minimal side effects following systemic administration. Efficient CNS targeting was achieved by nanogel modification with brain-specific peptide vectors. Novel dual and triple-drug nanoformulations, analogous to therapeutic NRTI cocktails, displayed equal or higher antiviral activity in HIV-infected macrophages compared to free drugs. Our results suggest potential alternative approach to HIV-1 treatment focused on the effective nanodrug delivery to viral reservoirs in the CNS and reduced neurotoxicity. PMID:25559020

  14. A structural study of lamellar phases formed by nucleoside-functionalized lipids

    CERN Document Server

    Berti, D; Baglioni, P; Dante, S; Hauss, T

    2002-01-01

    We report a neutron-scattering investigation of lamellar phases formed by novel phospholipids bearing nucleosides at the polar-head-group region. These nucleolipids can interact through stacking and H-bond interactions, following a pattern that resembles base-base coupling in natural nucleic acids (DNA, RNA), i.e. they have similar recognition properties. Bilayer stacks formed of DPP-adenosine, DPP-uridine and their 1:1 mixture were investigated after equilibration in a 98% relative humidity atmosphere. The DPP-adenosine spectrum can be accounted for (in analogy to DPPC) by a lamellar phase with a smectic period of about 60 A. DPP-uridine displays a not so straightforward behavior that we have tentatively ascribed to the coexistence of lamellae with different smectic periods. In the 1:1 mixture the lamellar mesophase of DPP-uridine is retained, suggesting a specific interaction of the uridine polar-head group with the adenosine moiety of DPP-adenosine. It should be stressed that this behavior can be considere...

  15. Nucleosides from Anthopleura stell%绿海葵中的核苷类成分

    Institute of Scientific and Technical Information of China (English)

    禚如朋; 付宏征; 张礼和; 林文翰

    2001-01-01

    目的 为了寻找抗肿瘤的活性成分。方法 利用溶剂法和色谱法对绿海葵进行了研究。结果 分离得到5 个核苷,经波谱学解析鉴定为2-羟基嘌呤核苷(Ⅰ),脱氧肌苷(Ⅱ),1-甲基黄嘌呤核苷(Ⅲ),脱氧鸟苷(Ⅳ),脱氧核糖胸腺嘧啶(Ⅴ)。结论 Ⅲ为一新天然产物,其余均为海洋生物中首次发现。%To study the chemical constituents of sea anemone, Anthopleura stell Verrill.Methods The chemical constituents were isolated and purified by chromatographic methods and their structures elucidated by chemical evidences and spectra data.Results 5 nucleosides were obtained and identified from the ethanolic extract as 2-hydroxy purine (Ⅰ); deoxyinosine (Ⅱ); 1-methylxanthosine (Ⅲ); deoxyguanosine (Ⅳ), and deoxyribo-thymidine (Ⅴ).Conclusion Compound Ⅲ was a new natural product, while the others were found from sea anemone for the first time.

  16. RNA 5'-triphosphatase, nucleoside triphosphatase, and guanylyltransferase activities of baculovirus LEF-4 protein.

    Science.gov (United States)

    Gross, C H; Shuman, S

    1998-12-01

    Autographa californica nuclear polyhedrosis virus late and very late mRNAs are transcribed by an RNA polymerase consisting of four virus-encoded polypeptides: LEF-8, LEF-9, LEF-4, and p47. The 464-amino-acid LEF-4 subunit contains the signature motifs of GTP:RNA guanylyltransferases (capping enzymes). Here, we show that the purified recombinant LEF-4 protein catalyzes two reactions involved in RNA cap formation. LEF-4 is an RNA 5'-triphosphatase that hydrolyzes the gamma phosphate of triphosphate-terminated RNA and a guanylyltransferase that reacts with GTP to form a covalent protein-guanylate adduct. The RNA triphosphatase activity depends absolutely on a divalent cation; the cofactor requirement is satisfied by either magnesium or manganese. LEF-4 also hydrolyzes ATP to ADP and Pi (Km = 43 microM ATP; Vmax = 30 s-1) and GTP to GDP and Pi. The LEF-4 nucleoside triphosphatase (NTPase) is activated by manganese or cobalt but not by magnesium. The RNA triphosphatase and NTPase activities of baculovirus LEF-4 resemble those of the vaccinia virus and Saccharomyces cerevisiae mRNA capping enzymes. We suggest that these proteins comprise a novel family of metal-dependent triphosphatases. PMID:9811740

  17. Lubrication of Individual Microcontacts by a Self-Assembled Alkyl Phosphonic Acid Monolayer on α-Al2O3(0001).

    Science.gov (United States)

    Paul, Jonas; Meltzer, Christian; Braunschweig, Björn; Peukert, Wolfgang

    2016-08-23

    We report on the tribological behavior of a self-assembled alkyl phosphonic acid monolayer on the microscale using the colloidal probe technique. Friction-load data and adhesion forces were measured with borosilicate glass particles on uncoated and octadecylphosphonic acid (ODPA) coated α-Al2O3(0001) surfaces. A significant decrease in friction force was observed after surface coating, while the adhesion force was only moderately reduced. We assume the lubrication effect of the ODPA self-assembled monolayer (SAM) to be close to the maximum obtainable of alkyl phosphonic acids in the studied system due to the high molecular order which was confirmed by vibrational sum-frequency generation. At small loads, a nonlinear dependence of friction force to load was maintained after surface coating. However, a shift from a contact behavior well described by the DMT model toward the JKR model occurred that is possibly related to the altered elastic properties of the coated surface. With increasing load, a linear friction-load behavior was observed on the coated samples. Molecular plowing and adhesive interactions were identified as responsible mechanisms. In all friction experiments, we could not detect any wear neither of the colloidal probes nor at the surfaces of uncoated and coated samples. This proves the high wear resistivity of the studied ODPA SAM. PMID:27478898

  18. Combining directed acyclic graphs and the change-in-estimate procedure as a novel approach to adjustment-variable selection in epidemiology

    Directory of Open Access Journals (Sweden)

    Evans David

    2012-10-01

    Full Text Available Abstract Background Directed acyclic graphs (DAGs are an effective means of presenting expert-knowledge assumptions when selecting adjustment variables in epidemiology, whereas the change-in-estimate procedure is a common statistics-based approach. As DAGs imply specific empirical relationships which can be explored by the change-in-estimate procedure, it should be possible to combine the two approaches. This paper proposes such an approach which aims to produce well-adjusted estimates for a given research question, based on plausible DAGs consistent with the data at hand, combining prior knowledge and standard regression methods. Methods Based on the relationships laid out in a DAG, researchers can predict how a collapsible estimator (e.g. risk ratio or risk difference for an effect of interest should change when adjusted on different variable sets. Implied and observed patterns can then be compared to detect inconsistencies and so guide adjustment-variable selection. Results The proposed approach involves i. drawing up a set of plausible background-knowledge DAGs; ii. starting with one of these DAGs as a working DAG, identifying a minimal variable set, S, sufficient to control for bias on the effect of interest; iii. estimating a collapsible estimator adjusted on S, then adjusted on S plus each variable not in S in turn (“add-one pattern” and then adjusted on the variables in S minus each of these variables in turn (“minus-one pattern”; iv. checking the observed add-one and minus-one patterns against the pattern implied by the working DAG and the other prior DAGs; v. reviewing the DAGs, if needed; and vi. presenting the initial and all final DAGs with estimates. Conclusion This approach to adjustment-variable selection combines background-knowledge and statistics-based approaches using methods already common in epidemiology and communicates assumptions and uncertainties in a standardized graphical format. It is probably best suited to

  19. Inhibition and Structure of Trichomonas vaginalis Purine Nucleoside Phosphorylase with Picomolar Transition State Analogues

    Energy Technology Data Exchange (ETDEWEB)

    Rinaldo-Matthis,A.; Wing, C.; Ghanem, M.; Deng, H.; Wu, P.; Gupta, A.; Tyler, P.; Evans, G.; Furneaux, R.; et al.

    2007-01-01

    Trichomonas vaginalis is a parasitic protozoan purine auxotroph possessing a unique purine salvage pathway consisting of a bacterial type purine nucleoside phosphorylase (PNP) and a purine nucleoside kinase. Thus, T. vaginalis PNP (TvPNP) functions in the reverse direction relative to the PNPs in other organisms. Immucillin-A (ImmA) and DADMe-Immucillin-A (DADMe-ImmA) are transition stte mimics of adenosine with geometric and electrostatic features that resemble early and late transition states of adenosine at the transition state stabilized by TvPNP. ImmA demonstrates slow-onset tight-binding inhibition with TvPNP, to give an equilibrium dissociation constant of 87 pM, an inhibitor release half-time of 17.2 min, and a K{sub m}/K{sub d} ratio of 70,100. DADMe-ImmA resembles a late ribooxacarbenium ion transition state for TvPNP to give a dissociation constant of 30 pM, an inhibitor release half-time of 64 min, and a K{sub m}/K{sub d} ratio of 203,300. The tight binding of DADMe-ImmA supports a late S{sub N}1 transition state. Despite their tight binding to TvPNP, ImmA and DADMe-ImmA are weak inhibitors of human and P. falciparum PNPs. The crystal structures of the TvPNP-ImmA{center_dot}PO{sub 4} and TvPNP{center_dot}DADMe-ImmA{center_dot}PO{sub 4} ternary complexes differ from previous structures with substrate anologues. The tight binding with DADMe-ImmA is in part due to a 2.7 {angstrom} ionic interaction between a PO{sub 4} oxygen and the N1 cation of the hydroxypyrrolidine and is weaker in the TvPNP{center_dot}ImmA{center_dot}PO{sub 4} structure at 3.5 {angstrom}. However, the TvPNP{center_dot}ImmA{center_dot}PO{sub 4} structure includes hydrogen bonds between the 2'-hydroxyl and the protein that are not present in TvPNP{center_dot}DADMe-ImmA{center_dot}PO{sub 4}. These structures explain why DADMe-ImmA binds tighter than ImmA. Immucillin-H is a 12 nM inhibitor of TvPNP but a 56 pM inhibitor of human PNP. And this difference is explained by isotope

  20. The chemoenzymatic synthesis of clofarabine and related 2′-deoxyfluoroarabinosyl nucleosides: the electronic and stereochemical factors determining substrate recognition by E. coli nucleoside phosphorylases

    OpenAIRE

    Fateev, Ilja V; Konstantin V. Antonov; Konstantinova, Irina D; Tatyana I. Muravyova; Frank Seela; Esipov, Roman S; Anatoly I. Miroshnikov; Mikhailopulo, Igor A.

    2014-01-01

    Two approaches to the synthesis of 2-chloro-9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine (1, clofarabine) were studied. The first approach consists in the chemical synthesis of 2-deoxy-2-fluoro-α-D-arabinofuranose-1-phosphate (12a, 2FAra-1P) via three step conversion of 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranose (9) into the phosphate 12a without isolation of intermediary products. Condensation of 12a with 2-chloroadenine catalyzed by the recombinant E. coli purine nucleosid...

  1. Identification of an alternative nucleoside triphosphate: 5'-deoxyadenosylcobinamide phosphate nucleotidyltransferase in Methanobacterium thermoautotrophicum delta H.

    Science.gov (United States)

    Thomas, M G; Escalante-Semerena, J C

    2000-08-01

    Computer analysis of the archaeal genome databases failed to identify orthologues of all of the bacterial cobamide biosynthetic enzymes. Of particular interest was the lack of an orthologue of the bifunctional nucleoside triphosphate (NTP):5'-deoxyadenosylcobinamide kinase/GTP:adenosylcobinamide-phosphate guanylyltransferase enzyme (CobU in Salmonella enterica). This paper reports the identification of an archaeal gene encoding a new nucleotidyltransferase, which is proposed to be the nonorthologous replacement of the S. enterica cobU gene. The gene encoding this nucleotidyltransferase was identified using comparative genome analysis of the sequenced archaeal genomes. Orthologues of the gene encoding this activity are limited at present to members of the domain Archaea. The corresponding ORF open reading frame from Methanobacterium thermoautotrophicum Delta H (MTH1152; referred to as cobY) was amplified and cloned, and the CobY protein was expressed and purified from Escherichia coli as a hexahistidine-tagged fusion protein. This enzyme had GTP:adenosylcobinamide-phosphate guanylyltransferase activity but did not have the NTP:AdoCbi kinase activity associated with the CobU enzyme of S. enterica. NTP:adenosylcobinamide kinase activity was not detected in M. thermoautotrophicum Delta H cell extract, suggesting that this organism may not have this activity. The cobY gene complemented a cobU mutant of S. enterica grown under anaerobic conditions where growth of the cell depended on de novo adenosylcobalamin biosynthesis. cobY, however, failed to restore adenosylcobalamin biosynthesis in cobU mutants grown under aerobic conditions where de novo synthesis of this coenzyme was blocked, and growth of the cell depended on the assimilation of exogenous cobinamide. These data strongly support the proposal that the relevant cobinamide intermediates during de novo adenosylcobalamin biosynthesis are adenosylcobinamide-phosphate and adenosylcobinamide-GDP, not adenosylcobinamide

  2. Metabolites of purine nucleoside phosphorylase (NP in serum have the potential to delineate pancreatic adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Shaiju K Vareed

    Full Text Available Pancreatic Adenocarcinoma (PDAC, the fourth highest cause of cancer related deaths in the United States, has the most aggressive presentation resulting in a very short median survival time for the affected patients. Early detection of PDAC is confounded by lack of specific markers that has motivated the use of high throughput molecular approaches to delineate potential biomarkers. To pursue identification of a distinct marker, this study profiled the secretory proteome in 16 PDAC, 2 carcinoma in situ (CIS and 7 benign patients using label-free mass spectrometry coupled to 1D-SDS-PAGE and Strong Cation-Exchange Chromatography (SCX. A total of 431 proteins were detected of which 56 were found to be significantly elevated in PDAC. Included in this differential set were Parkinson disease autosomal recessive, early onset 7 (PARK 7 and Alpha Synuclein (aSyn, both of which are known to be pathognomonic to Parkinson's disease as well as metabolic enzymes like Purine Nucleoside Phosphorylase (NP which has been exploited as therapeutic target in cancers. Tissue Microarray analysis confirmed higher expression of aSyn and NP in ductal epithelia of pancreatic tumors compared to benign ducts. Furthermore, extent of both aSyn and NP staining positively correlated with tumor stage and perineural invasion while their intensity of staining correlated with the existence of metastatic lesions in the PDAC tissues. From the biomarker perspective, NP protein levels were higher in PDAC sera and furthermore serum levels of its downstream metabolites guanosine and adenosine were able to distinguish PDAC from benign in an unsupervised hierarchical classification model. Overall, this study for the first time describes elevated levels of aSyn in PDAC as well as highlights the potential of evaluating NP protein expression and levels of its downstream metabolites to develop a multiplex panel for non-invasive detection of PDAC.

  3. Triazole pyrimidine nucleosides as inhibitors of Ribonuclease A. Synthesis, biochemical, and structural evaluation.

    Science.gov (United States)

    Parmenopoulou, Vanessa; Chatzileontiadou, Demetra S M; Manta, Stella; Bougiatioti, Stamatina; Maragozidis, Panagiotis; Gkaragkouni, Dimitra-Niki; Kaffesaki, Eleni; Kantsadi, Anastassia L; Skamnaki, Vassiliki T; Zographos, Spyridon E; Zounpoulakis, Panagiotis; Balatsos, Nikolaos A A; Komiotis, Dimitris; Leonidas, Demetres D

    2012-12-15

    Five ribofuranosyl pyrimidine nucleosides and their corresponding 1,2,3-triazole derivatives have been synthesized and characterized. Their inhibitory action to Ribonuclease A has been studied by biochemical analysis and X-ray crystallography. These compounds are potent competitive inhibitors of RNase A with low μM inhibition constant (K(i)) values with the ones having a triazolo linker being more potent than the ones without. The most potent of these is 1-[(β-D-ribofuranosyl)-1,2,3-triazol-4-yl]uracil being with K(i) = 1.6 μM. The high resolution X-ray crystal structures of the RNase A in complex with three most potent inhibitors of these inhibitors have shown that they bind at the enzyme catalytic cleft with the pyrimidine nucleobase at the B(1) subsite while the triazole moiety binds at the main subsite P(1), where P-O5' bond cleavage occurs, and the ribose at the interface between subsites P(1) and P(0) exploiting interactions with residues from both subsites. The effect of a susbsituent group at the 5-pyrimidine position at the inhibitory potency has been also examined and results show that any addition at this position leads to a less efficient inhibitor. Comparative structural analysis of these RNase A complexes with other similar RNase A-ligand complexes reveals that the triazole moiety interactions with the protein form the structural basis of their increased potency. The insertion of a triazole linker between the pyrimidine base and the ribose forms the starting point for further improvement of these inhibitors in the quest for potent ribonucleolytic inhibitors with pharmaceutical potential. PMID:23122937

  4. Nucleoside triphosphatase and RNA helicase activities associated with GB virus B nonstructural protein 3.

    Science.gov (United States)

    Zhong, W; Ingravallo, P; Wright-Minogue, J; Skelton, A; Uss, A S; Chase, R; Yao, N; Lau, J Y; Hong, Z

    1999-09-01

    GB virus B (GBV-B) is a positive-stranded RNA virus that belongs to the Flaviviridae family. This virus is closely related to hepatitis C virus (HCV) and causes acute hepatitis in tamarins (Saguinus species). Nonstructural protein 3 (NS3) of GBV-B contains sequence motifs predictive of three enzymatic activities: serine protease, nucleoside triphosphatase (NTPase), and RNA helicase. The N-terminal serine protease has been characterized and shown to share similar substrate specificity with the HCV NS3 protease. In this report, a full-length GBV-B NS3 protein was expressed in Escherichia coli and purified to homogeneity. This recombinant protein was shown to possess polynucleotide-stimulated NTPase and double-stranded RNA (dsRNA) unwinding activities. Both activities were abolished by a single amino acid substitution, from the Lys (K) residue in the conserved walker motif A (or Ia) "AXXXXGK(210)S" to an Ala (A), confirming that they are intrinsic to GBV-B NS3. Kinetic parameters (K(m) and k(cat)) for hydrolysis of various NTPs or dNTPs were obtained. The dsRNA unwinding activity depends on the presence of divalent metal ions and ATP and requires an RNA duplex substrate with 3' unpaired regions (RNAs with 5' unpaired regions only or with blunt ends are not suitable substrates for this enzyme). This indicates that GBV-B NS3 RNA helicase unwinds dsRNA in the 3' to 5' direction. Direct interaction of the GBV-B NS3 protein with a single-stranded RNA was established using a gel-based RNA bandshift assay. Finally, a homology model of GBV-B NS3 RNA helicase domain based on the 3-dimensional structure of the HCV NS3 helicase that shows a great similarity in overall structure and surface charge distribution between the two proteins was proposed. PMID:10497107

  5. Mycobacterium tuberculosis nucleoside diphosphate kinase inactivates small GTPases leading to evasion of innate immunity.

    Directory of Open Access Journals (Sweden)

    Jim Sun

    Full Text Available Defining the mechanisms of Mycobacterium tuberculosis (Mtb persistence in the host macrophage and identifying mycobacterial factors responsible for it are keys to better understand tuberculosis pathogenesis. The emerging picture from ongoing studies of macrophage deactivation by Mtb suggests that ingested bacilli secrete various virulence determinants that alter phagosome biogenesis, leading to arrest of Mtb vacuole interaction with late endosomes and lysosomes. While most studies focused on Mtb interference with various regulators of the endosomal compartment, little attention was paid to mechanisms by which Mtb neutralizes early macrophage responses such as the NADPH oxidase (NOX2 dependent oxidative burst. Here we applied an antisense strategy to knock down Mtb nucleoside diphosphate kinase (Ndk and obtained a stable mutant (Mtb Ndk-AS that displayed attenuated intracellular survival along with reduced persistence in the lungs of infected mice. At the molecular level, pull-down experiments showed that Ndk binds to and inactivates the small GTPase Rac1 in the macrophage. This resulted in the exclusion of the Rac1 binding partner p67(phox from phagosomes containing Mtb or Ndk-coated latex beads. Exclusion of p67(phox was associated with a defect of both NOX2 assembly and production of reactive oxygen species (ROS in response to wild type Mtb. In contrast, Mtb Ndk-AS, which lost the capacity to disrupt Rac1-p67(phox interaction, induced a strong ROS production. Given the established link between NOX2 activation and apoptosis, the proportion of Annexin V positive cells and levels of intracellular active caspase 3 were significantly higher in cells infected with Mtb Ndk-AS compared to wild type Mtb. Thus, knock down of Ndk converted Mtb into a pro-apoptotic mutant strain that has a phenotype of increased susceptibility to intracellular killing and reduced virulence in vivo. Taken together, our in vitro and in vivo data revealed that Ndk

  6. Recognition of Nucleoside Monophosphate Substrates by Haemophilus influenzae Class C Acid Phosphatase

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Harkewal; Schuermann, Jonathan P.; Reilly, Thomas J.; Calcutt, Michael J.; Tanner, John J. (Cornell); (UMC)

    2010-12-08

    The e (P4) phosphatase from Haemophilus influenzae functions in a vestigial NAD{sup +} utilization pathway by dephosphorylating nicotinamide mononucleotide to nicotinamide riboside. P4 is also the prototype of class C acid phosphatases (CCAPs), which are nonspecific 5{prime},3{prime}-nucleotidases localized to the bacterial outer membrane. To understand substrate recognition by P4 and other class C phosphatases, we have determined the crystal structures of a substrate-trapping mutant P4 enzyme complexed with nicotinamide mononucleotide, 5{prime}-AMP, 3{prime}-AMP, and 2{prime}-AMP. The structures reveal an anchor-shaped substrate-binding cavity comprising a conserved hydrophobic box that clamps the nucleotide base, a buried phosphoryl binding site, and three solvent-filled pockets that contact the ribose and the hydrogen-bonding edge of the base. The span between the hydrophobic box and the phosphoryl site is optimal for recognizing nucleoside monophosphates, explaining the general preference for this class of substrate. The base makes no hydrogen bonds with the enzyme, consistent with an observed lack of base specificity. Two solvent-filled pockets flanking the ribose are key to the dual recognition of 5{prime}-nucleotides and 3{prime}-nucleotides. These pockets minimize the enzyme's direct interactions with the ribose and provide sufficient space to accommodate 5{prime} substrates in an anti conformation and 3{prime} substrates in a syn conformation. Finally, the structures suggest that class B acid phosphatases and CCAPs share a common strategy for nucleotide recognition.

  7. Flagellar Radial Spokes Contain a Ca2+-stimulated Nucleoside Diphosphate Kinase

    Science.gov (United States)

    Patel-King, Ramila S.; Gorbatyuk, Oksana; Takebe, Sachiko; King, Stephen M.

    2004-01-01

    The radial spokes are required for Ca2+-initiated intraflagellar signaling, resulting in modulation of inner and outer arm dynein activity. However, the mechanochemical properties of this signaling pathway remain unknown. Here, we describe a novel nucleoside diphosphate kinase (NDK) from the Chlamydomonas flagellum. This protein (termed p61 or RSP23) consists of an N-terminal catalytic NDK domain followed by a repetitive region that includes three IQ motifs and a highly acidic C-terminal segment. We find that p61 is missing in axonemes derived from the mutants pf14 (lacks radial spokes) and pf24 (lacks the spoke head and several stalk components) but not in those from pf17 (lacking only the spoke head). The p61 protein can be extracted from oda1 (lacks outer dynein arms) and pf17 axonemes with 0.5 M KI, and copurifies with radial spokes in sucrose density gradients. Furthermore, p61 contains two classes of calmodulin binding site: IQ1 interacts with calmodulin-Sepharose beads in a Ca2+-independent manner, whereas IQ2 and IQ3 show Ca2+-sensitive associations. Wild-type axonemes exhibit two distinct NDKase activities, at least one of which is stimulated by Ca2+. This Ca2+-responsive enzyme, which accounts for ∼45% of total axonemal NDKase, is missing from pf14 axonemes. We found that purified radial spokes also exhibit NDKase activity. Thus, we conclude that p61 is an integral component of the radial spoke stalk that binds calmodulin and exhibits Ca2+-controlled NDKase activity. These observations suggest that nucleotides other than ATP may play an important role in the signal transduction pathway that underlies the regulatory mechanism defined by the radial spokes. PMID:15194815

  8. Structures and Spectroscopy Studies of Two M(II-Phosphonate Coordination Polymers Based on Alkaline Earth Metals (M = Ba, Mg

    Directory of Open Access Journals (Sweden)

    Kui-Rong Ma

    2013-01-01

    Full Text Available The two examples of alkaline-earth M(II-phosphonate coordination polymers, [Ba2(L(H2O9]·3H2O (1 and [Mg1.5(H2O9]·(L-H21.5·6H2O (2 (H4L = H2O3PCH2N(C4H8NCH2PO3H2, N,N′-piperazinebis(methylenephosphonic acid, (L-H2 = O3PH2CHN(C4H8NHCH2PO3 have been hydrothermally synthesized and characterized by elemental analysis, FT-IR, PXRD, TG-DSC, and single-crystal X-ray diffraction. Compound 1 possesses a 2D inorganic-organic alternate arrangement layer structure built from 1D inorganic chains through the piperazine bridge, in which the ligand L−4 shows two types of coordination modes reported rarely at the same time. In 1, both crystallographic distinct Ba(1 and Ba(2 ions adopt 8-coordination two caps and 9-coordination three caps triangular prism geometry structures, respectively. Compound 2 possesses a zero-dimensional mononuclear structure with two crystallographic distinct Mg(II ions. Free metal cations   [MgO6]n2+ and uncoordinated anions (L-H2n2- are joined together by static electric force. Results of photoluminescent measurement indicate three main emission bands centered at 300 nm, 378.5 nm, and 433 nm for 1 and 302 nm, 378 nm, and 434.5 nm for 2 (λex=235 nm, respectively. The high energy emissions could be derived from the intraligand π∗-n transition stations of H4L (310 nm and 382 nm, λex=235 nm, while the low energy emission (>400 nm of 1-2 may be due to the coordination effect with metal(II ions.

  9. Design and Synthesis of Novel Antimicrobial Acyclic and Heterocyclic Dyes and Their Precursors for Dyeing and/or Textile Finishing Based on 2-N-Acylamino-4,5,6,7-tetrahydro-benzo[b]thiophene Systems

    Directory of Open Access Journals (Sweden)

    Rafat Milad Mohareb

    2011-07-01

    Full Text Available A series of novel polyfunctionalized acyclic and heterocyclic dye precursors and their respective azo (hydrazone counterpart dyes and dye precursors based on conjugate enaminones and/or enaminonitrile moieties were synthesized. The dyes and their precursors are based on 2-cyano-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl-acetamide, 2-ethoxycarbonyl-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl-acetamide or 2-phenylcarbamoyl-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl-acetamide systems as precursors. The latter compounds were used to synthesize polyfunctional thiophene-, thiazole-, pyrazole, pyridine-, pyrimidine-, oxazine-, as well as acyclic moieties. The dyes and dye precursors were characterized by elemental analysis and spectral methods. All dyes and their precursors were screened in vitro and evaluated for both their antibacterial and antifungal activities. MIC data of the novel dye systems and their respective precursors showed significant antimicrobial activity against most tested organisms. Some compounds exhibited comparable or even higher efficiency than selected standards. Dyes were applied at 5% depth for disperse dyeing of nylon, acetate and polyester fabrics. Their spectral characteristics and fastness properties were measured and evaluated.

  10. Design and synthesis of novel antimicrobial acyclic and heterocyclic dyes and their precursors for dyeing and/or textile finishing based on 2-N-acylamino-4,5,6,7-tetrahydro-benzo[b]thiophene systems.

    Science.gov (United States)

    Shams, Hoda Zaki; Mohareb, Rafat Milad; Helal, Maher Helmy; Mahmoud, Amira El-Sayed

    2011-07-26

    A series of novel polyfunctionalized acyclic and heterocyclic dye precursors and their respective azo (hydrazone) counterpart dyes and dye precursors based on conjugate enaminones and/or enaminonitrile moieties were synthesized. The dyes and their precursors are based on 2-cyano-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-acetamide, 2-ethoxycarbonyl-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-acetamide or 2-phenylcarbamoyl-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-acetamide systems as precursors. The latter compounds were used to synthesize polyfunctional thiophene-, thiazole-, pyrazole, pyridine-, pyrimidine-, oxazine-, as well as acyclic moieties. The dyes and dye precursors were characterized by elemental analysis and spectral methods. All dyes and their precursors were screened in vitro and evaluated for both their antibacterial and antifungal activities. MIC data of the novel dye systems and their respective precursors showed significant antimicrobial activity against most tested organisms. Some compounds exhibited comparable or even higher efficiency than selected standards. Dyes were applied at 5% depth for disperse dyeing of nylon, acetate and polyester fabrics. Their spectral characteristics and fastness properties were measured and evaluated.

  11. Systematic analysis of enzymatic DNA polymerization using oligo-DNA templates and triphosphate analogs involving 2',4'-bridged nucleosides.

    Science.gov (United States)

    Kuwahara, Masayasu; Obika, Satoshi; Nagashima, Jun-ichi; Ohta, Yuki; Suto, Yoshiyuki; Ozaki, Hiroaki; Sawai, Hiroaki; Imanishi, Takeshi

    2008-08-01

    In order to systematically analyze the effects of nucleoside modification of sugar moieties in DNA polymerase reactions, we synthesized 16 modified templates containing 2',4'-bridged nucleotides and three types of 2',4'-bridged nucleoside-5'-triphospates with different bridging structures. Among the five types of thermostable DNA polymerases used, Taq, Phusion HF, Vent(exo-), KOD Dash and KOD(exo-), the KOD Dash and KOD(exo-) DNA polymerases could smoothly read through the modified templates containing 2'-O,4'-C-methylene-linked nucleotides at intervals of a few nucleotides, even at standard enzyme concentrations for 5 min. Although the Vent(exo-) DNA polymerase also read through these modified templates, kinetic study indicates that the KOD(exo-) DNA polymerase was found to be far superior to the Vent(exo-) DNA polymerase in accurate incorporation of nucleotides. When either of the DNA polymerase was used, the presence of 2',4'-bridged nucleotides on a template strand substantially decreased the reaction rates of nucleotide incorporations. The modified templates containing sequences of seven successive 2',4'-bridged nucleotides could not be completely transcribed by any of the DNA polymerases used; yields of longer elongated products decreased in the order of steric bulkiness of the modified sugars. Successive incorporation of 2',4'-bridged nucleotides into extending strands using 2',4'-bridged nucleoside-5'-triphospates was much more difficult. These data indicate that the sugar modification would have a greater effect on the polymerase reaction when it is adjacent to the elongation terminus than when it is on the template as well, as in base modification. PMID:18583360

  12. Synthesis and characterization of mixed ligand complexes of bio-metals with pyrimidine nucleoside (uridine) and amino acids

    Indian Academy of Sciences (India)

    P Rabindra Reddy; A Mohan Reddy

    2000-12-01

    The mixed ligand complexes of Cu(II), Ni(II) and Co(II) with uridine and amino acids, L-alanine, L-phenylalanine and L-tryptophan were synthesized and characterized by elemental analysis, conductivity data, infrared spectra, electronic spectra and magnetic susceptibility data. In these complexes, the nucleoside (uridine) acts as a monodentate ligand coordinating through O(4) under the conditions of investigation, whereas the amino acids coordinate through the carboxylate oxygen and the amino nitrogen. Distorted octahedral geometry for Cu(II) and octahedral geometries for both Ni(II) and Co(II) are proposed.

  13. Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

    Science.gov (United States)

    Wirth, Marius; Niro, Giuliana; Leyerer, Kristin

    2016-01-01

    Summary Muraymycins are a promising class of antimicrobial natural products. These uridine-derived nucleoside-peptide antibiotics inhibit the bacterial membrane protein translocase I (MraY), a key enzyme in the intracellular part of peptidoglycan biosynthesis. This review describes the structures of naturally occurring muraymycins, their mode of action, synthetic access to muraymycins and their analogues, some structure–activity relationship (SAR) studies and first insights into muraymycin biosynthesis. It therefore provides an overview on the current state of research, as well as an outlook on possible future developments in this field. PMID:27340469

  14. Exploitation of in situ generated sugar-based olefin keto-nitrones: synthesis of carbocycles, heterocycles, and nucleoside derivatives.

    Science.gov (United States)

    Das, Soumendra Nath; Chowdhury, Arpan; Tripathi, Neha; Jana, Prithwish K; Mandal, Sukhendu B

    2015-01-16

    Application of intramolecular 1,3-dipolar nitrone cycloaddition reaction on carbohydrate-derived precursors containing an olefin functionality at C-1 or C-3 or C-5 and a nitrone moiety at C-2 or C-3 as appropriate has resulted in the formation of structurally new cycloaddition products containing furanose-fused oxepane, thiepane, azepane, cyclopentane, cycloheptane, tetrahydrofuran, and pyranose-fused tetrahydrofuran rings. The structure and stereochemistry of these products have been characterized by spectral as well as single-crystal X-ray analyses. Two of the compounds have been transformed to the bicyclic nucleoside derivatives applying Vorbrüggen reaction conditions.

  15. ALKBH8-mediated formation of a novel diastereomeric pair of wobble nucleosides in mammalian tRNA

    DEFF Research Database (Denmark)

    van den Born, E.; Vagbo, C. B.; Songe-Moller, L.;

    2011-01-01

    Mammals have nine different homologues (ALKBH1-9) of the Escherichia coli DNA repair demethylase AlkB. ALKBH2 is a genuine DNA repair enzyme, but the in vivo function of the other ALKBH proteins has remained elusive. It was recently shown that ALKBH8 contains an additional transfer RNA ( t......RNA) methyltransferase domain, which generates the wobble nucleoside 5-methoxycarbonylmethyluridine (mcm(5)U) from its precursor 5-carboxymethyluridine (cm(5)U). In this study, we report that (R)- and (S)-5-methoxycarbonylhydroxymethyluridine (mchm(5)U), hydroxylated forms of mcm(5)U, are present in mammalian t...

  16. Metal ion-promoted cleavage of nucleoside diphosphosugars: a model for reactions of phosphodiester bonds in carbohydrates.

    Science.gov (United States)

    Dano, Meisa; Elmeranta, Marjukka; Hodgson, David R W; Jaakkola, Juho; Korhonen, Heidi; Mikkola, Satu

    2015-12-01

    Cleavage of five different nucleoside diphosphosugars has been studied in the presence of Cu(2+) and Zn(2+) complexes. The results show that metal ion catalysts promote the cleavage via intramolecular transesterification whenever a neighbouring HO group can adopt a cis-orientation with respect to the phosphate. The HO group attacks the phosphate and two monophosphate products are formed. If such a nucleophile is not available, Cu(2+) complexes are able to promote a nucleophilic attack of an external nucleophile, e.g. a water molecule or metal ion coordinated HO ligand, on phosphate. With the Zn(2+) complex, this was not observed.

  17. Mutation in the phosphoribosylpyrophosphate synthetase gene (prs) that results in simultaneous requirements for purine and pyrimidine nucleosides, nicotinamide nucleotide, histidine, and tryptophan in Escherichia coli

    DEFF Research Database (Denmark)

    Hove-Jensen, Bjarne

    1988-01-01

    , histidine, tryptophan, and nicotinamide mononucleotide were all added to the growth medium. Viability of the strain was dependent upon mutations in genes of the nucleoside salvage pathways that improved the utilization of exogenous nucleosides. The properties of the strain are those expected of a PRPP...

  18. Self-assembling of cytosine nucleoside into triply-bound dimers in acid media. A comprehensive evaluation of proton-bound pyrimidine nucleosides by electrospray tandem mass spectrometry, X-rays diffractometry, and theoretical calculations.

    Science.gov (United States)

    Armentano, Donatella; De Munno, Giovanni; Di Donna, Leonardo; Sindona, Giovanni; Giorgi, Gianluca; Salvini, Laura; Napoli, Anna

    2004-02-01

    Electrospray tandem mass spectrometry (ESI-MS/MS) is used to evaluate the assembling of cytosine and thymine nucleosides in the gas phase, through the formation of hydrogen bonded supermolecules. Mixtures of cytidine analogues and homologues deliver in the gas phase proton-bound heterodimers stabilized by multiple interactions, as proven by the kinetics of their dissociation into the corresponding protonated monomers. Theoretical calculations, performed on initial structures of methylcytosine homodimers available in the literature, converged to a minimized structure whereby the two pyrimidine rings interact through the formation of three hydrogen bonds of similar energy. The crystallographic data here reported show the equivalency of the two interacting pyrimidines which is attributable to the presence of an inversion center. Thymine and uracil pyrimidyl nucleosides form, by ESI, gaseous proton-bound dimers. The kinetic of their dissociation into the related protonated monomers shows that the nucleobases are weekly interacting through a single hydrogen bond. The minimized structure of the protonated heterodimer formed by thymine and N-1-methylthymine confirmed the existence of mainly one hydrogen bond which links the two nucleobases through the O4 oxygens. No crystallographic data exists on thymine proton-bound species, nor have we been able to obtain these aggregates in the solid phase. The gaseous phase, under high vacuum conditions, seems therefore a suitable environment where vanishing structures produced by ESI can be studied with a good degree of approximation.

  19. Which metabolic imaging, besides bone scan with 99mTc-phosphonates, for detecting and evaluating bone metastases in prostatic cancer patients? An open discussion.

    Science.gov (United States)

    Bombardieri, E; Setti, L; Kirienko, M; Antunovic, L; Guglielmo, P; Ciocia, G

    2015-12-01

    Prostate cancer bone metastases occur frequently in advanced cancer and this is matter of particular attention, due to the great impact on patient's management and considering that a lot of new emerging therapeutic options have been recently introduced. Imaging bone metastases is essential to localize lesions, to establish their size and number, to study characteristics and changes during therapy. Besides radiological imaging, nuclear medicine modalities can image their features and offer additional information about their metabolic behaviour. They can be classified according to physical characteristics, type of detection, mechanism of uptake, availability for daily use. The physiopathology of metastases formation and the mechanisms of tracer uptake are essential to understand the interpretation of nuclear medicine images. Therefore, radiopharmaceuticals for bone metastases can be classified in agents targeting bone (99mTc-phosphonates, 18F-fluoride) and those targeting prostatic cancer cells (18F-fluoromethylcholine, 11C-choline, 18F-fluorodeoxyglucose). The modalities using the first group of tracers are planar bone scan, SPECT or SPECT/CT with 99mTc-diphosphonates, and 18F-fluoride PET/CT, while the modalities using the second group include 18F/11C-choline derivatives PET/CT, 18F-FDG PET/CT and PET/CT scans with several other radiopharmaceuticals described in the literature, such as 18F/11C-acetate derivatives, 18F-fluoro-5α-dihydrotestosterone (FDHT), 18F-anti-1-amino-3-fluorocyclobutane-1-carboxylic acid (FACBC), 18F-2'-fluoro-5-methyl-1-β-D-arabinofuranosyluracil (FMAU) and 68Ga-labeled-prostate specific membrane antigen (PMSA) PET/TC. However, since data on clinical validation for these last novel modalities are not conclusive and/or are not still sufficient in number, at present they can be still considered as promising tools under evaluation. The present paper considers the nuclear modalities today available for the clinical routine. This overview wants

  20. Effective methylation of phosphonic acids related to chemical warfare agents mediated by trimethyloxonium tetrafluoroborate for their qualitative detection and identification by gas chromatography-mass spectrometry.

    Science.gov (United States)

    Valdez, Carlos A; Leif, Roald N; Alcaraz, Armando

    2016-08-24

    The effective methylation of phosphonic acids related to chemical warfare agents (CWAs) employing trimethyloxonium tetrafluoroborate (TMO·BF4) for their qualitative detection and identification by gas chromatography-mass spectrometry (GC-MS) is presented. The methylation occurs in rapid fashion (1 h) and can be conveniently carried out at ambient temperature, thus providing a safer alternative to the universally employed diazomethane-based methylation protocols. Optimization of the methylation parameters led us to conclude that methylene chloride was the ideal solvent to carry out the derivatization, and that even though methylated products can be observed surfacing after only 1 h, additional time was not found to be detrimental but beneficial to the process particularly when dealing with analytes at low concentrations (∼10 μg mL(-1)). Due to its insolubility in methylene chloride, TMO·BF4 conveniently settles to the bottom during the reaction and does not produce additional interfering by-products that may further complicate the GC-MS analysis. The method was demonstrated to successfully methylate a variety of Schedule 2 phosphonic acids, including their half esters, resulting in derivatives that were readily detected and identified using the instrument's spectral library. Most importantly, the method was shown to simultaneously methylate a mixture of the organophosphorus-based nerve agent hydrolysis products: pinacolyl methylphosphonate (PMPA), cyclohexyl methylphosphonate (CyMPA) and ethyl methylphosphonate (EMPA) (at a 10 μg mL(-1) concentration each) in a fatty acid ester-rich organic matrix (OPCW-PT-O3) featured in the 38th Organisation for the Prohibition of Chemical Weapons (OPCW) Proficiency Test. In addition, the protocol was found to effectively methylate N,N-diethylamino ethanesulfonic acid and N,N-diisopropylamino ethanesulfonic acid that are products arising from the oxidative degradation of the V-series agents VR and VX respectively. The

  1. Molecular Recognition of Bases and Nucleosides by Mono-substituted Mononuclear Complexes of 1,4,7,10-Tetraaza-cyclododecane

    Institute of Scientific and Technical Information of China (English)

    向清祥; 余孝其; 吴江; 刘培岩; 夏传琴; 谢如刚

    2003-01-01

    The mononuclear macrocyclic polyamine metal complexes 5a-5e have been shown to form stable 1 : 1 complexes with bases and nucleosides. Their binding constants (K) were determined by UV-visible spectrometric titration. The results show that recognition ability of the complexes 5a--5e for uracil, U (Uridine), dT (Thymidine) is higher than that for the other bases or nucleosides (such as Cytidine, Guanosine, Adenosine). The metal ion also plays an important role for the recognition ability of complexes.

  2. Systematic analysis of enzymatic DNA polymerization using oligo-DNA templates and triphosphate analogs involving 2′,4′-bridged nucleosides

    OpenAIRE

    Kuwahara, Masayasu; Obika, Satoshi; Nagashima, Jun-ichi; Ohta, Yuki; Suto, Yoshiyuki; Ozaki, Hiroaki; Sawai, Hiroaki; Imanishi, Takeshi

    2008-01-01

    In order to systematically analyze the effects of nucleoside modification of sugar moieties in DNA polymerase reactions, we synthesized 16 modified templates containing 2′,4′-bridged nucleotides and three types of 2′,4′-bridged nucleoside-5′-triphospates with different bridging structures. Among the five types of thermostable DNA polymerases used, Taq, Phusion HF, Vent(exo-), KOD Dash and KOD(exo-), the KOD Dash and KOD(exo-) DNA polymerases could smoothly read through the modified templates ...

  3. Purine Nucleoside Phosphorylase mediated molecular chemotherapy and conventional chemotherapy: A tangible union against chemoresistant cancer

    International Nuclear Information System (INIS)

    Late stage Ovarian Cancer is essentially incurable primarily due to late diagnosis and its inherent heterogeneity. Single agent treatments are inadequate and generally lead to severe side effects at therapeutic doses. It is crucial to develop clinically relevant novel combination regimens involving synergistic modalities that target a wider repertoire of cells and lead to lowered individual doses. Stemming from this premise, this is the first report of two- and three-way synergies between Adenovirus-mediated Purine Nucleoside Phosphorylase based gene directed enzyme prodrug therapy (PNP-GDEPT), docetaxel and/or carboplatin in multidrug-resistant ovarian cancer cells. The effects of PNP-GDEPT on different cellular processes were determined using Shotgun Proteomics analyses. The in vitro cell growth inhibition in differentially treated drug resistant human ovarian cancer cell lines was established using a cell-viability assay. The extent of synergy, additivity, or antagonism between treatments was evaluated using CalcuSyn statistical analyses. The involvement of apoptosis and implicated proteins in effects of different treatments was established using flow cytometry based detection of M30 (an early marker of apoptosis), cell cycle analyses and finally western blot based analyses. Efficacy of the trimodal treatment was significantly greater than that achieved with bimodal- or individual treatments with potential for 10-50 fold dose reduction compared to that required for individual treatments. Of note was the marked enhancement in apoptosis that specifically accompanied the combinations that included PNP-GDEPT and accordingly correlated with a shift in the expression of anti- and pro-apoptotic proteins. PNP-GDEPT mediated enhancement of apoptosis was reinforced by cell cycle analyses. Proteomic analyses of PNP-GDEPT treated cells indicated a dowregulation of proteins involved in oncogenesis or cancer drug resistance in treated cells with accompanying upregulation of

  4. Mitochondrial toxicities of nucleoside analogue reverse transcriptase inhibitors in AIDS cases

    Directory of Open Access Journals (Sweden)

    Yogesh S Marfatia

    2014-01-01

    Full Text Available The development of antiretroviral therapy (ART has been one of the most dramatic progressions in the history of medicine. Concomitant with this momentous therapeutic advance, the mitochondrial toxicities of ART were recognized as an important clinical entity. Aim: The aim was to study the mitochondrial toxicities in terms of peripheral neuropathy (PN, lipodystrophy (LD, hepatic steatosis, lactic academia (LA, and pancreatitis developing in AIDS cases on nucleoside analog reverse transcriptase inhibitors (NRTIs based ART regimens. Materials and Methods: An observational study, which included 90 AIDS cases, receiving first line ART regimens containing two NRTIs (zidovudine [AZT]/stavudine [d4T] with lamivudine [3TC] and one nonNRTIs (nevirapine/efavirenz was conducted at Skin-VD outpatient department of a tertiary care hospital attached to a Medical College. Thorough history was taken, and clinical examination was done. Cases were subjected to measurements of abdominal girth and mid-arm circumference, liver function tests, blood sugar, lipid profile, serum lactate, and amylase levels. Results: Of 90 cases on ART, 66% were males and 34% were females. Mitochondrial toxicities developed in 26 (30% cases out of 90, which included 3 (7% out of 42 cases on AZT + 3TC and 23 (48% out of 48 cases on d4T + 3TC. Most common toxicity was PN seen in 20 (22% cases; male cases developed PN at a lower CD4 count than female cases. LD was observed in total of 13 (14.5% cases; deposition of fat in the abdomen in seven cases and at the nape of the neck (buffalo hump in one case while loss of fat from extremities was seen in seven cases and loss of buccal fat in seven cases. Women presented more with fat accumulation (breast and abdomen, while men with loss of fat (limbs and buttocks. Both PN and LD were more common in d4T based regimen. LA was reported in one case on d4T. Hepatic steatosis was seen in three cases and pancreatitis in one case receiving AZT. Conclusion

  5. Ribonucleic acid stimulation of mammalian liver nuclear-envelope nucleoside triphosphatase. A possible enzymic marker for the nuclear envelope.

    Science.gov (United States)

    Agutter, P S; Harris, J R; Stevenson, I

    1977-03-15

    1. The specific activity of rat and pig liver nuclear-envelope nucleoside triphosphatase (EC 3.6.1.3) decreases when the system is depleted of RNA. The activity can be restored by adding high concentrations of yeast RNA to the assay medium. 2. Exogenous RNA also increases the activity of the enzyme in control envelopes (not RNA-depleted). The effect appears to be largely specific for poly(A) and poly(G); it is not stimulated by rRNA or tRNA preparations, ribonuclease-hydrolysed RNA, AMP, or double- or single-stranded DNA. 3. Inhibitors of the enzyme, in concentrations at which half-maximal inhibition of the enzyme is achieved, do not affect the percentage stimulation of the enzyme by yeast RNA. 4. The simulation is abolished by the inclusion of 150 mM-KCl or -NaCl in the assay medium, but not by increasing the assay pH to 8.5. 5. The results are discussed in the light of the possible role of the nucleoside triphosphatase in vivo in nucleo-cytoplasmic ribonucleoprotein translocation. 6. It is proposed that poly(G)-stimulated Mg2+-activated adenosine triphosphatase activity should be adopted as an enzymic marker for the nuclear envelope.

  6. Fast Simultaneous Determination of 13 Nucleosides and Nucleobases in Cordyceps sinensis by UHPLC–ESI–MS/MS

    Directory of Open Access Journals (Sweden)

    Shi-Yu Zong

    2015-12-01

    Full Text Available A reliable ultra-high-performance liquid chromatography–electrospray ionization–tandem mass spectrometry (UHPLC–ESI–MS/MS method for the fast simultaneous determination of 13 nucleosides and nucleobases in Cordyceps sinensis (C. sinensis with 2-chloroadenosine as internal standard was developed and validated. Samples were ultrasonically extracted in an ice bath thrice, and the optimum analyte separation was performed on an ACQUITY UPLCTM HSS C18 column (100 mm × 2.1 mm, 1.8 μm with gradient elution. All targeted analytes were separated in 5.5 min. Furthermore, all calibration curves showed good linear regression (r > 0.9970 within the test ranges, and the limits of quantitation and detection of the 13 analytes were less than 150 and 75 ng/mL, respectively. The relative standard deviations (RSDs of intra- and inter-day precisions were <6.23%. Recoveries of the quantified analytes ranged within 85.3%–117.3%, with RSD < 6.18%. The developed UHPLC–ESI–MS/MS method was successfully applied to determine nucleosides and nucleobases in 11 batches of C. sinensis samples from different regions in China. The range for the total content in the analyzed samples was 1329–2057 µg/g.

  7. Characterization of nucleoside triphosphate diphosphohydrolase activity in Trichomonas gallinae and the influence of penicillin and streptomycin in extracellular nucleotide hydrolysis.

    Science.gov (United States)

    Borges, Fernanda Pires; de Brum Vieira, Patrícia; Wiltuschnig, Renata C M; Tasca, Tiana; De Carli, Geraldo Attilio; Bonan, Carla Denise

    2008-06-01

    Here we described an nucleoside triphosphate diphosphohydrolase (NTPDase) activity in living trophozoites of Trichomonas gallinae. The enzyme hydrolyzes a variety of purine and pyrimidine nucleoside di- and triphosphates in an optimum pH range of 6.0-8.0. This enzyme activity was activated by high concentrations of divalent cations, such as calcium and magnesium. Contaminant activities were ruled out because the enzyme was not inhibited by classical inhibitors of ATPases (ouabain, 5.0 mM sodium azide, oligomycin) and alkaline phosphatases (levamisole). A significant inhibition of ATP hydrolysis (38%) was observed in the presence of 20 mM sodium azide. Sodium orthovanadate inhibited ATP and ADP hydrolysis (24% and 78%), respectively. The apparent K(M) (Michaelis constant) values were 667.62+/-13 microM for ATP and 125+/-5.3 microM for ADP. V(max) (maximum velocity) values were 0.44+/-0.007 nmol Pi min(-1) per 10(6) trichomonads and 0.91+/-0.12 nmol Pi min(-1) per 10(6) trichomonads for ATP and ADP, respectively. Moreover, we showed a marked decrease in ATP, ADP and AMP hydrolysis when the parasites were grown in the presence of penicillin and streptomycin. The existence of an NTPDase activity in T. gallinae may be involved in pathogenicity, protecting the parasite from the cytolytic effects of the extracellular nucleotides. PMID:18422631

  8. Characterization of Nucleosides and Nucleobases in Natural Cordyceps by HILIC–ESI/TOF/MS and HILIC–ESI/MS

    Directory of Open Access Journals (Sweden)

    Bin Yang

    2013-08-01

    Full Text Available A method combining hydrophilic interaction chromatography (HILIC and electrospray ionization mass spectrometry (ESI-MS was developed for the characterization and determination of natural Cordyceps. Separation was achieved on a Waters Xbridge Amide column with gradient elution. Identification of 15 target nucleosides and nucleobases was based on retention time, UV spectra and mass measurements of the protonated molecules ([M+H]+ and main fragment ions (ESI-TOF/MS. Eight non-target compounds were tentatively identified by ESI-TOF/MS. The 15 target compounds were quantified by HILIC-ESI-MS/MS using time-programmed selective ion monitoring or multiple reaction monitoring in positive-ion mode under optimized mass conditions. This technique showed good linearity, repeatability and recovery. This approach was also successfully implemented in the analysis of nucleosides and nucleobases in 12 batches of natural Cordyceps samples that were collected from different regions in China. The developed HILIC-ESI-MS method exhibited clear advantages in identifying and determining highly polar bioactive components in Cordyceps, as well as their quality control.

  9. Fast Simultaneous Determination of 13 Nucleosides and Nucleobases in Cordyceps sinensis by UHPLC-ESI-MS/MS.

    Science.gov (United States)

    Zong, Shi-Yu; Han, Han; Wang, Bing; Li, Ning; Dong, Tina Ting-Xia; Zhang, Tong; Tsim, Karl W K

    2015-01-01

    A reliable ultra-high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UHPLC-ESI-MS/MS) method for the fast simultaneous determination of 13 nucleosides and nucleobases in Cordyceps sinensis (C. sinensis) with 2-chloroadenosine as internal standard was developed and validated. Samples were ultrasonically extracted in an ice bath thrice, and the optimum analyte separation was performed on an ACQUITY UPLC(TM) HSS C18 column (100 mm × 2.1 mm, 1.8 μm) with gradient elution. All targeted analytes were separated in 5.5 min. Furthermore, all calibration curves showed good linear regression (r > 0.9970) within the test ranges, and the limits of quantitation and detection of the 13 analytes were less than 150 and 75 ng/mL, respectively. The relative standard deviations (RSDs) of intra- and inter-day precisions were <6.23%. Recoveries of the quantified analytes ranged within 85.3%-117.3%, with RSD < 6.18%. The developed UHPLC-ESI-MS/MS method was successfully applied to determine nucleosides and nucleobases in 11 batches of C. sinensis samples from different regions in China. The range for the total content in the analyzed samples was 1329-2057 µg/g. PMID:26690105

  10. Qualitative and quantitative analysis of glucosinolates and nucleosides in Radix Isatidis by HPLC and liquid chromatography tandem mass spectrometry

    Directory of Open Access Journals (Sweden)

    Xiuming Wang

    2013-09-01

    Full Text Available Multi-component fingerprinting and quantitation of the glucosinolates and nucleosides in samples of Radix Isatidis have been carried out using high-performance liquid chromatography with diode-array detection and electrospray ionization tandem mass spectrometry (HPLC–DAD–ESI/MS. Five nucleosides together with one glucosinolate were identified by comparing retention times, ultraviolet spectra, mass spectra and/or empirical molecular formulae of reference compounds. Quantitation of these six compounds was carried out simultaneously by HPLC on a Phenomenex Luna C18 column using gradient elution with methanol and water and detection at 254 nm. All calibration curves were linear (r>0.9994 within test ranges. Limits of detection and quantitation were 0.33 ng and 2.50 ng on column, respectively. Intra- and inter-day precision (as relative standard deviation for all analytes was <2.19% with recoveries in the range 99.6%–101.8% at three concentration levels. The validated method was successfully applied to fingerprinting and assay of 25 batches of Radix Isatidis sourced from different geographical regions of China. The method is simple and reliable and has potential value in the quality control of Radix Isatidis.

  11. Crystallization and preliminary X-ray structural analysis of nucleoside triphosphate hydrolases from Neospora caninum and Toxoplasma gondii

    International Nuclear Information System (INIS)

    Recombinant nucleoside triphosphate hydrolases from N. caninum and T. gondii have been purified and crystallized for X-ray structure analysis. The nucleoside triphosphate hydrolases that are produced by Neospora caninum (NcNTPase) and Toxoplasma gondii (TgNTPase-I) have a different physiological function from the ubiquitous ecto-ATPases. The recombinant enzymes were crystallized at 293 K using polyethylene glycol 3350 as a precipitant and X-ray diffraction data sets were collected for NcNTPase (to 2.8 Å resolution) and TgNTPase-I (to 3.1 Å resolution) at 100 K using synchrotron radiation. The crystals of NcNTPase and TgNTPase-I belonged to the orthorhombic space group I222 (unit-cell parameters a = 93.6, b = 140.8, c = 301.1 Å) and the monoclinic space group P21 (unit-cell parameters a = 87.1, b = 123.5, c = 120.2 Å, β = 96.6°), respectively, with two NcNTPase (VM = 3.7 Å3 Da−1) and four TgNTPase-I (VM = 2.7 Å3 Da−1) molecules per asymmetric unit. SAD phasing trials using a data set (λ = 0.97904 Å) collected from a crystal of selenomethionylated NcNTPase gave an initial electron-density map of sufficient quality to build a molecular model of NcNTPase

  12. Enzymatic regioselective acylation of nucleosides in biomass-derived 2-methyltetrahydrofuran: kinetic study and enzyme substrate recognition.

    Science.gov (United States)

    Gao, Wen-Li; Li, Ning; Zong, Min-Hua

    2013-03-10

    Enzymatic regioselective acylation of pyrimidine nucleosides was mediated by immobilized lipase from Penicillium expansum in 2-methyltetrahydrofuran (MeTHF), a bio-solvent derived from biomass. Despite of the moderate dissolution ability of MeTHF toward nucleosides, the initial enzymatic reaction rate was much higher in this eco-friendly solvent than in other commonly used organic solvents. This could be explained by the lower apparent activation energy of the enzymatic reaction (24.5 vs. 43.3-57.1kJ/mol) and the higher catalytic efficiency of the enzyme (Vmax/Km, 5.8 vs. 1.1-2.9h(-1)) in MeTHF. The enzymatic acylation of a group of ribonucleosides afforded the desirable 5'-esters with the conversions of 96-99% and 5'-regioselectivities of 96 to >99%. In enzymatic acylation of 2'-deoxynucleosides, however, 5'-regioselectivities showed a clear dependence on the 5-substituents present in the base moiety although the substrate conversions reached >98% within 1-3h. In the cases of 2',3'-dideoxynucleoside analogs, the reaction rate decreased markedly due to the lack of 3'-hydroxyl. PMID:23337886

  13. Oxidation half-reaction of aqueous nucleosides and nucleotides via photoelectron spectroscopy augmented by ab initio calculations.

    Science.gov (United States)

    Schroeder, Christi A; Pluhařová, Eva; Seidel, Robert; Schroeder, William P; Faubel, Manfred; Slavíček, Petr; Winter, Bernd; Jungwirth, Pavel; Bradforth, Stephen E

    2015-01-14

    Oxidative damage to DNA and hole transport between nucleobases in oxidized DNA are important processes in lesion formation for which surprisingly poor thermodynamic data exist, the relative ease of oxidizing the four nucleobases being one such example. Theoretical simulations of radiation damage and charge transport in DNA depend on accurate values for vertical ionization energies (VIEs), reorganization energies, and standard reduction potentials. Liquid-jet photoelectron spectroscopy can be used to directly study the oxidation half-reaction. The VIEs of nucleic acid building blocks are measured in their native buffered aqueous environment. The experimental investigation of purine and pyrimidine nucleotides, nucleosides, pentose sugars, and inorganic phosphate demonstrates that photoelectron spectra of nucleotides arise as a spectral sum over their individual chemical components; that is, the electronic interactions between each component are effectively screened from one another by water. Electronic structure theory affords the assignment of the lowest energy photoelectron band in all investigated nucleosides and nucleotides to a single ionizing transition centered solely on the nucleobase. Thus, combining the measured VIEs with theoretically determined reorganization energies allows for the spectroscopic determination of the one-electron redox potentials that have been difficult to establish via electrochemistry. PMID:25551179

  14. Bis(2-ethylhexyl)-N,N-diethylcarbamoylmethyl phosphonate as a synergist in the extraction of trivalent lanthanides by 1-phenyl-3-methyl-4-trifluoroacetyl-pyrazolone-5

    International Nuclear Information System (INIS)

    Synergism in the extraction of trivalent lanthanides such as Nd. Eu and Lu has been investigated using mixtures of 1-phenyl-3-methyl-4-trifluoroacetyl-pyrazolone-5 (HPMTFP) and bis(2-ethylhexyl)-N,N-diethylcarbamoylmethyl phosphonate (CMP) in chloroform. Lanthanides are found to be extracted from 0.01 mol/dm3 chloroacetate medium with HPMTFP as Ln(PMTFP)3 or Ln(PMTFP)3 . CMP in the absence or presence of CMP, respectively. The equilibrium constants of these synergistic species do not increase monotonically with atomic number but have a maximum at Eu. The addition of a synergist, CMP to the metal chelate system not only enhances the extraction efficiency but also improves the selectivities among these trivalent lanthanides. The IR results indicate that CMP acts as a bidentate ligand in these mixed-ligand systems. (orig.)

  15. In vitro ALP and osteocalcin gene expression analysis and in vivo biocompatibility of N-methylene phosphonic chitosan nanofibers for bone regeneration.

    Science.gov (United States)

    Datta, Pallab; Ghosh, Paulomi; Ghosh, Kuntal; Maity, Pritiprasanna; Samanta, Sintu Kumar; Ghosh, Sudip Kumar; Mohapatra, Pradeep Kumar Das; Chatterjee, Jyotirmoy; Dhara, Santanu

    2013-05-01

    Most polymeric nanofibers used for bone tissue engineering lack adequate functional groups for bioactivity. This study explores the potential of nanofibers of phosphate functionalized derivative of chitosan-N-methylene phosphonic chitosan (NMPC) for bone tissue engineering. Nanofibers were fabricated by electrospinning of NMPC/PVA blend solutions. NMPC/PVA nanofibers exhibited 172% higher viability of MG-63 cells compared to pure PVA nanofibers. ALP and Collagen type I genes revealed higher expression in NMPC nanofibers on day 3 whereas osteocalcin gene was expressed on day 7. In rabbit tibial defects, NMPC based electrospun graft showed presence of no adverse tissue reaction by histological examination while radiological examination suggested acceleration of bone healing by 300% compared to defects without any scaffold. Thus it is concluded NMPC based nanofibers may have potential for bone grafting applications. PMID:23802418

  16. The Sarin-like Organophosphorus Agent bis (isopropyl methyl)phosphonate Induces Apoptotic Cell Death and COX-2 Expression in SK-N-SH Cells.

    Science.gov (United States)

    Arima, Yosuke; Yoshimoto, Kanji; Namera, Akira; Makita, Ryosuke; Murata, Kazuhiro; Nagao, Masataka

    2016-03-01

    Organophosphorus compounds, such as sarin, are highly toxic nerve agents that inhibit acetylcholinesterase (AChE), but not cholinesterase, via multiple mechanisms. Recent studies have shown that organophosphorus compounds increase cyclooxygenase-2 (COX-2) expression and induce neurotoxicity. In this study, we examined the toxicity of the sarin-like organophosphorus agent bis(isopropyl methyl)phosphonate (BIMP) and the effects of BIMP on COX-2 expression in SK-N-SH human neuroblastoma cells. Exposure to BIMP changed cell morphology and induced caspase-dependent apoptotic cell death accompanied by cleavage of caspase 3, caspase 9, and poly (ADP-ribose) polymerase (PARP). It also increased COX-2 expression, while pretreatment with a COX inhibitor, ibuprofen, decreased BIMP-dependent cell death and COX-2 expression in SK-N-SH cells. Thus, our findings suggest that BIMP induces apoptotic cell death and upregulates COX-2 expression. PMID:27348899

  17. Mesoporous zirconium titanium oxides. Part 3. Synthesis and adsorption properties of unfunctionalized and phosphonate-functionalized hierarchical polyacrylonitrile-F-127-templated beads.

    Science.gov (United States)

    Sizgek, G Devlet; Griffith, Christopher S; Sizgek, Erden; Luca, Vittorio

    2009-10-01

    A method is presented for the preparation of zirconium titanate mixed oxides in bead form having hierarchical pore structure. This method entailed the use of both preformed polyacrylonitrile (PAN) polymer beads and surfactants as templates. The templates were removed by calcination at temperatures below about 500 degrees C, resulting in mixed oxide beads with trimodal pore size distributions and interconnected pores. The pore size distributions as determined using nitrogen adsorption-desorption showed clear maxima at 4.5 and 45 nm length scales and also clear evidence of microporosity. The macroporous framework morphology was a replica of the PAN beads with radial structure. The mesoporous framework possessed wormhole-like pores with pore size of about 6 nm that was consistent with the F-127 triblock copolymer template used. The mixed oxide beads exhibited surface areas of 215 and 185 m2/g after calcination at 500 and 600 degrees C. Thermal stability up to 650 degrees C is unprecedented for bulk systems. The adsorption properties were characterized using uranyl as the target cation and the mass transport in the beads with the present hierarchical architectures has been shown to be exceptional. The beads were functionalized with 4-amino,1-hydroxy,1,1-bis-phosphonic acid (HABDP) and amino-tris-methylene phosphonic acid (ATMP) and the adsorption properties for the extraction of uranyl sulfate complexes from acidic solution examined. Of the two molecules investigated, ATMP functionalization resulted in the best extraction efficiency with equilibrium uptake of about 90% of uranium available in solution between pH 1 and 2. The beads could potentially be utilized as catalysts, catalyst supports, adsorbents, and separation materials. PMID:19746937

  18. Effect of phosphonate monolayer adsorbate on the microwave photoresponse of TiO2 nanotube membranes mounted on a planar double ring resonator

    Science.gov (United States)

    Zarifi, Mohammad H.; Farsinezhad, Samira; Wiltshire, Benjamin D.; Abdorrazaghi, Mohammad; Mahdi, Najia; Kar, Piyush; Daneshmand, Mojgan; Shankar, Karthik

    2016-09-01

    In this study, the effects of a phosphonate molecular monolayer adsorbed on the surface of a free-standing self-organized TiO2 nanotube membrane, on the microwave photoresponse of the membrane are presented. This phenomenon is monitored using planar microwave sensors. A double ring resonator is utilized to monitor the permittivity and conductivity variation on the monolayer coated membrane and the sensor environment separately. It is shown that the rise time and subsequent decay of the amplitude (A), resonance frequency (f 0) and quality factor (Q) of the resonator depend on the existence and the type of the monolayer coating the membrane. Three different monolayers of n-decylphosphonic acid (DPA), 1H, 1H‧, 2H, 2H‧-perfluorodecyl phosphonic acid (PFDPA) and 16-phosphonohexadecanoic acid adsorbed on the titania nanotube membrane are investigated while monitoring their microwave properties during the illumination time period and in the relaxation period, which demonstrate different behavior in comparison to each other and to the bare nanotube membrane layer. The effect of humidity on the TiO2 nanotube membrane with and without different monolayers is also studied and the results demonstrate distinguishable microwave responses. While each of the monolayer-coated membranes exhibited an attenuation of the photo-induced change in A, f 0 and Q with respect to the bare membrane, PFDPA-coated membranes showed the smallest relative change in the monitored microwave parameters upon ultraviolet illumination and upon the introduction of different levels of humidity. These effects are explained on the basis of surface trap passivation by the monolayers as well as the hydrophobicity of the monolayers. Our work also shows how the interactions of self-assembled monolayers with charge carriers and surface states on metal oxides may be used to indirectly sense their presence through measurement of the microwave response.

  19. HILIC-UPLC-MS/MS combined with hierarchical clustering analysis to rapidly analyze and evaluate nucleobases and nucleosides in Ginkgo biloba leaves.

    Science.gov (United States)

    Yao, Xin; Zhou, Guisheng; Tang, Yuping; Guo, Sheng; Qian, Dawei; Duan, Jin-Ao

    2015-02-01

    Ginkgo biloba leaf extract has been widely used in dietary supplements and more recently in some foods and beverages. In addition to the well-known flavonol glycosides and terpene lactones, G. biloba leaves are also rich in nucleobases and nucleosides. To determine the content of nucleobases and nucleosides in G. biloba leaves at trace levels, a reliable method has been established by using hydrophilic interaction ultra performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry (HILIC-UPLC-TQ-MS/MS) working in multiple reaction monitoring mode. Eleven nucleobases and nucleosides were simultaneously determined in seven min. The proposed method was fully validated in terms of linearity, sensitivity, and repeatability, as well as recovery. Furthermore, hierarchical clustering analysis (HCA) was performed to evaluate and classify the samples according to the contents of the eleven chemical constituents. The established approach could be helpful for evaluation of the potential values as dietary supplements and the quality control of G. biloba leaves, which might also be utilized for the investigation of other medicinal herbs containing nucleobases and nucleosides.

  20. Multi-nucleoside reverse transcriptase inhibitor resistant HIV type-1 in a patient from Sierra Leone failing stavudine, lamivudine and nevirapine

    NARCIS (Netherlands)

    R.L. Hamers; A.M.J. Wensing; N.K.T. Back; M.S. Arcilla; J.P.H. Frissen

    2011-01-01

    We report a 33-year-old HIV type-1 (HIV-1)-infected male from Sierra Leone who harboured extensive drug resistance mutations to all nucleoside reverse transcriptase inhibitors (NRTIs) and non-NRTIs, including the multi-NRTI-resistance Q151M complex, K65R, M184I and Y181I, after using standard first-